Validation (intro, scope, merits, ich, who guidelines)

Presented By:
Ms. Prajakta Sawant
First Year M.Pharm (Roll No. 5)
(Dept. of Pharmaceutics)
Sub: Modern Pharmaceutics
Alard College Of Pharmacy,
Pune.
Under the Guidance of:
Dr. Nalanda Borkar
Head of Department
(Dept. of Pharmaceutics)
Sub: Modern Pharmaceutics
Alard College Of Pharmacy,
Pune.
Monday, March 08, 2021 1

 Introduction
 Need of Validation
 Planning for Validation
 Documentation of Validation
 Validation Master Plan
 Scope of Validation
 V Model for Validation
 Merits of Validation
 Types of Validation
⇨ Process Validation
⇨ Cleaning Validation
⇨ Equipment Validation
⇨Validation of Analytical method
 Conclusion for Validation
 ICH Guidelines
 WHO Guidelines
 References

 The concept of validation was first proposed by Food and Drug
Administration (FDA) officials, Ted Byers and Bud Loftus, in
the mid 1970s in order to improve the quality of
pharmaceuticals.
 Validation is "Establishing documented evidence that provides
a high degree of assurance that a specific process will
consistently produce a product meeting its pre-determined
specifications and quality attributes."
 This is to maintain and assure a higher degree of quality of
food and drug products.

 Customer satisfaction
 Customer mandated
 Product liability
 Control production cost
 The development of the next generation
 Safety

 Validation activities can be organized by preparing the
validation master plan (VMP). It should be brief, concise and
clear.
 The EEC guide recommends the following contents in a VMP.
 Validation Policy Organizational structure of validation
activities.
 Summary of facilities, systems, equipment and processes to be
validated.
 Documentation format Planning and scheduling Change
control reference to exiting documents.

The validation activity cannot be completed without proper
documentation of each and every minute activity with utmost
details. Documentation of validation is generally of different
types such as:
 Validation Master Plan(VMP)
 Validation Protocol(VP)
 Validation Reports(VR)
 Standard Operating Procedure(SOP)

 A Validation Master Plan is a document that summarizes the firm’s
overall philosophy, intention and approaches to be used for
establishing performance adequacy.
 A tool to track progress.
 Assignment of responsibility and team work.
 It identifies acceptance criteria before the start of validation.
 V.M.P gives idea about future performance:
What activities are to be performed?
Who is going to perform these activities?
When the activities should start and when they should get over?
What documents will be generated?
What the policy on revalidation?

 V.M.P. includes:
Premises
Processes
Products
Format for protocol and other documentation
List of relevant SOPs
Planning and scheduling
Location
Estimation of staffing requirements
A time plan of the project

 Guidelines on Preparing V.M.P.
V.M.P. write on A4 size paper.
File in a presentable form.
Have sufficient explanatory drawings.
Clearly divide the V.M.P. in different form.
It must be dated and signed properly by authorized persons.
If found any step inappropriate, discuss this with the F.D.A.
people in advance.
 Relationship between validation and qualification:
Qualification and validation are essentially the same. The term
qualification is normally used for equipment and utilities, and
validation is for systems and processes. In this sense,
qualification can be seen as a part of validation.

 Selection of raw material i.e. raw materials of desired quality attributes.
 Product design based on the expected performance.
 Process design to build the desired quality attributes in the product.
 Design of control parameters, such as change control, acceptance criteria,
tolerance limits, etc.
 In process quality control parameters and sampling plans
 Finished product testing or evaluation criteria.
 Validation of related analytical process.
 Validation of related system, facility and equipment.
 Personnel training.
 Validation involves careful determination of criteria variable of the
process, such as moisture content of granules, drying temperature of time,
etc. and then establishment of acceptable range and tolerance limit for the
same. A careful and continuous control of these variables will ensure
consistent product quality.

URS, FAT and SAT:
 User Requirement Specifications- Manufacturers should prepare a
document that describes, for example, the utility or equipment to
be sourced. The requirements and specifications for the utility or
equipment should be defined by the user and should be
documented in the URS.
 Factory Acceptance Test and Site Acceptance Test- Where
appropriate, FAT and SAT should be performed to verify the
suitability of the system at site, prior to the subsequent stages of
qualification. This should be appropriately documented.

 Assurance of quality compliance.
 Optimization of resources and manufacture product at lowest
possible cost.
 Fewer failures, fewer rejects, fewer retests, fewer reworks,
fewer wastage.
 It is a practice that must be followed for manufacturing,
distribution, selling or license.
 Efficient production operation.

