Basic GMP Requirement

PROCESS VALIDATION
ROCHAPON WACHAROTAYANKUN, PH.D.
Topic

 Process validation – What and Why?

 Principle of process validation
 Manufacturing process validation
 Aseptic process validation
 Other supportive process validation

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Key References
 PIC/S and EU GMP Annex 15: Qualification and Validation (Effective date 01 October 2015)

 Validation of Production Processes for Vaccines for WHO Prequalification-

Compliance Expectations (Draft): A note for guidance for the manufacture of prequalified vaccines for supply to
United Nations agencies, July, 2013

 WHO/BS/2015.2253 : WHO GMP for Biological Products Proposed replacement of: TRS 822, Annex 1

 US FDA Guidance for Industry -Process Validation: General Principles and Practices ,
January 2011

 ICH Q7

 EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1: Guideline on process validation for

finished products - information and data to be provided in regulatory submissions

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Definition of Process Validation (1/2)

 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

ICH Q7
Guideline on process validation for finished products - information and data to be provided
in regulatory submissions EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1
PIC/S and EU GMP Annex 15: Qualification and Validation (Effective date 01 October 2015)

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Definition (1/2)

 (Production) Process validation (PV) is the collection

and evaluation of data, from the process design stage
through commercial production, which establishes
scientific evidence that a manufacturing process is
capable of consistently delivering quality products.

Validation of Production Processes for Vaccines for WHO

Prequalification- Compliance Expectations
(Draft)
A note for guidance for the manufacture of prequalified vaccines
for supply to United Nations agencies
July, 2013
Vaccine Quality and Regulations (VQR)
Essential Medicines and Health Products
World Health Organization (WHO), Geneva, Switzerland
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 Why Process validation?

 Required by cGMP - essential element in assurance of drug quality

 Quality, safety, and efficacy are designed or built into the product.
 Each step of a manufacturing process is controlled to assure that the finished product
meets all quality attributes including specifications.
 Assures consistency of production process
 Demonstrates the capability of the commercial manufacturing process
to give a high degree of assurance of obtaining medicinal products
meeting the required quality attributes of safety, purity, and efficacy on
a continued basis.

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 …a meaningful process validation program based on the
assumption that “quality cannot be adequately assured merely by
in-process and finished-product inspection and testing”
 Offers assurance that a process is reasonably protected against
sources of variability that could affect production output, cause
supply problems, and negatively affect public health”.
 Proves that in spite of changes in operational parameters through
the necessary scale up of the production process, including new
facilities and equipment, the product characteristics will not vary.

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Lifecycle Approach : from R&D through clinical trials to
commercial scale
 “process validation should not be viewed as a one-time event but
rather as an activity that spans the product lifecycle linking product
and process development, validation of commercial manufacturing
process, and its maintenance during routine commercial production”

Life cycle approach

Product and Process Maintenance during

Validation of routine commercial
development commercial Mfg production: On-going
ICH Q8(R2) process verification

R&D Clinical trial Phase I, II, III Submission Commercial

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Knowledge and Risk based approach

Scientific Knowledge

Product Process

Risk based approach

 More scientific and risk based approach required for

Process validation- another new paradigm
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 Process validation (PV) stages

ICH Q8-11
PV Stage II
• Process description
• Process characterization • Definition of Operational Parameters • Change control
• Raw/ starting materials at commercial scale • Revalidation
• Extractables ,Leachables • Manufacturing of Consistency Lots program
• Seed bank • Manufacturing of Clinical Phase
• Cell lines, Cell bank Material • Continual
• Analytical methods • Bracketing, Family and Matrix monitoring
• Validation of production steps or Validation Approach
unit operations • Documentation Requirements
• Personnel Training and Qualification PV Stage III
• Process Technology Transfer
• Legacy products
• Design and Execution of Process
PV Stage I Validation Studies US FDA’s Continued
• Deviations Management Process Verification
• Final report
US FDA’s Process design

US FDA’s Process
Qualification *
Quality Risk Management applied

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CPP, CQA, Control strategy

 Critical process parameter (CPP):

 A process parameter whose variability has an impact on a critical quality attribute and
therefore should be monitored or controlled to ensure the process produces the desired
quality. (ICH Q8)

 Critical quality attribute (CQA):

 A physical, chemical, biological or microbiological property or characteristic that should be
within an appropriate limit, range, or distribution to ensure the desired product quality. (ICH
Q8)

 Control strategy:
 A planned set of controls, derived from current product and process understanding that
ensures process performance and product quality. The controls can include
parameters and attributes related to active substance and finished product materials
and components, facility and equipment operating conditions, in-process controls,
finished product specifications, and the associated methods and frequency of
monitoring and control. (ICH Q10)

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Quality Risk Management: applied through Life
cycle

 Critical quality attributes (CQA) identification

 Critical process parameters (CPP) identification
 Developing Control strategy including Process
validation
 Various tools can be applied:
 FMEA
 HACCP
 etc.

