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PMDA Perspective:
Regulatory Updates on Process
Validation Standard
1
Disclaimer:
The views and opinions expressed in this presentation are those of the presenter and
does not necessarily represent the views and opinions of the PMDA.
Kazunobu Oyama, PhD Office of Cellular and Tissue-based Products
PMDA, Japan
CMC Strategy Forum Japan 2014
Tokyo, Japan, December 8-9, 2014
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Outline
1.CMC Development • Understanding of quality
• Knowledge control
• Technical transfer
• Lifecycle Management
2.Revision of validation standard in Japan • Point of the amendment
3.Summary
2
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3
Overall picture of CMC development
Non-
Clinical
Study
【Typical Development】
Establishment of Design Quality and
Product Quality by CMC study
Clinical Study
Phase 1 Phase 2 Phase 3
Investigational Product GMP GMP
Post-
Approval
Control strategy Control strategy Control strategy
Process Parameters CPP
CQA Quality Attributes
Knowledge Control/Quality Risk Management
Control Strategy
Equivalency Consistency
Target product Profile
Process
Validation
Approval
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4
S.2.6 Manufacturing Process Development ・Development Strategy ・CPP, CQA identification ・Control Strategy ・ Analytical Method ・Comparability ・・・・etc
S.2.5 Process Validation and/or Evaluation ・Control Strategy ・Demonstration of Validated State/State of Control ・Process design is evaluated to demonstrate that the
control strategy is capable of delivering the desired
product quality for commercial launch ・・・・etc
Matters of description on application form
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5
ICH Q11
7. Process Validation/Evaluation For biotechnological processes, or for aseptic
processing and sterilisation process steps for
drug substances, the data provided in support of
process validation is included as part of the
marketing application (3.2.S.2.5)
Matters of description on application form
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Design
Quality
Product
Quality
Quality
Management
Procedure
Equipment
Process
Material
Quality Risk Management / Knowledge Control
6
Quality of the manufacturing is affected by various factors. Understanding the variables in the process, it is possible
to be control it, leading to quality control.
Understanding of Product Quality
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Quality target product profile
Identify the critical quality attributes based on the potential risks
Linking material attributes and process parameters to CQAs, in this case, risk assessment is useful
Mathematical analysis model, design space or real-time release testing (not required)
Establishment of control strategy
Knowledge and understanding could facilitate continual improvement
QTPP
CQAs
Risk Management
Option
Continual improvement
QbD Approach
Control strategy
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Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
GMP
Quote or altered from ICH Q10 Annex2
Management Responsibilities
Process Performance and Product Quality Monitoring System
Corrective Action / Preventive action system
Change Management System
Management Review
Knowledge Management
Quality Risk Management
PQS elements
Enabler
Investigational
Products
ICH Q10 Pharmaceutical Quality System
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Review of CPP, DoE and Design Space.
Revalidation
Life cycle Management
Knowledge control
R&D Manufacturer
QTPP
Define Quality target product profike
CQA
Identify critical quality attributes
Risk assessment
DoE
Control Strategy
Process understanding, Knowledge accumulation
QbD information
Evaluation of impact
Process
Assay
Master plan of transfer
Justification of control strategy
Tech.Transfer (Design
Space)
CPP
QbD
Scale-up
PV
Re-
evaluation
Process
Monitoring
Development Stage Transfer Commercial
Manufacturing Stage
Accumulation and transfer of knowledge
Product quality review
Change management (impact
assessment)
Deviation management (CAPA)
Process
Monitoring
Re-
evaluation
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Tech.Transfer
Process
A
Process
B
10
Knowledge accumulated in the development department
and manufacturing department, important to support
consistently the robustness of the process C
Tech. Transfer
Report
Technical Transfer
R&D Manufacturer
Development Stage Transfer Commercial
Manufacturing Stage
Process
C
Knowledge of
Development stage
Knowledge of Commercial
Manufacturing Stage
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Development Stage Transfer Commercial
Manufacturing Stage continual improvement
Transfer of accumulated knowledge in the
commercial manufacturing stage
Feedback of knowledge
Review of CPP, DoE and Design Space.