The major types of Validation :
Process validation
Cleaning validation
Equipment validation
Validation of analytical methods

As per FDA, the Process Validation is defined as :
"The collection of data from the process design
stage throughout production, which establishes
scientific evidence that a process is capable of
consistently delivering quality products. "

 Process validation life cycle/flow chart:
Stage 1 - Process design
Stage 2 - Process qualification
Stage 3 - Continued process verification

 Types of Process validation:
Prospective validation.
Retrospective validation.
Concurrent validation.
Revalidation.

1. Prospective validation
Establishing documented evidences during
development stage of process based on a
predefined protocol.
It is done prior to distribution of a new product or
whenever there is a major change in the product
characteristics.
It is compulsory for sterile products.
The activity continues till the first 3 batches are
manufactured at full scale.

 Steps in prospective validation:
1. Formation of validation team
2. Preparation of validation master plan and validation protocol
3. Formulation development (preformulation studies and optimization)
4. Process development (process design, control & challenges in critical
parameters etc.)
5. Facility development (building, support systems, staff)
6. Process qualification (checked for worst case conditions o ensure
reproducibility)
7. Product qualification
8. Change control

2. Concurrent Process validation
 Carried out during normal production.
 It is useful only if process is well understood during development stage.
 The nature and specifications of subsequent in- process and final tests are
based on the evaluation of the results of such monitoring.
3. Retrospective process validation (based on analysis of historical data)
 Carried out on the basis of database generated during previous production
of the product.
 Recorded difficulties, variation and failures in production are analysed to
determine the limits of process parameters.
 Thus, it is useful in establishing priorities for validation.

4. Revalidation
It is needed to ensure that the changes in process or
in process environment do not adversely affect the
process characteristic and product quality.
Revalidation is required when:-
a) There is a major change in facility, equipment,
process, etc.
b) Periodic revalidation is scheduled at regular
interval to control and identify a gradual change in
the process.

 Definition: “A process of attaining and documenting sufficient
evidence to give reasonable assurance, given the current state of
Science and Technology, that the cleaning process under
consideration does, and / or will do, what it purpose is to do.”
 Objective:
To minimize cross contamination.
To determine efficiency of cleaning process.
To do troubleshooting in case if problem is identified in the cleaning
process and give suggestions to improve the process.

 Source of contamination:
Cross contamination of one product into another.
Product contamination by a foreign material.
Microbial contamination.
 Cleaning methods:
Manual cleaning method.
Semi automated procedures.
Fully automated procedures.

 Factors Influencing Cleaning validation :
Product.
Equipment.
Facilities.
Cleaning methods.
Cleaning agents.
Sampling.
Testing, Limits, and acceptance criteria.

 Cleaning validation flow chart:

 Definition : As per FDA, "Action of proving that any equipment
works correctly and leads to the expected result is equipment
validation. It is not a single step activity but instead result from
many discrete activities. "
 Steps involved:
User requirement specification
Design qualification
Installation qualifications
Operational qualifications
Performance qualification

 Equipment Validation Flow Chart:

 Definition : “The process by, which it is established, by laboratory
studies, that the performance characteristics of the method meet
the requirements for the intended analytical application”.
 Accuracy : The closeness of test results obtained by that method to
the true value. This accuracy should be established across its range.
 Precision: The degree of agreement among individual test results
when the method is applied repeatedly to multiple sampling of a
homogenous sample.

 Specificity : The ability to assess unequivocally the analyte in the
presence of components that may be expected to be present, such
as impurities, degradation products and matrix components.
 Limit of Quantitation : A characteristic of quantitative assays for
low levels of compounds in sample matrices such as impurities in
bulk substances and degradation products in finished
pharmaceuticals. It is the lowest amount of analyte in a sample
that can be determined with acceptable precision and accuracy
under the stated experimental conditions.

 Range : Interval between the upper and lower of analyte
(including these levels) that have been demonstrated to be
determined with a suitable level of precision , accuracy and
linearity using the method as written. The range is normally
expressed in the same units as test results obtained by the
analytical method ( e.g. Percentage , parts per million, etc.).
 Ruggedness: The degree of reproducibility of test results
obtained by the analysis of the same sample under a variety of
conditions such as different laboratories, different analysts,
different instruments, different lots of reagents, different elapsed
assay times, different assay temperatures, different days, etc.

