Introduction and History of Validation

1. PROCESS
VALIDATION
BY.
MS. NEHA S. RAUT
ASSISTANT PROFESSOR
SMT. KISHORITAI BHOYAR COLLEGE OF PHARMACY, KAMPTEE

2. 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.
DEFINITION:
VALIDATION
DOCUMENTS

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. QA
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 Quality Assurance
& its meaning is “Action of providing an evidence”.
Validation is necessarily including process qualification (qualification
of raw materials, 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”.
HISTORICAL BACKGROUND FOR THE
REGULATORY BASIS

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. India:
CDSCO
European Union:
MHRA
USA :
Food and Drug
Administration
(FDA)
Australia :
Therapeutic Goods
Administration
New Zealand:
Medsafe
South Africa:
Medicines council
control
Japan:
Ministry of Health &
Labour Welfare
Switzerland:
Swissmedic
Brazil :
ANVISA (The
National Health
Surveillance
Agency)
Mexico:
The Federal
Commission for the
Protection against
Sanitary Risk)
Chile:
ISP
Columbia :
INVIMA
Argentina:
ANMAT
France:
Agence Française
de Sécurité Sanitaire
des Produits de
Santé
Germany :
Federal Institute for
Drugs and Medical
Devices
International Regulatory
Authorities
6

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. 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”
REGULATIONS FOR VALIDATION PROCESS
UNDER U.S.FDA & CGMP

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. 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.
REGULATORY REQUIREMENTS FOR
VALIDATION UNDER CGMP

11. VALIDATION REQUIREMENTS
UNDER WHO
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.
WHO validation definition:
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.
Typical OQ test for HPLC system are:
Pump-flow rate accuracy
Detector-response,linearity,wavelength accuracy
Column-resolution,HETP.

13. DQ-
Design
qualification
IQ-
Installation
qualification
OQ-
Operational
qualification
PQ-
Performance
qualification

14. 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.
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 .

15. 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.
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.
EU Validation Definition:
Traditional process verification
Contineous process validation.(CPV)
Critical process parameter.(CPP)
Critical quality attributes.(CQA)
Strategies of validation
under EU includes:

16. 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)
CONTINUOUS
PROCESS
VERIFICATION
(CPV)
CRITICAL
QUALITY
ATTRIBUTE
(CQA)
TRADITIONAL
PROCESS
VALIDATION
CRITICAL
PROCESS
PARAMETERS
(CPP)
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.

17. 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.
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.
Doc states:

18. Prerequisites For Successful Validation
Experience
Planning
Resources
Understanding & communication
Training
SOP,s instruments & methodologies.
Validation Master Plan.
Data analysis.
Validation report.

19. Validation Planning & Organization:
DEPARTMENT RESPONSIBILITIES
ENGINEERING
DEVELOPMENT
MANUFACTURING
QUALITY ASSURANCE
INSTALLATION,CERTIFICATION OF
PLANT,EQUIPMENTS.
DESIGNING,SPECIFICATIONS.
OPERATION&MAINTAINENCE,MANUFACTURI
NG PROCESS,SUPPORTING SYSTEMS.
ESTABLISHMENT OF VALIDATION
PROTOCOL,AUDITING,SAMPLING,TESTING.

20. Key elements Qualification stage Validation stage
Facilities &
equipment.
Process &
products.
Installation
Engineering phase Manufacturing start-up
(Validation protocols) Documents & records
Developmental
phase
Scale-up
phase
QA mnf.
phase
Time-line for new product introduction
operation checking
Validation Progress Chart:

21. Typical standard Operating Procedure (SOP) format.
Operation Dept :
Name: Date:
Compliance:
ABC PHARMACEUTICAL Ltd.
Plant operations.
Page 1-5
PREPARED BY
PREVIOUS DATE
ISSUE DATE
S.O.P No. 258-04,Revision 4
DEPT . PLANT.
STANDARD OPERATING PROCEDURE
TITLE:
AIR HANDLING SYSTEM 234A-ABC-04
CONDITIONS & PROCEDURE COVERING
THE OPERATION & MAINTAINANCE
Name: Date:
1.PURPOSE:
To define the Std. Operating conditions & SOP,s
for air handling system 234A-ABC-04.
2.GENERAL INFORMATION:
2.1 Supply Air Fan
Fan Manufacturer: Narayan.
Model: 325-567-2222.
Capacity: 30,000CMF.
RPM: 1500.
POWER: 440V,3Phase,60cycles.

22. 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.

23. Validation Report
1.List of new raw materials used
2.List of equipment used
3.Results of data collected.
4.Acceptance criteria evaluation.
5.Analysis of results.
VALIDATION MASTER PLAN
Validation protocol
1.Responsibility of personnel.
2.Critical parameters specified.
3.Sampling plan.
4.Testing plan.
5.Acceptance criteria.
Sampling Plan-Soft gelatin Capsule
1.Final mix-content uniformity.
2.Fill and shell weight-monograph testing.
3.Capsule-monograph testing.
Testing plan
In-process Finished Blend
1.Disintegration. 4.Hardness.
2.Avg.fill wt. 5.Content uniformity
3.Assay. 6.Dissolution profile.
(Final blend). 7.Avg.wt.

24. 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.