Revalidation
Life cycle Management
Knowledge control
Re-
evaluation
Process
Monitoring
Product quality review
Change management (impact
assessment)
Deviation management (CAPA)
Process
Monitoring
Re-
evaluation
R&D
QTPP
Define Quality target product profike
CQA
Identify critical quality attributes
Risk assessment
DoE
Control Strategy
Process understanding, Knowledge accumulation
QbD information
Evaluation of impact
Process
Assay
Master plan of transfer
Justification of control strategy
Tech.Transfer (Design
Space)
CPP
QbD
Scale-up
PV
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Development Stage Transfer Commercial
Manufacturing
Stage
Commercial
Manufacturing
Stage
Complaint
CAPA
Process
development
Change
Management
CAPA CAPA CAPA
Process Monitoring
・Process improvement ・Control strategy improvement ・Revalidation
• Knowledge is continuously accumulated
• Quality system of GMP to feedback the
knowledge in process control is important New variation factors
Product Quality Review
Knowledge management in the lifecycle
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Non-Clinical Research
Clinical Research After the Launch
Stage2 Stage3
Investigational Product Production in Pilot
&/or Commercial Scale
PPQ
Commercial Lots
PhaseIII~
FDA’s PV GL
Knowledge Control in Research &/or Development Div.
Stage1
13
Scheme of Process Validation in FDA
Guidance for Industry
Process Validation: General Principles and Practices
Consistency of Process and Product Quality
Knowledge Control in Mfg. Plant
Tech. Transfer
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In August 30, 2013, validation standard have been revised.
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Administrative notice
(GMP Question and Answer)
Administrative notice
(MHLW Research Report)
GMP Ministerial
Ordinance
GMP Enforcement
Notification
Enforcement
Ordinance of PAL
Enforcement
Notification
and
Administrative
notice (ICH
Q7, Q8, Q9,
Q10, Q11)
JP General
Information
PIC/S GMP Guide
GMP Regulatory Framework in Japan
Pharmaceutical
Affairs Law (PAL)
GCP Ministerial
Ordinance
Notification
(JP, Standard for BI)
Enforcement Notification for
Investigational Product GMP Required
Ris
k-b
ased
Appro
ach
-
GMP Regulatory Framework in Japan
Administrative notice
(GMP Question and Answer)
Administrative notice
(MHLW Research Report)
GMP Ministerial
Ordinance
GMP Enforcement
Notification
Enforcement
Ordinance of PAL
Enforcement
Notification
and
Administrative
notice (ICH
Q7, Q8, Q9,
Q10, Q11)
JP General
Information
PIC/S GMP Guide
Pharmaceutical
Affairs Law (PAL)
GCP Ministerial
Ordinance
Notification
(JP, Standard for BI)
Enforcement Notification for
Investigational Product GMP Required
Ris
k-b
ased
Appro
ach
Validation standard (Basic requirements of Validation)
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(1) Objectives of validation
(2) Implementation subjects
(3) Procedure for validation
(4) Responsibilities of responsible person in
validation
(5) Implementation of validation
a) Qualification (DQ, IQ, OQ, PQ)
b) Process validation (PV)
c) Cleaning validation
d) Revalidation
e) validation on change control
Contents of Validation Standard
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Important Concept on Validation
1. Quality risk management
2. Technical transfer
3. Knowledge control through the product
quality review
4. Validation master plan
5. Continuous/Continued Process Verification
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• Activities of validation: – Implementation based the quality risk : ICH Q9 – Clarification of qualification (DQ / IQ / OQ / PQ)
– Master plan that summarizes the overall validation
• Product lifecycle: ICH Q10 – Technical transfer
– Feedback from product quality review
• Continuous process verification: ICH Q8, Q11
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Key Points of the amendment
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Implementation of QRM(ICH Q9) Risk Assessment
Risk Control
Risk Communication
Risk Review
Quality Risk Management (QRM) GMP is a quality management system, QRM on the GMP, is
essential elements that constitutes the manufacturing and quality
management.