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 From Stephan Krause,
Medimmune, 201313
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 Process development, commercial
manufacturing capabilities, and the
quality system must be integrated in
order to achieve effective and compliant
commercial operations

 Process validation starts before

consistency lots are produced, and
continues during the commercial stage
during which the knowledge of the
product and process will continue to
increase.
 ..interdisciplinary approach incorporating
expertise from various disciplines (e.g.,
Engineering, Chemistry, Microbiology,
Statistics, Manufacturing, QC and QA)….
with full support by upper management.

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Common Sequence of
Process Validation Activities
(based on PDA´s Common
Timing of PV Enablers and
Deliverables to Validation
Stage Activities)

Validation of Production Processes for Vaccines for WHO

Prequalification- Compliance Expectations (Draft)
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Validation strategy
 Prospective validation
 Validation carried out before routine production of products intended for sale.
 Gold standard for both Traditional and Enhanced Mfg process

 Concurrent validation
 Validation carried out in EXCEPTIONAL CIRCUMSTANCES, justified on the
basis of significant patient benefit, where the validation protocol is executed
concurrently with commercialisation of the validation batches.

 Retrospective validation
 Existing process(es) in use but no formally documented process validation
 - Not acceptable

Not always magic number of THREE!

 Statistically sound number
 Bracketing approach possible
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Manufacturing process validation approach

 Traditional approach
 Prospective Process Validation
 Normally performed when the pharmaceutical development and/or process
development is concluded, after scale-up to production scale and prior to
marketing of the finished product.
 statistically sound number of PV batches,
 No. of batches depends on Process variability, complexity of the process/ product
and experience of manufacturer but should generally be a minimum of 3 batches.
 PV protocol includes Critical Quality Attributes, Critical Process Parameter and non
CQA, non CPP to be monitored, etc.

PIC/S EU GMP :Annex 15

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 Continuous process verification approach-
 An alternative approach to Traditional process validation in which
manufacturing process performance is continuously monitored and
evaluated. (ICH Q8)
 May be applicable for product developed by Quality by design (QbD),
Continuous process
 Required scientific control strategy,
 Involve monitoring of critical processing steps, and end point testing
of current production, to show that manufacturing process is in state
of control
 Hybrid approach
 Apply Traditional and Continuous verification approach for different
steps
PIC/S EU GMP :Annex 15
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 Design space verification
 Normally developed at laboratory or pilot scale.
 During scale-up, commercial process is conducted and validated in a specific
area of the design space, defined as the target interval or Normal Operating
Range (NOR).
 During product lifecycle, moving from one area to another within the design
space (i.e. change in the NOR) may represent higher or unknown risks not
previously identified during initial establishment of the design space.
 For this reason and depending on how the design space was originally
established and how the process was validated, there will be situations where it
will be necessary to confirm the suitability of the design space and verify that all
product quality attributes are still being met in the new area of operation within
the design space.

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Other requirements prior to PV

 Equipment, facilities, utilities and systems used for process

validation should be qualified.
 Test methods should be validated for their intended use .
 Batches manufactured by trained personnel –if done by
R&D, production personnel should be involved
 Qualified Raw mat,. Packaging mat. Quality Risk
Management applied

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 On-going Process Verification

 Ongoing Process Verification during Lifecycle

 Used throughout product lifecycle to support validated status of the
product as documented in the Product Quality Review.
 Incremental changes over time considered and the need for any
additional actions, e.g. enhanced sampling, should be assessed.

PIC/S EU GMP :Annex 15

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Manufacturing processes requiring validation

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 Process Validation :
What to validate and when?

 All product attributes and operational parameters should

be evaluated in terms of their roles in the process and
impact on the product or in-process material, and re-
evaluated as new information becomes available.
 This will contribute to identify critical operational
parameters.
 Therefore, PV activities may focus on those processes
which pose the greatest risk.

Validation of Production Processes for Vaccines for

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 Production processes to be validated (1/2)
 All critical biological processes are subject to process
validation.
 inoculation,
 multiplication,
 fermentation,
 cell disruption,
 inactivation,
 purification,
 virus removal,
 removal of toxic and harmful additives,
 filtration,
 formulation,
 aseptic filling,
 etc. WHO GMP for Biological Products Proposed replacement of:
TRS 822, Annex 1
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 Production processes to be validated (2/2)

 Some manufacturing processes requiring validation

covered in this WHO document:
Fermentation
Harvesting
Purification
Viral Clearance
Inactivation
Blending & Formulation
Lyophilization

Validation of Production Processes for Vaccines for

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Manufacturing control parameters to be validated

 may include:
 specific addition sequences,
 mixing speeds,
 time and temperature controls,
 limits of light exposure,
 containment and cleaning procedures.

