Le document traite de la validation pharmaceutique, définissant son importance pour garantir la qualité des produits tout au long du processus de production, et souligne l'historique de ce concept en réponse à des défaillances dans la stérilité des produits. Il aborde également les autorités responsables, les différents types de validation (y compris l'analyse, le nettoyage et l'équipement) et la nécessité d'un Plan Maître de Validation pour organiser ces processus. Finalement, il mentionne les directives de l'ICH et de l'OMS sur l'étalonnage des équipements nécessaires pour assurer la qualité des produits pharmaceutiques.

1. GOKAKRAJU RANGARAJU COLLEGE OF PHARMACY
Affiliated to OSMANIA UNIVERSITY
HYDERABAD
UNDER THE GUIDANCE OF –
Dr. G. SAILAJA, M. Pharm., Ph.D.
ASSOSCIATE PROFESSOR
Dept. of Pharmaceutics
1
PRESENTED BY –
KAUNAIN FATHEMA
M. Pharm, Sem – 1
Dept. of Pharmaceutics

2. CONTENT
1. WHAT IS PHARMACEUTICAL VALIDATION?
2. IMPORTANCE OF VALIDATION
3. SCOPE OF VALIDATION
4. HISTORY OF VALIDATION
5. VALIDATION AUTHORITIES
6. TYPES OF VALIDATION
7. VALIDATION MASTER PLAN (VMP)
8. ICH & WHO GUIDELINES FOR EQUIPMENT CALIBRATION
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3. WHAT IS PHARMACEUTICAL VALIDATION?
World Health Organization (WHO)
Documented act of demonstrating that a procedure, process, or activity
carried out in testing and then production maintains the desired level of
compliance at all stages.
U.S. Food and Drug Administration (FDA)
The collection and evaluation of data which establishes scientific evidence
that a process is capable of consistently delivering quality product throughout
the product lifecycle.
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4. IMPORTANCE OF VALIDATION
Assurance of quality
Process optimization
Reduction of cost
Reduction in rejections
Increased output
Improved efficiency
Improved productivity
4

5. SCOPE OF VALIDATION
Instrument Calibration
Analytical processes
Process Utility services
Raw materials
Packaging materials
Equipment
Product Design
Cleaning
Facilities
Manufacturing operations
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6. HISTORY
The concept of pharmaceutical validation was first proposed by Ted Byers
and Bud Loftus, two Food and Drug Administration (FDA) officials in the
USA in 1979.
The need for validation arose due to several problems in the sterility of large
and small volume parenteral market.
The origins of validation in the pharmaceutical industry can be traced back
to terminal sterilization process failures in the early 1970s.
One such incident was the 1971 Devonport incident, in which a batch of
5% dextrose IV bottles that were not correctly sterilized reached the market
and were administered to patients. Sadly, five patients at a Devonport,
England, hospital died after receiving the contaminated solution.
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7. VALIDATION AUTHORITIES
DEPARTMENT/DESIGNATION RESPONSIBILITY
Manager Production Manufacturing of batches and review of protocol and
report
Manager QC Samples collected
Executive QC Analysis of samples collection and submission to QC
Manager Maintenance Providing utilities and engineering support
Executive Production Preparation of protocol and manufacturing of
validation batches
Manager QA Protocol authorization and preparation of summary
report.
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8. TYPES OF VALIDATION
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1.Analytical
Method
Validation
1.Process
Validation
Equipment
Validation
Cleaning
Validation

9. 1. ANALYTICAL METHOD VALIDATION
Analytical method validation confirms and provides evidence to prove that that the
procedure chosen for a particular test is fit for the intended purpose and provides high
quality, reliable and consistent results.
Validation of analytical procedures is directed to the 4 most common types of analytical
procedures-
i. Identification tests.
ii. Quantitative tests for impurities' content.
iii.Limit tests for the control of impurities.
iv. Quantitative tests of the active moiety in samples of drug substance or drug
product or other selected component(s) in the drug product.
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10. 10
Accuracy
Precision
Specificity
Linearity
Detection Limit
Reproducibility
Repeatability
Range
Robustness
Quantitation Limit
Factors/ Elements of Analytical Method Validation

11. ANALYTICAL
PERFORMANCE
CHARACTERISTIC
IDENTIFICATION
TESTING FOR IMPURITIES ASSAY:
CONTENT
POTENCY
QUANTITATION LIMIT TEST
Accuracy
Precision
o Repeatability
o Intermediate precision
Specificity
Detection limit
Quantitation limit
Linearity
Range
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+
+
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+
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+
+
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+
+
+
+
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+
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Typical analytical performance characteristics (ICH)
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For Solid Oral Dosage Form

