PROCESS VALIDATION

SUBMITTED BY
ANJALI JOSHI
M.PHARM

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CONTENTS
 Introduction
 Regulatory requirements for Validation
 Validation Life Cycle
 Significance of Validation
 Types of Validation
 Process Validation
 Phases of Process Validation
 Types of Process Validation
 Example

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 INTRODUCTION
DEFINITION OF VALIDATION:-

 Validation is establishing documented evidence

which provides a high degree of assurance that a
specific process, procedure or activity carried out in
testing and then production maintains desired level
of compliance at all stages.

 Validation is a key process for effective Quality

Assurance its simple meaning is “ACTION OF
PROVING”
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CONT....

 QA is the heart and soul of Quality control.

QA = QC+ GMP
 Quality control is incomplete without
production.

 Validation generally involves controlling

of the critical step of a system which
results in output of repeatable attributes.
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Regulatory requirements for Validation

1. ROLE OF FDA
 It is federal science based law enforcement
agency mandated to protect public health.
 Validation process regulated by guideline
and restriction set forth by FDA.
 The actual validation protocol, document &
execution is responsibility of manufacturer
but more specially this is responsibility of
engineer.
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CONT....


2-CFR ( CODE OF FEDERAL REGULATION)

 This is body of regulation created by
government, that set forth the guidelines
pertaining to food and drug.
 The validation are embodied with in the scope
of existing cGMP.
 The specific term PROCEED THE VALIDATION
comes under the section 21CFR 211-100.

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CONT....
 21CFR 211-110:-

Control procedure shall be established

to monitor the output & to validate the
performance of the manufacturing
process that may be responsible for
causing variability in the characteristics
of in process material and drug
material.
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CONT....
21 CFR 211. 100

There should be a written procedure for

production and process control designed to
assure that the drug products have the
identify, strength, quality and purity they
purport or are represented to posses.

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CONT....
 21 CFR.113

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
validation of any sterilization process

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Cont....
 Validation under the document of cGMP
broadly covers overall process of mfg. most
of which are essentially facilities, equipment,
component, procedure, and process
qualification.

 Following sections of cGMP under 21 CFR

211 refer to the Validation:-

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SECTIONS DETAILS
OF cGMP

211. 68 Validation of computerized or automated process

211.84 (d) Validation of suppliers test results for components

(2) when these test results are accepted in lieu of in
house testing after receipt
211. 84 (d) Validation of suppliers test results for containers &
(3) closures when these tests result are accepted in lieu
of in house testing after receipt.
221. 110 Validation of mfg. Processes to ensure batch
(a) uniformity & integrity of drug products.

211.113 (b) Validation of sterilization processes.

211.165 (e) Validation of analytical methodologies. ( explicitly

defines validation)

211.194 (a) Validation of analytical methodologies. ( implicitly

(2) defines validation) 11
 CFR PART COVERS

Concerns current good

21 CFR Part 210 manufacturing process in mfg.
, processing, packaging of drug
21 CFR Part 211 Concerns cGMP for finished
pharmaceuticals.

21 CFR Part 600 Concerns to production of

biological derived product.

21 CFR Part 610 Safe distribution of biological

derived product.

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VALIDATION LIFE CYCLE

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 SIGNIFICANCE of validation

 It reduces the risk of regulatory non compliance.

 Reduce the chances of product recall from the
market.
 It may reduce the time to market the new drug
product.
 Reduce the defect cost.
 Make the process better understood and assuring
smooth running of process

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CONT....
 Validation therefore should be considered in
following situation:-
a) Totally new process
b) New equipment
c) Process & equipment which have been
altered to suit changing priorities
d) Process where the drug product test is
poor & unreliable indicator of product quality

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Types of validation
1. Analytical method validation.
2. Raw material validation.
3. Cleaning validation.
4. Calibration
5. Process validation
a) Retrospective validation
b) Concurrent validation
c) Prospective validation
d) Revalidation

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CONT....
6. Equipment validation
a) Design Qualification
b) Installation Qualification
c) Operational Qualification
d) Performance Qualification

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PROCESS VALIDATION
 It is defined as a documented programme which
provides a high degree of assurance that a specific
process will consistently produce a product meeting
its predetermined specification and quality
characteristics.

 Effective process validation contributes significantly

to assuring drug quality.

 The basic principle of quality assurance is that a drug

should be produced that is fit for its intended use.
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Cont......
 This principle incorporates the
understanding that the following conditions
exist:

 Quality, safety, and efficacy are designed or

built into the product.

