Project: PharmaInfoTech/01/PCS
Authors: Poulami Maity (B.pharm,BCDA of pharmacy and Technology)
& Jyotirmoy Roy (B.pharm,BCDA college of pharmacy and Technology)
Main components of pharmaceutical industry are----
• Quality
• Production
• Laboratory
• Materials
• Facilities & Equipment
• Packaging & Labeling
QUALITY ASSURANCE (QA)
WHAT IS QUALITY?
Quality is the degree to which a commodity meets the requirements of the customer at the start of its life. (iso 9000)
Product quality perception comes from your design specifications and the manufacture standards achieved. Service quality perception comes from your service process design and the customer contact impressions.
Most popular definitions for quality are listed below. All of them are right, as they each contain a key element of what quality means to users of products and services---
a. A degree of excellence
b. Conformance to requirements
c. Totality of characteristics which act to satisfy a need
d. Fitness for use
e. Fitness for purpose
f. Freedom from defects
IMPORTANT TERMS USED IN QUALITY ASSURANCE DEPARTMENT:
Batch manufacturing record (BMR)
Batch manufacturing record is a written document from the batch that is prepared during the pharmaceutical manufacturing process. It contains actual data of the batch manufacturing and whole manufacturing process step by step.
There are several stages of the pharmaceutical product manufacturing process. All stages are included in the batch manufacturing record from the issuance of the raw material to the final packaging.
Every batch has a separate BMR having the batch history of batch production. Documents and the proofs are attached to the BMR during the manufacturing process.
A good Batch Manufacturing Record format should contain following parts:
1. Batch Record:
A very first page of the BMR has all records about the batch as batch number, batch size, composition, master formula record referred the weight of the batch, shelf life, storage conditions, manufacturing license number, manufacturing date, expiry date, date of starting and date of completion.
2. General Instruction for Manufacturing:
Health and safety instructions to the operators and the manufacturing chemist are written those should be followed during the manufacturing process regarding the material and equipments used during manufacturing.
3. Equipment Cleaning Record:
Checklist of the cleaning of all equipments is prepared; those are used in the manufacturing of the batch including the previous product, batch and date of cleaning. Cleaning of the equipments should be checked by the quality assurance.
4. Bill of Materials:
List of the raw material should have the quantity of the materials with their AR numbers. Weights of the materials should be verified by quality assurance. If tablets are coated then coating material should be included.
5. Manufacturing Process:
Manufacturing process should be written step by step in easy language. Milling, sifting, drying, lubrication, compression, coating and packing having all instruction with process time should be written. Checklist for line clearance should also be attached before starting every process.
After completion of the every stage, tablets must be checked for the compliance of the specification of that stage. Results should be attached with the batch manufacturing record.
6. Yield:
Yield of the batch should be calculated at the end of every stage to calculate the process loss. Final yield should be calculated at the end of the manufacturing that should not be less than 99.00%.
7. Abbreviations:
List of the abbreviations used in the document should be made to understand the BMR easily.
8. History of Chances:
At the end, the document should have a list of the changes in the document including the revision number and the date of the change.
Master formula record (MFR):
What is master formula record?
A record of name of product, manufacturing procedure, ingredients/composition of product and their specifications, machinery used, batch size, dosage form, intermediate/final yield, storage conditions, step wise processing instruction etc and other related things for maintaining consisting of each and every batch. It is used as reference standard for manufacturing procedure.
A master formula record is prepared and endorsed by the competent technical staff like manufacturing chemist and analytical chemist etc. There should be master formula record related to all manufacturing procedures for each product and batch size to be manufactured. A master formula record should contain a complete description or reference code for understanding standard process.
Contents of Master Formula Records:
• The Name of Product together with product reference code relating to specifications
• Description of dosage form, strength, composition of product and batch size
• Patent, proprietary name of the product along with Generic Name of product and its ingredients along with excipients used
• Special mention of the substance that may disappear during manufacturing process
• Specifications and reference code of each and every ingredients/excipient used in manufacturing procedure
• Location and Machinery used in process, and their specifications including cleaning, assembling, calibrating, sterilizing, operating procedure etc
• Stepwise detailed processing instructions and time taken by each and every step
• Instruction related to in-process control i.e. quality checks, samples taken, test to be conducted etc
• Requirements for storage and processing conditions of the product including container, labeling and special storage conditions if any
• A statement regarding expected relevant intermediate and final yield with the acceptable limits
• Packaging material details i.e. labels, boxes, foils, bottles etc
• Any special precaution and instructions if any
Procedure to prepare a Master Formula Record:
A Master Formula Record is either prepared based upon experience of competent qualified staff like manufacturing chemist or analytical chemist or prepared based upon batch manufacturing record of a batch size.
Once Master Formula Record is prepared, it is transferred to previous staff to new staff. It is followed as standard documents for processing a batch. Master Formula record is consider as standard for making a Batch Manufacturing Record
Quality management system:
Quality Management System a set of interacting elements based on procedures, policies, resources, and objectives that are established collectively to guide an organization. Quality Management System takes into account all applicable guidelines and regulations that are designed to maintain its robustness.
Some factors are essential in developing a Quality Management System in organizations, and they include quality policy, quality risk management, and quality objectives.
Pharmaceutical market over the past few years has undergone significant change forcing pharmaceutical corporations to focus on the needs and internal efficiency to continue to compete effectively. Therefore, Quality Management System supports an active pharmaceutical industry to enhance the quality and availability of medicines around the globe in the interest of public health. Pharmaceutical quality management system demonstrates industry as well as regulatory authorities. Through the regulation of quality management system, organizations facilitate innovation along with continual improvement as well as strengthen the link between pharmaceutical development and manufacturing activities.
The areas of continual improvement in pharmaceutical industry include enhancements of the pharmaceutical quality system, identifying and prioritizing the quality of the products as well as consistently fulfilling the quality of drug manufacturers. Quality Management System in the pharmaceutical industry helps to develop an effective monitoring control based on the performance as well as product quality.
Further, the system provides assurance of continued suitability as well as the capability of processes that are useful in identifying the monitoring and controlling systems. The system is designed to meet the needs of life science and other regulated companies. Companies globally streamline, automate as well as manage efficiently their processes through the regulation of quality management systems. The pharmaceutical company is ultimately responsible for ensuring processes are in place to assure the control of outsourced activities and quality of purchased activities.
Quality Management System stems key regulations for the pharmaceutical industry. It designs a product and its manufacturing process for pharmaceutical organizations to consistently deliver the intended performance as well as meet the needs of healthcare professionals and patients. These approaches transfer product and production process knowledge between development and manufacturing so that to achieve product utilization.
Companies establish control strategy that attributes to drug substance and drug product materials that facilitate timely and appropriate corrective action as well as preventive measures. This approach helps the pharmaceutical industries to identify resources of variation affecting process presentation and product quality for possible improvement measures to reduce variation. Additionally, quality management systems provide the tools for measurement in the pharmaceutical industry for analysis as parameters that attribute to the control strategy. A well-defined scheme for process presentation and product superiority assures pharmaceutical industries performance and identifies improvement areas.
Monitoring for the duration of scale-up activities can offer a preliminary sign-off process presentation and the thriving integration into manufacturing. Ideally, knowledge obtained at some point in the transfer, and scale-up actions can be valuable in further increasing the control policy. Stability testing of the product in the pharmaceutical industry continues to be executed according to the regulations set by the Quality Management Systems.
The changes to the quality management systems in the pharmaceutical industry have evaluated the marketing authorization contributing the appropriate expertise and knowledge from relevant areas. The size of the company determines the level of management and the timely communication to raise related quality issues. Activities in the pharmaceutical industry through the quality management system is systematically planned as well as documented. This help to ensure consistency of performance and provide greater assurance that the ending will be suitable.
The overall idea of the quality management system is to support the quality manual and achievement of the short and long-term objectives of the pharmaceutical industry. The procedures help to establish and maintain a clear line of communication to ensure customer requirement is well understood. Subsequently, management reviews in the pharmaceutical industry contributed to determining the stability and the quality of the product.
Quality Management Systems assist the design and development process in the pharmaceutical industry to ensure that the resulting product meets the agreed specification. The industry can achieve this by establishing as well as maintaining documented procedures to verify and control the design and development of the product.
The plan developed by the quality management systems includes regular meetings to compare design verification and design validation. This can be achieved through stability testing as part of the development phase in the pharmaceutical industry.
Through the quality management system, pharmaceutical industry focuses on correcting as well as preventing problems within the sector. It is evident that preventing problems is cheaper as compared to fixing them after they occur. As such the range and the nature of manufacturing by-product, inherent variability in biological products are likely to be variable. The quality management systems help the pharmaceutical industry in the verification of activities.
This process involves inspection as well as testing at the supplier site before dispatching by the manufacturer. Management control over the quality of customer supplied product should be included in the scope of the manufacturer’s quality system. During these processes, there should be a written as well as approved contract between the contract giver and the contract acceptor to lay down the responsibilities of each party.
Additionally, items provided by the consumer should be without a doubt identifiable. The items should have their quality verified by the inspection and subsequently handled in such a way as to prevent damage. In conclusion, quality management systems in the pharmaceutical industry have monitored as well as controlled some parameters to ensure that the process is performing as intended by the process design.
It is evident that control parameters will be required to give the necessary level of confidence in the eminence of the end product in the drug industry. Therefore, the involvement of quality management systems in the industry has ensured that equipment is maintained to a standard sufficient capable of performing its intended functions.
Validation:
Introduction
The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated processes including environmental control, media fill, equipment sanitization and purified water production.
In a guideline, validation is act of demonstrating and documenting that any procedure, process, and activity will consistently lead to the expected results. It includes the qualification of systems and equipment. The goal of the validation is to ensure that quality is built into the system at every step, and not just tested for at the end, as such validation activities will commonly include training on production material and operating procedures, training of people involved and monitoring of the system whilst in production. In general, an entire process is validated and a particular object within that process is verified. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time.
Why validation is required:
The main reasons for validation are
1. Quality assurance: Quality cannot be assured by daily quality control testing because of the limitations of statistical samples and the limited facilities of finished product testing. Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria. A successful validation provides high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch.
2. Economics: Due to successful validation, there is a decrease in the sampling and testing procedures and there are less number of product rejections and retesting. This lead to cost-saving benefits.
3. Compliance: For compliance to current good manufacturing practices CGMPs, validation is essential.
Department Responsible:-
• Site validation committee (SVC): Develop Site master Validation plan, Prepare/execute/approve validation Studies
• Manufacturing department: Prepares the batches as a routine Production batch
• Quality assurance: Ensure compliance, see that documentations/procedures are in place, approves protocols and reports
• Quality control: Perform testing and reviews protocol and report as needed.
Responsible Authorities For Validation:-
The validation working party is convened to define progress, coordinate and ultimately, approve the entire effort, including all of the documentation generated. The working party would usually include the following staff members, preferably those with a good insight into the company's operation.
• Head of quality assurance
• Head of engineering
• Validation manager
• Production manager
• Specialist validation discipline: all areas
• Elements Of Validation:-
• Qualification is pre-requisite of validation. The qualification includes the following:
• 1. Design Qualification (DQ):-
In this qualification, compliance of design with GMP should be demonstrated. The principles of design should be such as to achieve the objectives of GMP with regard to equipment. Mechanical drawings and design features provided by the manufacturer of the equipment should be examined.
2. Installation Qualification (IQ):-
Installation qualification should be carried out on new or modified facilities, systems and equipment. The following main points should be includes in the installation qualification.
• Checking of installation of equipment, piping, services and instrumentation.
• Collection of supplier’s operating working instructions and maintenance requirements and their calibration requirements.
• Verification of materials of construction
• Sources of spares and maintenance
3. Operational Qualification (OQ):-
Operational qualification should follow IQ, OQ should include the following:
• Tests developed from the knowledge of the processes systems and equipment
• Defining lower and upper operating limits,. Sometimes, these are called ‘worst case’ conditions.
4. Performance Qualification (PQ):-
After IQ and OQ have been completed, the next qualification that should be completed is PQ. PQ should include the following:
• Tests using production materials, substitutes or simulated product. These can be developed from the knowledge of the process and facilities, systems or equipment.
• Tests to include conditions with upper and lower limits
Process Validation:
The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation:
Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics.
According to the FDA, assurance of product quality is derived from careful and systemic attention to a number of important factors, including: selection of quality components and materials, adequate product and process design, and (statistical) control of the process through in-process and end-product testing. Thus, it is through careful design (qualification) and validation of both the process and its control systems that a high degree of confidence can be established that all individual manufactured units of a given batch or succession of batches that meet specifications will be acceptable.
This guidance describes process validation activities in three stages.
Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Types of Process Validation:-
1. Prospective Validation: It is establishment of documented evidence of what a system does or what it purports to do based upon a plan. This validation is conducted prior to the distribution of new product.
2. Retrospective Validation: It is the establishment of documented evidence of what a system does or what it purports to do based upon the review and analysis of the existing information. This is conducted in a product already distributed based on accumulated data of production, testing and control.
3. Concurrent Validation: It is establishment of documented evidence of what a system does or what it purports to do information generated during implemented of the system.
4. Revalidation: Whenever there are changes in packaging, formulation, equipment or processes which could have impact on product effectiveness or product characteristics, there should be revalidation of the validated process.
Conditions that require revalidation studies are:
• Changes in critical component
• Change in facility or plant
• Increase or decrease in batch size
• Sequential batches that fail to conform product and process specifications
Change Control:-
Change control is defined as “a formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.”
Change control is a lifetime monitoring approach. Planning for well executed change control procedures includes the following aspects:
Validation Master Plan:-
It is important to draw up a summarized document that describes the whole project. It has become common practice in the industry to develop a “validation master plan” (VMP). This document would usually include the qualification aspects of a
project.
Validation Protocol:-
After preparing VMP, the next step is to prepare validation protocol. There are the following contents in a validation protocol.
1. General information
2. Objective
3. Background/Prevalidation Activities Summary of development and tech transfer (from R&D or another site) activities to justify in-process testing and controls; any previous validations.
4. List of equipment and their qualification status
5. Facilities qualification
6. Process flow chart
7. Manufacturing procedure narrative
8. List of critical processing parameters and critical excipients
9. Sampling, tests and specifications
10. Acceptance criteria
SOP
A Standard Operating Procedure (SOP) is a set of written instructions that document a routine or repetitive activity which is followed by employees in an organization. The development and use of SOPs are an integral part of a successful quality system. It provides information to perform a job properly, and consistently in order to achieve pre-determined specification and quality end-result.
In designing of SOP Following points are considered
OBJECTIVE:
To lay down procedure for the preparation of Standard Operating Procedures.
SCOPE:
This procedure is applicable to all the SOP’s throughout the organization.
RESPONSIBILITY:
Person Performing: Respective HOD’s of concerning departments
Person Monitoring: QA officer/ HOD QA
PROCEDURE:
All SOP’s shall be computer typed using Times New Roman font.
Format of SOP shall be as per Annexure SOP/QA/002/1. Each SOP has:
I) Header,
II) Signature block and
III) Body.
Header: Present on all the pages of SOP and includes
Company Logo, Name, address & Concerned Dept.: Company Logo, CHARAK Pharma Limited, Wagholi-Pune & Name of Concerned Department. (In capital bold letters of font size 16)
Document Type: Standard Operating Procedure (In capital bold letters of font size 14)
Ref. No.:It is like SOP/DC/YYY-Z Where DC depicts the department code as below:
PE: Personnel Department
PD: Production Department
MT: Maintenance Department
QA: Quality Assurance Department
QC: Quality Control Department
ST: Store Department
PU: Purchase Department
YYY is the sequential number starting from 001 for each department.
And Z is the revision status, starting from 0 for the original version and 1 for the next version and so on. (In capital letters of font size 12).
Supersedes: It is the Ref. No. of the earlier version. (In capital letters of font size 12).
Effective Date: It is the date from which the SOP shall be put in use. The date format has to be DD/MM/YYYY, where DD indicates the date, MM indicates the month & YYYY indicates the year (e.g. 01/11/2007). Date shall be written with blue indelible ink pen.
Review Date: It is the Month & Year during which the SOP shall be revised e.g. 21/2013, written with blue indelible ink pen. It shall be maximum 2 years from the effective date.
Page No.: It is like X OF Y. Where X is the individual page number and Y is the total number of pages. (In capital letters of font size 12)
Title: It shall be clear and descriptive. (In bold capital letters of font size 12).
Signature Block:It shall be below the header and only on the first page of the SOP.
(Titles in the rows & columns shall be in bold letters & other text in normal letters of font size 12. Name and designation shall be typed. And signature and date shall be put in blue indelible ink pen)
Prepared by: Signature with date, name and designation of the person from user department who has drafted the SOP.
Verified by: Signature with date, name and designation of the HOD or the person from user department who has verified the draft of the SOP.
Authorized by:Signature with date, name and designation of the person authorizing SOP, DGM QA or HOD QA.
e. Body: It shall contain the subject matter, which is written in the following Manner.
(Subtitles in capital bold letters and text matter in normal letters of font size 12).
OBJECTIVE: It shall define the purpose of the SOP.
SCOPE: It shall define the area of application.
GDP
Introduction
The GDP can be defined as “Good documentation practice is an essential part of the quality assurance and such, related to all aspects of GMP” this definition is based on WHO.
Clearly written documents prevent errors of various activities in pharma each and every activity is written in specific documents such as SOPs and strictly followed. Spoken communications may be create errors so that all important documents such as Master formula record , procedure and record must be free from errors and Documented.
It is difficult to make a list of required documents and totally depend upon Companies activity or environment. Followings are the activity factors considered during designing of any documents.
1. Type of formulation
2. Country requirements
3. Availability of ERP or SAP system
Purpose of Documentations
• Defines specifications and procedures for all materials and methods of manufacture and control
• Ensures all personnel know what to do and when to do it
• Ensure that authorized persons have all information necessary for release of product
• Ensures documented evidence, traceability, provide records and audit trail for investigation
• Ensures availability of data for validation, review and statistical analysis.
Classification of Documentation
Following are the classification of Documents
• For organization & Personnel.
• For Buildings & facilities
• For Equipments.
• For Handling of R.M.& P.M.
• For Production & process control.
• For Packaging & Labeling control.
• For Holding & Distribution
• For Laboratory Control.
• For Records & Reports.
• For Return & Salvaged finished products.
Type of documents used in pharmaceuticals
• Specifications: as per MHRA Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. We need specification for:
1. Active and inactive materials
2. Primary printed and packing materials
3. Intermediate and semi finished product
4. Finished product
• SOPs: it is a written, authorized functional instruction used as a reference by the person responsible for performance and are also used for training new operators in the performance of the procedure.
• Test method: it is a written and approved documents describe the detailed testing procedure.
• List: Documents contain a catalog of any object such as list of equipments.
• Certificates of Analysis: it is an authentic documents shows the analytical reports and decision of acceptance/rejections
• Label
• Records
• Organ gram
• Job description
• Batch Manufacturing records: it is an important document issued for every batch of product to assure, review and record keeping of any product batch. There are following major content of BMR.
Documentation:
Introduction
Documentation is any communicable material that is used to describe,explain or instruct regarding some attributes of an object,system,or procedure such as its part, assembly,installatio,maintenance and use.
Purpose of Documentations
• Defines specifications and procedures for all materials and methods of manufacture and control
• Ensures all personnel know what to do and when to do it
• Ensure that authorized persons have all information necessary for release of product
• Ensures documented evidence, traceability, provide records and audit trail for investigation
• Ensures availability of data for validation, review and statistical analysis.
Following are the classification of Documents
• For organization & Personnel.
• For Buildings & facilities
• For Equipments.
• For Handling of R.M.& P.M.
• For Production & process control.
• For Packaging & Labeling control.
• For Holding & Distribution
• For Laboratory Control.
• For Records & Reports.
• For Return & Salvaged finished products.
Type of documents used in pharmaceuticals
• Specifications: as per MHRA Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. We need specification for:
1. Active and inactive materials
2. Primary printed and packing materials
3. Intermediate and semi finished product
4. Finished product
• SOPs: it is a written, authorized functional instruction used as a reference by the person responsible for performance and are also used for training new operators in the performance of the procedure.
• Test method: it is a written and approved documents describe the detailed testing procedure.
• List: Documents contain a catalog of any object such as list of equipments.
• Certificates of Analysis: it is an authentic documents shows the analytical reports and decision of acceptance/rejections
• Label
• Records
• Organ gram
• Job description
• Batch Manufacturing records: it is an important document issued for every batch of product to assure, review and record keeping of any product batch.
LIQUID PARATIONS FOR ORAL USE
Revised daft proposal for The International Pharmacopoeia
(September 2007)
Note: This monograph does not apply to liquids intended for oromucosal administration (for
example, gargles and mouthwashes).
Definition
Liquid preparations for oral use are usually solutions, emulsions or suspensions containing one or
more active ingredients in a suitable vehicle; they may in some cases consist simply of a liquid
active ingredient used as such. Liquid preparations for oral use are either supplied in the finished
form or, with the exception of Oral emulsions, may also be prepared just before issue for use by
dissolving or dispersing granules or powder in the vehicle stated on the label.
The vehicle for any liquid preparation for oral use is chosen having regard to the nature of the
active ingredient(s) and to provide organoleptic characteristics appropriate to the intended use of the
preparation. Liquid preparations for oral use may contain suitable antimicrobial preservatives,
antioxidants and other excipients such as dispersing, suspending, thickening, emulsifying,
buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents and authorized
colouring matter.
Liquid preparations for oral use may be supplied as multidose or as single-dose preparations. Each
dose from a multidose container is administered by means of a device suitable for measuring the
prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof,
or an oral syringe for other volumes or, for Oral drops, a suitable dropper.
Additional information. Liquid preparations for oral use are often the dosage form of choice for
paediatric use.
[Note from the Secretariat: It is recommended in future to provide guidance on certain aspects of
the formulation of oral liquids for paediatric use under Supplementary Information: Preparations for
Paediatric Use. If and when such a section is included, a cross-reference can be given here.]
Owing to the wide range of liquid preparations for oral use and their long history of use, a variety
of terms has been used to describe different members of this category of preparation. These terms,
which are not mutually exclusive and the definitions of which have changed over time, include
elixirs, linctuses, milks, mixtures and syrups. Such terms are still used within the titles of certain
specific, long-established, traditional preparations (for example, ephedrine elixir, codeine linctus,
acid gentian mixture). With such exceptions, however, it is recommended that the titles of liquid
dosage forms for oral use are based on the terms used as sub-monograph headings in this general
monograph. The term syrup (denoting a solution containing a high proportion of sucrose) is used,
inter alia, for certain solutions (for example black currant syrup, lemon syrup) that are used as
vehicle ingredients for their sweetening and flavouring properties. Such syrups are not dosage formsin the pharmacopoeial sense: they do not contain any active ingredient and are not intended to be
administered as such.
Oral solutions containing one or more active ingredients dissolved in a vehicle containing a high
proportion of sucrose or a suitable polyhydric alcohol or alcohols and which may contain ethanol have
traditionally been called elixirs. Viscous oral solutions containing one or more active ingredients dissolved
in a vehicle containing a high proportion of sucrose, other sugars or a suitable polyhydric alcohol or
alcohols and which are intended for use in the treatment or relief of cough have traditionally been called
linctuses. They are intended to be sipped and swallowed slowly without the addition of water.
Manufacture
The manufacturing process for liquid preparations for oral use should meet the requirements of
Good Manufacturing Practice.
The following information is intended to provide broad guidelines concerning the critical steps to be
followed during production of liquid preparations for oral use.
In the manufacture of liquid preparations for oral use measures are taken to:
• ensure that all ingredients are of appropriate quality
• minimize the risk of microbial contamination (see recommendations described under 3.3
Microbial quality of pharmaceutical preparations);
• minimize the risk of cross-contamination
[Note from the Secretariat: It is recommended to change the title of General method text 3.3 from
"Microbial purity of pharmaceutical preparations" to "Microbial quality of pharmaceutical
preparations" in the First Supplement.]
During the development of a preparation, the formulation for which contains one or more
antimicrobial preservatives, the effectiveness of the chosen preservative system shall be
demonstrated to the satisfaction of the relevant regulatory authority.
[Note from the Secretariat: It was recommended at the informal consultation on specifications for
medicines and quality control laboratory issues held on 27-29 June 2007 that a text on Efficacy of
antimicrobial preservation (containing a suitable test method together with criteria for judging the
preservative properties of the formulation) be developed for inclusion in The International
Pharmacopoeia. It was suggested that as a first step a review should be carried out of the different
approaches adopted in various pharmacopoeias.]
Appropriate measures should also be taken to optimize the stability of the active ingredient in the
liquid formulation including those prepared from powder or granules. Additional measures should
be taken so that, when stored under the conditions stated on the label, oral solutions are not subject
to t precipitation and oral suspensions are not subject to fast sedimentation, lump formation or
caking.
During development of a single-dose liquid preparation for oral use it shall be demonstrated that the
nominal content can be withdrawn from the container. In the production of liquid preparations for oral use containing dispersed particles, measures are
taken to ensure a suitable and controlled particle size and, where appropriate, crystal structure
(polymorphic and/or solvated forms) with regard to the intended use.
Throughout manufacturing, certain procedures should be validated and monitored by carrying out
appropriate in-process controls. These should be designed to guarantee the effectiveness of each
stage of production. In-process controls during the manufacture of oral liquids should include pH
and fill volume. The validation of the manufacturing process and the in-process controls are
documented.
Safety concerns
An important aspect of good manufacturing practice for all pharmaceutical products is
assuring the quality of all the starting materials used. The need for analytical testing to check
the identity and quality of starting materials is explained in detail in (section 14 of ) the
current WHO GMP guidelines1
. Failure to ensure that starting materials are of the required
quality can have very serious consequences.
Increasingly countries are dependent on the importation of starting materials for use in the
production of medicines. Starting materials often change hands many times before reaching
the manufacturer of the final marketed product and there are many opportunities for the
material to undergo relabelling along the distribution and trade chain (see WHO Guideline on
Good Trade and Distribution Practices for Pharmaceutical Starting Materials1
). As a result,
starting materials required for production of pharmaceutical products can become
contaminated or materials may be supplied that no longer correspond to what is stated on the
label in terms of quality or identity, either accidentally or as a result of negligence and
sometimes fraud.
The most documented incidents of contamination involve liquid preparations for oral use
manufactured with excipients such as glycerol and propylene glycol that have been
contaminated, adulterated or mixed up with diethylene glycol. Such incidents have been
responsible for hundreds of deaths throughout the world (see, for example, editorial in WHO
Bulletin 2001, 79(2)). Ingestion of diethylene glycol often leads to death through kidney
failure.
1
For current edition of WHO guidelines, please consult the WHO Medicines website
http://www.who.int/medicines/en/
Uniformity of mass
Liquid preparations for oral use that are presented as single-dose preparations comply with the
following test. Weigh individually the contents of 20 containers, emptied as completely as possible,
and determine the average mass. Not more than 2 of the individual masses deviate by more than
10% from the average mass and none deviates by more than 20%.
Uniformity of mass of doses delivered by the measuring device. The measuring device provided
with a multidose liquid preparation for oral use complies with the following test. Weigh
individually 20 doses taken at random from one or more multidose containers with the measuring
device provided and determine the individual and average masses. Not more than two of the
individual masses deviate by more than 10% from the average mass and none deviates by more than
20%.
Containers
The containers should be made of material that will not adversely affect the quality of the
preparation by, for example, leaching or sorption. Liquid preparations for oral use that contain
light-sensitive active ingredients are supplied in containers that are light-resistant.
Except where indicated in the individual monograph, containers should be made from material that
is sufficiently transparent to permit the visual inspection of the contents.
If the preparation contains volatile ingredients, the liquid preparation for oral use should be kept in
a tightly closed container.
Labelling
Every pharmaceutical preparation must comply with the labelling requirements established under
Good Manufacturing Practice.
