The document discusses validation regulatory requirements from various authorities like the FDA, EU, WHO, and PIC/S. It outlines the objectives, historical background, and regulations for validation from these bodies. The three main stages of process validation are described as process design, process qualification, and continued process verification. Types of validation like prospective, concurrent, and retrospective are also defined.

1. Validation regulatory review
Arpit Rajaram Suralkar
M Pharmacy ( Quality Assurance )

2. Introduction
Validation - Process validation is the
establishment of documented evidence,
which provide a high degree of assurance that
a specific process (manufacturing of
pharmaceutical dosage form) will consistently
produce a product meeting its predetermined
specifications.

3. Objectives of validation:
• It reduces risk of regulatory non-compliance.
• Reduction of time to the market for the new
products.
• Eliminates the scrap & reduces the defect cost.
• Reduces the chances of product re-call from market.
• The final release of the product batch would be
expedited.
• It requires less in-process control & end process
testing.
• Parametric release of batch can be achieved in
validation.

4. HISTORICAL BACKGROUND FOR THE REGULATORY BASIS:
The emphasis on validation began in the late 1970s,
the requirement has been set at 1963 as CGMP regulations for
finished pharmaceuticals.
Validation is an integral part of QualityAssurance & its
meaning is “Action of providing an evidence”.
Validation is necessarily include process qualification
(qualification of rawmaterials,equipment,system) under the section
21 CFR 211.100 which states:
“There shall be written procedures for production
and process control designed to assure that the drug products
have the identity, strength, quality, and purity”.

5. The Kefauver-Harris Amendments to the FD&C Act
were approved in1962 with Section 501(a)(2)(B) as an
amendment.
The result of The Kefauver–Harris drug amendments,
Provided an additional powerful regulatory tool to FDA to
stop particular manufacturing process when the drug
product is deemed to adulteration.
The Drug Product Quality Assurance Program of the
1960s and 1970s involved first conducting a massive
sampling and testing program of finished batches.
The investigation of clinical failures of several products
(including Digoxin, Digitoxin, Prednisolone, and Prednisone)
by FDA found significant content uniformity problems that
were the result of poorly controlled manufacturing
processes.

6. COUNTRY WISE AUTORITIES
COUNTRY REGULATORY AUTHORITY
INDIA Indian FDA.
UNITED KINGDOM MHRA-Medicine Health & Regulatory Agency.
SOUTH AFRICA MCC-Medicinal Control Council.
CANADA
HPB-Health Protection Branch.
AUSTRALIA TGA-Therapeutic Goods Administration.
UGANDA NDA – National Drug Authority

7. Regulatory basis for validation
• The regulatory basis -validation program of process validation
is embodied within the regulations & guidelines provided by
cGMP & FDA.
• The ultimate legal authority is Sec501(a)(2)(B) by the FD&C
Act, which states
• “Drug is deemed to be adulterated due to the methods/
facilities used for the manufacturing, processing,
packing/holding fails to administer in conformity – CGMP”
Validation-Process validation is not just an FDA or U.S.
requirement. Similar requirements included in the World
Health Organization (WHO), the Pharmaceutical Inspection
Co-operation Scheme (PIC/S), and the European Union(EU).

8. REGULATIONS FOR VALIDATION PROCESS
UNDER U.S.FDA & CGMP
• Section211.100(a): Written procedures/deviations.
“There shall be written procedures for production and process control
designed to assure that the drug products have the identity,
strength, quality, and purity.”
• Section 211.110: Sampling and testing of in-process materials and
drug products.
"....control procedures shall be established to monitor the output and
Validate the performance of those manufacturing processes that
may be responsible for causing variability in the characteristics of
in-process material and the drug product” :

9. 21CFR211.133: Control of Microbiological
Contamination.
" Appropriate written procedures, designed to
prevent microbiological contamination of drug
products purporting to be sterile, shall be
established and followed. Such procedures
shall include Validation of any sterilization
process.“
FDA must inspect every drug manufacturing
establishment at least once every 2 years

10. REGULATORY REQUIREMENTS FOR
VALIDATION . UNDER CGMP
• The first CGMP regulations, based largely on the Pharmaceutical
Manufacturers Association’s- manufacturing control guidelines .
• Validation under document of cGMP covers procedure, process
qualification, equipment,& facilities.
• 211.68: validation of automated process.
• 211.84(d)(2): validation of supplier’s test results for components.
• 211.84(d)(3): validation of supplier’s test results for containers &
closures.
• 211.110(a): validation of manufacturing process to ensure content
uniformity& integrity.
• 211.1113(b): validation of sterilization process.
• 211.165: validation of analytical methods.

11. VALIDATION REQUIREMENTS UNDER
WHO
• WHO validation definition:
“The documented act of proving any procedure, process, equipment,
material, activity or system which actually leads to the expected
results”.
• WHO (World Health Organization) cGMP Guidelines state Validation
studies are an essential part of current good manufacturing practice
(CGMP) and should be conducted in accordance with predefined
protocols.
• Strategies of validation under WHO includes:
• DQ: Design Qualification
• IQ: Installation Qualification
• OQ :Operational Qualification
• PQ: Performance Qualification

12. DQ:
The compliance of the basic design (location plan) with
the user requirements & regulatory requirements
should be submitted & documented.
IQ:
Documentary evidence to prove that the premises &
equipment have been built & installed in compliance
with their specifications.
IQ include:
1.Preventive maintenance.
2 .Equipment info.
3. Calibration.
4.Verification of the equipment.
OQ:
A series of tests to measure the performance
capability of equipment. The OQ for HPLC system is the
operation of pump, injector & detector will be tested at
this stage.

