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1. PROCESS VALIDATION
Ravish Yadav

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:

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. 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”.
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. COUNTRY WISE AUTORITIES
COUNTRY: REGULATORY AUTHORITY:
INDIA
UNITED KINGDOM
SOUTH AFRICA
CANADA
AUSTRALIA
Indian FDA.
MHRA-Medicine Health
& Regulatory Agency.
MCC-Medicinal Control Council.
HPB-Health Protection Branch.
TGA-Therapeutic Goods Administration.

7. NETHERLANDS.
UGANDA.
WORLD-WIDE.
BRAZIL.
IDA-International Dispensary Association.
NDA-National Drug Authority.
WHO & ICH.
ANVISA-National Agency for Vigilance Sanitare.

8. 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).


9. 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 :

10. 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
.

11. 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:

12. 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

13. 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.

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

15. 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.
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 .

16. 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:

17. 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.
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)

18. 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:

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

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

21. 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:

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. PROCESS VALIDATION STEPS IN TABLET
MANUFACTURING :

29. PROCESS-VALIDATION: PROCESSING STEPS & IN-PROCESS
VARIABLES (TABLETS).
CONTENT UNIFORMITY
DISINTEGRATION
DISSOLUTION
GRANULATION
DRYING
PRE-BLENDING
OF POWDERS
BLEND
GRANULATION
SIZING
GRANULES
TABLET
COMPRESSION
BLENDING ADDITION OF
LUBRICANT
SPEED
TEMP SPEED
SPEED
SPEED
LOAD
LOAD
LOAD
TIME
TIME

30. Types of validation:
Validation
Prospective
Concurrent
RetrospectiveProspective 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.

31. 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.
PROSPECTIVE CONCURRENT RETROSPECTIVE
Three(3)consecutive
successful validation
Batches (commercial batch
size are required)
Three(3)consecutive
successful validation
Batches (commercial batch
size are required)
New products Existing products
Simultaneously
released
Released batch
by
batch
Selection of batches
depends upon the
requirements
Finished product
Batches
from
production line

32. Conclusion:
Regulatory authorities working on strategies to reduce the cost of process validation
and incorporate validation consideration during product design and development.
New technologies under development for 100% analysis of drug products and other
innovations in pharmaceutical industry may also have a significant effect on Validation
& basic regulatory authority's acceptance.
The future of process validation is also of great interest, especially with the
worldwide expansion of pharmaceutical manufacturing & for harmonizing in
international standards and requirements.

33. References:
Pharmaceutical Process Validation by R. Berry &
Robert A. Nash.
www.fda.gov/cder/guidance/pv.htm (US FDA).
Remington’s pharmaceutical science.
Pharmaceutical preformulations by j.j. Wells.
www.emea.eu.int/ (EU Audit Agency).