The label should include:
(1) the name of the pharmaceutical product;
(2) the name(s) of the active ingredients; INNs should be used wherever possible;
(3) the amount of active ingredient in a suitable dose-volume;
(4) the name and concentration of any antimicrobial preservative and the name of any other
excipient;
(5) the batch (lot) number assigned by the manufacturer;
(6) the expiry date and, when required, the date of manufacture;
(7) any special storage conditions or handling precautions that may be necessary;
(8) directions for use, warnings, and precautions that may be necessary;
(9) the name and address of the manufacturer or the person responsible for placing the product
on the market.
[Note from the Secretariat: At the meeting in June 2007 it was recommended that, during the
proposed review, consideration should be given to adding to all the general monographs for dosage
forms that the label should include the product licence number (marketing authorization number).]
If the Liquid preparation for oral use is supplied as granules or powder to be constituted just before
issue for use, the label should include:
(1) that the contents of the container are granules or powder for the preparation of an oral liquid;
(2) the strength as the amount of the active ingredient in a suitable dose-volume of the
constituted preparation;
(3) the directions for preparing the oral liquid including the nature and quantity of liquid to be
used;
(4) the storage conditions and shelf-life of the constituted preparation.
Requirements for specific types of liquid preparations for oral use
Oral solutions
Definition
Oral solutions are clear Liquid preparations for oral use containing one or more active ingredients
dissolved in a suitable vehicle.
Visual inspection
Inspect the solution. It should be clear and free from any precipitate. Discoloration or cloudiness of
solutions may indicate chemical degradation or microbial contamination.
Oral suspensions
Definition
Oral suspensions are Liquid preparations for oral use containing one or more active ingredients
suspended in a suitable vehicle. For oral suspensions containing more than one active ingredient,
some of the active ingredients may be in solution.
Oral suspensions may show a sediment which is readily dispersed on shaking to give a uniform
suspension which remains sufficiently stable to enable the correct dose to be delivered.
Visual inspection
Inspect the suspension. Evidence of physical instability is demonstrated by the formation of
flocculants or sediments that do not readily disperse on gentle shaking. Discoloration may indicate
chemical degradation or microbial contamination.
Uniformity of content. For oral suspensions that are presented as single-dose preparations and that
contain less than 5 mg of active ingredient per dose or in which the active ingredient is less than 5%
of the total weight per dose, carry out the following test. Shake and empty each container as
completely as possible and carry out the test as described under 5.5 Uniformity of content for
single-dose preparations. In such cases, the test for Uniformity of mass prescribed above, is not
required.
[Note from the Secretariat: It is intended to apply the requirements as given in method text 5.5 for
capsules, oral powders and suppositories; reference to oral suspensions will be added to the relevant
subheading in this method text in the first Supplement.]
Labelling
The label on the container should include a direction that the bottle should be shaken before use.
Definition
Oral emulsions are Liquid preparations for oral use containing one or more active ingredients. They
are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids.
Solids may also be suspended in Oral emulsions.
Oral emulsions may show evidence of phase separation but are readily redispersed on shaking.
Visual inspection
Inspect the emulsion. Evidence of physical instability is demonstrated by phase separation that is
not readily reversed on gentle shaking. Discoloration of emulsions may indicate chemical
degradation or microbial contamination.
Containers
When issued for use, Oral emulsions should be supplied in wide-mouthed bottles.
Labelling
The label on the container should include a direction that the bottle should be shaken before use
Oral drops
Definition
Oral drops are Liquid preparations for oral use that are intended to be administered in small
volumes with the aid of a suitable measuring device. They may be solutions, suspensions or
emulsions.
Visual inspection
Inspect the drops. Drops that are solutions should be clear and free from any precipitate. Evidence
of physical instability of drops that are suspensions is demonstrated by the formation of flocculants
or sediments that do not readily disperse on gentle shaking. Evidence of physical instability of drops
that are emulsions is demonstrated by phase separation that is not readily reversed on gentle
shaking. Discoloration (or cloudiness of solutions) may indicate chemical degradation or microbial
contamination of the drops.
Dose and uniformity of dose of oral drops
Into a suitable, graduated cylinder, introduce by means of the dropping device the number of drops
usually prescribed for one dose or introduce by means of the measuring device the usually
prescribed quantity. The dropping speed does not exceed 2 drops per second. Weigh the liquid,
repeat the addition, weigh again and carry on repeating the addition and weighing until a total of 10
masses are obtained. No single mass deviates by more than 10% from the average mass. The total
of 10 masses does not differ by more than 15% from the nominal mass of 10 doses. If appropriate,
measure the total volume of 10 doses. The volume does not differ by more than 15% from the
nominal volume of 10 doses.
Containers
Oral drops are normally supplied in suitable multidose containers that allow successive drops of the
preparation to be administered.
Powders for oral solutions, oral suspensions or oral drops
Definition
Powders for oral solutions, suspensions or drops are multidose preparations consisting of solid,
loose, dry particles of varying degrees of fineness. They contain one or more active ingredients,
with or without excipients and, if necessary, authorized colouring matter and flavouring substances.
They may contain antimicrobial preservatives and other excipients in particular to facilitate
dispersion or dissolution and to prevent caking.
[Note from the Secretariat: Single-dose presentations of powder (such as, for example, a small
sachet) that are intended to be issued to the patient as such, to be taken in or with water or another
suitable liquid, are outside the scope of this general monograph. Such preparations are controlled by
the monograph for Oral powders.]
After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral
solutions, Oral suspensions or Oral drops, as appropriate.
Manufacture
In the manufacture of powders for oral solutions, suspensions or drops, the components of the
powder mixture are passed through a sieve to remove lumps and particle aggregates. The weighed
masses of the sieved components, preferably of a narrow particle size distribution, are then
transferred to a suitable mixer. The greatest risk of segregation of the powder mixture usually
occurs when emptying the mixer container and when the powder mixture is dosed into the
containers. Ensuring the suitability of the mixing equipment and the dosing devices is, therefore,
critical.
Visual inspection
Inspect the powder. Evidence of physical l instability is demonstrated by noticeable changes in
physical appearance, including texture (for example, clumping). Discoloration or may indicate
chemical degradation or microbial contamination.
Granules for oral solutions or suspensions
Definition
Granules for oral solutions or suspensions are multidose preparations consisting of solid, dry
aggregates of powder particles sufficiently resistant to withstand handling. They contain one or
more active ingredients with or without excipients and, if necessary, authorized colouring matter
and flavouring substances. They may contain antimicrobial preservatives and other excipients in
particular to facilitate dispersion or dissolution and to prevent caking.
[Note from the Secretariat: Single-dose presentations of granules (such as, for example, a small
sachet) that are intended be issued to the patient as such, to be taken in or with water or another
suitable liquid, are outside the scope of this general monograph.]
After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral
solutions or Oral suspensions, as appropriate.
Visual inspection
Inspect the granules. Evidence of physical instability is demonstrated by noticeable changes in
physical appearance, including texture (for example, clumping of granules, presence of loose
powder) . Discoloration may indicate chemical degradation or microbial contamination.
GENERALITIES
4.3.2.1 Dosage Form
According to the FDA: “ A dosage form is the physical form in which a drug is produced and dispensed. In determining dosage form, FDA examines such factors as
(1) Elegance: physical appearance of the drug product, (2) Stability: physical form
of the drug product prior to dispensing to the patient, (3) Acceptability: the way the
product is administered, (4) Effi cacy: frequency of dosing, and (5) Safety: how pharmacists and other health professionals might recognize and handle the product ”
[11] . The term dosage form is different from “ dose, ” which is defi ned as a specifi c
amount of a therapeutic agent that can be taken at one time or at intervals.
4.3.2.2 Liquid Dosage Form
The physical form of a drug product that is pourable displays Newtonian or pseudoplastic fl ow behavior and conforms to its container at room temperature. In contrast, a semisolid is not pourable and does not fl ow at low shear stress or conform
to its container at room temperature [12] . According to its physical characteristics,
liquid dosage forms may be dispersed systems or solutions.
4.3.2.3 Dispersed Systems
Dispersed systems are dosage forms composed of two or more phases, where one
phase is distributed in another [2] . If a dispersed system is formed by liquid phases,
then it is known as an “ emulsion. ” In contrast, the dispersed system is named a
“ suspension ” when the liquid dosage form is accomplished by the distribution of a
solid phase suspended in a liquid matrix. The solid phase of a suspension is usually
the drug substance, which is insoluble or very poorly soluble in the matrix [12] .
4.3.2.4 Solutions
A solution refers two or more substances mixed homogeneously [2] . Although solubility refers to the concentration of a solute in a saturated solution at a specifi c
temperature, in pharmacy, solution liquid dosage forms are unsatured to avoid
crystallization of the drug by seeding of particles or changes of pH or temperature
[13] . The precipitation of drug crystals is one of the most important physical instabilities of solutions that may affect its performance [14] . Water is the most used
solvent in solutions manufacturing; however, there are also some commercial nonaqueous solutions in the pharmaceutical market [1] .
4.3.2.5 Manufacturing of Nonparenteral Liquid Dosage Forms
The manufacturing of liquid dosage forms with market - oriented planning includes
the following stages with respect to special good manufacturing practice (GMP)
requirements: planning of material requirements, liquid preparation, fi lling and
packing, sales of drug products, vendor handling, and customer service [15] . From
the viewpoint of product stability, each stage of the process includes critical batchesthat are more decisive than others. Also, each decisive batch contains one or several
unit operations that are more critical than others. The FDA inspection focuses on
those critical unit operations to ensure the safety and stability of the liquid dosage
forms [6] .
4.3.2.6 Optimizing Drug Development Strategies
According to Sokoll [16] : The phases of drug development include discovery, preclinical
development, clinical development, fi ling for licensure, approval/licensure and post -
approval. Discovery typically includes basic research, drug identifi cation and early -
stage process and analytical method development. . . . Emerging companies that review
their pipeline objectively and strike a balance between properly resourcing and developing their lead candidates in the clinic while nurturing their next generation of drug
candidates will have the best chance for success and sustainability.
4.3.2.7 Unit Operation or Batch
A “ batch ” job or operation is defi ned as a unit of work. Raw materials, semifi nished
drug products (bulk), and fi nished drug products are handled in batches. Each different type of material used during the process, such as product packing, should be
managed by batches. This applies also to process aids and operation facilities [15] .
4.3.2.8 Batch Management
The batch management of production simplifi es the process and makes it easier to
control the status of transformation between raw and fi nal products [2] . Some of
the data used to follow the material performance around and out of the product
manufacturing process are batch - where - used - list, initial status, batch determinations, master data, and expiration date check [15] .
The functionality of the overall process to manufacture liquid dosage forms
depends on the successful linkage of one unit operation to another. To use mathematical formulations to scale up the manufacturing process, it is necessary to divide
the process into stages, batches, and unit operations. Each single unit operation is
scalable, but the composite manufacturing process is not. Production problems
result from attempts to follow a process scale - up instead of a unit operation scale -
up. By using mathematical formulations, it is possible to understand the level of
similarity between two scale sizes. In addition, nonlinear similarities between two
scale sizes might require the use of conversion factors to achieve an extrapolation
point for the scale [2] .
4.3.2.9 Steps of Liquids Manufacturing Process
Establishing short - term goals makes it easier to measure effi ciency as well as evaluate the diffi culties [2] . Based on these concepts, the problems of manufacturing
liquid dosage forms can be approached as problems in one or more batches of the
following process steps [6, 15] :
Planning of Material Requirements Research and development of protocols and
selection of materials; acquisition and analysis of raw materials; physical plantdesign, building, and installation; equipment selection and acquisition; personnel selection and initial training; and monitoring information system.
Liquid Preparation Research and development of protocols concerning liquid
compounding; scale - up of the bulk product compounding; physical plant control and maintenance; equipment maintenance and renovation; continuous
training of personnel and personnel compensation plan; and supervision of
system reports.
Filling and Packing Research and development of protocols concerning fi lling
and packing; scale - up of the fi nished drug product fi lling and packing; physical
plant control and maintenance; equipment maintenance and renovation; continuous training of personnel and personnel compensation plan; and supervision of system reports.
Sales of Drug Products Research and development of protocols concerning
product storage; distribution process; continuous training of personnel and
personnel compensation plan; and supervision of system reports.
Vendor Handling Research and development protocols concerning precautions to maintain product stability; control of vendor stock; and sales system
reports.
Customer Service Research and development of protocols concerning home
storage and handling to maintain product stability; relations with health insurance companies and health care professionals; educational materials for patient
counseling; and customer service system reports.
4.3.2.10 Protocols
Protocols are patterns developed by repeating procedures and fi xing the identifi ed
problems each time that the procedure is followed. Therefore, protocols are dynamic
entities that originally can be developed at a laboratory level but must be adjusted
in every new step of the scal - up process. When the manufacturing process moves
up in scale, the number of people affected by the protocol increases geometrically.
Initially, the information can be obtained from library references, personal tests,
interpersonal training, and previous laboratory protocols. However, when the production is scaled up, the information required to fi ne tune the process comes from
monitoring the process itself [2] .
4.3.3 APPROACHES
Quality by Design is a systemic approach that applies the scientifi c method to the
process. QbD theory contains components of management, statistics, psychology,
and sociology. The FDA ’ s new century has identifi ed the QbD approach as its “ key
component ” based on process quality control before industry end results [3, 17] .
The cooperation between industry members and regulators is increased when the
industry explains clearly what it is doing and the agency can understand the formulation and production process. In these cases, regulatory relief appears when industry explores its issues and receives active guidance and programs from the FDA.
The agency takes the role of facilitator, or even partner of the industry, in order to
improve the strength of the process and formulation [3, 17] . To apply QbD as a systemic approach, the company starts by understanding,
step by step, the space design, the design of the dosage form, the manufacturing
process, and the critical process parameters to be controlled in order to reach the
new building block which is the expectation of variances within those critical
process parameters that can be accepted. This approach allows the establishment
of priorities and fl exible boundaries in the process [3] . Infl exible specifi cations
allow uncontrolled small variances that can follow the butterfl y effect of the theory
of chaos by producing unpredictable large variations in the long - term behavior of
the product shelf - life [18, 19] . In contrast, fl exibility, with knowledge of potential
variances, reduces changes in the approved spaces and manufacturing protocols
[3, 17] .
According to the FDA [6] , critical parameters during the manufacturing process
of nonparenteral liquid dosage forms may appear in the design of physical plant
systems, equipment, protocols of usage and maintenance, raw materials, compounding, microbiological quality control, uniformity of suspensions and emulsions, and
fi lling and packing [6] .
Process isolation and installation of an appropriate air fi ltration system in the
physical plant may reduce product exposition to chemical and microbiological
contaminations. In addition, the use of a suitable dust removal system as well as
a heating, ventilation, and air conditioning system (HVACS) may help to repress
product chemical instabilities [6] .
The equipment of sanitary design, including transfer lines, as well as appropriate
cleaning and sanitization protocols may reduce chemical and microbiological contaminations in the fi nal product. Chemical instabilities may be reduced by weighting
the right amount of liquids instead of using a volumetric measurement, avoiding the
common use of connections between processes, and using appropriate batching
equipment [6] .
Particle sizes of raw materials are critical to control dissolution in solutions as
well as uniformity in suspensions and emulsions. Temperature control during compounding is important since heat helps to support mixing and/or fi lling operations,
but, in contrast, high - energy mixers may produce adverse levels of heat that affect
product stability. Too much heat may cause chemical and physical instabilities such
as change of particle size or crystallization of drugs in suspensions, dissolution and
potency loss of drugs in suspensions, oxidation of components, and activation of
microbiological growth after degradation of compounds as well as precipitation of
dissolved compounds in solution [20] . In addition, uniformity of suspensions depends
on viscosity and segregation factors while solubility, particle size, and crystalline
form determine uniformity of emulsions. Application of pharmaceutical GMP for
product processes and storage assures microbiological quality. A defi cient deionizer
water - monitoring program and product preservative system facilitate microbial contamination. Filling uniformity is indispensable for potency uniformity of unit - dose
products and depends on the mixing operation. Calibration of provided measuring
devices and the use of clean containers will allow administering the right amount
of the expected components in the liquid dosage form [6] .
Principal product specifi cations are microbial limits and testing methods, particle
size, viscosity, pH, and dissolution of components. Process validation requires control
of critical parameters observed during compounding and scale - up. Product stability
examination is based on chemical degradation of the active components and interactions with closure systems, physical consequences of moisture loss, and microbial
contamination control [6] .
4.3.4 CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS
4.3.4.1 Physical Plant
Heating, Ventilation, and Air Conditioning System The manufacturer has to
warrant adequate heating, ventilation, and air conditioning in places where labile
drugs are processed [6] .
The effect of long processing times at suboptimal temperatures should be considered at the production scale in terms of the consequences on the physical or chemical
stability of individual ingredients and product. A pilot plant or production scale
differs from laboratory scale in that their volume - to - surface - area ratio is relatively
large. Thus, for prolonged suboptimal temperatures, jacketed vessels or immersion
heaters or cooling units with rapid circulation times are absolutely necessary [2] .
For heat - labile drugs, uncontrolled temperature increments can activate auto -
oxidation chains when the drug product ingredients react with oxygen and generate
free radicals but without drastic external interference. Vitamins, essential oils, and
almost all fats and oils can be oxidized. A good example of a heat - labile drug solution is clindamycin, which has to be stored at room temperature and away from
excess heat and moisture [19] . Auto - oxidation chains are fi nished when free radicals
react with each other or with antioxidant molecules (quenching). The tocopherols,
some esters of gallic acid, as well as BHA and BHT (butylated hydroxyanisole and
butylated hydroxytoluene) are common antioxidants used in the pharmaceutical
industry [1] .
Isolation of Processes To minimize cross - contamination and microbiological contamination, the manufacturer may develop special procedures for the isolation of
processes. The level of facilities isolation depends on the types of products to be
manufactured. For instance, steroids and sulfas require more isolation than over -
the - counter (OTC) oral products [6] . To minimize exposure of personnel to drug
aerosols and loss of product, a sealed pressure vessel must be used to compound
aerosol suspensions and emulsions [21] . An example of cross - contamination with
steroids was the controversial case of a topical drug manufactured for the treatment
of skin diseases. High - performance liquid chromatography/ultraviolet and mass
spectrometry (HPLC/UV, HPLC/MS) techniques were used by the FDA for the
detection of clobetasol propionate, a class 1 superpotent steroid, as an undeclared
steroid in zinc pyrithione formulations. The product was forbidden and a warning
was widely published [22] .
Dust Removal System The effi ciency of the dust removal system depends on the
amount and characteristics of dust generated during the addition of drug substance
and powdered excipients to manufacturing vessels [6] . Pharmaceutical industries
usually generate some type of dust or fume during processing. Important factors for
selecting dust collectors are maintenance, surrogate test, economics, and containment. In addition, reentrainment of the fi ne particles, vertical or horizontal position,
effi ciency, pressure resistant, service life time, as well as sealing capacity to workthrough the bag are signifi cant factors concerning fi lter selection of dust removal
systems. Some examples of dust collection applications in the manufacture of liquid
dosage forms are handling and pulverization of raw materials, spray dryers, and
general room ventilation [23] .
Air Filtration System The effi ciency of the air fi ltration system has to be demonstrated by surface or air - sampling data where the air is recirculated [6] . To monitor
the levels of contamination in the air, there are commercial automatic samplers for
microbiological contamination or gas presence. Air trace environmental samplers
for pharmaceutical industries are based on the slit - to - agar impaction technique for
the presence of viable microorganisms. Automatic samplers for compressed gas
analyze the presence of a specifi ed gas in 1 m 3
by absorbing air at a fi xed fl ow rate
for a sampling period of 1 h or a different adjusted time. These solutions to the
sampling needs of the pharmaceutical industry are robust, require low maintenance,
and are easy to use. This allows for validation of sampling data at the moment of
application fi lling to support the process control. Sampling time and selection of
microbiological growth media or analysis technique are important components to
consider when developing a sampling plan [24] .
4.3.4.2 Equipment
Sanitary Design Pumps, valves, fl owmeters, and other equipment should be easily
sanitized. Some examples of identifi ed sources of contamination are ball valves,
packing in pumps, and pockets in fl owmeters [6] .
The sanitary design and performance of equipment make it accessible for inspection, cleaning, and maintenance. It has to be cleanable at a microbiological level and
its performance during normal operations should contribute to sanitary conditions.
The materials used in the design have to assure hygienic compatibility with other
equipment, the product, the environment, other systems such as electrical, hydraulics, steam, air, and water, as well as the method and products used for cleaning and
sanitation. The equipment should be self - draining to assure product or liquid collection. Small niches, for example, pits, cracks, corrosion, recesses, open seams, gaps,
lap seams, protruding ledges, inside threads, bolt rivets, and dead ends, as well as
inaccessible cavities of equipment such as entrap and curlers must be eliminated
whenever possible; otherwise they have to be permanently sealed. Enclosures, for
example, push buttons, valve handles, switches, and touch screens, should be prepared for a hygienic design of maintenance. Standards have been developed by the
American Meat Institute [25] .
Standard Operating Procedures for Cleaning Production Equipments Current
GMPs are defi ned as the basic principles, procedures, and resources required to guarantee an environment appropriate for manufacturing products of adequate quality
[26] . To minimize cross - contamination and microbiological contamination, it is GMP
for a manufacturer to create and pursue written standard operating procedures
(SOPs) to clean and sanitize production equipment in a way that avoids contamination of in - progress and upcoming batches. When the drug is known as a potent generator of allergic reactions, such as steroids, antibiotics, or sulfas, cross - contamination
becomes an issue of safety [20] . In addition, validation and data analysis procedures, including drawings of the manufacturing and fi lling lines [6] , are especially important
for clean - in - place (CIP) systems, as indicated in Figures 1 and 2 .
Many companies have problems with standardizing operating procedures for
cleaning steps and materials used [6] . Appropriate SOPs are necessary to determine
the scope of the problem in investigations about possible cross - contaminations or
mix - ups. The best approach to validate a SOP is to test it, use it as a training tool,
and observe the results obtained by different persons. This includes the worst - case
situation in order to enhance the step - by - step writing methodology as well as standardizing the materials used. A typical SOP contains a header to present the SOP
title, date of issue, date of last review, total number of pages, responsible person,
and approval signature. Typically, a SOP includes position of responsible person,
SOP purpose and scope, defi nitions, equipment and materials, safety concerns, step -
by - step procedure, explanation of critical steps, tables to keep data, copies of forms
to fi ll, and references [26] . The forms to keep the records must show the date, time,
product, and lot number of each batch processed. However, the most important
points of the SOP are equipment identity, cleaning method(s) with documentation
of critical cleaning steps, materials approved for cleaning that have to be easily
removable, names and position of persons responsible for cleaning and inspection,
inspection methods, and maintenance and cleaning history of the equipment [20] .
Cleaning and Sanitizing Transfer Lines Pipes should be hard, easily cleaned, and
sanitized. To avoid moisture collection and microbiological contamination, hoses
should be stored in a way that allows them to drain rather than be looped. For
example, transfer lines are an important source of contamination when fl exible
hoses are handled by operators, lying on the fl oor, and after they are placed in
transfer or batching tanks [6] .
Heat is considered one of the most efficient physical treatments for sanitizing
pharmaceutical equipment and could be used for sanitizing hoses that have already
been cleaned. The recirculation of hot water at a temperature of 95 o
C for at least
100 min allows bacteria elimination [14] .
Due to the important amount of insoluble residues left on piping and transfer
lines after emulsion manufacturing, such as topical creams and ointments, equipment cleaning becomes difficult to address. To avoid cross - contamination, some
manufacturers have decided to dedicate lines and hoses to specific products.
However, these decisions have to appear in the written production protocols and
SOPs [20] .
Sampling Cleaned Surfaces for Presence of Residues The cleaning method is
validated by sampling the cleaned surfaces of the equipment for the existence of
residues. The equipment characteristics and residue solubility are factors to support
the selection of the sampling method to be used [6] . There are two acceptable
general types of sampling methods: direct surface sampling by swabbing of surfaces
and rinse sampling with a routine production in - process control. Although surface
residues will not be identical on each part of the surface, statistically the most
advantageous is direct surface sampling because it allows evaluation of the hardest
areas to clean as well as insoluble or “ dried - out ” residues by physical removal. The
type of sampling material and solvent used for extraction from the sampling material should be validated in order to determine their impact on the test data. The
second method, rinse sampling, is used for larger surfaces or inaccessible systems.
Contaminants that are physically occluded and insoluble residues are disadvantages of the rinse sampling method. To validate this cleaning process, direct measurement of the contaminant in the rinse water has to be tested instead of a simple
test for water quality. Routine production in - process control is used as indirect
testing for large equipment that has to be cleaned by the rinse sampling method.
The uncleaned equipment has to give an unacceptable result for the indirect
test [27] .
Establishing Appropriate Limits on Levels of Postequipment Cleaning
Residues Very low levels of residue are possible to be determined since technological advances offer more sensitive analytical methods. The manufacturer should
know the toxicological information of the materials used and potential amounts of
residues after exposure to the equipment surface. Accordingly, the manufacturer
has to establish proper limits of residues after equipment cleaning and scientifi cally
justify these limits. The established limits must be clinically and pharmaceutically
safe, realistic, viable, and verifi able [20] . The sensitivity of the analytical method will
determine the logic of the established limits since absence of residues could indicate
a low sensitivity of the analytical method or a poor sampling procedure. Sometimes
thin - layer chromatography (TLC) screening must be used in addition to chemical
analyses. Some practical levels established by manufacturers include 10 ppm of
chemicals, 1/1000 of the biological activity levels met on a normal therapeutic dose,
and no visible residues of particles determined organoleptically [27] .
Connections Connectors and manifolds should not be for common use. For
example, sharing connectors in a water supply, premix, or raw material supply tanks
may be a source of cross - contamination [6] .
Time between Completion of Manufacturing and Initiation of Cleaning The time
that may elapse from completion of a manufacturing operation to initiation of
equipment cleaning should also be stated where excessive delay may affect the
adequacy of the established cleaning procedure. For example, residual product may
dry and become more diffi cult to clean [20] .
SOPs are an example of defi ciency in many manufacturers regarding time limitations between batch cleaning and sanitization [6] . Lack of communication betweendepartments responsible for the production at different levels is the main cause of
time control problems. Typically each department, from human resources to fi nances,
manufacturing, and warehouse, has its own computer system optimized for the
particular ways that the department does its work. Therefore, time control becomes
a primordial issue when labile materials are transferred from one department to
another [28] .
To facilitate communication between different departments, some useful softwares have been developed. For example, ERP is an integrated approach which may
have positive payback if the manufacturer installs it correctly. An ERP is a type
of software that can improve communication between planning and resources. The
software attempts to integrate all departments and functions in a company onto a
single computer system that can serve each particular need, such as fi nance, human
resources, manufacturing management, process manufacturing management, inventory management, purchasing management, quality management, and sales management. Each department has its own software, except now the software is linked
together, so that, for example, someone in manufacturing can look into the maintenance software to see if specifi c batch cleaning and sanitization have been scheduled
or realized and someone in fi nance can review the warehouse software to see if a
specifi c order has been shipped. The information is online and not in someone ’ s
heads or on papers that can be misplaced. People in different departments may see
the same information, update it if they are allowed to do, and make right decisions
faster. However, the software is less important than the changes companies make
in the ways they work. Reorganization and training are the keys of ERP ’ s success
to fi x integration problems. There are three different ways to install an ERP: big
bang, franchising strategy, and slam dunk. Big bang is the most ambitious way
whereby companies install a single ERP across the entire company. By the franchising strategy, departments do not share many common processes across, whereas
slam dunk is focused on just a few key processes [28] .