 Robustness: A measure of its capacity to remain unaffected by small
but deliberate variations in method parameters and provides an
indication of its reliability during normal usage.
 Linearity : Its ability to elicit tests that are directly or by a well defined
mathematical transformations proportional to the concentration of
analyte in samples within a given range.
 Limit of Detection : The lowest amount of analyte in a sample that can
be detected but not necessarily quantitated, under the stated
experimental conditions.

 Validation has been proven assurance for the process efficiency
and sturdiness and it is the full fledged quality attributing tool
for the pharmaceutical industries.
 Validation is the commonest word in the areas of drug
development, manufacturing and specification of finished
products. It also renders reduction in the cost linked with
process monitoring, sampling and testing.
 Apart from all the consistency and reliability of a validated
process to produce a quality product, it is very important for an
industry.

The International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human
Use (ICH) is a unique project that brings together the
regulatory authorities of Europe, Japan and the United States
and experts from the pharmaceutical industry in the three
regions to discuss scientific and technical aspects of product
registration.

AIM :
 The International Conference on Harmonization of Technical
Requirements for the Registration of Pharmaceuticals for Human
Use (ICH) was established in 1990 as a joint regulatory/industry
project to improve, through harmonization, the efficiency of the
process for developing and registering new medicinal products in
Europe, Japan and the United States, in order to make these
products available to patients with a minimum of delay.
 The six parties to ICH represent the regulatory and research-
based industry in the three regions, Europe, Japan and the USA,
where the vast majority of new medicines are currently
developed.

 European Commission - European Union (EU).
 European Federation of Pharmaceutical Industries and
Associations (EFPIA).
 Ministry of Health, Labour and Welfare, Japan (MHLW).
 Japan Pharmaceutical Manufacturers Association (JPMA).
 US Food and Drug Administration (FDA).
 Pharmaceutical Research and Manufacturers of America
(PhRMA).

More economical use of human, animal, and
material resources.
Elimination of unnecessary delay in the global
development & availability of new medicines.
Maintaining safeguards on Quality, safety, efficacy
and regulatory obligations to protect public health.

 Four Broad Categories - QSEM
1) Quality (Q): those relating to chemical and pharmaceutical
Quality Assurance (Stability Testing, Impurity Testing,
etc.)
2) Safety (S): those relating to in vitro and in vivo pre-clinical
studies (Carcinogenicity Testing, Genotoxicity Testing,
etc.)
3) Efficacy (E): those relating to clinical studies in human
subject (Dose Response Studies, Good Clinical Practices,
etc.)
4) Multidisciplinary (M): cross-cutting Topics which do not
fit uniquely into one of the above categories (MedDRA,
ESTRI, M3, CTD, M5)

 QUALITY:
Q1A(R2): STABILITY TESTING OF NEW DRUGS AND PRODUCTS
Q1B: PHOTOSTABILITY TESTING
Q1C : STABILITY TESTING OF NEW DOSAGE FORMS
Q1D: BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING
OF DRUG SUBSTANCES AND DRUG PRODUCTS.
Q1E: EVALUATION OF STABILITY DATA
Q1F: STABILITY DATA PACKAGE FOR REGISTRATION IN CLIMATIC ZONES
III AND IV
Q2A: DEFINTIONS AND TERMINOLOGY: ANALYTICAL VALIDATION
Q2B: METHODOLOGY
Q3A(R2) : IMPURITIES IN NEW DRUG SUBSTANCES Q3B(R2) : IMPURITIES
IN NEW DRUG PRODUCT
Q3C(R3) : IMPURITIES GUIDELINES FOR RESIDUAL SOLVENTS

Q4: PHARMACOPOEIA
Q4A: PHARMACOPOEIAL HARMONIZATION
Q5A: VIRAL SAFETY EVALUATION
Q5B: GENETIC STABILITY
Q5C: STABILITY OF BIOTECHNOLOGY PRODUCTS
Q5D: CELL SUBSTRATES 12
Q6A: SPECIFICATIONS, TEST PROCEDURES AND ACCEPTANCE
CRITERIA FOR NEW DRUG SUBSTANCES AND PRODUCTS
Q6B : SPECIFICATION TEST PROCEDURE AND ACCEPTANCE
CRITRIA FOR BIOTECHNOLOGICAL/ BIOLOGICAL PRODUCTS
Q7A: GMP FOR ACTIVE PHARMACEUTICAL INGREDIENTS
Q8: PHARMACEUTICAL DEVELOPMENT
Q9: QUALITY RISK MANAGEMENT
Q10: PHARMACEUTICAL QUALITY SYSTEM