13. • Typical OQ test for HPLC system are:
Pump-flow rate accuracy
Detector-response,linearity,wavelength accuracy
Column-resolution,HETP.
PQ:
Process to verify that the system is repeatable & capable for
consistently producing a quality product.
Ex: HPLC system-resolution can be tested by injecting repeatedly a
standard mixtures of analytes like phenol ,toulene etc & by
measuring RT, Peak area etc
Dossier Requirements Regarding Process validation:
A Dossier is a collection of document submitted to a foreign
country for marketing of a drug product.
For dossier submission purpose, Process validation protocol
should include such requirements according to dossier guidelines

14. VALIDATION REQUIREMENTS UNDER EU:
The European Union requirements for validation is an extract
from ICH Q8, Q9 and Q10 documented guidelines and helps to
study continuous process verification.
EU Validation Definition:
Documented evidence that the process, operated within
established parameters, can perform effectively and reproducibly,
To produce a medicinal product meeting its predetermined
specifications and quality attributes.
Strategies of validation under EU includes
Traditional process verification (TPV)
Contineous process validation.(CPV)
Critical process parameter.(CPP)
Critical quality attributes.(CQA)

15. Traditional Process Validation:
Process validation should focus on the control strategy, which
primarily includes critical process parameters, and other relevant studies
demonstrating that the process is capable of delivering the desired
product quality.
Continuous Process Verification:
An alternative approach to process validation in which
manufacturing process performance is continuously monitored &
evaluated. (ICH Q8)
Critical Process Parameter (CPP):
A process parameter whose variability has an impact on a critical
quality attribute and therefore should be controlled to ensure the process
produces the desired quality. (ICH Q8)
Critical Quality Attribute (CQA):
A physical, chemical, biological or microbiological property should be
within an appropriate limit, range,to ensure product quality. (ICH Q8)

16. VALIDATION REQUIREMENTS UNDER PIC/S:
According the EU Guidelines to Good Manufacturing
Practice for Medicinal Products in Annex 15 the principles of
qualification & validation of the PIC/S is given under document
PIC/S PI 006-3.
This document applies primarily to inspectorates of
the PIC/S member for whom it is intended as instruction for
preparing an inspection, and as an advanced training aid for
qualification/validation.
Doc document PIC/S PI 006-3 states:
GMP for medicinal products (Recommendations on
Validation Master Plan Installation and Operational Qualification
Non- Sterile Process Validation Cleaning Validation) can assist with
the interpretation and the implementation.

17. Prerequisites for successful validation
• Experience
• Planning
• Resources
• Understanding & communication
• Training
• SOP,s instruments & methodologies.
• Validation Master Plan.
• Data analysis.
• Validation report.

18. Validation planning & organization
DEPARTMENT RESPONSIBILITIES
ENGINEERING INSTALLATION,CERTIFICATION OF PLANT,EQUIPMENTS.
DEVELOPMENT DESIGNING,SPECIFICATIONS.
MANUFACTURING OPERATION&MAINTAINENCE,MANUFACTURING
PROCESS,SUPPORTING SYSTEMS
QUALITY ASSURENCE ESTABLISHMENT OF VALIDATION
PROTOCOL,AUDITING,SAMPLING,TESTING.

19. VALIDATION MASTER PLAN:
The complete overview of validation operation,
organization structure, content &planning in the form of a
document is the VMP.
VMP should contain the fallowing data:
• Validation policy of company, location& schedule.
• List of product,processes&system to be validated.
• Installation &qualification for new equipment.
• Key acceptance criteria.
• Documentation format used for protocols & report.
• Time planning & scheduling of project.
A VMP Helps:
Members of validation team to know their task &
responsibility.

20. VALIDATION REPORT:
The validation report should be approved prior
to product distribution and kept permanently on file
in quality assurance.
The validation report should have a conclusion
that explains the manufacturing specialist’s
(preparer’s) statement and opinion.
The validation report should contain the
approved validation protocol, tabulated or graphical
results, process monitoring (forms), and all analytical
results of the validation batches.

21. Process validation:
Process validation is defined 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 quality product.
A series of activities taking place over the
lifecycle of the product and process.
stage1: Process design.
stage2: Process qualification.
stage3: Continued process verification.

22. 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:
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.

23. • Types of validation:
Prospective validation:
The Validation that has been made before an entry of a new
product or employing a new formula/process & also is been carried
out if there is a change in the manufacturing process is called–PV.
Concurrent validation:
validation that has to be carried out for the existing products
that is taken from manufacturing line in a batch wise manner
.extensive testing during validation may verify quality attributes.
Retrospective validation:
This type of validation is acceptable only for well established
process where critical process parameters are able to identify &
documented, which reduces excessive process failure leading to
operational errors & equipment errors.