Weight in Formulations Flow properties of liquids rarely vary due to their constant density at a constant temperature. Oral solutions and suspensions are formulated on a weight basis (gravimetry) in order to be able to measure the fi nal volume
by weight before fi lling and packing. Volumetric measurements of liquid amounts
to be used for manufacturing liquid dosage forms have shown greater variability
than weighted liquids. For instance, the inaccurate measurement of the fi nal volume
by using dip sticks or a line on a tank may cause further analytical errors and
potency changes [6] .
The importance of selecting gravimetry instead of volumetry to measure liquid
amounts in the pharmaceutical industry of liquid dosage forms is well illustrated by
the volume contraction of water – ethanol and volume expansion of ethyl acetate –
carbon disulfi de liquid mixtures as well as a CS2 – ethyl acetate system. The National
Formulary (NF) diluted alcohol is a typical example of the volume nonadditivity of
liquid mixtures [29] . This solution is prepared by mixing equal volumes of alcohol
[U.S. Pharmacopeia (USP)] USP and purifi ed water (USP). The fi nal volume of this
solution is about 3% less than the sum of the individual volumes because of the
contraction due to the mixing phenomenon [1] . In addition, molecular interactions
of surfactants in mixed monolayers at the air – aqueous solution interface and in
mixed micelles in aqueous media also cause some contraction of volume upon
mixing [30]
Location of Bottom Discharge Valve in Batching Tank The bottom discharge
valve should be located exactly at the bottom of the tank. In some cases valves have
been found to be several inches to a foot above the bottom of the tank [6] .
For a tank suspected of having substantial deposits at the bottom, a fi ber - optic
camera can be inserted in the tank to provide a view and positive confi rmation of
the tank bottom condition. These camera and light vision systems are sanitary equipment able to provide a computational real - time visual inspection of the inside tank
under process conditions or pressure vessel. In addition, they are used to control
several parameters during the manufacturing process, such as product level and
thickness, solids level, uniformity of suspensions, foam, and interface and/or cake
detection [31] .
Batching Equipment to Mix Solution Ingredients of solutions have to be completely dissolved. For instance, it has been observed that some low - solubility drugs
or preservatives can be kept in the “ dead leg ” below the tank, and the initial samples
have reduced potency [6] . When there is inadequate solubility of the drug in the
chosen vehicle, the dose is unable to contain the correct amount of drug in a manageable size unit, that is, one teaspoonful or one tablespoonful. Thus, ingredients
as well as handling and storage conditions should be chosen to manage the problem
[14] .
In solutions, the most important physical factors that infl uence the solubility of
ingredients are type of fl uid, mixing equipment, and mixing operations. Generalized
Newtonian fl uids are ideal fl uids for which the ratio of the shear rate to the shear
stress is constant at a particular time. Unfortunately, in practice, usually liquid
dosage forms and their ingredients are non - Newtonian fl uids in which the ratio of
the shear rate to the shear stress varies. As a result, non - Newtonian fl uids may not
have a well - defi ned viscosity [32] .
When all the ingredients are miscible liquids, the combination and distribution
of these components to obtain a homogeneous mixture are called blending. Whenever possible, ingredients should be added together and the impeller mixer often is
located near the bottom of the vessel [21] . Mixing of high - viscosity materials requires
higher velocity gradients in the mixing zone than regular blending operations. In
fact, the fundamental laws of physics regarding the performance of Newtonian fl uids
in the production process may be studied using computational tools. For example,
VisiMix is a software that is routinely used to calculate shear rates [2] .
Finally, if it is determined that there is a bigger problem of insolubility
coming from the formulation, then addition of cosolvents, surfactants, as well as
the preparation of the ionized form of an acid or base, drug derivatization, and
solid - state manipulation are approaches to manipulating the solubility of the drug
[14] .
Batching Equipment to Mix Suspension In the case of suspensions, the fl ow necessary to overcome settling in a satisfactory suspension depends on the mixing
equipment and is predicted by Stokes ’ s law. Thus, to use the Stokes ’ s law, suspensions are considered as Newtonian fl uids if the percentage of solids is below 50%.
Mixing equipment uses a mechanical device that moves through the liquid at a given
velocity. Dispersing and emulsifying equipment is categorized as “ high - shear ” mixing
equipment. The maximum shear rate with such equipment occurs very close to themixing impeller. Therefore, the diameter of the impeller and the impeller speed
directly infl uence the power applied by the mixer to the liquid [21] .
Batching Equipment to Mix Emulsion The most common problems of mixing
emulsions are removing “ dead spots ” of the mixture and scrapping internal walls of
the mixer. Dead spots are quantities of ingredients that are not mixed and become
immobile. Where dead spots are present, that quantity of the formula has to be
recirculated or removed and not used. If the inside walls of the mixer keep residual
material, operators should use hard spatulas to scrape the walls; otherwise the
residual material will become part of the next batch. In both cases, the result may
be nonuniformity. Stainless steel mixers have to include blades made of hard plastic,
such as Tefl on, to facilitate the scrapping of the mixer walls without damaging the
mixer. Scrapper blades should be fl exible enough to remove internal material but
not too rigid to avoid damaging the mixer [20] . The mixing will be successful if the
macroscale mixing offers suffi cient fl ow of components in all areas in the mixing
tank and the microscopic examination shows a correct particle size distribution
[33] .
4.3.4.3 Particle Size of Raw Materials
Raw materials in Solution The types of raw materials used to be part of solutions
are presented in Table 1 . They have different purposes and can be cosolvents, electrolytes, buffers, antioxidants, preservatives, coloring, fl avoring and sweetener agents,
among others.
Particle Size of Raw Materials in Solution Particle size is affected by the breaking process of the particle, crystal form, and/or salt form of the drug. The particle
size can affect the rate of dissolution of raw materials in the manufacturing process.
Raw materials of a fi ner particle size may dissolve faster because they have a larger
surface area in contact with the solvent than those of a larger particle size when the
product is compounded [6] . Mixing faster causes the particle to break down and
dissolve more quickly. In addition, hydrated particles are less soluble than their
anhydrous partners [37] .
Solid drugs may occur as pure crystalline substances of defi nite identifi able shape
or as amorphous particles without defi nite structure. In addition, when a drug particle is broken up, the total surface area is increased as well as its rate of dissolution.
The amorphous form of a chemical is usually more soluble than the crystalline form
while the crystalline form usually is more stable than the amorphous form [37] .
Processing conditions used for providers to obtain raw materials can dramatically
impact their quality and stability; for instance, the presence of different polymorphs
may depend on the thermal history of freezing, concentration of solvents, and drying
conditions [38] . The polymorphism of a crystalline form is the capacity of a chemical
to form different types of crystals, depending on the conditions of temperature,
solvents, and time followed for its crystallization. Among different polymorphs, only
one crystalline form is stable at a given temperature and pressure. Over time, the
other crystalline forms, called metastable forms, will be transformed into stable
forms. Transformations longer than the shelf - life of metastable forms into stable
forms of a drug are very common in fi nal products and compromise its stability and
effi cacy to different extents depending on quality control [37] .
While the metastable forms offer higher dissolution rates, many manufacturers
use a particular amorphous, crystalline, salt, or ester form of a drug with the solubility needed to be dissolved in the established conditions, for instance, to prepare a
chloramphenicol ophthalmic solution [39] . Thus, the selection of amorphous or
crystalline form of a drug may be of considerable importance to facilitate the formulation, handling, and stability [37] .
However, the dissolution rate of an equal sample of a slowly soluble raw material
usually will increase with increasing temperature or rate of agitation as well as with
reduce viscosity, changes of pH or nature of the solvent. In addition, other alternative mechanisms to enhance the solubility of insoluble drugs are: 1) hydrophilization: the reduction in contact angle or angle between the liquid and solid surface
[40] , which can be accessed by intensive mixing of the hydrophobic drug with a small
amount of methylcellulose solution [41] ; 2) the formation of microemulsions: by
covering small particles with surfactants to obtain micromicelles that are visible only
in the form of an opalescence; and, 3) the formation of complexing compounds: by
adding a soluble substance to form soluble reversible complexes. However, the last
method is used with some restrictions [42] .
Raw Materials in Suspension The types of raw materials used to be part of suspensions are presented in Table 2 . They have different purposes and can be wetting
agents, salt formation ingredients, buffers, polymers, suspending agents, fl occulating
agents, electrolytes, antioxidants, poorly soluble Active Product Ingredients, preservatives, coloring, fl avoring and sweetener agents, among others.
Particle Size of Drug in Suspension The physical stability of a suspension can be
enhanced by controlling the particle size distribution [43] . Uncontrolled changes of
drug particle size in a suspension affect the dissolution and absorption of the drug
in the patient. Drug substances of fi ner particle size may be absorbed faster and
bigger particles may not be absorbed. Aggregation or crystal growth is evaluated
by particle size measurements using microscopy and a Coulter counter [21] or preferably techniques that allow samples to be investigated in the natural state. Allen
[44] offers an academic and industrial discussion about particle characterization.
Powder properties and behavior, sampling, numerous potential particle size measuring devices, available equipment as well as surface and pore size are his principal
themes.
Particles are usually very fi ne (1 – 50 μ m). For instance, topical suspensions use
less than 25 μ m particle size [6] . The particle size of the drug is the most important
consideration in the formulation of a suspension, since the sedimentation rate of
disperse systems is affected by changes in particle size. Finer particles become interconnected and produce particle aggregation followed by the formation of nonresuspendable sediment, known as caking of the product. The two main causes of
aggregation and caking are energetic bonding and bonding through shared material.
A statistical wide distribution of particle sizes gives more compact packing and
energetic bonding than narrower distributions. It has been observed that heat treatments can cause agglomeration of particles, not only due to energetic bonding but
also by formation of crystal bridges. Also, when the application of shear forces to
mix and homogenize the suspension uses too high energy inputs, then the probability for aggregation increases [43] .
Examples of oral suspensions in which a specifi c and well - defi ned particle size
specifi cation for the drug substance is important are phenytoin suspension, carbamazepine suspension, trimethoprim and sulfamethoxazole suspension, and hydrocortisone suspension [6] .
There are some useful methods to improve the physical stability of a suspension,
such as decreasing the salt concentration, addition of additives to regulate the
osmolarity, as well as changes in excipient concentrations, unit operations in the
process, origin and synthesis of the drug substance, polymorphic behavior of
the drug substance crystals, and other particle characteristics. However, methods
based on changes of the particle properties and the surfactants used are the most
successful [43]
To approach physical stability problems of suspensions, effectiveness and stability
of surfactants as well as salt concentrations must be checked with accelerated aging.
In addition, unit operations affecting particle size distribution, surface area, and
surfactant effectiveness should be approached, taking into account that different
types of distributions, for instance, volume or number weighted, give a different
average diameter for an equal sample [43] .
Raw Materials in Emulsions The types of raw materials used to be part of emulsions are presented in table 3 . They have different purposes and can be buffers,
polymers, emulsifying agents, penetration enhancers, gelling agents, stabilizers, antioxidants, preservatives, coloring, fl avoring and sweetener agents, among others.
Particle Size in Emulsions When a solid drug is suspended in an emulsion, the
liquid dosage form is known as a coarse dispersion. In addition, a colloidal dispersion has solid particles as small as 10 nm – 5 μ m and is considered a liquid between
a true solution and a coarse dispersion [44] .
Compounding: Effects of Heat and Process Time
Oxygen Oxygen removal for processing materials that require oxygen to degrade
is possible by methods such as nitrogen purging, storage in sealed tanks, as well
as special instructions for manufacturing operations [6] . For instance, sealing glass
ampules containing a liquid dosage form with heat under an inert atmosphere is a
packing mechanism used to prevent oxidation. Some aspects of oxygen sensitiveness
that should be taken into account are the necessity of water and headspace deoxygenation in ampules before sealing, the avoidance of multidose vials that facilitate
oxygen contact with the product after opened, and rubber stoppers for vial sealing
that are permeable to oxygen as well as release additives to catalyze oxidative reac-tions. Rubber stoppers soften and get sticky over time because all rubber products
degrade as sulfur bonds induced during vulcanization revert. Connors et al. [45]
present the oxygen content of water at different temperatures and an interesting
discussion of calculations for the case of captopril as an oxygen - sensitive drug.
Dissolution of Drugs in Solutions Although some compounds, such as poloxamers, decrease their aqueous solubility with an increase in temperature [46] , usually,
drugs dissolve more quickly when the temperature increases because particle vibration is augmented and the molecules move apart to form a liquid. Chemical instabilities by oxidation due to high temperature or prolonged periods of heat exposure
can occur when trying to increase the dissolution of poorly soluble raw materials.
To control such instabilities, charts of time and amount of temperature treatments
to dissolve materials as well as tests of dissolution are required [6] . In addition,
precipitations and other reactions may occur between salts in solution and can be
anticipated by using heat - of - mixing data and activation energy calculations for
decomposition reactions. Connors et al. [45] provide examples of calculations about
effects of temperature on chemical stability of pharmaceuticals in solution. Regarding the instability of the product, the reasons to limit temperature amounts can go
from controlling fi nal concentration changes to controlling burn - on/fouling when
too - high temperatures are applied [45] . Usually salts are more soluble in water and
alcohol than weak acids or bases. The reason salts are not always the best choice to
increase the solubility of a drug is its permeability. Oral drug absorption depends
not only on solubility and dissolution but also on permeability through the cellular
membrane. Drugs have to be able to dissolve not only in the aqueous fl uids of the
body before reaching the intestinal wall but also in the lipophilic environment of
the cellular membrane in order to reach the internal part of the cell and interfere
with its functionability. Therefore, the cosolvent approach is essential if the drug
presents problems in dissolving in the media. The dielectric constant of a solvent is
a relative measure of its polarity. Comparing the hydroxyl – carbon ratio of the
solvent molecule allows establishing the relative polarity of the cosolvent as determined by its dielectric constant [47] . Remington describes the formulations of some
solutions, such as the ferrous sulfate syrup, amantadine hydrochloride syrup, phenobarbital elixir, and theophylline elixir [1] .
Potency of Drugs in Suspension To avoid degradation of the suspended drug substance by high temperature or prolonged periods of heat exposure, it is necessary
to record the time and amount of temperature treatments on charts [6] . The rate
of dissolution of a suspended drug increases with the increase in temperature. The
potency stability of a suspended drug depends on the concentration of the dissolved
drug since drug decomposition occurs only in solution [48] . The goal is to avoid
the dissolution of suspensions. Changing the pH of the vehicle or replacing the drug
with a less soluble molecule may result in enhanced potency stability of the suspended drug [48] .
For instance, when the chemical stability of a suspension of ibuprofen powder
and other ibuprofen – wax microspheres was studied with a modifi ed HPLC procedure for three months, the amount of drug released from the microspheres was
affected by the medium pH, type of suspending agent, and storage temperature
without observing chemical degradation of the drug [49
Temperature Uniformity in Emulsions During the preparation of emulsions, heat
may be increased as part of the manufacturing protocol or mixing operation system.
Temperature measurements should be monitored and documented continuously
using a recording thermometer if the temperature control is critical or using a hand -
held thermometer if it is not a critical factor. Temperature may be critical in the
manufacturing process depending on the thermosensitivity of the drug product and
excipients as well as the type of mixer used. To guarantee the temperature uniformity during the mixing operation, manufacturers may consider the relation between
the container size, mixer speed, blade design, viscosity of the contents, and rate of
heat transfer [20] .
Fong - Spaven and Hollenbeck [50] studied the apparent viscosity as a function
of the temperature from 25 to 75 ° C of an oil – water emulsion stabilized with 5%
triethanolamine stearate (TEAS) using a Brookfi eld digital viscometer. They
observed that the viscosity decreased when the temperature reached about 48 ° C,
but surprisingly viscosity increased to a small peak at 54 ° C and then continued
decreasing after that peak. The viscosity peak was attributed to a transitional gellike
arrangement molecular structure of TEAS that is destroyed as soon as the temperature continues increasing, the TEAS crystalline form reappears, and viscosity again
decreases [36] .
Microbiological Control To avoid chemical instabilities that yield microbiological
and physical instabilities, as a result of high temperature or prolonged periods of
exposure, it is necessary to record the time and amount of temperature treatments
on charts [6] .
Product Uniformity Charts of storage and transfer operation times for the bulk
product are required to control the risk of segregation. Transfers to the fi lling line
and during the fi lling operation are the most critical moments to keep the suspension uniformity [6] . The implementation of an ERP for time scheduling is the best
solution for time control and organization of resources. However, it could be diffi -
cult due to the reluctance of people to change [10] . The constant fl ow of the liquid
through the piping, the constant mixing of the bulk product in the tank, as well as
the transfer of small amounts near the end of the fi lling process to a smaller tank
during the fi lling process may minimize segregation risks [6] .
Final Volume Excess heating produces variations of the fi nal volume over time
[6] . Although increasing solute concentration can elevate the boiling point and
reduce evaporation of water, changes in drug concentration are undesirable because
they yield different fi nal products. Regarding the instability of the product, the
reasons to limit temperature amounts can go from controlling fi nal concentration
changes to controlling burn - on/fouling when too - high temperatures are applied
[36] .
A solution is a liquid at room temperature that passes into the gaseous state when
heated at very high temperature, forming a vapor with determined vapor pressure,
through a process called vaporization. The kinetic energy is not evenly distributed
between the molecules of the liquid. When the liquid is in a closed container at a
constant temperature, the molecules with the highest kinetic energy leave the surface
of the liquid and become gas molecules. Some of the gas molecules remain as gas
and others condense and return to the liquid. When, at a determined temperature, the rate of condensation equals the rate of vaporization, the equilibrium vapor pressure is reached. However, vapor pressure increases with increases in liquid temperature, resulting in more molecules leaving the liquid surface and becoming gas
molecules [51] .
Storage Charts of time and temperature of storage are important to control the
increased levels of degradedness [6] . Shelf life is defi ned as the amount of time in
storage that a product can maintain quality and is equivalent to the time taken to
reach 90% of the composition claim or have 10% degradation. The availability of
an expiration date is assumed under specifi ed conditions of temperature. Based on
zero - and fi rst - order reaction calculations, Connors et al. [45] show the estimation
methods to determine the shelf life of a drug product at temperatures different from
the one specifi ed under standard conditions.
4.3.4.5 Uniformity of Oral Suspensions
Keeping the particles uniformly distributed throughout the dispersion is an important aspect of physical stability in suspensions. Based on Stokes ’ s law for dilute
suspensions where the particles do not interfere with one another, there are different factors that control the velocity of particle sedimentation in a suspension, for
instance, particle diameter, densities of the dispersed phase and the dispersion
medium, as well as viscosity of the dispersion medium [36] . Remington describes
the formulation of trisulfapyrimidines oral suspension [1] . In addition, Lieberman
et al. [42, 48] are also good sources of typical formulations for suspensions.
Viscosity Depending upon the viscosity, many suspensions require continuous or
periodic agitation during the fi lling process [6] .
Segregation in Transfer Lines When the stored bulk of a nonviscous product is
transferred to fi lling equipment through delivery lines, some level of segregation is
expected. The manufacturer has to write the procedures and diagrams for line setup
prior to fi lling the product [6] . Delivery lines of suspensions increase the tendency
of particles of the same size to assemble together. However, slightly increasing the
global mixing in the lines can easily reverse the segregation without enhancing the
global mixing [52] . Shear stress versus rate of shear can be plotted to determine
the fl ow pattern of a specifi c suspension as pseudoplastic, Newtonian, or dilatant.
The type of fl ow is determined by the slope of the plot. While shaking increases the
yield stress and causes particles fl ow, the cessation of shear and rest rebuilds the
order of the system. A good - quality suspension is known as a thixotrophic system
and is obtained when the particles at rest avoid or show reduced sedimentation. The
rheogram of a thixotrope system presents a typical hysteresis or curve representing
different shear stresses over time [33] .
Quality Control The GMPs for suspensions include testing samples at different
checkpoints in the procedure, at the beginning, middle, and end, as well as samples
from the bulk tank. The uniformity will be successful only if, on microscopic analysis,
the components are dispersed to the expected particle size distribution established
by product development. Visual and microscopic examinations should consist of
looking for verifi cation of foam formation, segregation, and settling, although testingfor viscosity is important to determine agitation during the fi lling process. Samples
used for tests should not be combined again with the lot [6, 33] .
4.3.4.6 Uniformity of Emulsions
Remington describes the following three typical formulas of emulsions: type A
gelatin, mineral oil emulsion (USP), and oral emulsion (O/W) containing an insoluble drug [1] . In addition, Lieberman et al. [42, 50] are also good sources of typical
formulations for emulsions. The components of the emulsion system may present
physical and chemical instabilities refl ected on the distribution of an active ingredient, component migration from one phase to another, polymorphic changes in
components, and chemical degradation of components [33] .
Solubility The soluble active ingredient should be added to the liquid phase that
will be its carrier vehicle. Data of solubility have to be determined as part of the
process validation. Potency uniformity has to be tested by demonstrating satisfactory distribution in the emulsifi ed mix [20] .
Particle Size Regarding globule diameter in emulsions, the size – frequency distribution of particles in an emulsion over time may be the only method for determining
stability [36] . Drug activity and potency uniformity of insoluble active ingredients
depend upon control of particle size and distribution in the mix [6] . In addition,
aggregation of the internal phase droplets, formation of larger droplets, and phase
separation are categorized as emulsion system instabilities that are refl ected in the
particle size distribution of the emulsion. The measurement of particle size distribution over time allows the characterization of the emulsion stability and determines
the rheological behavior of the emulsion. Well - accepted approaches to determine
particle size distribution include microscopy, sedimentation, chromatography, and
spectroscopy. However, these analyses are problematic in a multiphase emulsion
[33] .
Crystalline Form Uncontrolled temperature or shear can induce changes in component crystallinity or solubility. For this reason, analytes originally present in each
phase of the product should be counted as well possible interactions with the container or closure and the processing equipment analyzed. Some techniques used to
obtain information about the emulsion system and its components are microscopic
examination, macro - and microlaser Raman, and rheological studies [33] . The FDA
guidance offers the following example: “ in one instance, residual water remaining
in the manufacturing vessel, used to produce an ophthalmic ointment, resulted in
partial solubilization and subsequent recrystallization of the drug substance; the
substance recrystallized in a larger particle size than expected and thereby raised
questions about the product effi cacy ” [20] .
4.3.4.7 Microbiological Quality
Microbial Specifi cations These specifi cations are determined by the manufacturer. The USP Chapters 61, 62, and 1111 present the microbial limits to assess the
signifi cance of microbial contamination in a dosage form [53] . However, the USPdoes not determine specifi c methods for water - insoluble topical products. The
microbial specifi cations are presented as a manufacturer ’ s document that details the
methods to isolate and identify the organisms as well as the number of organisms
permitted and action levels to be taken when limits are exceed and the potential
causes are investigated [6] . The Pharmaceutical Microbiology Newsletter (PMF)
presents several articles to discuss topics such as microbial identifi cation, methods,
data analysis, and preservation as well as topics related to USP and FDA regulations
[54] . To minimize the differences about microbial limits and test methods, the USP
is trying to harmonize the standards with the European Pharmacopoeia (EP) [55] .
Microbial Test Methods The selected microbial test methods determine specifi c
sampling and analytical procedures. When the product has a potential antimicrobial
effect and/or preservative, the spread technique on microbial test plates must be
validated. In addition, the personnel performing the analytical techniques have to
be qualifi ed and adequately trained for this purpose [6] .
Usually, total aerobic bacteria, molds, and yeasts are counted by using a standard
plate count in order to test the microbial limits. The microbial limit test may be
customized by performing a screening for the occurrence of Staphylococcus aureus,
Pseudomonas aeruginosa, Pseudomonas cepacia, Escherichia coli, and Salmonella
sp. [56] .
Investigation of Exceeded Microbiological Limits A high number of organisms
may indicate defi ciencies in the manufacturing process, such as excessive high
temperature, component quality, inadequate preservative system, and/or container
integrity. Information about the health hazards of all organisms isolated from the
product has different meanings depending on the type of dosage form and group
of patients to be treated. For instance, in oral liquids, pseudomonads are usually a
high - risk contamination. Examples presented by the FDA are Nystatin antifungal
suspension, used as prophylaxis in AIDS patients [57] ; antacids, with which P. aeruginosa contamination can promote gastric ulceration [58] ; and the presence of
Pseudomona putida , which could indicate the presence of other signifi cant contaminants such as P. aeruginosa [6] .
Deionizer Water - Monitoring Program Deionizing systems must be controlled in
order to produce purifi ed water, required for liquid dosage forms and USP tests and
assays [1] . The monitoring program has to include the manufacturer ’ s documentation about time between recharging and sanitizing, microbial quality and chlorine
levels of feed water, establishment of water microbial quality specifi cations, conductivity monitoring intervals, methods of microbial testing, action levels when microbial limits are exceeded, description of sanitization and sterilization procedures for
deionizer parts, and processing conditions such as temperature, fl ow rates, use
and sanitization frequency, and regenerant chemicals for ion exchange resin beds
[6, 59] .
Effectiveness of Preservative Manufacturing controls and shelf life must ensure
that the specifi ed preservative level is present and effective as part of the stability
program [6] . Depending on the type of product, the selection of the preservative
system is based on different considerations, such as site of use, interactions, spectrum, stability, toxicity, cost, taste, odor, solubility, pH, and comfort. The
USP and other organizations describe methods to validate the preservative
system used in the dosage form. Compounds used as preservatives are alcohols,
acids, esters, and quaternary ammonium compounds, among others. For instance, to
preserve ophthalmic liquid dosage forms, these products are autoclaved or fi ltrated
and require an antimicrobial preservative to resist contamination throughout
their shelf life, such as chlorobutanol, benzalkonium chloride, or phenylmercuric
nitrate [1] .
4.3.4.8 Filling and Packing
Constant Mixing during Filling Process Due to the tendency of suspensions to
segregate during transport through transfer lines, special attention is required on
suspension uniformity during the fi lling process. Appropriate constant mixing of the
bulk to keep homogeneity during the fi lling process and sampling of fi nished products and other critical points are indispensable conditions to assure an acceptable
quality level during the fi lling and packing process [20] .
Mixing Low Levels of Bulk Near End of Filling Process Constant mixing during
the fi lling process includes mixing low levels of bulk near the end of the fi lling
process. Large - size batches of bulk suspension require the transfer of the residual
material to a smaller tank in order to assure appropriate mixing of components
before fi lling and packing the containers [20] .
Potency Uniformity of Unit - Dose Products Products manufactured have to be of
quality at least as good as the established acceptable quality level (AQL). The quality
level should be based on the limits specifi ed by the USP. However, when the bulk
product is not properly mixed during fi lling and packing processes, liquid dosage
forms, and specially suspensions, are not homogeneous and unit - dose products
contain very different amounts of the active component and potency. For these
reasons, fi nished products have to be tested to assure that the fi nal volume and/or
weight as well as the amount of active ingredient are within the specifi ed limits [6] .
Calibration of Provided Measuring Devices Measuring devices consist of droppers, spoons for liquid dosage forms, and cups labeled with both tsp and mL. Measuring devices have to be properly calibrated in order to assure the right amount
of ingredients per volume to be administered [6] .
Container Cleanliness of Marketing Product The previous cleanliness of containers fi lled with the product will depend on their transportation exposure, composition, and storage conditions. Glass containers usually carry at least mold spores of
different microorganisms, especially if they are transported in cardboard boxes.
Other containers and closures made with aluminum, Tefl on, metal, or plastic usually
have smooth surfaces and are free from microbial contamination but may contain
fi bers or insects [45] . Some manufacturers receive containers individually wrapped
to reduce contamination risks and others use compressed air to clean them. However,
the cleanliness of wrapped containers will depend on the provider ’ s guarantee of
the manufacturing process and compressed - air equipment may release vapors or
oils that have to be tested and validated [6] 4.3.4.9 Stability
The typical stability problems are color change, loss of active component, and clarity
changes for solutions; inability to resuspend the particles and loss of signifi cant
amounts of the active component for suspensions; and creaming and breaking
(or coalescence) for emulsions [1] . These instabilities are usually related to the
following:
Active and Primary Degradant. A liquid dosage form is stable while it remains
within its product specifi cations. When chemical degradation products are
known, for stability study and expiration dating, the regulatory requirements
for the primary degradant of a active component are chemical structure, biological effect and signifi cance at the concentrations to be determined, mechanism of formation and order of reaction, physical and chemical properties,
limits and methods for quantitating the active component and its degradant
molecule at the levels expected to be present, and pharmacological action or
inaction [45] . Examples of drugs in liquid dosage forms that are easily degraded
are vitamins and phenothiazines [6] .