 SAFETY :
S1A: GUIDELINE ON THE NEED FOR CARCINOGENICITY
STUDIES OF PHARMACEUTICALS
S1B: TESTING FOR CARCINOGENICITY OF
PHARMACEUTICALS
S1C(R2): DOSE SELECTION FOR CARCINOGENICITY STUDIES
OF PHARMACEUTICALS
S2(R1): GUIDANCE ON GENOTOXICITY TESTING AND DATA
INTERPRETATION FOR PHARMACEUTICALS INTENDED FOR
HUMAN USE
S3A: NOTE FOR GUIDANCE ON TOXICOKINETICS: THE
ASSESSMENT OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES
S3B: PHARMACOKINETICS:GUIDANCE FOR REPEATED DOSE
TISSUE DISTRIBUTION STUDIES
S4: DURATION OF CHRONIC TOXICITY TESTING IN ANIMALS
(RODENT AND NON RODENT TOXICITY TESTING)

S5(R2): DETECTION OF TOXICITY TO REPRODUCTION FOR
MEDICINAL PRODUCTS & TOXICITY TO MALE FERTILITY
S6(R1): ADDENDUM TO ICH S6: PRECLINICAL SAFETY
EVALUATION OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALS
S6: PRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY-
DERIVED PHARMACEUTICALS
S7A: SAFETY PHARMACOLOGY STUDIES FOR HUMAN
PHARMACEUTICALS
S7B: THE NON-CLINICAL EVALUATION OF THE POTENTIAL FOR
DELAYED VENTRICULAR REPOLARIZATION (QT INTERVAL
PROLONGATION) BY HUMAN PHARMACEUTICALS
S8: IMMUNOTOXICITY STUDIES FOR HUMAN PHARMACEUTICALS
S9: NONCLINICAL EVALUATION FOR ANTICANCER
PHARMACEUTICALS

 3) EFFICACY:
E1: THE EXTENT OF POPULATION EXPOSURE TO ASSESS CLINICAL
SAFETY
E2A: CLINICAL SAFETY DATA MANAGEMENT
E2B(R2): MAINTENANCE OF THE ICH GUIDELINE ON CLINICAL
SAFETY DATA MANAGEMENT
E2B(R3): REVISION OF THE ICH GUIDELINE ON CLINICAL SAFETY
DATA MANAGEMENT
DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE
SAFETY REPORTS
E2C(R1): CLINICAL SAFETY DATA MANAGEMENT: PERIODIC
SAFETY UPDATE REPORTS FOR MARKETED DRUGS
E2D: POST-APPROVAL SAFETY DATA MANAGEMENT: DEFINITIONS
AND STANDARDS FOR EXPEDITED REPORTING

E2E: PHARMACOVIGILANCE PLANNING
E2F: DEVELOPMENT SAFETY UPDATE REPORT
E3: STRUCTURE AND CONTENT OF CLINICAL STUDY
REPORTS
E4: DOSE-RESPONSE INFORMATION TO SUPPORT DRUG
REGISTRATION
E5(R1): ETHNIC FACTORS IN THE ACCEPTABILITY OF
FOREIGN CLINICAL DATA
E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE
E7: STUDIES IN SUPPORT OF SPECIAL
POPULATIONS:GERIATRICS 19
E8: GENERAL CONSIDERATIONS FOR CLINICAL TRIALS

 MULTIDISCIPLINARY GUIDELINES:
M1- MedDRA : Medical Terminology
M2- ESTRI: Electronic Standards for the Transfer of
Regulatory Information
M3- (R2): Nonclinical Safety Studies for the Conduct of
Human Clinical Trials and Marketing Authorization for
Pharmaceuticals
M4- CTD: The Common Technical Document
M5 : Data Elements and Standards for Drug Dictionaries

 These guidelines focus mainly on the overall concept of validation
and are not intended to be prescriptive in specific validation
requirements.
 This document serves as general guidance only and the principles
may be considered useful in its application in the manufacture and
control of starting materials and finished pharmaceutical products
(FPPs), as well as other areas.
 Validation of specific processes and systems, for example, in sterile
product manufacture, requires much more consideration and a
detailed approach that is beyond the scope of this document.

