The document discusses various aspects of process validation including: - The three stages of process validation: process design, process qualification, and continued process verification. - Key definitions related to process validation including qualification, validation, and continued process verification. - The importance of process validation in ensuring consistent quality and reducing risk. - Key documents required for stage 1 process design including development reports and control strategy documents.

1. RA Manager – Boston Biopharma Ltd

2. 9/29/2021
Stages of PV
History of
PV
New
approach
of CPV
Current PV
guidelines
Validation vs
Qualification
Importance
of
validation
Definitions
of PV
Process
steps to be
validated
Objectives
of PV
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle

3.  We validate processes & qualify equipment to reduce the variables in the
manufacturing process.
 We qualify equipment to ensure that it operates as expected & within known
tolerances.
 We calibrate instruments to ensure that the data being collected is accurate.
 We validate process to define & verify the proven acceptance ranges that
produce a product that will meet specification.
o The proven acceptance ranges is defined by design of process understanding
experiments prior to verification by process performance verification.
Importance of validation

4. 9/29/2021
Stages of PV
History of
PV
New
approach
of CPV
Current PV
guidelines
Validation vs
Qualification
Importance
of
validation
Process
steps to be
validated
Objectives
of PV
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV

5. • The collection & 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.
• Documented evidence which provides a high degree of assurance
that a specific process will consistently result in a product that meets
predetermined specifications and quality characteristics.
• The 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.
Definitions of of process validation

6. 9/29/2021
Stages of PV
History of
PV
New
approach
of CPV
Current PV
guidelines
Validation vs
Qualification
Importance
of
validation
Process
steps to be
validated
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV

7.  To provide the highest assurance that all production batches (unit
doses) will be consistently efficacious as the clinical batch(es).
 To reduce risk to safety via the highest assurance of acceptable
and consistent quality of the product and its components.
Objectives of process validation

8. 9/29/2021
Stages of PV
History of
PV
New
approach
of CPV
Current PV
guidelines
Validation vs
Qualification
Importance
of
validation
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated

9. • All steps that are generally considered critical (medium & high risk steps)
should be monitored/scrutinized:
 by summarizing actual process parameters applied & observations recorded
 e.g. sifting stage, wet & dry granulation stages
 observations serve as a feedback for future refinement of process parameters
• In addition, where feasible, sampling & testing should be performed
 e.g. drying, mixing steps, compression, filling
 results measure effectiveness and consistency of the immediate as
well as preceding steps:
 e.g. final blend characteristics are mainly shaped by wet/dry
granulation process
Process steps to be validated

10. 9/29/2021
Stages of PV
New
approach
of CPV
Current PV
guidelines
Validation vs
Qualification
Importance
of
validation
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
History of
PV

11. • FDA released “Guideline on General Principles of Process Validation” in 1987.
• This guideline emphasize that process validation is complete with the 3 validation
lots at the commercial scale.
• An alternative approach to this traditional process validation is the continuous
process verification (CPV), known as life-cycle approach which is the essence of
the concept of QbD.
• In Aug 2009, ICH released a guideline Q8R(2) (Step 4) to guide the industry in the
implementation of (QbD) in Section 3.2.P.2 (Pharmaceutical Development) for DPs
as defined in Module 3 of the CTD (ICH guideline M4).
• ICH Q8 - Continuous Process Verification An alternative approach to process
validation in which manufacturing process performance is continuously
monitored & evaluated.
• FDA PV guide - Continued Process Verification Documented evidence that the
process remains in a state of control during commercial manufacture.
History of PV

12. 9/29/2021
Stages of PV
History of
PV
Current PV
guidelines
Validation vs
Qualification
Importance
of
validation
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV

13. This guidance incorporated:
• QbD
• Process Analytical Technology (PAT)
• Risk management
• The concept of life cycle approach to PV
New approach of CPV