Interactions with Closure Systems. Elastomeric and plastic container and closure
systems release leachable compounds into the liquid dosage form, such as
nitrosamines, monomers, plasticizers, accelerators, antioxidants, and vulcanizing agents [44] . Each type of container and closure with different composition
and/or design proposed for marketing the drug or physician ’ s samples has to
be tested and stability data should be developed. Containers should be stored
upright, on their side, and inverted in order to determine if container – closure
interactions affect product stability [6, 45] .
Moisture Loss. When the containers are inappropriately closed, part of the
vaporized solvent is released and the concentration and potency of the active
component may be increased [6] .
Microbiological Contamination. Inappropriate closure systems also increase the
possibilities of microbial contamination when opening and closing containers
[6] .
4.3.4.10 Process Validation
Objective Process validation has the objectives of identifying and controlling
critical points that may vary product specifi cations through the manufacturing
process [6] .
Amount of Data To validate the manufacturing process, the manufacturer has to
design and specify in the protocol the use of data sheets to keep information about
the control of product specifi cations from each batch in - process as well as fi nished -
product tests. Some formats are common to different products, though each type of
product has some specifi c information to be kept on special sheets. Thus, the amount
of data varies from one type of product to another [6] .
Scale - Up Process Data obtained using special batches for the validation of the
scale - up process are compared with data from full - scale batches and batches used
for clinical essays [Product Specifi cations The most important specifi cations or established limits for
liquid dosage forms are microbial limits and test methods, medium pH, dissolution
of components, viscosity, as well as particle size uniformity of suspended components and emulsifi ed droplets. Effectiveness of the preservative system depends on
the dissolution of preservative components and may be affected by the medium pH
and viscosity. In addition, dissolved oxygen levels are important for components
sensitive to oxygen and/or light [6] .
Bioequivalence or Clinical Study In the patient, the general or systemic circulation is responsible for carrying molecules to different tissues of the body. To assure
the expected bioactivity of a product, the amount of drug that reaches the systemic
circulation per unit of time is analyzed and is known as bioavailability. Bioequivalence is the comparison of the bioavailability of a product with a reference product.
While oral solutions may not always need bioequivalence studies because they are
considered self - evidente, suspensions usually require bioequivalence or clinical
studies in order to demonstrate effectiveness. However, OTC suspension products
such as antacids are exempt from these studies [6] .
Control of Changes to Approved Protocol The manufacturing process of a specifi c
product is validated and approved internally by the quality control unit and externally by the FDA. Any change in the approved protocol has to be documented to
explain the purpose and demonstrate that the change will not unfavorably affect
product safety and effi cacy. Factors include potency and/or bioactivity as well as
product specifi cations. However, the therapeutic activity and uniformity of the
product are the main concerns after formulation and process changes [20] .
4.3.5 LIQUID DOSAGE FORMS *
Douche A liquid preparation, intended for the irrigative cleansing of the vagina,
that is prepared from powders, liquid solutions, or liquid concentrates and
contains one or more chemical substances dissolved in a suitable solvent or
mutually miscible solvents.
Elixir A clear, pleasantly fl avored, sweetened hydroalcoholic liquid containing
dissolved medicinal agents; it is intended for oral use.
Emulsion A dosage form consisting of a two - phase system comprised of at least
two immiscible liquids, one of which is dispersed as droplets (internal or dispersed phase) within the other liquid (external or continuous phase), generally
stabilized with one or more emulsifying agents. (Note: Emulsion is used as a
dosage form term unless a more specifi c term is applicable, e.g. cream, lotion,
ointment.).
Enema A rectal preparation for therapeutic, diagnostic, or nutritive purposes.
Extract A concentrated preparation of vegetable or animal drugs obtained by
removal of the active constituents of the respective drugs with a suitable menstrua, evaporation of all or nearly all of the solvent, and adjustment of the
residual masses or powders to the prescribed standards. For Solution A product, usually a solid, intended for solution prior to
administration.
For Suspension A product, usually a solid, intended for suspension prior to
administration.
For Suspension, Extended Release A product, usually a solid, intended for suspension prior to administration; once the suspension is administered, the drug
will be released at a constant rate over a specifi ed period.
Granule, Effervescent A small particle or grain containing a medicinal agent in
a dry mixture usually composed of sodium bicarbonate, citric acid, and tartaric
acid which, when in contact with water, has the capability to release gas, resulting in effervescence.
Inhalant A special class of inhalations consisting of a drug or combination of
drugs, that by virtue of their high vapor pressure can be carried by an air
current into the nasal passage where they exert their effect; the container from
which the inhalant generally is administered is known as an inhaler.
Injection A sterile preparation intended for parenteral use; fi ve distinct classes
of injections exist as defi ned by the USP.
Injection, Emulsion An emulsion consisting of a sterile, pyrogen - free preparation intended to be administered parenterally.
Injection, Solution A liquid preparation containing one or more drug substances
dissolved in a suitable solvent or mixture of mutually miscible solvents that is
suitable for injection.
Injection, Solution, Concentrate A sterile preparation for parenteral use which,
upon the addition of suitable solvents, yields a solution conforming in all
respects to the requirements for injections.
Injection, Suspension A liquid preparation, suitable for injection, which consists
of solid particles dispersed throughout a liquid phase in which the particles
are not soluble. It can also consist of an oil phase dispersed throughout an
aqueous phase, or vice - versa.
Injection, Suspension, Liposomal A liquid preparation, suitable for injection,
which consists of an oil phase dispersed throughout an aqueous phase in such
a manner that liposomes (a lipid bilayer vesicle usually composed of phospholipids which is used to encapsulate an active drug substance, either within a
lipid bilayer or in an aqueous space) are formed.
Injection, Suspension, Sonicated A liquid preparation, suitable for injection,
which consists of solid particles dispersed throughout a liquid phase in which
the particles are not soluble. In addition, the product is sonicated while a gas
is bubbled through the suspension and these result in the formation of microspheres by the solid particles.
Irrigant A sterile solution intended to bathe or fl ush open wounds or body
cavities; they ’ re used topically, never parenterally.
Linament A solution or mixture of various substances in oil, alcoholic solutions
of soap, or emulsions intended for external application.
Liquid A dosage form consisting of a pure chemical in its liquid state. This
dosage form term should not be applied to solutions. Liquid, Extended Release A liquid that delivers a drug in such a manner to allow
a reduction in dosing frequency as compared to that drug (or drugs) presented
as a conventional dosage form.
Lotion An emulsion, liquid dosage form. This dosage form is generally for
external application to the skin.
Lotion/Shampoo A lotion dosage form which has a soap or detergent that is
usually used to clean the hair and scalp; it is often used as a vehicle for dermatologic agents.
Mouthwash An aqueous solution which is most often used for its deodorant,
refreshing, or antiseptic effect.
Oil An unctuous, combustible substance which is liquid, or easily liquefi able, on
warming, and is soluble in ether but insoluble in water. Such substances,
depending on their origin, are classifi ed as animal, mineral, or vegetable oils.
Rinse A liquid used to cleanse by fl ushing.
Soap Any compound of one or more fatty acids, or their equivalents, with an
alkali; soap is detergent and is much employed in liniments, enemas, and in
making pills. It is also a mild aperient, antacid and antiseptic.
Solution A clear, homogeneous liquid dosage form that contains one or more
chemical substances dissolved in a solvent or mixture of mutually miscible
solvents.
Solution, Concentrate A liquid preparation (i.e., a substance that fl ows readily
in its natural state) that contains a drug dissolved in a suitable solvent or
mixture of mutually miscible solvents; the drug has been strengthened by the
evaporation of its nonactive parts.
Solution, for Slush A solution for the preparation of an iced saline slush, which
is administered by irrigation and used to induce regional hypothermia (in
conditions such as certain open heart and kidney surgical procedures) by its
direct application.
Solution, Gel Forming/Drops A solution, which after usually being administered in a drop - wise fashion, forms a gel.
Solution, Gel Forming, Extended Release A solution that forms a gel when it
comes in contact with ocular fl uid, and which allows at least a reduction in
dosing frequency.
Solution/Drops A solution which is usually administered in a drop - wise
fashion.
Spray A liquid minutely divided as by a jet of air or steam.
Spray, Metered A non - pressurized dosage form consisting of valves which allow
the dispensing of a specifi ed quantity of spray upon each activation.
Spray, Suspension A liquid preparation containing solid particles dispersed in
a liquid vehicle and in the form of coarse droplets or as fi nely divided solids
to be applied locally, most usually to the nasal - pharyngeal tract, or topically
to the skin.
Suspension A liquid dosage form that contains solid particles dispersed in a
liquid vehicle.
Suspension, Extended Release A liquid preparation consisting of solid particles
dispersed throughout a liquid phase in which the particles are not soluble; the
suspension has been formulated in a manner to allow at least a reduction in
dosing frequency as compared to that drug presented as a conventional dosage
form (e.g., as a solution or a prompt drug - releasing, conventional solid dosage
form).
Suspension/Drops A suspension which is usually administered in a dropwise
fashion.
Syrup An oral solution containing high concentrations of sucrose or other
sugars; the term has also been used to include any other liquid dosage form
prepared in a sweet and viscid vehicle, including oral suspensions.
Tincture An alcoholic or hydroalcoholic solution prepared from vegetable
materials or from chemical substances.
Notes :
1. A liquid is pourable; it fl ows and conforms to its container at room temperature. It displays Newtonian or pseudoplastic fl ow behavior.
2. Previously the defi nition of a lotion was “ The term lotion has been used to
categorize many topical suspensions, solutions, and emulsions intended for
application to the skin. ” The current defi nition of a lotion is restricted to an
emulsion.
3. A semisolid is not pourable; it does not fl ow or conform to its container at
room temperature. It does not fl ow at low shear stress and generally exhibits
plastic fl ow behavior.
4. A colloidal dispersion is a system in which particles of colloidal dimension
(i.e., typically between 1 nm and 1 μ m) are distributed uniformly throughout a
liquid.
Pharmacovigilence
DEFINITION : Pharmacovigilance – also known as drug safety - is a broad term that describes the collection, analysis, monitoring and prevention of adverse effects in drugs and therapies. It is a completely scientific and process-driven area within pharma.
The purpose of pharmacovigilance
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. Recently, its concerns have been widened to include:(4)
• herbals
• traditional and complementary medicines
• blood products
• biologicals
• medical devices
• vaccines.
Many other issues are also of relevance to the science:
• substandard medicines
• medication errors
• lack of efficacy reports
• use of medicines for indications that are not approved and for which there is inadequate scientific basis
• case reports of acute and chronic poisoning
• assessment of drug-related mortality
• abuse and misuse of medicines
• adverse interactions of medicines with chemicals, other medicines, and food.
The specific aims of pharmacovigilance are to:
• improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions,
• improve public health and safety in relation to the use of medicines,
• contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use, and
• promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.(5)
Pharmacovigilance has developed and will continue to develop in response to the special needs and according to the particular strengths of members of the WHO Programme and beyond. Such active influence needs to be encouraged and fostered; it is a source of vigour and originality that has contributed much to international practice and standards.
Terms commonly used in drug safety
Pharmacovigilance has its own unique terminology that is important to understand. Most of the following terms are used within this article and are peculiar to drug safety, although some are used by other disciplines within the pharmaceutical sciences as well.
Adverse drug reaction is a side effect (non intended reaction to the drug) occurring with a drug where a positive (direct) causal relationship between the event and the drug is thought, or has been proven, to exist.
Adverse event (AE) is a side effect occurring with a drug. By definition, the causal relationship between the AE and the drug is unknown.
Benefits are commonly expressed as the proven therapeutic good of a product but should also include the patient's subjective assessment of its effects.
Causal relationship is said to exist when a drug is thought to have caused or contributed to the occurrence of an adverse drug reaction.
Clinical trial (or study) refers to an organised program to determine the safety and/or efficacy of a drug (or drugs) in patients. The design of a clinical trial will depend on the drug and the phase of its development.
Control group is a group (or cohort) of individual patients that is used as a standard of comparison within a clinical trial. The control group may be taking a placebo (where no active drug is given) or where a different active drug is given as a comparator.
Dechallenge and rechallenge refer to a drug being stopped and restarted in a patient, respectively. A positive dechallenge has occurred, for example, when an adverse event abates or resolves completely following the drug's discontinuation. A positive rechallenge has occurred when the adverse event re-occurs after the drug is restarted. Dechallenge and rechallenge play an important role in determining whether a causal relationship between an event and a drug exists.
Effectiveness is the extent to which a drug works under real world circumstances, i.e., clinical practice.
Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical trials.
Event refers to an adverse event (AE).
Harm is the nature and extent of the actual damage that could be or has been caused.
Implied causality refers to spontaneously reported AE cases where the causality is always presumed to be positive unless the reporter states otherwise.
Individual Case Study Report (ICSR) is an adverse event report for an individual patient.
Life-threatening refers to an adverse event that places a patient at the immediate risk of death.
Phase refers to the four phases of clinical research and development: I – small safety trials early on in a drug's development; II – medium-sized trials for both safety and efficacy; III – large trials, which includes key (or so-called "pivotal") trials; IV – large, post-marketing trials, typically for safety reasons. There are also intermediate phases designated by an "a" or "b", e.g. Phase IIb.
Risk is the probability of harm being caused, usually expressed as a percent or ratio of the treated population.
Risk factor is an attribute of a patient that may predispose, or increase the risk, of that patient developing an event that may or may not be drug-related. For instance, obesity is considered a risk factor for a number of different diseases and, potentially, ADRs. Others would be high blood pressure, diabetes, possessing a specific mutated gene, for example, mutations in the BRCA1 and BRCA2 genes increase propensity to develop breast cancer.
Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a post-marketing trial to study the issue.
Temporal relationship is said to exist when an adverse event occurs when a patient is taking a given drug. Although a temporal relationship is absolutely necessary in order to establish a causal relationship between the drug and the AE, a temporal relationship does not necessarily in and of itself prove that the event was caused by the drug.
Triage refers to the process of placing a potential adverse event report into one of three categories: 1) non-serious case; 2) serious case; or 3) no case (minimum criteria for an AE case are not fulfilled).
What is an adverse event?
The definition of an adverse event is any reaction within a patient’s body caused by a drug/candidate molecule – a side effect. A serious adverse event is a life-threatening side effect that causes hospitalisation, incapacity, permanent damage or, in extreme cases, the death of a patient. Adverse event reporting is mandatory for all clinical research investigators, even if the side effects are only suspected.
The role of pharmacovigilance is to determine which adverse events cross the line of a drug’s efficacy. In other words, analysing which side effects are worth the risk to patients compared with how effective they are at treating a disease. For instance, chemotherapy is known to cause some very serious side effects but when faced with life-threatening cancer, these side effects are considered acceptable given the potential to cure a patient. However, if a drug used to cure a headache caused similar side effects, the risk to the patient would be considered too great and the benefit not substantial enough to justify the potential damage.
Adverse event reporting
The activity that is most commonly associated with pharmacovigilance (PV), and which consumes a significant amount of resources for drug regulatory authorities (or similar government agencies) and drug safety departments in pharmaceutical companies, is that of adverse event reporting. Adverse event (AE) reporting involves the receipt, triage, data entering, assessment, distribution, reporting (if appropriate), and archiving of AE data and documentation. The source of AE reports may include: spontaneous reports from healthcare professionals or patients (or other intermediaries); solicited reports from patient support programs; reports from clinical or post-marketing studies; reports from literature sources; reports from the media (including social media and websites); and reports reported to drug regulatory authorities themselves. For pharmaceutical companies, AE reporting is a regulatory requirement in most countries. AE reporting also provides data to these companies and drug regulatory authorities that play a key role in assessing the risk-benefit profile of a given drug. The following are several facets of AE reporting:
The "4 Elements" of an Individual Case Safety Report
One of the fundamental principles of adverse event reporting is the determination of what constitutes an Individual Case Safety Report (ICSR). During the triage phase of a potential adverse event report, it is important to determine if the "four elements" of a valid ICSR are present: (1) an identifiable patient, (2) an identifiable reporter, (3) a suspect drug, and (4) an adverse event.
If one or more of these four elements is missing, the case is not a valid ICSR. Although there are no exceptions to this rule there may be circumstances that may require a judgment call. For example, the term "identifiable" may not always be clear-cut. If a physician reports that he/she has a patient X taking drug Y who experienced Z (an AE), but refuses to provide any specifics about patient X, the report is still a valid case even though the patient is not specifically identified. This is because the reporter has first-hand information about the patient and is identifiable (i.e. a real person) to the physician. Identifiability is important so as not only to prevent duplicate reporting of the same case, but also to permit follow-up for additional information.
The concept of identifiability also applies to the other three elements. Although uncommon, it is not unheard of for fictitious adverse event "cases" to be reported to a company by an anonymous individual (or on behalf of an anonymous patient, disgruntled employee, or former employee) trying to damage the company's reputation or a company's product. In these and all other situations, the source of the report should be ascertained (if possible). But anonymous reporting is also important, as whistle blower protection is not granted in all countries. In general, the drug must also be specifically named. Note that in different countries and regions of the world, drugs are sold under various tradenames. In addition, there are a large number of generics which may be mistaken for the trade product. Finally, there is the problem of counterfeit drugs producing adverse events. If at all possible, it is best to try to obtain the sample which induced the adverse event, and send it to either the EMA, FDA or other government agency responsible for investigating AE reports.
If a reporter can't recall the name of the drug they were taking when they experienced an adverse event, this would not be a valid case. This concept also applies to adverse events. If a patient states that they experienced "symptoms", but cannot be more specific, such a report might technically be considered valid, but will be of very limited value to the pharmacovigilance department of the company or to drug regulatory authorities.
Coding of adverse events
Adverse event coding is the process by which information from an AE reporter, called the "verbatim", is coded using standardized terminology from a medical coding dictionary, such as MedDRA (the most commonly used medical coding dictionary). The purpose of medical coding is to convert adverse event information into terminology that can be readily identified and analyzed. For instance, Patient 1 may report that they had experienced "a very bad headache that felt like their head was being hit by a hammer" [Verbatim 1] when taking Drug X. Or, Patient 2 may report that they had experienced a "slight, throbbing headache that occurred daily at about two in the afternoon" [Verbatim 2] while taking Drug Y. Neither Verbatim 1 nor Verbatim 2 will exactly match a code in the MedDRA coding dictionary. However, both quotes describe different manifestations of a headache. As a result, in this example both quotes would be coded as PT Headache (PT = Preferred Term in MedDRA).
Seriousness determination
An adverse event is considered serious if it meets one or more of the following criteria:
1. results in death, or is life-threatening;
2. requires inpatient hospitalization or prolongation of existing hospitalization;
3. results in persistent or significant disability or incapacity;
4. results in a congenital anomaly (birth defect); or
5. is otherwise "medically significant" —i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.
Aside from death, each of these categories is subject to some interpretation. Life-threatening, as it used in the drug safety world, specifically refers to an adverse event that places the patient at an immediate risk of death, such as cardiac or respiratory arrest. By this definition, events such as myocardial infarction, which would be hypothetically life-threatening, would not be considered life-threatening unless the patient went into cardiac arrest following the MI. Defining what constitutes hospitalization can be problematic as well. Although typically straightforward, it's possible for a hospitalization to occur even if the events being treated are not serious. By the same token, serious events may be treated without hospitalization, such as the treatment of anaphylaxis may be successfully performed with epinephrine. Significant disability and incapacity, as a concept, is also subject to debate. While permanent disability following a stroke would no doubt be serious, would "complete blindness for 30 seconds" be considered "significant disability"? For birth defects, the seriousness of the event is usually not in dispute so much as the attribution of the event to the drug. Finally, "medically significant events" is a category that includes events that may be always serious, or sometimes serious, but will not fulfill any of the other criteria. Events such as cancer might always be considered serious, whereas liver disease, depending on its CTCAE (Common Terminology Criteria for Adverse Events) grade—Grades 1 or 2 are generally considered non-serious and Grades 3-5 serious—may be considered non-serious.
Expedited reporting
This refers to ICSRs (individual case safety reports) that involve a serious and unlisted event (an event not described in the drug's labeling) that is considered related to the use of the drug. (Spontaneous reports are typically considered to have a positive causality, whereas a clinical trial case will typically be assessed for causality by the clinical trial investigator and/or the license holder.) In most countries, the timeframe for reporting expedited cases is 7/15 calendar days from the time a drug company receives notification (referred to as "Day 0") of such a case. Within clinical trials such a case is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction). If the SUSAR involves an event that is life-threatening or fatal, it may be subject to a 7-day "clock". Cases that do not involve a serious, unlisted event may be subject to non-expedited or periodic reporting.
Clinical trial reporting
Also known as SAE (serious adverse event) reporting from clinical trials, safety information from clinical studies is used to establish a drug's safety profile in humans and is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny market authorization (market approval) for a drug. SAE reporting occurs as a result of study patients (subjects) who experience serious adverse events during the conducting of clinical trials. (Non-serious adverse events are also captured separately.) SAE information, which may also include relevant information from the patient's medical background, are reviewed and assessed for causality by the study investigator. This information is forwarded to a sponsoring entity (typically a pharmaceutical company) that is responsible for the reporting of this information, as appropriate, to drug regulatory authorities.
Spontaneous reporting
Spontaneous reports are termed spontaneous as they take place during the clinician's normal diagnostic appraisal of a patient, when the clinician is drawing the conclusion that the drug may be implicated in the causality of the event. Spontaneous reporting system relies on vigilant physicians and other healthcare professionals who not only generate a suspicion of an ADR, but also report it. It is an important source of regulatory actions such as taking a drug off the market or a label change due to safety problems. Spontaneous reporting is the core data-generating system of international pharmacovigilance, relying on healthcare professionals (and in some countries consumers) to identify and report any adverse events to their national pharmacovigilance center, health authority (such as EMA or FDA), or to the drug manufacturer itself.Spontaneous reports are, by definition, submitted voluntarily although under certain circumstances these reports may be encouraged, or "stimulated", by media reports or articles published in medical or scientific publications, or by product lawsuits. In many parts of the world adverse event reports are submitted electronically using a defined message standard.
One of the major weaknesses of spontaneous reporting is that of under-reporting, where, unlike in clinical trials, less than 100% of those adverse events occurring are reported. Further complicating the assessment of adverse events, AE reporting behavior varies greatly between countries and in relation to the seriousness of the events, but in general probably less than 10% (some studies suggest less than 5%) of all adverse events that occur are actually reported. The rule-of-thumb is that on a scale of 0 to 10, with 0 being least likely to be reported and 10 being the most likely to be reported, an uncomplicated non-serious event such as a mild headache will be closer to a "0" on this scale, whereas a life-threatening or fatal event will be closer to a "10" in terms of its likelihood of being reported. In view of this, medical personnel may not always see AE reporting as a priority, especially if the symptoms are not serious. And even if the symptoms are serious, the symptoms may not be recognized as a possible side effect of a particular drug or combination thereof. In addition, medical personnel may not feel compelled to report events that are viewed as expected. This is why reports from patients themselves are of high value. The confirmation of these events by a healthcare professional is typically considered to increase the value of these reports. Hence it is important not only for the patient to report the AE to his health care provider (who may neglect to report the AE), but also report the AE to both the biopharmaceutical company and the FDA, EMA, ... This is especially important when one has obtained one's pharmaceutical from a compounding pharmacy.
Aggregate reporting
Aggregate reporting, also known as periodic reporting, plays a key role in the safety assessment of drugs. Aggregate reporting involves the compilation of safety data for a drug over a prolonged period of time (months or years), as opposed to single-case reporting which, by definition, involves only individual AE reports. The advantage of aggregate reporting is that it provides a broader view of the safety profile of a drug. Worldwide, the most important aggregate report is the Periodic Safety Update Report (PSUR) and Development safety updated report (DSUR). This is a document that is submitted to drug regulatory agencies in Europe, the US and Japan (ICH countries), as well as other countries around the world. The PSUR was updated in 2012 and is now referred to in many countries as the Periodic Benefit Risk Evaluation report (PBRER). the PBRER's focus is on the benefit-risk profile of the drug, which includes a review of relevant safety data compiled for a drug product since its development.
What are the main areas of pharmacovigilance?
Pharmacovigilance is a huge and encompassing discipline, but we can broadly divide pharmacovigilance into four main sub-specialisms:
Operations:
This sector is where many life science professionals interested in drug safety jobs will begin their career. Typical jobs within drug safety operations include case processor, drug safety officer/associate and drug safety manager, and of course team lead and directorships. These professionals will collect and record information during preclinical development and clinical trials, in addition to gathering real world evidence (RWE) of adverse events reported by doctors and patients post-market. Operations are also usually responsible for creating standard operating procedures (SOPs), individual case study reports, literature screening and regulatory expedited reporting.
Surveillance:
Professionals who focus more within surveillance tend to look towards risk management and signal detection jobs. This also involves performing analysis of the data collated by the wider division. Professionals in this area can hold an array of titles, the most common of which are pharmacovigilance scientist and drug safety physician, but like in all teams, there are many degrees of seniority and remit available. These professionals perform analysis on the drug safety information gathered by the wider department and assist with the creation and review of aggregate reports. They also create development safety update reports (DSURs) for drugs in clinical research, and periodic benefit risk evaluation reports (PBRER) for post-market drugs. These reports ultimately help the team to draw conclusions around the safety and efficacy of a drug or candidate molecule.
Systems:
This division is concerned with the building and ongoing development of a fully robust and innovative system, charged with the responsibility for housing and allowing access (in various forms) to vast quantities of safety data. This safety data is usually collated by those working in operationally focused roles, but is accessed by all. The systems division is constantly having to improve, and stay in line with, changing regulations and requirements for the business/ health authorities, making this a very challenging and vital aspect of drug safety.
Qualified Person for Pharmacovigilance (QPPV)
QPPVs jobs are mainly concerned with marketed drugs and those about to be authorised, but as QPPVs are considered by many to be subject matter experts, their expertise is utilised across the discipline and wider business. These senior pharmacovigilance roles will only be held by very experienced professionals and their focus is to understand, plan for and advise upon the regulations and requirements that companies must adhere to across the EU. This is a highly strategic appointment and one of great importance.
Fortunately for drug safety professionals, there are several pharmacovigilance jobs available to them due to the different types of companies within life sciences, including global pharmas, small pharmas, generics companies, drug safety consultancies and health authorities.
Why is pharmacovigilance important?
Pharmacovigilance is arguably the most essential function within a life science company. To develop, manufacture and commercialise a drug a company must adhere to strict regulations. Many of these regulations will focus on the patient’s safety and the added benefit to the patient derived from the drug. This, in a nutshell, is the mission of drug safety and highlights why this discipline plays such a central and important role within pharmaceuticals.
Patient safety and continuous vigilance
By definition, drug safety ensures that a patient’s safety and wellbeing is safeguarded throughout the entire drug development lifecycle, including when the drug is readily available on the market. Indeed, drugs are continuously monitored for other side effects on patients, and any new data is collected and reported to health authorities on a regular basis. While other areas focus on improving patient lives in everything that they do, no other department has such a sharp focus on patient safety as an end-point.
Power and authority
This continuous vigilance does mean that, alongside others in the business, senior leaders within a drug safety team have the responsibility and authority to recommend that a development process is stopped, or that an approved drug is pulled from the market. EU QPPVs are especially important in this process, and again this goes to demonstrate the importance and central role of drug safety.