12. 2. CLEANING VALIDATION
The process of cleaning validation in pharma ensures that a system
or piece of equipment is cleaned to the highest standard. This is to
ensure that there are no contaminants, which could include residues,
microbes, and other airborne materials.
Main purpose: Prevent contamination and cross contamination
which could heavily affect the results or integrity of any test or
product within the lab.
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13. Basic mechanisms to remove residues from equipment
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 - Brushing
 - Scrubbing
 - Pressurized water to remove particulates.
Mechanical
action
- Oxidation
 - Hydrolysis
Chemical
reactions
 - Wetting agents - Emulsifiers
 - Solubilizers - Dispersants
Detergency
Dissolution
- Aqueous solvents
- Non-aqueous solvents

14. Types of Sampling in Cleaning Validation
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Swab sampling: This method of sampling is the
most commonly used and involve taking an inert
material (cotton wool) on the end of probe and
rubbing it methodically across the surface.
Rinse sampling: In this method, measured area of
clean surface is rinsed or washed with solvent and
the solvent is collected and tested for traces of
contaminants.

15. TESTING PARAMETER ACCEPTANCE CRITERIA
Physical determination The equipment should be visually clean. i.e., no residue should
be visible on equipment after cleaning.
Chemical determination a) NMT 0.1% of the normal therapeutic dose of any product to
appear in the maximum daily dose of the subsequent product.
b) NMT 10 ppm of any product to appear in the next product
(basis for heavy metals in starting materials).
c) For certain allergic ingredients, penicillin, cephalosporins or
potent steroids and cytotoxins, the limit should be below the
limit of detection by best available analytical methods
Microbial contamination Total aerobic counts
a) NMT 10 cfu/100 ml by rinse method.
b) NMT 5 cfu/25 cm² by swab method.
Acceptance criteria for Cleaning Validation
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16. 3. EQUIPMENT VALIDATION
Equipment validation ensures that all instruments used within the
production process operate for their intended uses. Equipment
validation sees that all equipment is installed correctly, operates
correctly, and produces and performs for its intended purpose
correctly.
Qualification - The act of proving and documenting that equipment
or ancillary systems are properly installed, work correctly, and
comply with specified requirements. Qualification is part of
validation.
Therefore, Equipment Validation is also referred as Equipment
Qualification.
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17. Types of Equipment Qualification:
Performance qualification (PQ)
Operational qualification (OQ)
Installation qualification (IQ)
Design qualification (DQ)
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18. Phases of Qualification:
Pre-Validation/
Qualification
Phase
• Design
Qualification(DQ)
• Installation
Qualification (IQ)
Process
Validation/
Process
Qualification
Phase
• Operational
Qualification(OQ)
• Performance
Qualification(PQ)
• Revalidation
Validation
Maintenance
Phase
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19. Design Qualification
• List user requirement
specifications
• Determine functional
(design)
specifications
• Perform vendor
qualification
Installation
Qualification
• Check complete
arrival as
purchased
• Check correct
installation of
computer and
network hardware
and software
• Validation Plan
Operational
Qualification
• Test key operational
functions of
hardware and
software
• Test security
functions
Performance
Qualification
• System for specified
application
• Establish preventive
maintenance routine
• Determine backup
and contingency
planning procedures
• Establish change
control and security
maintenance
protocols
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Revalidation- Repeating the original validation effort or any part of it,
and includes investigative review of existing performance data.

20. 4. PROCESS VALIDATION
The FDA defines process validation as the collection and evaluation of
data, from the process design stage through commercial production,
which establishes scientific evidence that a process is capable of
consistently delivering a quality product.
Pharmaceutical process validation activities provide confirmation that a
manufacturing process is protected to the extent possible from variances
that could interfere with the final pharmaceutical product, the intended
supply chain, or public health.
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21. Types of Process Validation:
• Pre-market validation, is carried out during the
development stage of a product. The results help in finding
the risk analysis on the production process.
1. Prospective
Validation
• Establish documented evidence that a facility and
processes do what they purport to do, based on
information generated during investigation of the process.
2. Concurrent
Validation
• Check a system that has been in operation for some time
to ensure that it is still complying with the set standards
and regulations.
3. Retrospective
Validation
• Final part of process validation. Checks whether a system
is operating after a substantial change of circumstances.
4. Revalidation
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22. Process Validation Lifecycle
Stage 1 – PROCESS DESIGN:
The commercial 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
confirmed as being 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.
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23. VALIDATION MASTER PLAN
World Health Organization (WHO)
A Validation Master Plan (VMP) is a high-level document that
summarizes the manufacturer's overall philosophy and approach, to be
used for establishing performance adequacy.
The Validation Master Plan (VMP) is a summary of the planned
validation activities.
It provides information on the manufacturer’s qualification and validation
work programme and defines details of and timelines for the work to be
performed, including a statement of the responsibilities of those
implementing the plan.
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24. Format of VMP
1. Introduction: Validation policy, scope, location and schedule.
2. Organizational structure:Personnel responsibilities.
3. Plant/process/product description: Rational for inclusions or exclusions
and extent of validation. Specific process considerations that are critical
and those requiring extra attention.
4. Key acceptance criteria.
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25. 5. Documentation format.
6. Reference to the required SOPs.
7. Time plans of each validation project and sub-project.
8. List of products/ processes/ systems to revalidated, summarized in
a matrix format, validation approach.
9. Re-validation activities, actual status and future planning.
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26. VALIDATION PROTOCOL:
A written plan of actions stating how
process validation will be conducted-
specify who will conduct various
tasks, define testing parameters,
testing methods, equipment to be
used, etc.
VALIDATION REPORT:
At the conclusion of validation
activities, a final report should be
prepared. This report should
summarize and reference all
protocols and results.
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27. ICH GUIDELINES FOR EQUIPMENT CALIBRATION
5.30
5.31
5.32
5.33
5.34
5.35
27
Control, measuring, monitoring and test equipment that is critical for assuring the
quality of intermediates or APIs should be calibrated according to written procedures
Equipment calibrations should be performed using standards traceable to
certified standards, if existing.
Records of these calibrations should be maintained
The current calibration status of critical equipment should be known and
verifiable.
Instruments that do not meet calibration criteria should not be used.
Deviations from approved standards of calibration on critical instruments
should be investigated
CALIBRATION ( ICH Q7 CHAPTER 5 ) :