WHO GMP for Biological Products Proposed replacement of:

TRS 822, Annex 1
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Biosafety concern

 Critical processes for inactivation or elimination of potentially harmful

microorganisms of Biosafety Risk Group 2 or above, including
genetically modified ones, are subject to validation.

 After initial validation, “Continued process verification” to be

implemented

WHO GMP for Biological Products Proposed replacement of:

TRS 822, Annex 1
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Process Revalidation

 May be triggered immediately by a process change, as part of the

change control system.

 In addition, because of the variability of processes, products and

methods, process revalidation may be conducted at
predetermined regular intervals according to risk considerations.

 A detailed review of all changes, trends and deviations occurring

within a defined time period (e.g. 1 year, based on the regular
Product Quality Review) may require process revalidation.
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Other Supportive Critical Processes requiring
Validation (1/2)
 Cleaning of product contact equipment
 Sanitization of areas
 Depyrogenation
 Sterilization
 Aseptic Filling or encapsulation process of Final Product

 Utilities, facility and equipment qualification, analytical assay

validation, and validation of computerized systems

Validation of Production Processes for Vaccines for WHO

Prequalification- Compliance Expectations (Draft)
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PIC/S 007-6: Aseptic Process Validation

 § 2.3.2 Validation of aseptic processes relies upon

 Prospective,
 Concurrent and
 Retrospective validation (not recommended for APV)
 Re-validation
.
.
 § 2.3.7 It is Sum total of all validation data providing
the necessary level of assurance for aseptically
produced products.

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 § 2.3.3 Prospective studies
Aseptic Process Validation:
Prospective studies

Product Prospective
IQ/OQ of new simulation process
or renovated validation with
facilities studies
original product
(Media Fills)

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 § 2.3.4 Concurrent validation
Aseptic Process Validation:
Concurrent validation

 § 2.3.4 Concurrent validation

Product
Concurrent
process
Qualified
validation with
facilities and simulation
product during
equipment studies routine
production

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 § 2.3.5 RE-VALIDATION

Aseptic Process Validation:

Monitoring Re-validation
Environment Routine
Regular maintenance and
Equipment performance requalification of
Disinfection cleaning & of process equipment
procedure Sterilisation eg.autoclave,
simulation HVAC, Oven, Water
studies systems, etc.
Container / closure
cleaning &
(Media Fills)
Sterility
sterilisation
testing
Regular integrity
testing of product
Re-validation filters, container/
after Changes closures, vent filters
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 § 2.3.8 Process simulation studies (Media fills)

Formulation

 Simulating the whole process in order to

evaluate the sterility confidence of the Filtration
process.
 Process simulation studies include formulation
(compounding), filtration and filling with suitable media. Filling
 Simulations made to ensure that the regular process for
commercial batches repeatedly and reliably produces the Using suitable
media
finished product of the required quality. Ensure
that
 However, each process simulation trial is unique and so it is
not possible to extrapolate these results directly to actual Regular process is
production contamination rates. REPEATEDLY and
RELIABLY produced product
of REQUIRED UALITY
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 Process simulation test -Media Fills

To verify WEAK points in the chains of linked factors/ activities/ processes

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Other Supportive Critical Processes requiring
Validation (2/2)
 The integrity and specified hold times of containers used
to store intermediate products should be validated
 unless such intermediate products are freshly prepared
and used immediately, as appropriate.

Validation of Production Processes for Vaccines for WHO

Prequalification- Compliance Expectations (Draft)
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WHO Pre-Qualification process Expectations

 During the manufacturing of Phase 3 clinical material,

consistency lots (i.e. PV lots) will be produced as part
of adequate validation studies.
 Validation studies be reviewed in detail by NRA and
NCL of country of origin before granting the marketing
authorization of the product.

Validation of Production Processes for Vaccines for WHO

Prequalification- Compliance Expectations (Draft)
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 WHO PQ process focuses on adequacy of the following
aspects:
 Inclusion of Risk assessment in validation studies,
 Conformance of current validation activities,
 Policies for routine validation and revalidation
 Change control and Deviation management
 Critical validation deviations like failure to have cleaning
validation of critical steps, inactivation validation, uncontrolled
risk of cross-contamination, etc.
 Continued process verification through trend analysis.

Validation of Production Processes for Vaccines for WHO

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Prequalification- Compliance Expectations (Draft) 39
Q&A

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