Authors: Poulami Maity (B.pharm,BCDA of pharmacy and Technology)
& Jyotirmoy Roy (B.pharm,BCDA college of pharmacy and Technology)
Main components of pharmaceutical industry are----
• Quality
• Production
• Laboratory
• Materials
• Facilities & Equipment
• Packaging & Labeling
QUALITY ASSURANCE (QA)
WHAT IS QUALITY?
Quality is the degree to which a commodity meets the requirements of the customer at the start of its life. (iso 9000)
Product quality perception comes from your design specifications and the manufacture standards achieved. Service quality perception comes from your service process design and the customer contact impressions.
Most popular definitions for quality are listed below. All of them are right, as they each contain a key element of what quality means to users of products and services---
a. A degree of excellence
b. Conformance to requirements
c. Totality of characteristics which act to satisfy a need
d. Fitness for use
e. Fitness for purpose
f. Freedom from defects
IMPORTANT TERMS USED IN QUALITY ASSURANCE DEPARTMENT:
Batch manufacturing record (BMR)
Batch manufacturing record is a written document from the batch that is prepared during the pharmaceutical manufacturing process. It contains actual data of the batch manufacturing and whole manufacturing process step by step.
There are several stages of the pharmaceutical product manufacturing process. All stages are included in the batch manufacturing record from the issuance of the raw material to the final packaging.
Every batch has a separate BMR having the batch history of batch production. Documents and the proofs are attached to the BMR during the manufacturing process.
A good Batch Manufacturing Record format should contain following parts:
1. Batch Record:
A very first page of the BMR has all records about the batch as batch number, batch size, composition, master formula record referred the weight of the batch, shelf life, storage conditions, manufacturing license number, manufacturing date, expiry date, date of starting and date of completion.
2. General Instruction for Manufacturing:
Health and safety instructions to the operators and the manufacturing chemist are written those should be followed during the manufacturing process regarding the material and equipments used during manufacturing.
3. Equipment Cleaning Record:
Checklist of the cleaning of all equipments is prepared; those are used in the manufacturing of the batch including the previous product, batch and date of cleaning. Cleaning of the equipments should be checked by the quality assurance.
4. Bill of Materials:
List of the raw material should have the quantity of the materials with their AR numbers. Weights of the materials should be verified by quality assurance. If tablets are coated then coating material should be included.
5. Manufacturing Process:
Manufacturing process should be written step by step in easy language. Milling, sifting, drying, lubrication, compression, coating and packing having all instruction with process time should be written. Checklist for line clearance should also be attached before starting every process.
After completion of the every stage, tablets must be checked for the compliance of the specification of that stage. Results should be attached with the batch manufacturing record.
6. Yield:
Yield of the batch should be calculated at the end of every stage to calculate the process loss. Final yield should be calculated at the end of the manufacturing that should not be less than 99.00%.
7. Abbreviations:
List of the abbreviations used in the document should be made to understand the BMR easily.
8. History of Chances:
At the end, the document should have a list of the changes in the document including the revision number and the date of the change.
Master formula record (MFR):
What is master formula record?
A record of name of product, manufacturing procedure, ingredients/composition of product and their specifications, machinery used, batch size, dosage form, intermediate/final yield, storage conditions, step wise processing instruction etc and other related things for maintaining consisting of each and every batch. It is used as reference standard for manufacturing procedure.
A master formula record is prepared and endorsed by the competent technical staff like manufacturing chemist and analytical chemist etc. There should be master formula record related to all manufacturing procedures for each product and batch size to be manufactured. A master formula record should contain a complete description or reference code for understanding standard process.
Contents of Master Formula Records:
• The Name of Product together with product reference code relating to specifications
• Description of dosage form, strength, composition of product and batch size
• Patent, proprietary name of the product along with Generic Name of product and its ingredients along with excipients used
• Special mention of the substance that may disappear during manufacturing process
• Specifications and reference code of each and every ingredients/excipient used in manufacturing procedure
• Location and Machinery used in process, and their specifications including cleaning, assembling, calibrating, sterilizing, operating procedure etc
• Stepwise detailed processing instructions and time taken by each and every step
• Instruction related to in-process control i.e. quality checks, samples taken, test to be conducted etc
• Requirements for storage and processing conditions of the product including container, labeling and special storage conditions if any
• A statement regarding expected relevant intermediate and final yield with the acceptable limits
• Packaging material details i.e. labels, boxes, foils, bottles etc
• Any special precaution and instructions if any
Procedure to prepare a Master Formula Record:
A Master Formula Record is either prepared based upon experience of competent qualified staff like manufacturing chemist or analytical chemist or prepared based upon batch manufacturing record of a batch size.
Once Master Formula Record is prepared, it is transferred to previous staff to new staff. It is followed as standard documents for processing a batch. Master Formula record is consider as standard for making a Batch Manufacturing Record
Quality management system:
Quality Management System a set of interacting elements based on procedures, policies, resources, and objectives that are established collectively to guide an organization. Quality Management System takes into account all applicable guidelines and regulations that are designed to maintain its robustness.
Some factors are essential in developing a Quality Management System in organizations, and they include quality policy, quality risk management, and quality objectives.
Pharmaceutical market over the past few years has undergone significant change forcing pharmaceutical corporations to focus on the needs and internal efficiency to continue to compete effectively. Therefore, Quality Management System supports an active pharmaceutical industry to enhance the quality and availability of medicines around the globe in the interest of public health. Pharmaceutical quality management system demonstrates industry as well as regulatory authorities. Through the regulation of quality management system, organizations facilitate innovation along with continual improvement as well as strengthen the link between pharmaceutical development and manufacturing activities.
The areas of continual improvement in pharmaceutical industry include enhancements of the pharmaceutical quality system, identifying and prioritizing the quality of the products as well as consistently fulfilling the quality of drug manufacturers. Quality Management System in the pharmaceutical industry helps to develop an effective monitoring control based on the performance as well as product quality.
Further, the system provides assurance of continued suitability as well as the capability of processes that are useful in identifying the monitoring and controlling systems. The system is designed to meet the needs of life science and other regulated companies. Companies globally streamline, automate as well as manage efficiently their processes through the regulation of quality management systems. The pharmaceutical company is ultimately responsible for ensuring processes are in place to assure the control of outsourced activities and quality of purchased activities.
Quality Management System stems key regulations for the pharmaceutical industry. It designs a product and its manufacturing process for pharmaceutical organizations to consistently deliver the intended performance as well as meet the needs of healthcare professionals and patients. These approaches transfer product and production process knowledge between development and manufacturing so that to achieve product utilization.
Companies establish control strategy that attributes to drug substance and drug product materials that facilitate timely and appropriate corrective action as well as preventive measures. This approach helps the pharmaceutical industries to identify resources of variation affecting process presentation and product quality for possible improvement measures to reduce variation. Additionally, quality management systems provide the tools for measurement in the pharmaceutical industry for analysis as parameters that attribute to the control strategy. A well-defined scheme for process presentation and product superiority assures pharmaceutical industries performance and identifies improvement areas.
Monitoring for the duration of scale-up activities can offer a preliminary sign-off process presentation and the thriving integration into manufacturing. Ideally, knowledge obtained at some point in the transfer, and scale-up actions can be valuable in further increasing the control policy. Stability testing of the product in the pharmaceutical industry continues to be executed according to the regulations set by the Quality Management Systems.
The changes to the quality management systems in the pharmaceutical industry have evaluated the marketing authorization contributing the appropriate expertise and knowledge from relevant areas. The size of the company determines the level of management and the timely communication to raise related quality issues. Activities in the pharmaceutical industry through the quality management system is systematically planned as well as documented. This help to ensure consistency of performance and provide greater assurance that the ending will be suitable.
The overall idea of the quality management system is to support the quality manual and achievement of the short and long-term objectives of the pharmaceutical industry. The procedures help to establish and maintain a clear line of communication to ensure customer requirement is well understood. Subsequently, management reviews in the pharmaceutical industry contributed to determining the stability and the quality of the product.
Quality Management Systems assist the design and development process in the pharmaceutical industry to ensure that the resulting product meets the agreed specification. The industry can achieve this by establishing as well as maintaining documented procedures to verify and control the design and development of the product.
The plan developed by the quality management systems includes regular meetings to compare design verification and design validation. This can be achieved through stability testing as part of the development phase in the pharmaceutical industry.
Through the quality management system, pharmaceutical industry focuses on correcting as well as preventing problems within the sector. It is evident that preventing problems is cheaper as compared to fixing them after they occur. As such the range and the nature of manufacturing by-product, inherent variability in biological products are likely to be variable. The quality management systems help the pharmaceutical industry in the verification of activities.
This process involves inspection as well as testing at the supplier site before dispatching by the manufacturer. Management control over the quality of customer supplied product should be included in the scope of the manufacturer’s quality system. During these processes, there should be a written as well as approved contract between the contract giver and the contract acceptor to lay down the responsibilities of each party.
Additionally, items provided by the consumer should be without a doubt identifiable. The items should have their quality verified by the inspection and subsequently handled in such a way as to prevent damage. In conclusion, quality management systems in the pharmaceutical industry have monitored as well as controlled some parameters to ensure that the process is performing as intended by the process design.
It is evident that control parameters will be required to give the necessary level of confidence in the eminence of the end product in the drug industry. Therefore, the involvement of quality management systems in the industry has ensured that equipment is maintained to a standard sufficient capable of performing its intended functions.
Validation:
Introduction
The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated processes including environmental control, media fill, equipment sanitization and purified water production.
In a guideline, validation is act of demonstrating and documenting that any procedure, process, and activity will consistently lead to the expected results. It includes the qualification of systems and equipment. The goal of the validation is to ensure that quality is built into the system at every step, and not just tested for at the end, as such validation activities will commonly include training on production material and operating procedures, training of people involved and monitoring of the system whilst in production. In general, an entire process is validated and a particular object within that process is verified. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time.
Why validation is required:
The main reasons for validation are
1. Quality assurance: Quality cannot be assured by daily quality control testing because of the limitations of statistical samples and the limited facilities of finished product testing. Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria. A successful validation provides high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch.
2. Economics: Due to successful validation, there is a decrease in the sampling and testing procedures and there are less number of product rejections and retesting. This lead to cost-saving benefits.
3. Compliance: For compliance to current good manufacturing practices CGMPs, validation is essential.
Department Responsible:-
• Site validation committee (SVC): Develop Site master Validation plan, Prepare/execute/approve validation Studies
• Manufacturing department: Prepares the batches as a routine Production batch
• Quality assurance: Ensure compliance, see that documentations/procedures are in place, approves protocols and reports
• Quality control: Perform testing and reviews protocol and report as needed.
Responsible Authorities For Validation:-
The validation working party is convened to define progress, coordinate and ultimately, approve the entire effort, including all of the documentation generated. The working party would usually include the following staff members, preferably those with a good insight into the company's operation.
• Head of quality assurance
• Head of engineering
• Validation manager
• Production manager
• Specialist validation discipline: all areas
• Elements Of Validation:-
• Qualification is pre-requisite of validation. The qualification includes the following:
• 1. Design Qualification (DQ):-
In this qualification, compliance of design with GMP should be demonstrated. The principles of design should be such as to achieve the objectives of GMP with regard to equipment. Mechanical drawings and design features provided by the manufacturer of the equipment should be examined.
2. Installation Qualification (IQ):-
Installation qualification should be carried out on new or modified facilities, systems and equipment. The following main points should be includes in the installation qualification.
• Checking of installation of equipment, piping, services and instrumentation.
• Collection of supplier’s operating working instructions and maintenance requirements and their calibration requirements.
• Verification of materials of construction
• Sources of spares and maintenance
3. Operational Qualification (OQ):-
Operational qualification should follow IQ, OQ should include the following:
• Tests developed from the knowledge of the processes systems and equipment
• Defining lower and upper operating limits,. Sometimes, these are called ‘worst case’ conditions.
4. Performance Qualification (PQ):-
After IQ and OQ have been completed, the next qualification that should be completed is PQ. PQ should include the following:
• Tests using production materials, substitutes or simulated product. These can be developed from the knowledge of the process and facilities, systems or equipment.
• Tests to include conditions with upper and lower limits
Process Validation:
The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation:
Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics.
According to the FDA, assurance of product quality is derived from careful and systemic attention to a number of important factors, including: selection of quality components and materials, adequate product and process design, and (statistical) control of the process through in-process and end-product testing. Thus, it is through careful design (qualification) and validation of both the process and its control systems that a high degree of confidence can be established that all individual manufactured units of a given batch or succession of batches that meet specifications will be acceptable.
This guidance describes process validation activities in three stages.
Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Types of Process Validation:-
1. Prospective Validation: It is establishment of documented evidence of what a system does or what it purports to do based upon a plan. This validation is conducted prior to the distribution of new product.
2. Retrospective Validation: It is the establishment of documented evidence of what a system does or what it purports to do based upon the review and analysis of the existing information. This is conducted in a product already distributed based on accumulated data of production, testing and control.
3. Concurrent Validation: It is establishment of documented evidence of what a system does or what it purports to do information generated during implemented of the system.
4. Revalidation: Whenever there are changes in packaging, formulation, equipment or processes which could have impact on product effectiveness or product characteristics, there should be revalidation of the validated process.
Conditions that require revalidation studies are:
• Changes in critical component
• Change in facility or plant
• Increase or decrease in batch size
• Sequential batches that fail to conform product and process specifications
Change Control:-
Change control is defined as “a formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.”
Change control is a lifetime monitoring approach. Planning for well executed change control procedures includes the following aspects:
Validation Master Plan:-
It is important to draw up a summarized document that describes the whole project. It has become common practice in the industry to develop a “validation master plan” (VMP). This document would usually include the qualification aspects of a
project.
Validation Protocol:-
After preparing VMP, the next step is to prepare validation protocol. There are the following contents in a validation protocol.
1. General information
2. Objective
3. Background/Prevalidation Activities Summary of development and tech transfer (from R&D or another site) activities to justify in-process testing and controls; any previous validations.
4. List of equipment and their qualification status
5. Facilities qualification
6. Process flow chart
7. Manufacturing procedure narrative
8. List of critical processing parameters and critical excipients
9. Sampling, tests and specifications
10. Acceptance criteria
SOP
A Standard Operating Procedure (SOP) is a set of written instructions that document a routine or repetitive activity which is followed by employees in an organization. The development and use of SOPs are an integral part of a successful quality system. It provides information to perform a job properly, and consistently in order to achieve pre-determined specification and quality end-result.
In designing of SOP Following points are considered
OBJECTIVE:
To lay down procedure for the preparation of Standard Operating Procedures.
SCOPE:
This procedure is applicable to all the SOP’s throughout the organization.
RESPONSIBILITY:
Person Performing: Respective HOD’s of concerning departments
Person Monitoring: QA officer/ HOD QA
PROCEDURE:
All SOP’s shall be computer typed using Times New Roman font.
Format of SOP shall be as per Annexure SOP/QA/002/1. Each SOP has:
I) Header,
II) Signature block and
III) Body.
Header: Present on all the pages of SOP and includes
Company Logo, Name, address & Concerned Dept.: Company Logo, CHARAK Pharma Limited, Wagholi-Pune & Name of Concerned Department. (In capital bold letters of font size 16)
Document Type: Standard Operating Procedure (In capital bold letters of font size 14)
Ref. No.:It is like SOP/DC/YYY-Z Where DC depicts the department code as below:
PE: Personnel Department
PD: Production Department
MT: Maintenance Department
QA: Quality Assurance Department
QC: Quality Control Department
ST: Store Department
PU: Purchase Department
YYY is the sequential number starting from 001 for each department.
And Z is the revision status, starting from 0 for the original version and 1 for the next version and so on. (In capital letters of font size 12).
Supersedes: It is the Ref. No. of the earlier version. (In capital letters of font size 12).
Effective Date: It is the date from which the SOP shall be put in use. The date format has to be DD/MM/YYYY, where DD indicates the date, MM indicates the month & YYYY indicates the year (e.g. 01/11/2007). Date shall be written with blue indelible ink pen.
Review Date: It is the Month & Year during which the SOP shall be revised e.g. 21/2013, written with blue indelible ink pen. It shall be maximum 2 years from the effective date.
Page No.: It is like X OF Y. Where X is the individual page number and Y is the total number of pages. (In capital letters of font size 12)
Title: It shall be clear and descriptive. (In bold capital letters of font size 12).
Signature Block:It shall be below the header and only on the first page of the SOP.
(Titles in the rows & columns shall be in bold letters & other text in normal letters of font size 12. Name and designation shall be typed. And signature and date shall be put in blue indelible ink pen)
Prepared by: Signature with date, name and designation of the person from user department who has drafted the SOP.
Verified by: Signature with date, name and designation of the HOD or the person from user department who has verified the draft of the SOP.
Authorized by:Signature with date, name and designation of the person authorizing SOP, DGM QA or HOD QA.
e. Body: It shall contain the subject matter, which is written in the following Manner.
(Subtitles in capital bold letters and text matter in normal letters of font size 12).
OBJECTIVE: It shall define the purpose of the SOP.
SCOPE: It shall define the area of application.
GDP
Introduction
The GDP can be defined as “Good documentation practice is an essential part of the quality assurance and such, related to all aspects of GMP” this definition is based on WHO.
Clearly written documents prevent errors of various activities in pharma each and every activity is written in specific documents such as SOPs and strictly followed. Spoken communications may be create errors so that all important documents such as Master formula record , procedure and record must be free from errors and Documented.
It is difficult to make a list of required documents and totally depend upon Companies activity or environment. Followings are the activity factors considered during designing of any documents.
1. Type of formulation
2. Country requirements
3. Availability of ERP or SAP system
Purpose of Documentations
• Defines specifications and procedures for all materials and methods of manufacture and control
• Ensures all personnel know what to do and when to do it
• Ensure that authorized persons have all information necessary for release of product
• Ensures documented evidence, traceability, provide records and audit trail for investigation
• Ensures availability of data for validation, review and statistical analysis.
Classification of Documentation
Following are the classification of Documents
• For organization & Personnel.
• For Buildings & facilities
• For Equipments.
• For Handling of R.M.& P.M.
• For Production & process control.
• For Packaging & Labeling control.
• For Holding & Distribution
• For Laboratory Control.
• For Records & Reports.
• For Return & Salvaged finished products.
Type of documents used in pharmaceuticals
• Specifications: as per MHRA Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. We need specification for:
1. Active and inactive materials
2. Primary printed and packing materials
3. Intermediate and semi finished product
4. Finished product
• SOPs: it is a written, authorized functional instruction used as a reference by the person responsible for performance and are also used for training new operators in the performance of the procedure.
• Test method: it is a written and approved documents describe the detailed testing procedure.
• List: Documents contain a catalog of any object such as list of equipments.
• Certificates of Analysis: it is an authentic documents shows the analytical reports and decision of acceptance/rejections
• Label
• Records
• Organ gram
• Job description
• Batch Manufacturing records: it is an important document issued for every batch of product to assure, review and record keeping of any product batch. There are following major content of BMR.
Documentation:
Introduction
Documentation is any communicable material that is used to describe,explain or instruct regarding some attributes of an object,system,or procedure such as its part, assembly,installatio,maintenance and use.
Purpose of Documentations
• Defines specifications and procedures for all materials and methods of manufacture and control
• Ensures all personnel know what to do and when to do it
• Ensure that authorized persons have all information necessary for release of product
• Ensures documented evidence, traceability, provide records and audit trail for investigation
• Ensures availability of data for validation, review and statistical analysis.
Following are the classification of Documents
• For organization & Personnel.
• For Buildings & facilities
• For Equipments.
• For Handling of R.M.& P.M.
• For Production & process control.
• For Packaging & Labeling control.
• For Holding & Distribution
• For Laboratory Control.
• For Records & Reports.
• For Return & Salvaged finished products.
Type of documents used in pharmaceuticals
• Specifications: as per MHRA Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. We need specification for:
1. Active and inactive materials
2. Primary printed and packing materials
3. Intermediate and semi finished product
4. Finished product
• SOPs: it is a written, authorized functional instruction used as a reference by the person responsible for performance and are also used for training new operators in the performance of the procedure.
• Test method: it is a written and approved documents describe the detailed testing procedure.
• List: Documents contain a catalog of any object such as list of equipments.
• Certificates of Analysis: it is an authentic documents shows the analytical reports and decision of acceptance/rejections
• Label
• Records
• Organ gram
• Job description
• Batch Manufacturing records: it is an important document issued for every batch of product to assure, review and record keeping of any product batch.
LIQUID PARATIONS FOR ORAL USE
Revised daft proposal for The International Pharmacopoeia
(September 2007)
Note: This monograph does not apply to liquids intended for oromucosal administration (for
example, gargles and mouthwashes).
Definition
Liquid preparations for oral use are usually solutions, emulsions or suspensions containing one or
more active ingredients in a suitable vehicle; they may in some cases consist simply of a liquid
active ingredient used as such. Liquid preparations for oral use are either supplied in the finished
form or, with the exception of Oral emulsions, may also be prepared just before issue for use by
dissolving or dispersing granules or powder in the vehicle stated on the label.
The vehicle for any liquid preparation for oral use is chosen having regard to the nature of the
active ingredient(s) and to provide organoleptic characteristics appropriate to the intended use of the
preparation. Liquid preparations for oral use may contain suitable antimicrobial preservatives,
antioxidants and other excipients such as dispersing, suspending, thickening, emulsifying,
buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents and authorized
colouring matter.
Liquid preparations for oral use may be supplied as multidose or as single-dose preparations. Each
dose from a multidose container is administered by means of a device suitable for measuring the
prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof,
or an oral syringe for other volumes or, for Oral drops, a suitable dropper.
Additional information. Liquid preparations for oral use are often the dosage form of choice for
paediatric use.
[Note from the Secretariat: It is recommended in future to provide guidance on certain aspects of
the formulation of oral liquids for paediatric use under Supplementary Information: Preparations for
Paediatric Use. If and when such a section is included, a cross-reference can be given here.]
Owing to the wide range of liquid preparations for oral use and their long history of use, a variety
of terms has been used to describe different members of this category of preparation. These terms,
which are not mutually exclusive and the definitions of which have changed over time, include
elixirs, linctuses, milks, mixtures and syrups. Such terms are still used within the titles of certain
specific, long-established, traditional preparations (for example, ephedrine elixir, codeine linctus,
acid gentian mixture). With such exceptions, however, it is recommended that the titles of liquid
dosage forms for oral use are based on the terms used as sub-monograph headings in this general
monograph. The term syrup (denoting a solution containing a high proportion of sucrose) is used,
inter alia, for certain solutions (for example black currant syrup, lemon syrup) that are used as
vehicle ingredients for their sweetening and flavouring properties. Such syrups are not dosage formsin the pharmacopoeial sense: they do not contain any active ingredient and are not intended to be
administered as such.
Oral solutions containing one or more active ingredients dissolved in a vehicle containing a high
proportion of sucrose or a suitable polyhydric alcohol or alcohols and which may contain ethanol have
traditionally been called elixirs. Viscous oral solutions containing one or more active ingredients dissolved
in a vehicle containing a high proportion of sucrose, other sugars or a suitable polyhydric alcohol or
alcohols and which are intended for use in the treatment or relief of cough have traditionally been called
linctuses. They are intended to be sipped and swallowed slowly without the addition of water.
Manufacture
The manufacturing process for liquid preparations for oral use should meet the requirements of
Good Manufacturing Practice.
The following information is intended to provide broad guidelines concerning the critical steps to be
followed during production of liquid preparations for oral use.
In the manufacture of liquid preparations for oral use measures are taken to:
• ensure that all ingredients are of appropriate quality
• minimize the risk of microbial contamination (see recommendations described under 3.3
Microbial quality of pharmaceutical preparations);
• minimize the risk of cross-contamination
[Note from the Secretariat: It is recommended to change the title of General method text 3.3 from
"Microbial purity of pharmaceutical preparations" to "Microbial quality of pharmaceutical
preparations" in the First Supplement.]
During the development of a preparation, the formulation for which contains one or more
antimicrobial preservatives, the effectiveness of the chosen preservative system shall be
demonstrated to the satisfaction of the relevant regulatory authority.
[Note from the Secretariat: It was recommended at the informal consultation on specifications for
medicines and quality control laboratory issues held on 27-29 June 2007 that a text on Efficacy of
antimicrobial preservation (containing a suitable test method together with criteria for judging the
preservative properties of the formulation) be developed for inclusion in The International
Pharmacopoeia. It was suggested that as a first step a review should be carried out of the different
approaches adopted in various pharmacopoeias.]
Appropriate measures should also be taken to optimize the stability of the active ingredient in the
liquid formulation including those prepared from powder or granules. Additional measures should
be taken so that, when stored under the conditions stated on the label, oral solutions are not subject
to t precipitation and oral suspensions are not subject to fast sedimentation, lump formation or
caking.
During development of a single-dose liquid preparation for oral use it shall be demonstrated that the
nominal content can be withdrawn from the container. In the production of liquid preparations for oral use containing dispersed particles, measures are
taken to ensure a suitable and controlled particle size and, where appropriate, crystal structure
(polymorphic and/or solvated forms) with regard to the intended use.
Throughout manufacturing, certain procedures should be validated and monitored by carrying out
appropriate in-process controls. These should be designed to guarantee the effectiveness of each
stage of production. In-process controls during the manufacture of oral liquids should include pH
and fill volume. The validation of the manufacturing process and the in-process controls are
documented.
Safety concerns
An important aspect of good manufacturing practice for all pharmaceutical products is
assuring the quality of all the starting materials used. The need for analytical testing to check
the identity and quality of starting materials is explained in detail in (section 14 of ) the
current WHO GMP guidelines1
. Failure to ensure that starting materials are of the required
quality can have very serious consequences.
Increasingly countries are dependent on the importation of starting materials for use in the
production of medicines. Starting materials often change hands many times before reaching
the manufacturer of the final marketed product and there are many opportunities for the
material to undergo relabelling along the distribution and trade chain (see WHO Guideline on
Good Trade and Distribution Practices for Pharmaceutical Starting Materials1
). As a result,
starting materials required for production of pharmaceutical products can become
contaminated or materials may be supplied that no longer correspond to what is stated on the
label in terms of quality or identity, either accidentally or as a result of negligence and
sometimes fraud.
The most documented incidents of contamination involve liquid preparations for oral use
manufactured with excipients such as glycerol and propylene glycol that have been
contaminated, adulterated or mixed up with diethylene glycol. Such incidents have been
responsible for hundreds of deaths throughout the world (see, for example, editorial in WHO
Bulletin 2001, 79(2)). Ingestion of diethylene glycol often leads to death through kidney
failure.
1
For current edition of WHO guidelines, please consult the WHO Medicines website
http://www.who.int/medicines/en/
Uniformity of mass
Liquid preparations for oral use that are presented as single-dose preparations comply with the
following test. Weigh individually the contents of 20 containers, emptied as completely as possible,
and determine the average mass. Not more than 2 of the individual masses deviate by more than
10% from the average mass and none deviates by more than 20%.
Uniformity of mass of doses delivered by the measuring device. The measuring device provided
with a multidose liquid preparation for oral use complies with the following test. Weigh
individually 20 doses taken at random from one or more multidose containers with the measuring
device provided and determine the individual and average masses. Not more than two of the
individual masses deviate by more than 10% from the average mass and none deviates by more than
20%.
Containers
The containers should be made of material that will not adversely affect the quality of the
preparation by, for example, leaching or sorption. Liquid preparations for oral use that contain
light-sensitive active ingredients are supplied in containers that are light-resistant.
Except where indicated in the individual monograph, containers should be made from material that
is sufficiently transparent to permit the visual inspection of the contents.
If the preparation contains volatile ingredients, the liquid preparation for oral use should be kept in
a tightly closed container.
Labelling
Every pharmaceutical preparation must comply with the labelling requirements established under
Good Manufacturing Practice.