28. WHO GUIDELINES FOR EQUIPMENT CALIBRATION
15.1
15.2
15.3
15.4
15.5
28
Calibration and verification of equipment, instruments and other devices, as applicable, should
be initiated during installation qualification, to ensure that the system operates according to the
described specifications
It should be performed at regular intervals in accordance with a calibration programme and
SOPs.
Personnel who carry out calibration and preventive maintenance should have appropriate
qualification and training.
A calibration programme should be available and should provide information such as calibration
standards and limits, responsible persons, calibration intervals, etc.
There should be traceability to standards (e.g. national, regional or international standards) used in
the calibration. A valid certificate of calibration should be maintained, which is dated and includes
reference to and traceability.
CALIBRATION AND VERIFICATION (WHO ANNEX 3, 15.0 GUIDELINE) :

29. 15.6
15.7
15.8
15.9
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Calibrated equipment, instruments and other devices should be labelled, coded or
otherwise identified, to indicate the status of calibration and the date on which
recalibration is due.
When the equipment, instruments and other devices have not been used for a certain
period of time, their function and calibration status should be verified and shown to
be satisfactory before use.
Equipment, instruments and other devices should be calibrated before or on the due
date for calibration, to ensure that they are used in a calibrated state.
Where instruments and devices are identified as critical or non-critical, or impacting and
non-impacting for the purpose of calibration, documented evidence of the decision-
making process should be available.

30. REFERENCES
1. The FDA Group. A basic guide to process validation in the pharmaceutical industry. The FDA Group; 2022.
2. Annex 3 Good manufacturing practices: guidelines on validation Background, 2014.
3. Process Equipment & Cleaning Validation PDA -PIC/S ICH Q7 Training, 2015.
4. Ich harmonised tripartite guideline good manufacturing practice guide for active pharmaceutical ingredients Q7,
2000.
5. Chandan S. An overview of industrial process validation of tablets – core, 2013.
6. Das B. Validation protocol: First step of a lean-total quality management principle in a new laboratory set-up in a
tertiary care hospital in India. Indian Journal of Clinical Biochemistry. 2011;26(3):235–43.
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31. 7. Jain K. Process validation of tablet dosage form: A comprehensive review- 2018. The Pharma Innovation Journal
2018; 7(3): 433-438.
8. Sabne A, Sontakke M, Rathi V, Gholve S. Pharmaceutical validation: A Review. JETIR (www.jetir.org); 2023.
9. P. Nethercote. Method validation in pharmaceutical analysis: A Guide to Best Practice, Second, Completely
Revised and Updated Edition. ResearchGate, 2014.
10. Maurya S, Goyal D, Verma C; Cleaning Validation in Pharmaceutical Industry- An Overview; PharmaTutor; 2016;
4(9); 14-20
11. Khan, F. Cleaning validation in pharmaceutical industries – IJRPC 2020, 10(2), 205-214
12. Jindal D, Kaur H, Patil RK, Patil HC. Validation – In pharmaceutical industry: Equipment validation: A brief
review. Adesh University Journal of Medical Sciences & Research. 2020 Dec 19;2(2):94–8.
13. Sumeet S, Gurpreet S. Process validation in pharmaceutical industry: An overview. Journal of Drug Delivery &
Therapeutics [Internet]. 2013(3):184.
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