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PROCESS VALIDATION
SUBMITTED BY
ANJALI JOSHI
M.PHARM
1
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
2
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”
3
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.
4
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.
5
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.
6
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.
7
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.
8
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
9
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:-
10
SECTIONS
OF cGMP
DETAILS
211. 68 Validation of computerized or automated process
211.84 (d)
(2)
Validation of suppliers test results for components
when these test results are accepted in lieu of in
house testing after receipt
211. 84 (d)
(3)
Validation of suppliers test results for containers &
closures when these tests result are accepted in lieu
of in house testing after receipt.
221. 110
(a)
Validation of mfg. Processes to ensure batch
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)
(2)
Validation of analytical methodologies. ( implicitly
defines validation) 11
CFR PART COVERS
21 CFR Part 210
Concerns current good
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.
12
VALIDATION LIFE CYCLE
13
14
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
15
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
16
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
17
CONT....
6. Equipment validation
a) Design Qualification
b) Installation Qualification
c) Operational Qualification
d) Performance Qualification
18
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.
19
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.
20
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
21
22
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.
23
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
24
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.
25
26
27
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.
28
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.
29
Types of process validation
Generally there are four basic type of process
validation:-
a) Prospective validation
b) Concurrent validation
c) Retrospective validation
d) Revalidation
30
31
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.
32
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.
33
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
34
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.
35
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.
36
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.
37
TABLET MANUFACTURING CRITICAL
PARAMETER
38
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.
39
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.
40
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.
41
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.
42
43

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Process validation and its types

  • 2. 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 2
  • 3. 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” 3
  • 4. 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. 4
  • 5. 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. 5
  • 6. 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. 6
  • 7. 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. 7
  • 8. 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. 8
  • 9. 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 9
  • 10. 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:- 10
  • 11. SECTIONS OF cGMP DETAILS 211. 68 Validation of computerized or automated process 211.84 (d) (2) Validation of suppliers test results for components when these test results are accepted in lieu of in house testing after receipt 211. 84 (d) (3) Validation of suppliers test results for containers & closures when these tests result are accepted in lieu of in house testing after receipt. 221. 110 (a) Validation of mfg. Processes to ensure batch 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) (2) Validation of analytical methodologies. ( implicitly defines validation) 11
  • 12. CFR PART COVERS 21 CFR Part 210 Concerns current good 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. 12
  • 14. 14
  • 15. 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 15
  • 16. 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 16
  • 17. 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 17
  • 18. CONT.... 6. Equipment validation a) Design Qualification b) Installation Qualification c) Operational Qualification d) Performance Qualification 18
  • 19. 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. 19
  • 20. 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. 20
  • 21. 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 21
  • 22. 22
  • 23. 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. 23
  • 24. 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 24
  • 25. 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. 25
  • 26. 26
  • 27. 27
  • 28. 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. 28
  • 29. 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. 29
  • 30. Types of process validation Generally there are four basic type of process validation:- a) Prospective validation b) Concurrent validation c) Retrospective validation d) Revalidation 30
  • 31. 31
  • 32. 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. 32
  • 33. 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. 33
  • 34. 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 34
  • 35. 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. 35
  • 36. 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. 36
  • 37. 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. 37
  • 39. 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. 39
  • 40. 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. 40
  • 41. 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. 41
  • 42. 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. 42
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