The label should include:
(1) the name of the pharmaceutical product;
(2) the name(s) of the active ingredients; INNs should be used wherever possible;
(3) the amount of active ingredient in a suitable dose-volume;
(4) the name and concentration of any antimicrobial preservative and the name of any other
excipient;
(5) the batch (lot) number assigned by the manufacturer;
(6) the expiry date and, when required, the date of manufacture;
(7) any special storage conditions or handling precautions that may be necessary;
(8) directions for use, warnings, and precautions that may be necessary;
(9) the name and address of the manufacturer or the person responsible for placing the product
on the market.
[Note from the Secretariat: At the meeting in June 2007 it was recommended that, during the
proposed review, consideration should be given to adding to all the general monographs for dosage
forms that the label should include the product licence number (marketing authorization number).]
If the Liquid preparation for oral use is supplied as granules or powder to be constituted just before
issue for use, the label should include:
(1) that the contents of the container are granules or powder for the preparation of an oral liquid;
(2) the strength as the amount of the active ingredient in a suitable dose-volume of the
constituted preparation;
(3) the directions for preparing the oral liquid including the nature and quantity of liquid to be
used;
(4) the storage conditions and shelf-life of the constituted preparation.
Requirements for specific types of liquid preparations for oral use
Oral solutions
Definition
Oral solutions are clear Liquid preparations for oral use containing one or more active ingredients
dissolved in a suitable vehicle.
Visual inspection
Inspect the solution. It should be clear and free from any precipitate. Discoloration or cloudiness of
solutions may indicate chemical degradation or microbial contamination.
Oral suspensions
Definition
Oral suspensions are Liquid preparations for oral use containing one or more active ingredients
suspended in a suitable vehicle. For oral suspensions containing more than one active ingredient,
some of the active ingredients may be in solution.
Oral suspensions may show a sediment which is readily dispersed on shaking to give a uniform
suspension which remains sufficiently stable to enable the correct dose to be delivered.
Visual inspection
Inspect the suspension. Evidence of physical instability is demonstrated by the formation of
flocculants or sediments that do not readily disperse on gentle shaking. Discoloration may indicate
chemical degradation or microbial contamination.
Uniformity of content. For oral suspensions that are presented as single-dose preparations and that
contain less than 5 mg of active ingredient per dose or in which the active ingredient is less than 5%
of the total weight per dose, carry out the following test. Shake and empty each container as
completely as possible and carry out the test as described under 5.5 Uniformity of content for
single-dose preparations. In such cases, the test for Uniformity of mass prescribed above, is not
required.
[Note from the Secretariat: It is intended to apply the requirements as given in method text 5.5 for
capsules, oral powders and suppositories; reference to oral suspensions will be added to the relevant
subheading in this method text in the first Supplement.]
Labelling
The label on the container should include a direction that the bottle should be shaken before use.
Definition
Oral emulsions are Liquid preparations for oral use containing one or more active ingredients. They
are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids.
Solids may also be suspended in Oral emulsions.
Oral emulsions may show evidence of phase separation but are readily redispersed on shaking.
Visual inspection
Inspect the emulsion. Evidence of physical instability is demonstrated by phase separation that is
not readily reversed on gentle shaking. Discoloration of emulsions may indicate chemical
degradation or microbial contamination.
Containers
When issued for use, Oral emulsions should be supplied in wide-mouthed bottles.
Labelling
The label on the container should include a direction that the bottle should be shaken before use
Oral drops
Definition
Oral drops are Liquid preparations for oral use that are intended to be administered in small
volumes with the aid of a suitable measuring device. They may be solutions, suspensions or
emulsions.
Visual inspection
Inspect the drops. Drops that are solutions should be clear and free from any precipitate. Evidence
of physical instability of drops that are suspensions is demonstrated by the formation of flocculants
or sediments that do not readily disperse on gentle shaking. Evidence of physical instability of drops
that are emulsions is demonstrated by phase separation that is not readily reversed on gentle
shaking. Discoloration (or cloudiness of solutions) may indicate chemical degradation or microbial
contamination of the drops.
Dose and uniformity of dose of oral drops
Into a suitable, graduated cylinder, introduce by means of the dropping device the number of drops
usually prescribed for one dose or introduce by means of the measuring device the usually
prescribed quantity. The dropping speed does not exceed 2 drops per second. Weigh the liquid,
repeat the addition, weigh again and carry on repeating the addition and weighing until a total of 10
masses are obtained. No single mass deviates by more than 10% from the average mass. The total
of 10 masses does not differ by more than 15% from the nominal mass of 10 doses. If appropriate,
measure the total volume of 10 doses. The volume does not differ by more than 15% from the
nominal volume of 10 doses.
Containers
Oral drops are normally supplied in suitable multidose containers that allow successive drops of the
preparation to be administered.
Powders for oral solutions, oral suspensions or oral drops
Definition
Powders for oral solutions, suspensions or drops are multidose preparations consisting of solid,
loose, dry particles of varying degrees of fineness. They contain one or more active ingredients,
with or without excipients and, if necessary, authorized colouring matter and flavouring substances.
They may contain antimicrobial preservatives and other excipients in particular to facilitate
dispersion or dissolution and to prevent caking.
[Note from the Secretariat: Single-dose presentations of powder (such as, for example, a small
sachet) that are intended to be issued to the patient as such, to be taken in or with water or another
suitable liquid, are outside the scope of this general monograph. Such preparations are controlled by
the monograph for Oral powders.]
After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral
solutions, Oral suspensions or Oral drops, as appropriate.
Manufacture
In the manufacture of powders for oral solutions, suspensions or drops, the components of the
powder mixture are passed through a sieve to remove lumps and particle aggregates. The weighed
masses of the sieved components, preferably of a narrow particle size distribution, are then
transferred to a suitable mixer. The greatest risk of segregation of the powder mixture usually
occurs when emptying the mixer container and when the powder mixture is dosed into the
containers. Ensuring the suitability of the mixing equipment and the dosing devices is, therefore,
critical.
Visual inspection
Inspect the powder. Evidence of physical l instability is demonstrated by noticeable changes in
physical appearance, including texture (for example, clumping). Discoloration or may indicate
chemical degradation or microbial contamination.
Granules for oral solutions or suspensions
Definition
Granules for oral solutions or suspensions are multidose preparations consisting of solid, dry
aggregates of powder particles sufficiently resistant to withstand handling. They contain one or
more active ingredients with or without excipients and, if necessary, authorized colouring matter
and flavouring substances. They may contain antimicrobial preservatives and other excipients in
particular to facilitate dispersion or dissolution and to prevent caking.
[Note from the Secretariat: Single-dose presentations of granules (such as, for example, a small
sachet) that are intended be issued to the patient as such, to be taken in or with water or another
suitable liquid, are outside the scope of this general monograph.]
After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral
solutions or Oral suspensions, as appropriate.
Visual inspection
Inspect the granules. Evidence of physical instability is demonstrated by noticeable changes in
physical appearance, including texture (for example, clumping of granules, presence of loose
powder) . Discoloration may indicate chemical degradation or microbial contamination.
GENERALITIES
4.3.2.1 Dosage Form
According to the FDA: “ A dosage form is the physical form in which a drug is produced and dispensed. In determining dosage form, FDA examines such factors as
(1) Elegance: physical appearance of the drug product, (2) Stability: physical form
of the drug product prior to dispensing to the patient, (3) Acceptability: the way the
product is administered, (4) Effi cacy: frequency of dosing, and (5) Safety: how pharmacists and other health professionals might recognize and handle the product ”
[11] . The term dosage form is different from “ dose, ” which is defi ned as a specifi c
amount of a therapeutic agent that can be taken at one time or at intervals.
4.3.2.2 Liquid Dosage Form
The physical form of a drug product that is pourable displays Newtonian or pseudoplastic fl ow behavior and conforms to its container at room temperature. In contrast, a semisolid is not pourable and does not fl ow at low shear stress or conform
to its container at room temperature [12] . According to its physical characteristics,
liquid dosage forms may be dispersed systems or solutions.
4.3.2.3 Dispersed Systems
Dispersed systems are dosage forms composed of two or more phases, where one
phase is distributed in another [2] . If a dispersed system is formed by liquid phases,
then it is known as an “ emulsion. ” In contrast, the dispersed system is named a
“ suspension ” when the liquid dosage form is accomplished by the distribution of a
solid phase suspended in a liquid matrix. The solid phase of a suspension is usually
the drug substance, which is insoluble or very poorly soluble in the matrix [12] .
4.3.2.4 Solutions
A solution refers two or more substances mixed homogeneously [2] . Although solubility refers to the concentration of a solute in a saturated solution at a specifi c
temperature, in pharmacy, solution liquid dosage forms are unsatured to avoid
crystallization of the drug by seeding of particles or changes of pH or temperature
[13] . The precipitation of drug crystals is one of the most important physical instabilities of solutions that may affect its performance [14] . Water is the most used
solvent in solutions manufacturing; however, there are also some commercial nonaqueous solutions in the pharmaceutical market [1] .
4.3.2.5 Manufacturing of Nonparenteral Liquid Dosage Forms
The manufacturing of liquid dosage forms with market - oriented planning includes
the following stages with respect to special good manufacturing practice (GMP)
requirements: planning of material requirements, liquid preparation, fi lling and
packing, sales of drug products, vendor handling, and customer service [15] . From
the viewpoint of product stability, each stage of the process includes critical batchesthat are more decisive than others. Also, each decisive batch contains one or several
unit operations that are more critical than others. The FDA inspection focuses on
those critical unit operations to ensure the safety and stability of the liquid dosage
forms [6] .
4.3.2.6 Optimizing Drug Development Strategies
According to Sokoll [16] : The phases of drug development include discovery, preclinical
development, clinical development, fi ling for licensure, approval/licensure and post -
approval. Discovery typically includes basic research, drug identifi cation and early -
stage process and analytical method development. . . . Emerging companies that review
their pipeline objectively and strike a balance between properly resourcing and developing their lead candidates in the clinic while nurturing their next generation of drug
candidates will have the best chance for success and sustainability.
4.3.2.7 Unit Operation or Batch
A “ batch ” job or operation is defi ned as a unit of work. Raw materials, semifi nished
drug products (bulk), and fi nished drug products are handled in batches. Each different type of material used during the process, such as product packing, should be
managed by batches. This applies also to process aids and operation facilities [15] .
4.3.2.8 Batch Management
The batch management of production simplifi es the process and makes it easier to
control the status of transformation between raw and fi nal products [2] . Some of
the data used to follow the material performance around and out of the product
manufacturing process are batch - where - used - list, initial status, batch determinations, master data, and expiration date check [15] .
The functionality of the overall process to manufacture liquid dosage forms
depends on the successful linkage of one unit operation to another. To use mathematical formulations to scale up the manufacturing process, it is necessary to divide
the process into stages, batches, and unit operations. Each single unit operation is
scalable, but the composite manufacturing process is not. Production problems
result from attempts to follow a process scale - up instead of a unit operation scale -
up. By using mathematical formulations, it is possible to understand the level of
similarity between two scale sizes. In addition, nonlinear similarities between two
scale sizes might require the use of conversion factors to achieve an extrapolation
point for the scale [2] .
4.3.2.9 Steps of Liquids Manufacturing Process
Establishing short - term goals makes it easier to measure effi ciency as well as evaluate the diffi culties [2] . Based on these concepts, the problems of manufacturing
liquid dosage forms can be approached as problems in one or more batches of the
following process steps [6, 15] :
Planning of Material Requirements Research and development of protocols and
selection of materials; acquisition and analysis of raw materials; physical plantdesign, building, and installation; equipment selection and acquisition; personnel selection and initial training; and monitoring information system.
Liquid Preparation Research and development of protocols concerning liquid
compounding; scale - up of the bulk product compounding; physical plant control and maintenance; equipment maintenance and renovation; continuous
training of personnel and personnel compensation plan; and supervision of
system reports.
Filling and Packing Research and development of protocols concerning fi lling
and packing; scale - up of the fi nished drug product fi lling and packing; physical
plant control and maintenance; equipment maintenance and renovation; continuous training of personnel and personnel compensation plan; and supervision of system reports.
Sales of Drug Products Research and development of protocols concerning
product storage; distribution process; continuous training of personnel and
personnel compensation plan; and supervision of system reports.
Vendor Handling Research and development protocols concerning precautions to maintain product stability; control of vendor stock; and sales system
reports.
Customer Service Research and development of protocols concerning home
storage and handling to maintain product stability; relations with health insurance companies and health care professionals; educational materials for patient
counseling; and customer service system reports.
4.3.2.10 Protocols
Protocols are patterns developed by repeating procedures and fi xing the identifi ed
problems each time that the procedure is followed. Therefore, protocols are dynamic
entities that originally can be developed at a laboratory level but must be adjusted
in every new step of the scal - up process. When the manufacturing process moves
up in scale, the number of people affected by the protocol increases geometrically.
Initially, the information can be obtained from library references, personal tests,
interpersonal training, and previous laboratory protocols. However, when the production is scaled up, the information required to fi ne tune the process comes from
monitoring the process itself [2] .
4.3.3 APPROACHES
Quality by Design is a systemic approach that applies the scientifi c method to the
process. QbD theory contains components of management, statistics, psychology,
and sociology. The FDA ’ s new century has identifi ed the QbD approach as its “ key
component ” based on process quality control before industry end results [3, 17] .
The cooperation between industry members and regulators is increased when the
industry explains clearly what it is doing and the agency can understand the formulation and production process. In these cases, regulatory relief appears when industry explores its issues and receives active guidance and programs from the FDA.
The agency takes the role of facilitator, or even partner of the industry, in order to
improve the strength of the process and formulation [3, 17] . To apply QbD as a systemic approach, the company starts by understanding,
step by step, the space design, the design of the dosage form, the manufacturing
process, and the critical process parameters to be controlled in order to reach the
new building block which is the expectation of variances within those critical
process parameters that can be accepted. This approach allows the establishment
of priorities and fl exible boundaries in the process [3] . Infl exible specifi cations
allow uncontrolled small variances that can follow the butterfl y effect of the theory
of chaos by producing unpredictable large variations in the long - term behavior of
the product shelf - life [18, 19] . In contrast, fl exibility, with knowledge of potential
variances, reduces changes in the approved spaces and manufacturing protocols
[3, 17] .
According to the FDA [6] , critical parameters during the manufacturing process
of nonparenteral liquid dosage forms may appear in the design of physical plant
systems, equipment, protocols of usage and maintenance, raw materials, compounding, microbiological quality control, uniformity of suspensions and emulsions, and
fi lling and packing [6] .
Process isolation and installation of an appropriate air fi ltration system in the
physical plant may reduce product exposition to chemical and microbiological
contaminations. In addition, the use of a suitable dust removal system as well as
a heating, ventilation, and air conditioning system (HVACS) may help to repress
product chemical instabilities [6] .
The equipment of sanitary design, including transfer lines, as well as appropriate
cleaning and sanitization protocols may reduce chemical and microbiological contaminations in the fi nal product. Chemical instabilities may be reduced by weighting
the right amount of liquids instead of using a volumetric measurement, avoiding the
common use of connections between processes, and using appropriate batching
equipment [6] .
Particle sizes of raw materials are critical to control dissolution in solutions as
well as uniformity in suspensions and emulsions. Temperature control during compounding is important since heat helps to support mixing and/or fi lling operations,
but, in contrast, high - energy mixers may produce adverse levels of heat that affect
product stability. Too much heat may cause chemical and physical instabilities such
as change of particle size or crystallization of drugs in suspensions, dissolution and
potency loss of drugs in suspensions, oxidation of components, and activation of
microbiological growth after degradation of compounds as well as precipitation of
dissolved compounds in solution [20] . In addition, uniformity of suspensions depends
on viscosity and segregation factors while solubility, particle size, and crystalline
form determine uniformity of emulsions. Application of pharmaceutical GMP for
product processes and storage assures microbiological quality. A defi cient deionizer
water - monitoring program and product preservative system facilitate microbial contamination. Filling uniformity is indispensable for potency uniformity of unit - dose
products and depends on the mixing operation. Calibration of provided measuring
devices and the use of clean containers will allow administering the right amount
of the expected components in the liquid dosage form [6] .
Principal product specifi cations are microbial limits and testing methods, particle
size, viscosity, pH, and dissolution of components. Process validation requires control
of critical parameters observed during compounding and scale - up. Product stability
examination is based on chemical degradation of the active components and interactions with closure systems, physical consequences of moisture loss, and microbial
contamination control [6] .
4.3.4 CRITICAL ASPECTS OF LIQUIDS MANUFACTURING PROCESS
4.3.4.1 Physical Plant
Heating, Ventilation, and Air Conditioning System The manufacturer has to
warrant adequate heating, ventilation, and air conditioning in places where labile
drugs are processed [6] .
The effect of long processing times at suboptimal temperatures should be considered at the production scale in terms of the consequences on the physical or chemical
stability of individual ingredients and product. A pilot plant or production scale
differs from laboratory scale in that their volume - to - surface - area ratio is relatively
large. Thus, for prolonged suboptimal temperatures, jacketed vessels or immersion
heaters or cooling units with rapid circulation times are absolutely necessary [2] .
For heat - labile drugs, uncontrolled temperature increments can activate auto -
oxidation chains when the drug product ingredients react with oxygen and generate
free radicals but without drastic external interference. Vitamins, essential oils, and
almost all fats and oils can be oxidized. A good example of a heat - labile drug solution is clindamycin, which has to be stored at room temperature and away from
excess heat and moisture [19] . Auto - oxidation chains are fi nished when free radicals
react with each other or with antioxidant molecules (quenching). The tocopherols,
some esters of gallic acid, as well as BHA and BHT (butylated hydroxyanisole and
butylated hydroxytoluene) are common antioxidants used in the pharmaceutical
industry [1] .
Isolation of Processes To minimize cross - contamination and microbiological contamination, the manufacturer may develop special procedures for the isolation of
processes. The level of facilities isolation depends on the types of products to be
manufactured. For instance, steroids and sulfas require more isolation than over -
the - counter (OTC) oral products [6] . To minimize exposure of personnel to drug
aerosols and loss of product, a sealed pressure vessel must be used to compound
aerosol suspensions and emulsions [21] . An example of cross - contamination with
steroids was the controversial case of a topical drug manufactured for the treatment
of skin diseases. High - performance liquid chromatography/ultraviolet and mass
spectrometry (HPLC/UV, HPLC/MS) techniques were used by the FDA for the
detection of clobetasol propionate, a class 1 superpotent steroid, as an undeclared
steroid in zinc pyrithione formulations. The product was forbidden and a warning
was widely published [22] .
Dust Removal System The effi ciency of the dust removal system depends on the
amount and characteristics of dust generated during the addition of drug substance
and powdered excipients to manufacturing vessels [6] . Pharmaceutical industries
usually generate some type of dust or fume during processing. Important factors for
selecting dust collectors are maintenance, surrogate test, economics, and containment. In addition, reentrainment of the fi ne particles, vertical or horizontal position,
effi ciency, pressure resistant, service life time, as well as sealing capacity to workthrough the bag are signifi cant factors concerning fi lter selection of dust removal
systems. Some examples of dust collection applications in the manufacture of liquid
dosage forms are handling and pulverization of raw materials, spray dryers, and
general room ventilation [23] .
Air Filtration System The effi ciency of the air fi ltration system has to be demonstrated by surface or air - sampling data where the air is recirculated [6] . To monitor
the levels of contamination in the air, there are commercial automatic samplers for
microbiological contamination or gas presence. Air trace environmental samplers
for pharmaceutical industries are based on the slit - to - agar impaction technique for
the presence of viable microorganisms. Automatic samplers for compressed gas
analyze the presence of a specifi ed gas in 1 m 3
by absorbing air at a fi xed fl ow rate
for a sampling period of 1 h or a different adjusted time. These solutions to the
sampling needs of the pharmaceutical industry are robust, require low maintenance,
and are easy to use. This allows for validation of sampling data at the moment of
application fi lling to support the process control. Sampling time and selection of
microbiological growth media or analysis technique are important components to
consider when developing a sampling plan [24] .
4.3.4.2 Equipment
Sanitary Design Pumps, valves, fl owmeters, and other equipment should be easily
sanitized. Some examples of identifi ed sources of contamination are ball valves,
packing in pumps, and pockets in fl owmeters [6] .
The sanitary design and performance of equipment make it accessible for inspection, cleaning, and maintenance. It has to be cleanable at a microbiological level and
its performance during normal operations should contribute to sanitary conditions.
The materials used in the design have to assure hygienic compatibility with other
equipment, the product, the environment, other systems such as electrical, hydraulics, steam, air, and water, as well as the method and products used for cleaning and
sanitation. The equipment should be self - draining to assure product or liquid collection. Small niches, for example, pits, cracks, corrosion, recesses, open seams, gaps,
lap seams, protruding ledges, inside threads, bolt rivets, and dead ends, as well as
inaccessible cavities of equipment such as entrap and curlers must be eliminated
whenever possible; otherwise they have to be permanently sealed. Enclosures, for
example, push buttons, valve handles, switches, and touch screens, should be prepared for a hygienic design of maintenance. Standards have been developed by the
American Meat Institute [25] .
Standard Operating Procedures for Cleaning Production Equipments Current
GMPs are defi ned as the basic principles, procedures, and resources required to guarantee an environment appropriate for manufacturing products of adequate quality
[26] . To minimize cross - contamination and microbiological contamination, it is GMP
for a manufacturer to create and pursue written standard operating procedures
(SOPs) to clean and sanitize production equipment in a way that avoids contamination of in - progress and upcoming batches. When the drug is known as a potent generator of allergic reactions, such as steroids, antibiotics, or sulfas, cross - contamination
becomes an issue of safety [20] . In addition, validation and data analysis procedures, including drawings of the manufacturing and fi lling lines [6] , are especially important
for clean - in - place (CIP) systems, as indicated in Figures 1 and 2 .
Many companies have problems with standardizing operating procedures for
cleaning steps and materials used [6] . Appropriate SOPs are necessary to determine
the scope of the problem in investigations about possible cross - contaminations or
mix - ups. The best approach to validate a SOP is to test it, use it as a training tool,
and observe the results obtained by different persons. This includes the worst - case
situation in order to enhance the step - by - step writing methodology as well as standardizing the materials used. A typical SOP contains a header to present the SOP
title, date of issue, date of last review, total number of pages, responsible person,
and approval signature. Typically, a SOP includes position of responsible person,
SOP purpose and scope, defi nitions, equipment and materials, safety concerns, step -
by - step procedure, explanation of critical steps, tables to keep data, copies of forms
to fi ll, and references [26] . The forms to keep the records must show the date, time,
product, and lot number of each batch processed. However, the most important
points of the SOP are equipment identity, cleaning method(s) with documentation
of critical cleaning steps, materials approved for cleaning that have to be easily
removable, names and position of persons responsible for cleaning and inspection,
inspection methods, and maintenance and cleaning history of the equipment [20] .
Cleaning and Sanitizing Transfer Lines Pipes should be hard, easily cleaned, and
sanitized. To avoid moisture collection and microbiological contamination, hoses
should be stored in a way that allows them to drain rather than be looped. For
example, transfer lines are an important source of contamination when fl exible
hoses are handled by operators, lying on the fl oor, and after they are placed in
transfer or batching tanks [6] .
Heat is considered one of the most efficient physical treatments for sanitizing
pharmaceutical equipment and could be used for sanitizing hoses that have already
been cleaned. The recirculation of hot water at a temperature of 95 o
C for at least
100 min allows bacteria elimination [14] .
Due to the important amount of insoluble residues left on piping and transfer
lines after emulsion manufacturing, such as topical creams and ointments, equipment cleaning becomes difficult to address. To avoid cross - contamination, some
manufacturers have decided to dedicate lines and hoses to specific products.
However, these decisions have to appear in the written production protocols and
SOPs [20] .
Sampling Cleaned Surfaces for Presence of Residues The cleaning method is
validated by sampling the cleaned surfaces of the equipment for the existence of
residues. The equipment characteristics and residue solubility are factors to support
the selection of the sampling method to be used [6] . There are two acceptable
general types of sampling methods: direct surface sampling by swabbing of surfaces
and rinse sampling with a routine production in - process control. Although surface
residues will not be identical on each part of the surface, statistically the most
advantageous is direct surface sampling because it allows evaluation of the hardest
areas to clean as well as insoluble or “ dried - out ” residues by physical removal. The
type of sampling material and solvent used for extraction from the sampling material should be validated in order to determine their impact on the test data. The
second method, rinse sampling, is used for larger surfaces or inaccessible systems.
Contaminants that are physically occluded and insoluble residues are disadvantages of the rinse sampling method. To validate this cleaning process, direct measurement of the contaminant in the rinse water has to be tested instead of a simple
test for water quality. Routine production in - process control is used as indirect
testing for large equipment that has to be cleaned by the rinse sampling method.
The uncleaned equipment has to give an unacceptable result for the indirect
test [27] .
Establishing Appropriate Limits on Levels of Postequipment Cleaning
Residues Very low levels of residue are possible to be determined since technological advances offer more sensitive analytical methods. The manufacturer should
know the toxicological information of the materials used and potential amounts of
residues after exposure to the equipment surface. Accordingly, the manufacturer
has to establish proper limits of residues after equipment cleaning and scientifi cally
justify these limits. The established limits must be clinically and pharmaceutically
safe, realistic, viable, and verifi able [20] . The sensitivity of the analytical method will
determine the logic of the established limits since absence of residues could indicate
a low sensitivity of the analytical method or a poor sampling procedure. Sometimes
thin - layer chromatography (TLC) screening must be used in addition to chemical
analyses. Some practical levels established by manufacturers include 10 ppm of
chemicals, 1/1000 of the biological activity levels met on a normal therapeutic dose,
and no visible residues of particles determined organoleptically [27] .
Connections Connectors and manifolds should not be for common use. For
example, sharing connectors in a water supply, premix, or raw material supply tanks
may be a source of cross - contamination [6] .
Time between Completion of Manufacturing and Initiation of Cleaning The time
that may elapse from completion of a manufacturing operation to initiation of
equipment cleaning should also be stated where excessive delay may affect the
adequacy of the established cleaning procedure. For example, residual product may
dry and become more diffi cult to clean [20] .
SOPs are an example of defi ciency in many manufacturers regarding time limitations between batch cleaning and sanitization [6] . Lack of communication betweendepartments responsible for the production at different levels is the main cause of
time control problems. Typically each department, from human resources to fi nances,
manufacturing, and warehouse, has its own computer system optimized for the
particular ways that the department does its work. Therefore, time control becomes
a primordial issue when labile materials are transferred from one department to
another [28] .
To facilitate communication between different departments, some useful softwares have been developed. For example, ERP is an integrated approach which may
have positive payback if the manufacturer installs it correctly. An ERP is a type
of software that can improve communication between planning and resources. The
software attempts to integrate all departments and functions in a company onto a
single computer system that can serve each particular need, such as fi nance, human
resources, manufacturing management, process manufacturing management, inventory management, purchasing management, quality management, and sales management. Each department has its own software, except now the software is linked
together, so that, for example, someone in manufacturing can look into the maintenance software to see if specifi c batch cleaning and sanitization have been scheduled
or realized and someone in fi nance can review the warehouse software to see if a
specifi c order has been shipped. The information is online and not in someone ’ s
heads or on papers that can be misplaced. People in different departments may see
the same information, update it if they are allowed to do, and make right decisions
faster. However, the software is less important than the changes companies make
in the ways they work. Reorganization and training are the keys of ERP ’ s success
to fi x integration problems. There are three different ways to install an ERP: big
bang, franchising strategy, and slam dunk. Big bang is the most ambitious way
whereby companies install a single ERP across the entire company. By the franchising strategy, departments do not share many common processes across, whereas
slam dunk is focused on just a few key processes [28] .