14. 9/29/2021
Stages of PV
History of
PV
Validation vs
Qualification
Importance
of
validation
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines

15. FDA, January 2011 WHO, Annex 3
WHO Technical Report Series, No.
992, 2015
EMA, November 2016
CPV CPV Alternative approaches:
* Traditional approach
* CPV
Process design and Initial
validation (process
qualification- PPQ) are initial
phases of CPV.
Process design and initial
validation (initial process
verification) are initial phases
of CPV.
CPV protocol to be supported
by extensive development
information & lab or pilot
scale data. Executed on each
production batch.
No mention of number of
batches for initial process
performance
qualification/validation
(rather must be justified based
on overall product & process
understanding)
Mentions data on at least
three pilot or production
batches collected as part of
process design.
Number of batches specified
for traditional approach:
* minimum of three
production batches unless
other wise justified.
Current PV guidelines

16. 9/29/2021
Stages of PV
History of
PV
Importance
of
validation
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification

17. Validation vs Qualification
Validation Qualification
Validation is establishing a documented
evidence to provide a high degree of
assurance that a specific system,
process or facility will consistently
produce a product meeting its
predetermined specifications & quality
attributes.
Qualification is a process of assurance
that the specific system, premises or
equipment are able to achieve the
predetermined acceptance criteria, to
confirm the attribute that it claimed to
do.
It is documented evidence that a
specific piece of equipment, facility or
system is fit/ready for intended use.
Processes/Procedures (the way we use
things) are validated, e.g. cleaning,
manufacturing process & analytical
methods
Equipment, Instruments & utility systems
are qualified

18. 9/29/2021
Stages of PV
History of
PV
Importance
of
validation
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Life cycle
approach

19. Verification
Distribution
to market
In control
Stage 1 –
Process Design
Facility
Design
Facility &
Equipment
Qualification
Process
Performance
Qualification
(PV)
Stage 3 –
CPV
Life cycle approach
Stage 2 –
Process Qualification
Identification of
process variables
Control strategy
Process
monitoring &
improvement

20. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Stage I PD
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV

21. Stages of PV
Stage 1 –
Process Design
(PD)
Process validation comprises three stages that take place over the life cycle of product
• Risk assessment on CPPs & CQAs
• Finalize the control plan
• Finalize batch record
The commercial
process is defined
during this stage based
on knowledge gained
through development
and scale-up activities.
• R&D – ICH Q8 “Identify
quality characteristics,
identify process parameters,
IPC controls, operating range,
acceptable range”
• Define likely CPPs & CQAs
• Develop a control plan “SPx,
target product profile,
determine upper & lower
limits for operating &
acceptable ranges”
Stage 2 –
Process
Qualification (PQ)
Stage 3 –
Continued Process
Verification (CPV)
Sampling
&
testing
During this stage, the process
design is evaluated to determine
if the process is capable of
reproducible commercial
manufacturing. (stage prior to
commercialization or prior to
submitting a registration
application)
• Equipment/Utility/Facility
Qualification (EQ)
• Process Performance Qualification
(PPQ), IPC, release & shelf life
spx, approved validation protocols
& reports with test data &
summary.
• Transfer to operations
• Ongoing assurance is
gained during routine
production that the
process remains in a state
of control. (includes
products that are
commercialized & currently
marketed products with
completed prospective
validation)
• Variation detection
“Understanding Process
Variability”
• Process Signals During
Routine Monitoring
• Ongoing monitoring of some
CPPs & CQAs
• PQRs & APQRs

22. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Definition of QbD
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD

23. Development report
A detailed history of how product/process was
developed including source documents for the
control strategy & design space.
Risk assessment report
• A report conducted early in the development
process & updated after completion of
development studies & focused on what needs to
be studies related to the process.
• This document is used to develop design space &
control strategy.
Control strategy
document
This document outlines the control strategy of the
process including a list of any CPPs.
Final manufacturing
process description
document
This document is written based on scale-up
experience which describes the intended process for
process performance qualification (PPQ).
Stage 1 - Process Design
To proceed from stage 1 PC to stage 2 PQ, the following documents must be
completed and approved internally by the company:

24. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
QbD
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD

25. QbD is defined as:
“a systematic approach to development that begins with predefined
objectives & emphasizes product & process understanding & process
control, based on sound science & quality risk management.” (ICH Q8)
This is a more systematic approach to development which include, for
example:
• incorporation of prior knowledge,
• results of studies using design of experiments,
• use of quality risk management (ICH Q9),
• and use of knowledge management (ICH Q10) throughout the lifecycle
of the product.
Definition of QbD

26. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

27.  The first crucial step in any formulation development is to understand the
product profile which is called as Quality Target Product Profile (QTPP) in
terms of regulatory.
 Once QTPP is identified, formulation scientists need to define what the
“potential” critical qualities attributes of the product (CQAs).
 Risk assessment to be carried out to link raw material attributes and process
parameters to CQAs, based on risk assessment control strategy shall be
designed and implemented.
 Once control strategy is implemented, there is a need to manage product life
cycle within the design and which becomes part of continual improvement.
QbD

28. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

29. The key action elements to process design:
1. Develop Quality by Design (QbD) Comprehensive Evaluation
2. Identify Critical Quality Attributes (CQAs)
3. Provide Risk Assessment
4. Execute Product/Process Development
5. Develop Critical Process Parameters (CPPs)
6. Establish Product/Process Design Space
7. Plan Control Strategy
Key elements to process design

30. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

31. 1. Develop QbD Comprehensive Evaluation:
A company should develop consistent internal evaluation systems & identify material attributes (e.g., API &
critical excipient) & process parameters, to product critical quality attributes (e.g., CQAs).
2. Identify CQAs:
All quality attributes for the product should be evaluated by a company based on a quality target product
profile (QTPP). Potential CQAs should be identified based on an evaluation of the severity of the attribute
in terms of the impact, which is based on clinical experience and in-vitro studies.
3. Provide Risk Assessment:
A company must assess the impact of material, process, & environmental variables on the potential CQAs.
A risk assessment enables the synthesis of important information for the development of control strategy.
This strategy can be revised on an ongoing basis to continue to enhance the company's understanding of its
product and processes.
4. Execute Product/Process Development:
A company should conduct process design experiments on generally accepted scientific principles. Only
those experiments that result in material being used for clinical trials need to be conducted under cGMP
conditions. The subjectivity within a process, such as different API lots, production operators, limitations of
commercial manufacturing equipment, environmental conditions, and measurement systems should be
considered in the product design process. While validating analytical methods is not necessarily required,
analytical methods adopted by the company should be well-defined and provide accurate & consistent
results that can be relied upon.
Steps of process design

32. 5. Develop CPPs:
CPPs should be developed based on the knowledge gained during process development. CPPs should be
consistent with corresponding CQAs.
6. Establish Product/Process Design Space:
While not necessary for each operation, design space is developed by relying on knowledge gained from the
process development studies and input from is a specific defined process that have been demonstrated to
provide quality.
7. Plan Control Strategy:
A control strategy is a planned set of controls, derived from product and process understanding which
assures process performance and product quality. Control strategies should consider material quality,
equipment monitoring and environmental conditions. Control strategies are expected and are needed for
stage 2.
Steps of process design

33. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

34. Stage 2 - Process Qualification
Protocol for process
performance
qualification (PPQ)
Protocol designing the requirement of the process
performance quality study.
PPQ report
Report summarizing the results and outcome of the
process performance qualification strategy.
To proceed from stage 2 to stage 3: an approved report must be completed and
approved as well:

35. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

36. Stage 3 - CPV
Process risk
assessment report
A risk assessment is required for all manufacturing
processes. This should be used to determine the
frequency of testing defined in the CPV plan.
CPV plan
Outlines what should be monitored on an outgoing
basis, how the data should be monitored, analyzed,
& reviewed.
CPV report
Summaries of the process monitoring data with
conclusions & recommendations actions.

37. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

38. Types & stages of PV
Stage I
PD
Stage I
PD
Prospective
validation
Product development/design
• Trial plan, product knowledge &
understanding & control strategy-CPP & CQA.
• Define commercial production process risk
analysis for each separate process step.
• Conducted prior to the distribution of new
product.
Stage Type
Concurrent
validation
• Generally the first 3 production scale batches are
monitored for all process parameters to give
insights on variability & current controls.
• Qualification of utilities & equipment.
• Statistical techniques, sampling plans.
• Process performance qualification, validation
protocol & report.
Ongoing
validated state
Ongoing
maintenance of
validated state
• Examination/ analysis of the past experience
process data & evaluation of the procedure,
composition & equipment remain unchanged.
• Trend analysis performed to determine if the
process parameters adhere to the permissible
range.
Revalidation
• Introduction of new elements in the manufacturing
process e.g. starting material, packaging material,
formulation, change in batch size, process, equipment &
support systems or production & packaging areas
(facility change/technology transfer) which have
impact on product effectiveness or characterization.
Retrospective validation is
no longer considered an
acceptable approach (EU
Regulatory Requirements)
Stage II
PQ
Stage II
PQ
Stage III
CPV
Stage III
CPV

39. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

40. Success of PV
It Depends on:
 Information & knowledge from product & process development.
 Controlling the manufacturing process to get specified quality attributes.
 Understanding the sources of variation
 Detecting the presence & degree of variation.
 Understanding the impact of variation on the process & ultimately on product attributes.
 Controlling the variation in a manner corresponding to the risk it represents to the process &
product.

41. 9/29/2021
History of
PV
Importance
of
validation
Life cycle
approach
Key elements to PD
Steps of PD
Types &
stages of PV
Stage II PQ Stage III CPV
Success of
PV
Automated
PV lifecycle
Definitions
of PV
Objectives
of PV
Process
steps to be
validated
New
approach
of CPV
Current
PV
guidelines
Current
PV
guidelines
Validation vs
Qualification
Stages of PV
Stage I PD
Definition of QbD
QbD

42. The ValGenesis VLMS automates the validation life cycle by
integrating all the stages of process validation,
from process deign to qualification and
continuous/continued process verification.
Automated process validation lifecycle

43. References
• US FDA Process Validation: General Principles and Practices
https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf
• WHO Technical Report Series, No. 937, 2006 Annex 4 Supplementary guidelines on good manufacturing practices: validation
https://www.who.int/medicines/areas/quality_safety/quality_assurance/SupplementaryGMPValidationTRS937Annex4.pdf
• Annex 3 Guidelines on good manufacturing practices: validation, Appendix 7: non-sterile process validation
https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex3-TRS992.pdf?ua=1
• WHO Technical Report Series, No. 961, 2011 Annex 7 WHO guidelines on transfer of technology in pharmaceutical manufacturing
https://www.who.int/medicines/areas/quality_safety/quality_assurance/TransferTechnologyPharmaceuticalManufacturingTRS961Annex7.pdf?ua=1
• Guideline on process validation for finished products - information and data to be provided in regulatory submissions 21 November 2016 EMA/CHMP/CVMP/QWP/BWP/70278/2012-
Rev1,Corr.1
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-process-validation-finished-products-information-data-be-provided-regulatory-submissions_en.pdf
• EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines, Annex 15: Qualification and Validation
https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-4/2015-10_annex15.pdf
• EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines, Annex 15: Qualification and Validation
https://www.ema.europa.eu/en/documents/scientific-guideline/note-guidance-development-pharmaceutics_en.pdf
• ICH guideline Q8 (R2) on pharmaceutical development
https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-11.pdf