RA Manager – Boston Biopharma Ltd

Importance Process
Definitions Objectives
of steps to be
of PV of PV
validation validated

Current PV New History of

Validation vs
guidelines approach PV
Qualification
of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Importance of validation

 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 Process
Definitions Objectives
of steps to be
of PV of PV
validation validated

Current PV New History of

Validation vs
guidelines approach PV
Qualification
of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Definitions of of process validation

• 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.
Importance Process
Definitions Objectives
of steps to be
of PV of PV
validation validated

Current PV New History of

Validation vs
guidelines approach PV
Qualification
of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Objectives of process validation

 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.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Current PV New History of

Validation vs
guidelines approach PV
Qualification
of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Process steps to be validated

• 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
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Current PV New History of

Validation vs
guidelines approach PV
Qualification
of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 History of PV

• 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.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

New History of
Validation vs Current PV
approach PV
Qualification guidelines
of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 New approach of CPV

This guidance incorporated:

• QbD

• Process Analytical Technology (PAT)

• Risk management

• The concept of life cycle approach to PV

 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Current New History of

Validation vs approach
PV PV
Qualification of CPV
guidelines

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Current PV guidelines

FDA, January 2011 WHO, Annex 3 EMA, November 2016

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

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Validation vs Qualification

Validation Qualification
Validation is establishing a documented Qualification is a process of assurance
evidence to provide a high degree of that the specific system, premises or
assurance that a specific system, equipment are able to achieve the
process or facility will consistently predetermined acceptance criteria, to
produce a product meeting its confirm the attribute that it claimed to
predetermined specifications & quality do.
attributes. 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 Equipment, Instruments & utility systems
things) are validated, e.g. cleaning, are qualified
manufacturing process & analytical
methods
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Life cycle Stages of PV
stages of PV PV
approach

Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Life cycle approach

Identification of
process variables
Stage 1 – Stage 2 –
Process Design Control strategy Process Qualification

Verification
Facility
Process
Design
Performance
Facility &
Qualification
Equipment
(PV)
Qualification

In control
Distribution Stage 3 –
to market CPV

Process
monitoring &
improvement
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Stages of PV
Process validation comprises three stages that take place over the life cycle of product

Stage 1 – Stage 2 – Stage 3 –

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

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 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:

A detailed history of how product/process was

Development report developed including source documents for the
control strategy & design space.

• A report conducted early in the development

process & updated after completion of
development studies & focused on what needs to
Risk assessment report
be studies related to the process.
• This document is used to develop design space &
control strategy.

Control strategy This document outlines the control strategy of the

document process including a list of any CPPs.

Final manufacturing This document is written based on scale-up

process description experience which describes the intended process for
document process performance qualification (PPQ).
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Definition of QbD

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.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated

9/29/2021 PV lifecycle
 QbD

 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.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated
9/29/2021 PV lifecycle
 Key elements to process design

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

 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated

9/29/2021 PV lifecycle
 Steps of process design

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

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.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated

9/29/2021 PV lifecycle
 Stage 2 - Process Qualification

To proceed from stage 2 to stage 3: an approved report must be completed and
approved as well:

Protocol for process

Protocol designing the requirement of the process
performance
performance quality study.
qualification (PPQ)

Report summarizing the results and outcome of the

PPQ report
process performance qualification strategy.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated

9/29/2021 PV lifecycle
 Stage 3 - CPV

A risk assessment is required for all manufacturing

Process risk
processes. This should be used to determine the
assessment report
frequency of testing defined in the CPV plan.

Outlines what should be monitored on an outgoing

CPV plan basis, how the data should be monitored, analyzed,
& reviewed.

Summaries of the process monitoring data with

CPV report
conclusions & recommendations actions.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV
Life cycle stages of PV PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated

9/29/2021 PV lifecycle
 Types & stages of PV

Stage Type Product development/design

• Trial plan, product knowledge &
understanding & control strategy-CPP & CQA.
• Define commercial production process risk
Stage I Prospective analysis for each separate process step.
• Conducted prior to the distribution of new
PD validation product.
• Generally the first 3 production scale batches are
monitored for all process parameters to give
insights on variability & current controls.
Stage II Concurrent
• Qualification of utilities & equipment.
• Statistical techniques, sampling plans.
PQ validation • Process performance qualification, validation
protocol & report.

• Examination/ analysis of the past experience

process data & evaluation of the procedure,
composition & equipment remain unchanged.
Stage III Ongoing • Trend analysis performed to determine if the
maintenance of process parameters adhere to the permissible
CPV validated state range.

• Introduction of new elements in the manufacturing

Retrospective validation is process e.g. starting material, packaging material,
Revalidation formulation, change in batch size, process, equipment &
no longer considered an
acceptable approach (EU support systems or production & packaging areas
Regulatory Requirements) (facility change/technology transfer) which have
impact on product effectiveness or characterization.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV PV
Life cycle stages of PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated

9/29/2021 PV lifecycle
 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.
 Process
Importance Objectives
Definitions steps to be
of of PV
of PV validated
validation

Validation vs Current New History of

Qualification PV approach PV
guidelines of CPV

Types & Success of

Stages of PV PV
Life cycle stages of PV
approach
Stage I PD Stage II PQ Stage III CPV

Definition of QbD Key elements to PD

QbD Steps of PD Automated

9/29/2021 PV lifecycle
 Automated process validation lifecycle

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.
 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