QRM can be useful for identifying potential risks to quality,
establishing a scientific evaluation and control systems for the
manufacturing process.
QRM can be effective approaches for promoting continuous
improvement of performance of the manufacturing process and
product quality, thereby, manufacturers are intended to
encourage the use of science and risk based approaches on
GMP.
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Objectives of Validation
The purpose of validation is to verify that the manner of
manufacturing control and quality control on the facilities,
systems and equipment, procedures and processes achieve
the intended results, and documented the evidence that the
process, operated within established parameters, can
perform reproducibly to produce a product meeting its
predetermined specifications and quality attributes.
To achieve its purpose, all validation activities should be
considered using knowledge and information accumulated
throughout the product lifecycle, including medicinal product
development, process monitoring/process verification and
product quality review.
Implementation of validation
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Implementation of validation Process validation is to confirm that processes operating under
permissible parameters defined based on consideration for variable
factors (material attribute, operating conditions, etc.), which have been
predetermined as affecting product quality based on knowledge of
industrialization research and past manufacturing similar products, are
valid for consistently manufacturing products meeting its predetermined
specifications and quality attributes, and these are documented.
(1) Before starting process validation, confirm that qualification of the
facilities, system or equipment used for validation has been
appropriately completed, and evaluate the validity of the test
method used to evaluate validation.
(2) Batches made for process validation should be the same size as
the intended industrial scale batches. It is generally considered
acceptable that three consecutive batches within the finally agreed
parameters or equivalent approaches would constitute a validation
of the process.
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It might be acceptable for an equivalent approach as an
alternative to process validation of three consecutive batches
with same size as the intended industrial scale, if the
manufacturing process has been developed based on the
"enhanced approach" of ICH Q11 can be verified according to
continuous process verification (ICH Q8).
Continuous process verification can be acceptable to utilize,
where development is conducted on the basis of the "enhanced
approach" and control strategy have been established. If going
to adapt the CPV for existing products, it is necessary to develop
a manufacturing process and control strategy based on the ICH
Q11.
Application of Continuous/Continued Process Verification
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Points to consider on implementation of process validation in the
application of the continuous process verification is as follows,
It needs to be appropriately evaluated at each stage of process
validation throughout the product lifecycle, process design,
process performance qualification, continued process verification.
It is necessary to describe the validation plan applying continuous
process verification.
It is necessary to verify consistency of process through the
product life cycle, according to review the products quality on the
basis of data obtained from continuous monitoring. Justification of
the control strategy which subsequently yields reproducibly a
product meeting its predefined quality criteria should be evaluated
by the product quality review, as a result, revalidation will be
performed.
Application of Continuous/Continued Process Verification
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Product Quality Review
Report of Research and Development
Process Research
Process Validation
Overall picture of activities through the product life cycle
Cycle that connects
development and
commercial production
Commercial Production Development
Technical Transfer
Technical Transfer
Technical Transfer
Knowledge
Quality Improvement
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Research and Development Transfer
Commercial Manufacturing
Investigational products’ Production
(Pilot &/or Commercial Scale)
PV
(PPQ)
Commercial Batches Manufacturing
Consistency of Process and Product Quality
Validation ・Qualification of Equipment ・Process Validation/Verification ・Change Control ・Revalidation
Manufacturing Process Design 【Development】
Manufacturing Process
【Improvement】
Manufacturing Process
【Verification】
Stage
Knowledge Control and Tech. Transfer
Activity
Approach of Evaluation
Verification Process, Cleaning method of
Investigational product
Validation Analytical method, Computer Systems,
Sterility assurance, etc.
Knowledge Control in Research &/or
Development Div.
Knowledge Control in
Mfg. Plant
Technical
Transfer
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Summary
Manufacturing Process
【Process Monitoring】
Control Strategy
Control Strategy
Knowledge Control
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Thank you for
your attention!
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