The definitions given below apply to the terms used in these guidelines. They may
have different meanings in other contexts.
 Calibration
The set of operations that establish, under specified conditions, the relationship
between values indicated by an instrument or system for measuring (for example,
weight, temperature and pH), recording, and controlling, or the values represented
by a material measure, and the corresponding known values of a reference
standard. Limits for acceptance of the results of measuring should be established.
 Computer
Validation Documented evidence which provides a high degree of assurance that a
computerized system analyses, controls and records data correctly and that data
processing complies with predetermined specifications.
 Commissioning
The setting up, adjustment and testing of equipment or a system to ensure that it
meets all the requirements, as specified in the user requirement specification, and
capacities as specified by the designer or developer. Commissioning is carried out
before qualification and validation.

 Concurrent Validation
 Cleaning Validation
 Design Qualification (DQ)
 Installation Qualification (IQ)
 Operational Qualification (OQ)
 Performance Qualification (PQ)
 Process Validation
 Prospective Validation
 Retrospective Validation
 Revalidation
 Validation
 Validation Master Plan (VMP)

 Good Engineering Practices (GEP) :Established engineering methods and
standards that are applied throughout the project life-cycle to deliver
appropriate, cost-effective solutions.
 Qualification: Action of proving and documenting that any premises,
systems and equipment are properly installed, and/or work correctly and lead
to the expected results. Qualification is often a part (the initial stage) of
validation, but the individual qualification steps alone do not constitute
process validation.
 Standard operating procedure (SOP): An authorized written procedure
giving instructions for performing operations not necessarily specific to a
given product or material but of a more general nature (e.g. equipment
operation, maintenance and cleaning; validation; cleaning of premises and
environmental control; sampling and inspection). Certain SOPs may be used
to supplement product-specific master batch production documentation.

 Validation Protocol (or plan) (VP): A document describing the
activities to be performed in a validation, including the acceptance
criteria for the approval of a manufacturing process or a part thereof for
routine use.
 Validation Report (VR): A document in which the records, results and
evaluation of a completed validation programme are assembled and
summarized. It may also contain proposals for the improvement of
processes and/or equipment.
 Verification: The application of methods, procedures, tests and other
evaluations, in addition to monitoring, to determine compliance with
the GMP principles.
 Worst Case: A condition or set of conditions encompassing the upper
and lower processing limits for operating parameters and
circumstances, within SOPs, which pose the greatest chance of product
or process failure when compared to ideal conditions. Such conditions
do not necessarily include product or process failure.

 Periodic revalidation:
• Periodic revalidation should be performed to assess process changes that may
occur gradually over a period of time, or because of wear of equipment.
• The following should be considered when periodic revalidation is performed:
master formulae and specifications; SOPs; records (e.g. of calibration,
maintenance and cleaning); and analytical methods.
 Revalidation after change:
• Revalidation should be performed following a change that could have an
effect on the process, procedure, quality of the product and/or the product
characteristics.
• Revalidation should be considered as part of the change control procedure.
• The extent of revalidation will depend on the nature and significance of the
change(s).
• Changes should not adversely affect product quality or process
characteristics.
• Changes requiring revalidation should be defined in the validation plan.

 CHANGE CONTROL:
• Changes should be controlled in accordance with a SOP as changes may
have an impact on a qualified utility, system or piece of equipment, and a
validated process and/or procedure.
• The procedure should describe the actions to be taken, including the need
for and extent of qualification or validation to be done.
• Changes should be formally requested, documented and approved before
implementation. Records should be maintained.
 PERSONNEL:
• Personnel should demonstrate that they are appropriately qualified,
where relevant.
• Personnel requiring qualification include, for example:
— laboratory analysts;
— personnel following critical procedures;
— personnel doing data entry in computerized systems; and
— risk assessors.

 https://www.slideshare.net/ManikantPrasadShah/validation-scope-
of-validation-urs-who-guidelines-for-validation Assessed Date:
08/03/2021
 https://www.slideshare.net/shettyuc/new-who-guidance-on-process-
validation Assessed Date: 08/03/2021
 https://www.slideshare.net/Anshul2593/ich-guidelines-72292250
 https://www.slideshare.net/rks19761/pharmaceutical-process-
validation?next_slideshow=1 Assessed Date: 08/03/2021
 https://www.slideshare.net/dalvirahul16/pharmaceutical-validation-
ppt Assessed Date: 08/03/2021
 https://www.slideshare.net/sagarsavale1/cleaning-validation-
62056468 Assessed Date: 08/03/2021
 https://www.who.int/medicines/areas/quality_safety/quality_assuran
ce/SupplementaryGMPValidationTRS937Annex4.pdf?ua=1
Assessed Date: 08/03/2021
 https://www.slideshare.net/ssuserfe3019/ich-who-guidelines-on-
validation Assessed Date: 08/03/2021

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