 Quality cannot be adequately assured merely

by in-process and finished-product
inspection or testing.
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PHASES OF PROCESS VALIDATION
1- Process capability design/ Process
development
2- Process qualification
a) Design of facility
b) Qualification of utilities and equipment
c) Process performance qualification
d) PPQ protocol
e) Process execution & report
3- Validation maintenance phase

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 1. PROCESS DEVELOPMENT
 Process development activities begin after the
formulation has been developed.
 The process development program meet the
following objectives:-
1. Develop a suitable process to produce a product
which meets all
a) Product specification
b) Current good manufacturing process
2. Identify the crucial parameters that will affect the
final product.

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cont....

 FDA in its Process Validation guideline states that

a manufacturer should evaluate all factors that
affect product quality when designing and
undertaking a process validation study.

 Not all the parameters are crucial in order to

define the final product characteristics so it is
important to identify critical parameters

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CONT....
 Process development is mainly done to
determine:-
 The no. and relative importance of critical
parameters that influence process output.
 The numerical value and range for each of the
critical parameters that result in acceptable
process output.
 If the process capability is properly defined the
process should result into output of consistence
attributes when operated within defined limits
of critical process parameters.

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 2-PROCESS QUALIFICATION PHASE
It is generally designed to verify that all established
limits of the critical process parameters are valid &
satisfactory product can be produced even under the
worst condition. It represents the actual study to
show:-
 That all system, sub-systems of a mfg. process
perform as intended.
 That all critical parameters operate within their
assigned control limits.
 Such studies & trials which form the basis of process
capability design and testing are verifiable and
certifiable through proper documentation.

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 3- VALIDATION MAINTAINENCE PHASE
 It requires frequent review of all process related
requirements/ documents including validation
audit report to assure that there have been no
changes, deviation, failures, modification to the
production process & that all SOP’S have been
followed including change control procedures.

 At this stage the validation team also assured that

there have been no change/ deviation that should
have results in requalification and revalidation.

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 Types of process validation

Generally there are four basic type of process

validation:-
a) Prospective validation
b) Concurrent validation
c) Retrospective validation
d) Revalidation

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 1- PROSPECTIVE VALIDATION
 Prospective validation means validation done
during the product development stage.

 When we develop a new manufacturing process

each step in new process is required to be
established that it will give us desired result.

 During this step the input resources are selected

and clearly specified.

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Cont....
 E.g. - Material specification is clearly defined.
- Equipment & process parameter are defined.
-Operating condition if any specified.
-Level of training of people can also be defined

 Infact, validation by this approach often leads to

transfer of the manufacturing process from the
development function to production.

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 2- CONCURRENT VALIDATION

 Concurrent validation is validation which is

carried out during production.
 Concurrent validation is appropriate when:-
- It is more appropriate to validate process during
routine production due to well understanding of
process.
- Extensive testing & monitoring ensure the
desired quality characteristics of product with
high degree of confidence

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CONT...
 After three initial commercial batches are
taken and process is handled over to mfg.
personnel verification of process parameter
still goes on.

 The process parameter is evaluated for mfg.

facilities batch after batch & studied if any
change or deviation is observed or required.

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 3-RETROSPECTIVE VALIDATION
 It is used for facilities, processes and process
control parameters used in operation that have
not undergone in documented validation process.
 Validation of these facilities, processes and
process control parameters is possible using
historical data (QA/QC records) to provide the
necessary documented evidence that the process
is doing what is believed to do.
 Therefore this type of validation is only acceptable
for well established processes.

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 4- REVALIDATION
Revalidation is the repetition of the validation
process & it is required under following
circumstances:-
 Change of formula, equipments, procedures or
quality of raw material or even in physical
variation of raw material i.e. Particle size.
 Major changes in critical process parameters.
 Changes in facilities & installation which influence
process.
 On appearance of difference in result.

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TABLET MANUFACTURING CRITICAL
PARAMETER

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 example
VALIDATION OF WET GRANULATION PROCESS
Parameters to be considered during development &
validation are-
 BINDER CONCENTRATION & ADDITION
The optimal binder conc. will be need to be
determined for the formulation. If the binder
solution is sprayed, it is needed to be diluted
enough so that it can be pumped through the
nozzle. It should also be sufficiently concentrated to
form granules without over wetting the materials.

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Cont....

 AMOUNT OF BINDER SOLUTION-

Too much binder or solvent solution will over wet
the materials and prolong the drying time.

 BINDER SOLUTION ADDITION RATE-

Define the rate at which the binder solution can
be added to the material.

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CONT....
 MIXING RATE
It is the rate required to ensure the proper
formation of granules. Over mixing of the
granules can lead to harder granules and a lower
dissolution rate.

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 REFERENCES
 Jain N.K. “Pharmaceutical Product
Development” , CBS Publishers &
Distributors, 2008. Page no. 524-549.
 Nash R.A. “Pharmaceutical Process
Validation” 3 edition, Marcel & Dekker
publication, Page no. 20-47.
 Guidance for Pharmaceutical Industry on
Process Validation, USFDA, January 2011.

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