Weight in Formulations Flow properties of liquids rarely vary due to their constant density at a constant temperature. Oral solutions and suspensions are formulated on a weight basis (gravimetry) in order to be able to measure the fi nal volume
by weight before fi lling and packing. Volumetric measurements of liquid amounts
to be used for manufacturing liquid dosage forms have shown greater variability
than weighted liquids. For instance, the inaccurate measurement of the fi nal volume
by using dip sticks or a line on a tank may cause further analytical errors and
potency changes [6] .
The importance of selecting gravimetry instead of volumetry to measure liquid
amounts in the pharmaceutical industry of liquid dosage forms is well illustrated by
the volume contraction of water – ethanol and volume expansion of ethyl acetate –
carbon disulfi de liquid mixtures as well as a CS2 – ethyl acetate system. The National
Formulary (NF) diluted alcohol is a typical example of the volume nonadditivity of
liquid mixtures [29] . This solution is prepared by mixing equal volumes of alcohol
[U.S. Pharmacopeia (USP)] USP and purifi ed water (USP). The fi nal volume of this
solution is about 3% less than the sum of the individual volumes because of the
contraction due to the mixing phenomenon [1] . In addition, molecular interactions
of surfactants in mixed monolayers at the air – aqueous solution interface and in
mixed micelles in aqueous media also cause some contraction of volume upon
mixing [30]
Location of Bottom Discharge Valve in Batching Tank The bottom discharge
valve should be located exactly at the bottom of the tank. In some cases valves have
been found to be several inches to a foot above the bottom of the tank [6] .
For a tank suspected of having substantial deposits at the bottom, a fi ber - optic
camera can be inserted in the tank to provide a view and positive confi rmation of
the tank bottom condition. These camera and light vision systems are sanitary equipment able to provide a computational real - time visual inspection of the inside tank
under process conditions or pressure vessel. In addition, they are used to control
several parameters during the manufacturing process, such as product level and
thickness, solids level, uniformity of suspensions, foam, and interface and/or cake
detection [31] .
Batching Equipment to Mix Solution Ingredients of solutions have to be completely dissolved. For instance, it has been observed that some low - solubility drugs
or preservatives can be kept in the “ dead leg ” below the tank, and the initial samples
have reduced potency [6] . When there is inadequate solubility of the drug in the
chosen vehicle, the dose is unable to contain the correct amount of drug in a manageable size unit, that is, one teaspoonful or one tablespoonful. Thus, ingredients
as well as handling and storage conditions should be chosen to manage the problem
[14] .
In solutions, the most important physical factors that infl uence the solubility of
ingredients are type of fl uid, mixing equipment, and mixing operations. Generalized
Newtonian fl uids are ideal fl uids for which the ratio of the shear rate to the shear
stress is constant at a particular time. Unfortunately, in practice, usually liquid
dosage forms and their ingredients are non - Newtonian fl uids in which the ratio of
the shear rate to the shear stress varies. As a result, non - Newtonian fl uids may not
have a well - defi ned viscosity [32] .
When all the ingredients are miscible liquids, the combination and distribution
of these components to obtain a homogeneous mixture are called blending. Whenever possible, ingredients should be added together and the impeller mixer often is
located near the bottom of the vessel [21] . Mixing of high - viscosity materials requires
higher velocity gradients in the mixing zone than regular blending operations. In
fact, the fundamental laws of physics regarding the performance of Newtonian fl uids
in the production process may be studied using computational tools. For example,
VisiMix is a software that is routinely used to calculate shear rates [2] .
Finally, if it is determined that there is a bigger problem of insolubility
coming from the formulation, then addition of cosolvents, surfactants, as well as
the preparation of the ionized form of an acid or base, drug derivatization, and
solid - state manipulation are approaches to manipulating the solubility of the drug
[14] .
Batching Equipment to Mix Suspension In the case of suspensions, the fl ow necessary to overcome settling in a satisfactory suspension depends on the mixing
equipment and is predicted by Stokes ’ s law. Thus, to use the Stokes ’ s law, suspensions are considered as Newtonian fl uids if the percentage of solids is below 50%.
Mixing equipment uses a mechanical device that moves through the liquid at a given
velocity. Dispersing and emulsifying equipment is categorized as “ high - shear ” mixing
equipment. The maximum shear rate with such equipment occurs very close to themixing impeller. Therefore, the diameter of the impeller and the impeller speed
directly infl uence the power applied by the mixer to the liquid [21] .
Batching Equipment to Mix Emulsion The most common problems of mixing
emulsions are removing “ dead spots ” of the mixture and scrapping internal walls of
the mixer. Dead spots are quantities of ingredients that are not mixed and become
immobile. Where dead spots are present, that quantity of the formula has to be
recirculated or removed and not used. If the inside walls of the mixer keep residual
material, operators should use hard spatulas to scrape the walls; otherwise the
residual material will become part of the next batch. In both cases, the result may
be nonuniformity. Stainless steel mixers have to include blades made of hard plastic,
such as Tefl on, to facilitate the scrapping of the mixer walls without damaging the
mixer. Scrapper blades should be fl exible enough to remove internal material but
not too rigid to avoid damaging the mixer [20] . The mixing will be successful if the
macroscale mixing offers suffi cient fl ow of components in all areas in the mixing
tank and the microscopic examination shows a correct particle size distribution
[33] .
4.3.4.3 Particle Size of Raw Materials
Raw materials in Solution The types of raw materials used to be part of solutions
are presented in Table 1 . They have different purposes and can be cosolvents, electrolytes, buffers, antioxidants, preservatives, coloring, fl avoring and sweetener agents,
among others.
Particle Size of Raw Materials in Solution Particle size is affected by the breaking process of the particle, crystal form, and/or salt form of the drug. The particle
size can affect the rate of dissolution of raw materials in the manufacturing process.
Raw materials of a fi ner particle size may dissolve faster because they have a larger
surface area in contact with the solvent than those of a larger particle size when the
product is compounded [6] . Mixing faster causes the particle to break down and
dissolve more quickly. In addition, hydrated particles are less soluble than their
anhydrous partners [37] .
Solid drugs may occur as pure crystalline substances of defi nite identifi able shape
or as amorphous particles without defi nite structure. In addition, when a drug particle is broken up, the total surface area is increased as well as its rate of dissolution.
The amorphous form of a chemical is usually more soluble than the crystalline form
while the crystalline form usually is more stable than the amorphous form [37] .
Processing conditions used for providers to obtain raw materials can dramatically
impact their quality and stability; for instance, the presence of different polymorphs
may depend on the thermal history of freezing, concentration of solvents, and drying
conditions [38] . The polymorphism of a crystalline form is the capacity of a chemical
to form different types of crystals, depending on the conditions of temperature,
solvents, and time followed for its crystallization. Among different polymorphs, only
one crystalline form is stable at a given temperature and pressure. Over time, the
other crystalline forms, called metastable forms, will be transformed into stable
forms. Transformations longer than the shelf - life of metastable forms into stable
forms of a drug are very common in fi nal products and compromise its stability and
effi cacy to different extents depending on quality control [37] .
While the metastable forms offer higher dissolution rates, many manufacturers
use a particular amorphous, crystalline, salt, or ester form of a drug with the solubility needed to be dissolved in the established conditions, for instance, to prepare a
chloramphenicol ophthalmic solution [39] . Thus, the selection of amorphous or
crystalline form of a drug may be of considerable importance to facilitate the formulation, handling, and stability [37] .
However, the dissolution rate of an equal sample of a slowly soluble raw material
usually will increase with increasing temperature or rate of agitation as well as with
reduce viscosity, changes of pH or nature of the solvent. In addition, other alternative mechanisms to enhance the solubility of insoluble drugs are: 1) hydrophilization: the reduction in contact angle or angle between the liquid and solid surface
[40] , which can be accessed by intensive mixing of the hydrophobic drug with a small
amount of methylcellulose solution [41] ; 2) the formation of microemulsions: by
covering small particles with surfactants to obtain micromicelles that are visible only
in the form of an opalescence; and, 3) the formation of complexing compounds: by
adding a soluble substance to form soluble reversible complexes. However, the last
method is used with some restrictions [42] .
Raw Materials in Suspension The types of raw materials used to be part of suspensions are presented in Table 2 . They have different purposes and can be wetting
agents, salt formation ingredients, buffers, polymers, suspending agents, fl occulating
agents, electrolytes, antioxidants, poorly soluble Active Product Ingredients, preservatives, coloring, fl avoring and sweetener agents, among others.
Particle Size of Drug in Suspension The physical stability of a suspension can be
enhanced by controlling the particle size distribution [43] . Uncontrolled changes of
drug particle size in a suspension affect the dissolution and absorption of the drug
in the patient. Drug substances of fi ner particle size may be absorbed faster and
bigger particles may not be absorbed. Aggregation or crystal growth is evaluated
by particle size measurements using microscopy and a Coulter counter [21] or preferably techniques that allow samples to be investigated in the natural state. Allen
[44] offers an academic and industrial discussion about particle characterization.
Powder properties and behavior, sampling, numerous potential particle size measuring devices, available equipment as well as surface and pore size are his principal
themes.
Particles are usually very fi ne (1 – 50 μ m). For instance, topical suspensions use
less than 25 μ m particle size [6] . The particle size of the drug is the most important
consideration in the formulation of a suspension, since the sedimentation rate of
disperse systems is affected by changes in particle size. Finer particles become interconnected and produce particle aggregation followed by the formation of nonresuspendable sediment, known as caking of the product. The two main causes of
aggregation and caking are energetic bonding and bonding through shared material.
A statistical wide distribution of particle sizes gives more compact packing and
energetic bonding than narrower distributions. It has been observed that heat treatments can cause agglomeration of particles, not only due to energetic bonding but
also by formation of crystal bridges. Also, when the application of shear forces to
mix and homogenize the suspension uses too high energy inputs, then the probability for aggregation increases [43] .
Examples of oral suspensions in which a specifi c and well - defi ned particle size
specifi cation for the drug substance is important are phenytoin suspension, carbamazepine suspension, trimethoprim and sulfamethoxazole suspension, and hydrocortisone suspension [6] .
There are some useful methods to improve the physical stability of a suspension,
such as decreasing the salt concentration, addition of additives to regulate the
osmolarity, as well as changes in excipient concentrations, unit operations in the
process, origin and synthesis of the drug substance, polymorphic behavior of
the drug substance crystals, and other particle characteristics. However, methods
based on changes of the particle properties and the surfactants used are the most
successful [43]
To approach physical stability problems of suspensions, effectiveness and stability
of surfactants as well as salt concentrations must be checked with accelerated aging.
In addition, unit operations affecting particle size distribution, surface area, and
surfactant effectiveness should be approached, taking into account that different
types of distributions, for instance, volume or number weighted, give a different
average diameter for an equal sample [43] .
Raw Materials in Emulsions The types of raw materials used to be part of emulsions are presented in table 3 . They have different purposes and can be buffers,
polymers, emulsifying agents, penetration enhancers, gelling agents, stabilizers, antioxidants, preservatives, coloring, fl avoring and sweetener agents, among others.
Particle Size in Emulsions When a solid drug is suspended in an emulsion, the
liquid dosage form is known as a coarse dispersion. In addition, a colloidal dispersion has solid particles as small as 10 nm – 5 μ m and is considered a liquid between
a true solution and a coarse dispersion [44] .
Compounding: Effects of Heat and Process Time
Oxygen Oxygen removal for processing materials that require oxygen to degrade
is possible by methods such as nitrogen purging, storage in sealed tanks, as well
as special instructions for manufacturing operations [6] . For instance, sealing glass
ampules containing a liquid dosage form with heat under an inert atmosphere is a
packing mechanism used to prevent oxidation. Some aspects of oxygen sensitiveness
that should be taken into account are the necessity of water and headspace deoxygenation in ampules before sealing, the avoidance of multidose vials that facilitate
oxygen contact with the product after opened, and rubber stoppers for vial sealing
that are permeable to oxygen as well as release additives to catalyze oxidative reac-tions. Rubber stoppers soften and get sticky over time because all rubber products
degrade as sulfur bonds induced during vulcanization revert. Connors et al. [45]
present the oxygen content of water at different temperatures and an interesting
discussion of calculations for the case of captopril as an oxygen - sensitive drug.
Dissolution of Drugs in Solutions Although some compounds, such as poloxamers, decrease their aqueous solubility with an increase in temperature [46] , usually,
drugs dissolve more quickly when the temperature increases because particle vibration is augmented and the molecules move apart to form a liquid. Chemical instabilities by oxidation due to high temperature or prolonged periods of heat exposure
can occur when trying to increase the dissolution of poorly soluble raw materials.
To control such instabilities, charts of time and amount of temperature treatments
to dissolve materials as well as tests of dissolution are required [6] . In addition,
precipitations and other reactions may occur between salts in solution and can be
anticipated by using heat - of - mixing data and activation energy calculations for
decomposition reactions. Connors et al. [45] provide examples of calculations about
effects of temperature on chemical stability of pharmaceuticals in solution. Regarding the instability of the product, the reasons to limit temperature amounts can go
from controlling fi nal concentration changes to controlling burn - on/fouling when
too - high temperatures are applied [45] . Usually salts are more soluble in water and
alcohol than weak acids or bases. The reason salts are not always the best choice to
increase the solubility of a drug is its permeability. Oral drug absorption depends
not only on solubility and dissolution but also on permeability through the cellular
membrane. Drugs have to be able to dissolve not only in the aqueous fl uids of the
body before reaching the intestinal wall but also in the lipophilic environment of
the cellular membrane in order to reach the internal part of the cell and interfere
with its functionability. Therefore, the cosolvent approach is essential if the drug
presents problems in dissolving in the media. The dielectric constant of a solvent is
a relative measure of its polarity. Comparing the hydroxyl – carbon ratio of the
solvent molecule allows establishing the relative polarity of the cosolvent as determined by its dielectric constant [47] . Remington describes the formulations of some
solutions, such as the ferrous sulfate syrup, amantadine hydrochloride syrup, phenobarbital elixir, and theophylline elixir [1] .
Potency of Drugs in Suspension To avoid degradation of the suspended drug substance by high temperature or prolonged periods of heat exposure, it is necessary
to record the time and amount of temperature treatments on charts [6] . The rate
of dissolution of a suspended drug increases with the increase in temperature. The
potency stability of a suspended drug depends on the concentration of the dissolved
drug since drug decomposition occurs only in solution [48] . The goal is to avoid
the dissolution of suspensions. Changing the pH of the vehicle or replacing the drug
with a less soluble molecule may result in enhanced potency stability of the suspended drug [48] .
For instance, when the chemical stability of a suspension of ibuprofen powder
and other ibuprofen – wax microspheres was studied with a modifi ed HPLC procedure for three months, the amount of drug released from the microspheres was
affected by the medium pH, type of suspending agent, and storage temperature
without observing chemical degradation of the drug [49
Temperature Uniformity in Emulsions During the preparation of emulsions, heat
may be increased as part of the manufacturing protocol or mixing operation system.
Temperature measurements should be monitored and documented continuously
using a recording thermometer if the temperature control is critical or using a hand -
held thermometer if it is not a critical factor. Temperature may be critical in the
manufacturing process depending on the thermosensitivity of the drug product and
excipients as well as the type of mixer used. To guarantee the temperature uniformity during the mixing operation, manufacturers may consider the relation between
the container size, mixer speed, blade design, viscosity of the contents, and rate of
heat transfer [20] .
Fong - Spaven and Hollenbeck [50] studied the apparent viscosity as a function
of the temperature from 25 to 75 ° C of an oil – water emulsion stabilized with 5%
triethanolamine stearate (TEAS) using a Brookfi eld digital viscometer. They
observed that the viscosity decreased when the temperature reached about 48 ° C,
but surprisingly viscosity increased to a small peak at 54 ° C and then continued
decreasing after that peak. The viscosity peak was attributed to a transitional gellike
arrangement molecular structure of TEAS that is destroyed as soon as the temperature continues increasing, the TEAS crystalline form reappears, and viscosity again
decreases [36] .
Microbiological Control To avoid chemical instabilities that yield microbiological
and physical instabilities, as a result of high temperature or prolonged periods of
exposure, it is necessary to record the time and amount of temperature treatments
on charts [6] .
Product Uniformity Charts of storage and transfer operation times for the bulk
product are required to control the risk of segregation. Transfers to the fi lling line
and during the fi lling operation are the most critical moments to keep the suspension uniformity [6] . The implementation of an ERP for time scheduling is the best
solution for time control and organization of resources. However, it could be diffi -
cult due to the reluctance of people to change [10] . The constant fl ow of the liquid
through the piping, the constant mixing of the bulk product in the tank, as well as
the transfer of small amounts near the end of the fi lling process to a smaller tank
during the fi lling process may minimize segregation risks [6] .
Final Volume Excess heating produces variations of the fi nal volume over time
[6] . Although increasing solute concentration can elevate the boiling point and
reduce evaporation of water, changes in drug concentration are undesirable because
they yield different fi nal products. Regarding the instability of the product, the
reasons to limit temperature amounts can go from controlling fi nal concentration
changes to controlling burn - on/fouling when too - high temperatures are applied
[36] .
A solution is a liquid at room temperature that passes into the gaseous state when
heated at very high temperature, forming a vapor with determined vapor pressure,
through a process called vaporization. The kinetic energy is not evenly distributed
between the molecules of the liquid. When the liquid is in a closed container at a
constant temperature, the molecules with the highest kinetic energy leave the surface
of the liquid and become gas molecules. Some of the gas molecules remain as gas
and others condense and return to the liquid. When, at a determined temperature, the rate of condensation equals the rate of vaporization, the equilibrium vapor pressure is reached. However, vapor pressure increases with increases in liquid temperature, resulting in more molecules leaving the liquid surface and becoming gas
molecules [51] .
Storage Charts of time and temperature of storage are important to control the
increased levels of degradedness [6] . Shelf life is defi ned as the amount of time in
storage that a product can maintain quality and is equivalent to the time taken to
reach 90% of the composition claim or have 10% degradation. The availability of
an expiration date is assumed under specifi ed conditions of temperature. Based on
zero - and fi rst - order reaction calculations, Connors et al. [45] show the estimation
methods to determine the shelf life of a drug product at temperatures different from
the one specifi ed under standard conditions.
4.3.4.5 Uniformity of Oral Suspensions
Keeping the particles uniformly distributed throughout the dispersion is an important aspect of physical stability in suspensions. Based on Stokes ’ s law for dilute
suspensions where the particles do not interfere with one another, there are different factors that control the velocity of particle sedimentation in a suspension, for
instance, particle diameter, densities of the dispersed phase and the dispersion
medium, as well as viscosity of the dispersion medium [36] . Remington describes
the formulation of trisulfapyrimidines oral suspension [1] . In addition, Lieberman
et al. [42, 48] are also good sources of typical formulations for suspensions.
Viscosity Depending upon the viscosity, many suspensions require continuous or
periodic agitation during the fi lling process [6] .
Segregation in Transfer Lines When the stored bulk of a nonviscous product is
transferred to fi lling equipment through delivery lines, some level of segregation is
expected. The manufacturer has to write the procedures and diagrams for line setup
prior to fi lling the product [6] . Delivery lines of suspensions increase the tendency
of particles of the same size to assemble together. However, slightly increasing the
global mixing in the lines can easily reverse the segregation without enhancing the
global mixing [52] . Shear stress versus rate of shear can be plotted to determine
the fl ow pattern of a specifi c suspension as pseudoplastic, Newtonian, or dilatant.
The type of fl ow is determined by the slope of the plot. While shaking increases the
yield stress and causes particles fl ow, the cessation of shear and rest rebuilds the
order of the system. A good - quality suspension is known as a thixotrophic system
and is obtained when the particles at rest avoid or show reduced sedimentation. The
rheogram of a thixotrope system presents a typical hysteresis or curve representing
different shear stresses over time [33] .
Quality Control The GMPs for suspensions include testing samples at different
checkpoints in the procedure, at the beginning, middle, and end, as well as samples
from the bulk tank. The uniformity will be successful only if, on microscopic analysis,
the components are dispersed to the expected particle size distribution established
by product development. Visual and microscopic examinations should consist of
looking for verifi cation of foam formation, segregation, and settling, although testingfor viscosity is important to determine agitation during the fi lling process. Samples
used for tests should not be combined again with the lot [6, 33] .
4.3.4.6 Uniformity of Emulsions
Remington describes the following three typical formulas of emulsions: type A
gelatin, mineral oil emulsion (USP), and oral emulsion (O/W) containing an insoluble drug [1] . In addition, Lieberman et al. [42, 50] are also good sources of typical
formulations for emulsions. The components of the emulsion system may present
physical and chemical instabilities refl ected on the distribution of an active ingredient, component migration from one phase to another, polymorphic changes in
components, and chemical degradation of components [33] .
Solubility The soluble active ingredient should be added to the liquid phase that
will be its carrier vehicle. Data of solubility have to be determined as part of the
process validation. Potency uniformity has to be tested by demonstrating satisfactory distribution in the emulsifi ed mix [20] .
Particle Size Regarding globule diameter in emulsions, the size – frequency distribution of particles in an emulsion over time may be the only method for determining
stability [36] . Drug activity and potency uniformity of insoluble active ingredients
depend upon control of particle size and distribution in the mix [6] . In addition,
aggregation of the internal phase droplets, formation of larger droplets, and phase
separation are categorized as emulsion system instabilities that are refl ected in the
particle size distribution of the emulsion. The measurement of particle size distribution over time allows the characterization of the emulsion stability and determines
the rheological behavior of the emulsion. Well - accepted approaches to determine
particle size distribution include microscopy, sedimentation, chromatography, and
spectroscopy. However, these analyses are problematic in a multiphase emulsion
[33] .
Crystalline Form Uncontrolled temperature or shear can induce changes in component crystallinity or solubility. For this reason, analytes originally present in each
phase of the product should be counted as well possible interactions with the container or closure and the processing equipment analyzed. Some techniques used to
obtain information about the emulsion system and its components are microscopic
examination, macro - and microlaser Raman, and rheological studies [33] . The FDA
guidance offers the following example: “ in one instance, residual water remaining
in the manufacturing vessel, used to produce an ophthalmic ointment, resulted in
partial solubilization and subsequent recrystallization of the drug substance; the
substance recrystallized in a larger particle size than expected and thereby raised
questions about the product effi cacy ” [20] .
4.3.4.7 Microbiological Quality
Microbial Specifi cations These specifi cations are determined by the manufacturer. The USP Chapters 61, 62, and 1111 present the microbial limits to assess the
signifi cance of microbial contamination in a dosage form [53] . However, the USPdoes not determine specifi c methods for water - insoluble topical products. The
microbial specifi cations are presented as a manufacturer ’ s document that details the
methods to isolate and identify the organisms as well as the number of organisms
permitted and action levels to be taken when limits are exceed and the potential
causes are investigated [6] . The Pharmaceutical Microbiology Newsletter (PMF)
presents several articles to discuss topics such as microbial identifi cation, methods,
data analysis, and preservation as well as topics related to USP and FDA regulations
[54] . To minimize the differences about microbial limits and test methods, the USP
is trying to harmonize the standards with the European Pharmacopoeia (EP) [55] .
Microbial Test Methods The selected microbial test methods determine specifi c
sampling and analytical procedures. When the product has a potential antimicrobial
effect and/or preservative, the spread technique on microbial test plates must be
validated. In addition, the personnel performing the analytical techniques have to
be qualifi ed and adequately trained for this purpose [6] .
Usually, total aerobic bacteria, molds, and yeasts are counted by using a standard
plate count in order to test the microbial limits. The microbial limit test may be
customized by performing a screening for the occurrence of Staphylococcus aureus,
Pseudomonas aeruginosa, Pseudomonas cepacia, Escherichia coli, and Salmonella
sp. [56] .
Investigation of Exceeded Microbiological Limits A high number of organisms
may indicate defi ciencies in the manufacturing process, such as excessive high
temperature, component quality, inadequate preservative system, and/or container
integrity. Information about the health hazards of all organisms isolated from the
product has different meanings depending on the type of dosage form and group
of patients to be treated. For instance, in oral liquids, pseudomonads are usually a
high - risk contamination. Examples presented by the FDA are Nystatin antifungal
suspension, used as prophylaxis in AIDS patients [57] ; antacids, with which P. aeruginosa contamination can promote gastric ulceration [58] ; and the presence of
Pseudomona putida , which could indicate the presence of other signifi cant contaminants such as P. aeruginosa [6] .
Deionizer Water - Monitoring Program Deionizing systems must be controlled in
order to produce purifi ed water, required for liquid dosage forms and USP tests and
assays [1] . The monitoring program has to include the manufacturer ’ s documentation about time between recharging and sanitizing, microbial quality and chlorine
levels of feed water, establishment of water microbial quality specifi cations, conductivity monitoring intervals, methods of microbial testing, action levels when microbial limits are exceeded, description of sanitization and sterilization procedures for
deionizer parts, and processing conditions such as temperature, fl ow rates, use
and sanitization frequency, and regenerant chemicals for ion exchange resin beds
[6, 59] .
Effectiveness of Preservative Manufacturing controls and shelf life must ensure
that the specifi ed preservative level is present and effective as part of the stability
program [6] . Depending on the type of product, the selection of the preservative
system is based on different considerations, such as site of use, interactions, spectrum, stability, toxicity, cost, taste, odor, solubility, pH, and comfort. The
USP and other organizations describe methods to validate the preservative
system used in the dosage form. Compounds used as preservatives are alcohols,
acids, esters, and quaternary ammonium compounds, among others. For instance, to
preserve ophthalmic liquid dosage forms, these products are autoclaved or fi ltrated
and require an antimicrobial preservative to resist contamination throughout
their shelf life, such as chlorobutanol, benzalkonium chloride, or phenylmercuric
nitrate [1] .
4.3.4.8 Filling and Packing
Constant Mixing during Filling Process Due to the tendency of suspensions to
segregate during transport through transfer lines, special attention is required on
suspension uniformity during the fi lling process. Appropriate constant mixing of the
bulk to keep homogeneity during the fi lling process and sampling of fi nished products and other critical points are indispensable conditions to assure an acceptable
quality level during the fi lling and packing process [20] .
Mixing Low Levels of Bulk Near End of Filling Process Constant mixing during
the fi lling process includes mixing low levels of bulk near the end of the fi lling
process. Large - size batches of bulk suspension require the transfer of the residual
material to a smaller tank in order to assure appropriate mixing of components
before fi lling and packing the containers [20] .
Potency Uniformity of Unit - Dose Products Products manufactured have to be of
quality at least as good as the established acceptable quality level (AQL). The quality
level should be based on the limits specifi ed by the USP. However, when the bulk
product is not properly mixed during fi lling and packing processes, liquid dosage
forms, and specially suspensions, are not homogeneous and unit - dose products
contain very different amounts of the active component and potency. For these
reasons, fi nished products have to be tested to assure that the fi nal volume and/or
weight as well as the amount of active ingredient are within the specifi ed limits [6] .
Calibration of Provided Measuring Devices Measuring devices consist of droppers, spoons for liquid dosage forms, and cups labeled with both tsp and mL. Measuring devices have to be properly calibrated in order to assure the right amount
of ingredients per volume to be administered [6] .
Container Cleanliness of Marketing Product The previous cleanliness of containers fi lled with the product will depend on their transportation exposure, composition, and storage conditions. Glass containers usually carry at least mold spores of
different microorganisms, especially if they are transported in cardboard boxes.
Other containers and closures made with aluminum, Tefl on, metal, or plastic usually
have smooth surfaces and are free from microbial contamination but may contain
fi bers or insects [45] . Some manufacturers receive containers individually wrapped
to reduce contamination risks and others use compressed air to clean them. However,
the cleanliness of wrapped containers will depend on the provider ’ s guarantee of
the manufacturing process and compressed - air equipment may release vapors or
oils that have to be tested and validated [6] 4.3.4.9 Stability
The typical stability problems are color change, loss of active component, and clarity
changes for solutions; inability to resuspend the particles and loss of signifi cant
amounts of the active component for suspensions; and creaming and breaking
(or coalescence) for emulsions [1] . These instabilities are usually related to the
following:
Active and Primary Degradant. A liquid dosage form is stable while it remains
within its product specifi cations. When chemical degradation products are
known, for stability study and expiration dating, the regulatory requirements
for the primary degradant of a active component are chemical structure, biological effect and signifi cance at the concentrations to be determined, mechanism of formation and order of reaction, physical and chemical properties,
limits and methods for quantitating the active component and its degradant
molecule at the levels expected to be present, and pharmacological action or
inaction [45] . Examples of drugs in liquid dosage forms that are easily degraded
are vitamins and phenothiazines [6] .
Interactions with Closure Systems. Elastomeric and plastic container and closure
systems release leachable compounds into the liquid dosage form, such as
nitrosamines, monomers, plasticizers, accelerators, antioxidants, and vulcanizing agents [44] . Each type of container and closure with different composition
and/or design proposed for marketing the drug or physician ’ s samples has to
be tested and stability data should be developed. Containers should be stored
upright, on their side, and inverted in order to determine if container – closure
interactions affect product stability [6, 45] .
Moisture Loss. When the containers are inappropriately closed, part of the
vaporized solvent is released and the concentration and potency of the active
component may be increased [6] .
Microbiological Contamination. Inappropriate closure systems also increase the
possibilities of microbial contamination when opening and closing containers
[6] .
4.3.4.10 Process Validation
Objective Process validation has the objectives of identifying and controlling
critical points that may vary product specifi cations through the manufacturing
process [6] .
Amount of Data To validate the manufacturing process, the manufacturer has to
design and specify in the protocol the use of data sheets to keep information about
the control of product specifi cations from each batch in - process as well as fi nished -
product tests. Some formats are common to different products, though each type of
product has some specifi c information to be kept on special sheets. Thus, the amount
of data varies from one type of product to another [6] .
Scale - Up Process Data obtained using special batches for the validation of the
scale - up process are compared with data from full - scale batches and batches used
for clinical essays [Product Specifi cations The most important specifi cations or established limits for
liquid dosage forms are microbial limits and test methods, medium pH, dissolution
of components, viscosity, as well as particle size uniformity of suspended components and emulsifi ed droplets. Effectiveness of the preservative system depends on
the dissolution of preservative components and may be affected by the medium pH
and viscosity. In addition, dissolved oxygen levels are important for components
sensitive to oxygen and/or light [6] .
Bioequivalence or Clinical Study In the patient, the general or systemic circulation is responsible for carrying molecules to different tissues of the body. To assure
the expected bioactivity of a product, the amount of drug that reaches the systemic
circulation per unit of time is analyzed and is known as bioavailability. Bioequivalence is the comparison of the bioavailability of a product with a reference product.
While oral solutions may not always need bioequivalence studies because they are
considered self - evidente, suspensions usually require bioequivalence or clinical
studies in order to demonstrate effectiveness. However, OTC suspension products
such as antacids are exempt from these studies [6] .
Control of Changes to Approved Protocol The manufacturing process of a specifi c
product is validated and approved internally by the quality control unit and externally by the FDA. Any change in the approved protocol has to be documented to
explain the purpose and demonstrate that the change will not unfavorably affect
product safety and effi cacy. Factors include potency and/or bioactivity as well as
product specifi cations. However, the therapeutic activity and uniformity of the
product are the main concerns after formulation and process changes [20] .
4.3.5 LIQUID DOSAGE FORMS *
Douche A liquid preparation, intended for the irrigative cleansing of the vagina,
that is prepared from powders, liquid solutions, or liquid concentrates and
contains one or more chemical substances dissolved in a suitable solvent or
mutually miscible solvents.
Elixir A clear, pleasantly fl avored, sweetened hydroalcoholic liquid containing
dissolved medicinal agents; it is intended for oral use.
Emulsion A dosage form consisting of a two - phase system comprised of at least
two immiscible liquids, one of which is dispersed as droplets (internal or dispersed phase) within the other liquid (external or continuous phase), generally
stabilized with one or more emulsifying agents. (Note: Emulsion is used as a
dosage form term unless a more specifi c term is applicable, e.g. cream, lotion,
ointment.).
Enema A rectal preparation for therapeutic, diagnostic, or nutritive purposes.
Extract A concentrated preparation of vegetable or animal drugs obtained by
removal of the active constituents of the respective drugs with a suitable menstrua, evaporation of all or nearly all of the solvent, and adjustment of the
residual masses or powders to the prescribed standards. For Solution A product, usually a solid, intended for solution prior to
administration.
For Suspension A product, usually a solid, intended for suspension prior to
administration.
For Suspension, Extended Release A product, usually a solid, intended for suspension prior to administration; once the suspension is administered, the drug
will be released at a constant rate over a specifi ed period.
Granule, Effervescent A small particle or grain containing a medicinal agent in
a dry mixture usually composed of sodium bicarbonate, citric acid, and tartaric
acid which, when in contact with water, has the capability to release gas, resulting in effervescence.
Inhalant A special class of inhalations consisting of a drug or combination of
drugs, that by virtue of their high vapor pressure can be carried by an air
current into the nasal passage where they exert their effect; the container from
which the inhalant generally is administered is known as an inhaler.
Injection A sterile preparation intended for parenteral use; fi ve distinct classes
of injections exist as defi ned by the USP.
Injection, Emulsion An emulsion consisting of a sterile, pyrogen - free preparation intended to be administered parenterally.
Injection, Solution A liquid preparation containing one or more drug substances
dissolved in a suitable solvent or mixture of mutually miscible solvents that is
suitable for injection.
Injection, Solution, Concentrate A sterile preparation for parenteral use which,
upon the addition of suitable solvents, yields a solution conforming in all
respects to the requirements for injections.
Injection, Suspension A liquid preparation, suitable for injection, which consists
of solid particles dispersed throughout a liquid phase in which the particles
are not soluble. It can also consist of an oil phase dispersed throughout an
aqueous phase, or vice - versa.
Injection, Suspension, Liposomal A liquid preparation, suitable for injection,
which consists of an oil phase dispersed throughout an aqueous phase in such
a manner that liposomes (a lipid bilayer vesicle usually composed of phospholipids which is used to encapsulate an active drug substance, either within a
lipid bilayer or in an aqueous space) are formed.
Injection, Suspension, Sonicated A liquid preparation, suitable for injection,
which consists of solid particles dispersed throughout a liquid phase in which
the particles are not soluble. In addition, the product is sonicated while a gas
is bubbled through the suspension and these result in the formation of microspheres by the solid particles.
Irrigant A sterile solution intended to bathe or fl ush open wounds or body
cavities; they ’ re used topically, never parenterally.
Linament A solution or mixture of various substances in oil, alcoholic solutions
of soap, or emulsions intended for external application.
Liquid A dosage form consisting of a pure chemical in its liquid state. This
dosage form term should not be applied to solutions. Liquid, Extended Release A liquid that delivers a drug in such a manner to allow
a reduction in dosing frequency as compared to that drug (or drugs) presented
as a conventional dosage form.
Lotion An emulsion, liquid dosage form. This dosage form is generally for
external application to the skin.
Lotion/Shampoo A lotion dosage form which has a soap or detergent that is
usually used to clean the hair and scalp; it is often used as a vehicle for dermatologic agents.
Mouthwash An aqueous solution which is most often used for its deodorant,
refreshing, or antiseptic effect.
Oil An unctuous, combustible substance which is liquid, or easily liquefi able, on
warming, and is soluble in ether but insoluble in water. Such substances,
depending on their origin, are classifi ed as animal, mineral, or vegetable oils.
Rinse A liquid used to cleanse by fl ushing.
Soap Any compound of one or more fatty acids, or their equivalents, with an
alkali; soap is detergent and is much employed in liniments, enemas, and in
making pills. It is also a mild aperient, antacid and antiseptic.
Solution A clear, homogeneous liquid dosage form that contains one or more
chemical substances dissolved in a solvent or mixture of mutually miscible
solvents.
Solution, Concentrate A liquid preparation (i.e., a substance that fl ows readily
in its natural state) that contains a drug dissolved in a suitable solvent or
mixture of mutually miscible solvents; the drug has been strengthened by the
evaporation of its nonactive parts.
Solution, for Slush A solution for the preparation of an iced saline slush, which
is administered by irrigation and used to induce regional hypothermia (in
conditions such as certain open heart and kidney surgical procedures) by its
direct application.
Solution, Gel Forming/Drops A solution, which after usually being administered in a drop - wise fashion, forms a gel.
Solution, Gel Forming, Extended Release A solution that forms a gel when it
comes in contact with ocular fl uid, and which allows at least a reduction in
dosing frequency.
Solution/Drops A solution which is usually administered in a drop - wise
fashion.
Spray A liquid minutely divided as by a jet of air or steam.
Spray, Metered A non - pressurized dosage form consisting of valves which allow
the dispensing of a specifi ed quantity of spray upon each activation.
Spray, Suspension A liquid preparation containing solid particles dispersed in
a liquid vehicle and in the form of coarse droplets or as fi nely divided solids
to be applied locally, most usually to the nasal - pharyngeal tract, or topically
to the skin.
Suspension A liquid dosage form that contains solid particles dispersed in a
liquid vehicle.
Suspension, Extended Release A liquid preparation consisting of solid particles
dispersed throughout a liquid phase in which the particles are not soluble; the
suspension has been formulated in a manner to allow at least a reduction in
dosing frequency as compared to that drug presented as a conventional dosage
form (e.g., as a solution or a prompt drug - releasing, conventional solid dosage
form).
Suspension/Drops A suspension which is usually administered in a dropwise
fashion.
Syrup An oral solution containing high concentrations of sucrose or other
sugars; the term has also been used to include any other liquid dosage form
prepared in a sweet and viscid vehicle, including oral suspensions.
Tincture An alcoholic or hydroalcoholic solution prepared from vegetable
materials or from chemical substances.
Notes :
1. A liquid is pourable; it fl ows and conforms to its container at room temperature. It displays Newtonian or pseudoplastic fl ow behavior.
2. Previously the defi nition of a lotion was “ The term lotion has been used to
categorize many topical suspensions, solutions, and emulsions intended for
application to the skin. ” The current defi nition of a lotion is restricted to an
emulsion.
3. A semisolid is not pourable; it does not fl ow or conform to its container at
room temperature. It does not fl ow at low shear stress and generally exhibits
plastic fl ow behavior.
4. A colloidal dispersion is a system in which particles of colloidal dimension
(i.e., typically between 1 nm and 1 μ m) are distributed uniformly throughout a
liquid.
Pharmacovigilence
DEFINITION : Pharmacovigilance – also known as drug safety - is a broad term that describes the collection, analysis, monitoring and prevention of adverse effects in drugs and therapies. It is a completely scientific and process-driven area within pharma.
The purpose of pharmacovigilance
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. Recently, its concerns have been widened to include:(4)
• herbals
• traditional and complementary medicines
• blood products
• biologicals
• medical devices
• vaccines.
Many other issues are also of relevance to the science:
• substandard medicines
• medication errors
• lack of efficacy reports
• use of medicines for indications that are not approved and for which there is inadequate scientific basis
• case reports of acute and chronic poisoning
• assessment of drug-related mortality
• abuse and misuse of medicines
• adverse interactions of medicines with chemicals, other medicines, and food.
The specific aims of pharmacovigilance are to:
• improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions,
• improve public health and safety in relation to the use of medicines,
• contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use, and
• promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.(5)
Pharmacovigilance has developed and will continue to develop in response to the special needs and according to the particular strengths of members of the WHO Programme and beyond. Such active influence needs to be encouraged and fostered; it is a source of vigour and originality that has contributed much to international practice and standards.
Terms commonly used in drug safety
Pharmacovigilance has its own unique terminology that is important to understand. Most of the following terms are used within this article and are peculiar to drug safety, although some are used by other disciplines within the pharmaceutical sciences as well.
Adverse drug reaction is a side effect (non intended reaction to the drug) occurring with a drug where a positive (direct) causal relationship between the event and the drug is thought, or has been proven, to exist.
Adverse event (AE) is a side effect occurring with a drug. By definition, the causal relationship between the AE and the drug is unknown.
Benefits are commonly expressed as the proven therapeutic good of a product but should also include the patient's subjective assessment of its effects.
Causal relationship is said to exist when a drug is thought to have caused or contributed to the occurrence of an adverse drug reaction.
Clinical trial (or study) refers to an organised program to determine the safety and/or efficacy of a drug (or drugs) in patients. The design of a clinical trial will depend on the drug and the phase of its development.
Control group is a group (or cohort) of individual patients that is used as a standard of comparison within a clinical trial. The control group may be taking a placebo (where no active drug is given) or where a different active drug is given as a comparator.
Dechallenge and rechallenge refer to a drug being stopped and restarted in a patient, respectively. A positive dechallenge has occurred, for example, when an adverse event abates or resolves completely following the drug's discontinuation. A positive rechallenge has occurred when the adverse event re-occurs after the drug is restarted. Dechallenge and rechallenge play an important role in determining whether a causal relationship between an event and a drug exists.
Effectiveness is the extent to which a drug works under real world circumstances, i.e., clinical practice.
Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical trials.
Event refers to an adverse event (AE).
Harm is the nature and extent of the actual damage that could be or has been caused.
Implied causality refers to spontaneously reported AE cases where the causality is always presumed to be positive unless the reporter states otherwise.
Individual Case Study Report (ICSR) is an adverse event report for an individual patient.
Life-threatening refers to an adverse event that places a patient at the immediate risk of death.
Phase refers to the four phases of clinical research and development: I – small safety trials early on in a drug's development; II – medium-sized trials for both safety and efficacy; III – large trials, which includes key (or so-called "pivotal") trials; IV – large, post-marketing trials, typically for safety reasons. There are also intermediate phases designated by an "a" or "b", e.g. Phase IIb.
Risk is the probability of harm being caused, usually expressed as a percent or ratio of the treated population.
Risk factor is an attribute of a patient that may predispose, or increase the risk, of that patient developing an event that may or may not be drug-related. For instance, obesity is considered a risk factor for a number of different diseases and, potentially, ADRs. Others would be high blood pressure, diabetes, possessing a specific mutated gene, for example, mutations in the BRCA1 and BRCA2 genes increase propensity to develop breast cancer.
Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a post-marketing trial to study the issue.
Temporal relationship is said to exist when an adverse event occurs when a patient is taking a given drug. Although a temporal relationship is absolutely necessary in order to establish a causal relationship between the drug and the AE, a temporal relationship does not necessarily in and of itself prove that the event was caused by the drug.
Triage refers to the process of placing a potential adverse event report into one of three categories: 1) non-serious case; 2) serious case; or 3) no case (minimum criteria for an AE case are not fulfilled).
What is an adverse event?
The definition of an adverse event is any reaction within a patient’s body caused by a drug/candidate molecule – a side effect. A serious adverse event is a life-threatening side effect that causes hospitalisation, incapacity, permanent damage or, in extreme cases, the death of a patient. Adverse event reporting is mandatory for all clinical research investigators, even if the side effects are only suspected.
The role of pharmacovigilance is to determine which adverse events cross the line of a drug’s efficacy. In other words, analysing which side effects are worth the risk to patients compared with how effective they are at treating a disease. For instance, chemotherapy is known to cause some very serious side effects but when faced with life-threatening cancer, these side effects are considered acceptable given the potential to cure a patient. However, if a drug used to cure a headache caused similar side effects, the risk to the patient would be considered too great and the benefit not substantial enough to justify the potential damage.
Adverse event reporting
The activity that is most commonly associated with pharmacovigilance (PV), and which consumes a significant amount of resources for drug regulatory authorities (or similar government agencies) and drug safety departments in pharmaceutical companies, is that of adverse event reporting. Adverse event (AE) reporting involves the receipt, triage, data entering, assessment, distribution, reporting (if appropriate), and archiving of AE data and documentation. The source of AE reports may include: spontaneous reports from healthcare professionals or patients (or other intermediaries); solicited reports from patient support programs; reports from clinical or post-marketing studies; reports from literature sources; reports from the media (including social media and websites); and reports reported to drug regulatory authorities themselves. For pharmaceutical companies, AE reporting is a regulatory requirement in most countries. AE reporting also provides data to these companies and drug regulatory authorities that play a key role in assessing the risk-benefit profile of a given drug. The following are several facets of AE reporting:
The "4 Elements" of an Individual Case Safety Report
One of the fundamental principles of adverse event reporting is the determination of what constitutes an Individual Case Safety Report (ICSR). During the triage phase of a potential adverse event report, it is important to determine if the "four elements" of a valid ICSR are present: (1) an identifiable patient, (2) an identifiable reporter, (3) a suspect drug, and (4) an adverse event.
If one or more of these four elements is missing, the case is not a valid ICSR. Although there are no exceptions to this rule there may be circumstances that may require a judgment call. For example, the term "identifiable" may not always be clear-cut. If a physician reports that he/she has a patient X taking drug Y who experienced Z (an AE), but refuses to provide any specifics about patient X, the report is still a valid case even though the patient is not specifically identified. This is because the reporter has first-hand information about the patient and is identifiable (i.e. a real person) to the physician. Identifiability is important so as not only to prevent duplicate reporting of the same case, but also to permit follow-up for additional information.
The concept of identifiability also applies to the other three elements. Although uncommon, it is not unheard of for fictitious adverse event "cases" to be reported to a company by an anonymous individual (or on behalf of an anonymous patient, disgruntled employee, or former employee) trying to damage the company's reputation or a company's product. In these and all other situations, the source of the report should be ascertained (if possible). But anonymous reporting is also important, as whistle blower protection is not granted in all countries. In general, the drug must also be specifically named. Note that in different countries and regions of the world, drugs are sold under various tradenames. In addition, there are a large number of generics which may be mistaken for the trade product. Finally, there is the problem of counterfeit drugs producing adverse events. If at all possible, it is best to try to obtain the sample which induced the adverse event, and send it to either the EMA, FDA or other government agency responsible for investigating AE reports.
If a reporter can't recall the name of the drug they were taking when they experienced an adverse event, this would not be a valid case. This concept also applies to adverse events. If a patient states that they experienced "symptoms", but cannot be more specific, such a report might technically be considered valid, but will be of very limited value to the pharmacovigilance department of the company or to drug regulatory authorities.
Coding of adverse events
Adverse event coding is the process by which information from an AE reporter, called the "verbatim", is coded using standardized terminology from a medical coding dictionary, such as MedDRA (the most commonly used medical coding dictionary). The purpose of medical coding is to convert adverse event information into terminology that can be readily identified and analyzed. For instance, Patient 1 may report that they had experienced "a very bad headache that felt like their head was being hit by a hammer" [Verbatim 1] when taking Drug X. Or, Patient 2 may report that they had experienced a "slight, throbbing headache that occurred daily at about two in the afternoon" [Verbatim 2] while taking Drug Y. Neither Verbatim 1 nor Verbatim 2 will exactly match a code in the MedDRA coding dictionary. However, both quotes describe different manifestations of a headache. As a result, in this example both quotes would be coded as PT Headache (PT = Preferred Term in MedDRA).
Seriousness determination
An adverse event is considered serious if it meets one or more of the following criteria:
1. results in death, or is life-threatening;
2. requires inpatient hospitalization or prolongation of existing hospitalization;
3. results in persistent or significant disability or incapacity;
4. results in a congenital anomaly (birth defect); or
5. is otherwise "medically significant" —i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.
Aside from death, each of these categories is subject to some interpretation. Life-threatening, as it used in the drug safety world, specifically refers to an adverse event that places the patient at an immediate risk of death, such as cardiac or respiratory arrest. By this definition, events such as myocardial infarction, which would be hypothetically life-threatening, would not be considered life-threatening unless the patient went into cardiac arrest following the MI. Defining what constitutes hospitalization can be problematic as well. Although typically straightforward, it's possible for a hospitalization to occur even if the events being treated are not serious. By the same token, serious events may be treated without hospitalization, such as the treatment of anaphylaxis may be successfully performed with epinephrine. Significant disability and incapacity, as a concept, is also subject to debate. While permanent disability following a stroke would no doubt be serious, would "complete blindness for 30 seconds" be considered "significant disability"? For birth defects, the seriousness of the event is usually not in dispute so much as the attribution of the event to the drug. Finally, "medically significant events" is a category that includes events that may be always serious, or sometimes serious, but will not fulfill any of the other criteria. Events such as cancer might always be considered serious, whereas liver disease, depending on its CTCAE (Common Terminology Criteria for Adverse Events) grade—Grades 1 or 2 are generally considered non-serious and Grades 3-5 serious—may be considered non-serious.
Expedited reporting
This refers to ICSRs (individual case safety reports) that involve a serious and unlisted event (an event not described in the drug's labeling) that is considered related to the use of the drug. (Spontaneous reports are typically considered to have a positive causality, whereas a clinical trial case will typically be assessed for causality by the clinical trial investigator and/or the license holder.) In most countries, the timeframe for reporting expedited cases is 7/15 calendar days from the time a drug company receives notification (referred to as "Day 0") of such a case. Within clinical trials such a case is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction). If the SUSAR involves an event that is life-threatening or fatal, it may be subject to a 7-day "clock". Cases that do not involve a serious, unlisted event may be subject to non-expedited or periodic reporting.
Clinical trial reporting
Also known as SAE (serious adverse event) reporting from clinical trials, safety information from clinical studies is used to establish a drug's safety profile in humans and is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny market authorization (market approval) for a drug. SAE reporting occurs as a result of study patients (subjects) who experience serious adverse events during the conducting of clinical trials. (Non-serious adverse events are also captured separately.) SAE information, which may also include relevant information from the patient's medical background, are reviewed and assessed for causality by the study investigator. This information is forwarded to a sponsoring entity (typically a pharmaceutical company) that is responsible for the reporting of this information, as appropriate, to drug regulatory authorities.
Spontaneous reporting
Spontaneous reports are termed spontaneous as they take place during the clinician's normal diagnostic appraisal of a patient, when the clinician is drawing the conclusion that the drug may be implicated in the causality of the event. Spontaneous reporting system relies on vigilant physicians and other healthcare professionals who not only generate a suspicion of an ADR, but also report it. It is an important source of regulatory actions such as taking a drug off the market or a label change due to safety problems. Spontaneous reporting is the core data-generating system of international pharmacovigilance, relying on healthcare professionals (and in some countries consumers) to identify and report any adverse events to their national pharmacovigilance center, health authority (such as EMA or FDA), or to the drug manufacturer itself.Spontaneous reports are, by definition, submitted voluntarily although under certain circumstances these reports may be encouraged, or "stimulated", by media reports or articles published in medical or scientific publications, or by product lawsuits. In many parts of the world adverse event reports are submitted electronically using a defined message standard.
One of the major weaknesses of spontaneous reporting is that of under-reporting, where, unlike in clinical trials, less than 100% of those adverse events occurring are reported. Further complicating the assessment of adverse events, AE reporting behavior varies greatly between countries and in relation to the seriousness of the events, but in general probably less than 10% (some studies suggest less than 5%) of all adverse events that occur are actually reported. The rule-of-thumb is that on a scale of 0 to 10, with 0 being least likely to be reported and 10 being the most likely to be reported, an uncomplicated non-serious event such as a mild headache will be closer to a "0" on this scale, whereas a life-threatening or fatal event will be closer to a "10" in terms of its likelihood of being reported. In view of this, medical personnel may not always see AE reporting as a priority, especially if the symptoms are not serious. And even if the symptoms are serious, the symptoms may not be recognized as a possible side effect of a particular drug or combination thereof. In addition, medical personnel may not feel compelled to report events that are viewed as expected. This is why reports from patients themselves are of high value. The confirmation of these events by a healthcare professional is typically considered to increase the value of these reports. Hence it is important not only for the patient to report the AE to his health care provider (who may neglect to report the AE), but also report the AE to both the biopharmaceutical company and the FDA, EMA, ... This is especially important when one has obtained one's pharmaceutical from a compounding pharmacy.
Aggregate reporting
Aggregate reporting, also known as periodic reporting, plays a key role in the safety assessment of drugs. Aggregate reporting involves the compilation of safety data for a drug over a prolonged period of time (months or years), as opposed to single-case reporting which, by definition, involves only individual AE reports. The advantage of aggregate reporting is that it provides a broader view of the safety profile of a drug. Worldwide, the most important aggregate report is the Periodic Safety Update Report (PSUR) and Development safety updated report (DSUR). This is a document that is submitted to drug regulatory agencies in Europe, the US and Japan (ICH countries), as well as other countries around the world. The PSUR was updated in 2012 and is now referred to in many countries as the Periodic Benefit Risk Evaluation report (PBRER). the PBRER's focus is on the benefit-risk profile of the drug, which includes a review of relevant safety data compiled for a drug product since its development.
What are the main areas of pharmacovigilance?
Pharmacovigilance is a huge and encompassing discipline, but we can broadly divide pharmacovigilance into four main sub-specialisms:
Operations:
This sector is where many life science professionals interested in drug safety jobs will begin their career. Typical jobs within drug safety operations include case processor, drug safety officer/associate and drug safety manager, and of course team lead and directorships. These professionals will collect and record information during preclinical development and clinical trials, in addition to gathering real world evidence (RWE) of adverse events reported by doctors and patients post-market. Operations are also usually responsible for creating standard operating procedures (SOPs), individual case study reports, literature screening and regulatory expedited reporting.
Surveillance:
Professionals who focus more within surveillance tend to look towards risk management and signal detection jobs. This also involves performing analysis of the data collated by the wider division. Professionals in this area can hold an array of titles, the most common of which are pharmacovigilance scientist and drug safety physician, but like in all teams, there are many degrees of seniority and remit available. These professionals perform analysis on the drug safety information gathered by the wider department and assist with the creation and review of aggregate reports. They also create development safety update reports (DSURs) for drugs in clinical research, and periodic benefit risk evaluation reports (PBRER) for post-market drugs. These reports ultimately help the team to draw conclusions around the safety and efficacy of a drug or candidate molecule.
Systems:
This division is concerned with the building and ongoing development of a fully robust and innovative system, charged with the responsibility for housing and allowing access (in various forms) to vast quantities of safety data. This safety data is usually collated by those working in operationally focused roles, but is accessed by all. The systems division is constantly having to improve, and stay in line with, changing regulations and requirements for the business/ health authorities, making this a very challenging and vital aspect of drug safety.
Qualified Person for Pharmacovigilance (QPPV)
QPPVs jobs are mainly concerned with marketed drugs and those about to be authorised, but as QPPVs are considered by many to be subject matter experts, their expertise is utilised across the discipline and wider business. These senior pharmacovigilance roles will only be held by very experienced professionals and their focus is to understand, plan for and advise upon the regulations and requirements that companies must adhere to across the EU. This is a highly strategic appointment and one of great importance.
Fortunately for drug safety professionals, there are several pharmacovigilance jobs available to them due to the different types of companies within life sciences, including global pharmas, small pharmas, generics companies, drug safety consultancies and health authorities.
Why is pharmacovigilance important?
Pharmacovigilance is arguably the most essential function within a life science company. To develop, manufacture and commercialise a drug a company must adhere to strict regulations. Many of these regulations will focus on the patient’s safety and the added benefit to the patient derived from the drug. This, in a nutshell, is the mission of drug safety and highlights why this discipline plays such a central and important role within pharmaceuticals.
Patient safety and continuous vigilance
By definition, drug safety ensures that a patient’s safety and wellbeing is safeguarded throughout the entire drug development lifecycle, including when the drug is readily available on the market. Indeed, drugs are continuously monitored for other side effects on patients, and any new data is collected and reported to health authorities on a regular basis. While other areas focus on improving patient lives in everything that they do, no other department has such a sharp focus on patient safety as an end-point.
Power and authority
This continuous vigilance does mean that, alongside others in the business, senior leaders within a drug safety team have the responsibility and authority to recommend that a development process is stopped, or that an approved drug is pulled from the market. EU QPPVs are especially important in this process, and again this goes to demonstrate the importance and central role of drug safety.
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