ICH Q12 - Step 4

Technical and
Regulatory
Considerations for
Pharmaceutical
Product Lifecycle
Management
ICH Q12 - Step 4
 ICH Q12 - Step 4
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 ICH Q12 - Step 4
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 ICH Q12 - Step 4
Background
 This document has been signed off as Step 4
document on 20 November 2019 to be implemented
by the ICH Regulatory Members
 This document was developed based on a Concept
Paper (9 September 2014) and Business Plan (9
September 2014)
 ICH Q12 - Step 4
Key Principles:
This guideline: Provides a framework to facilitate the
management of post approval Chemistry,
Manufacturing and Controls (CMC) changes in a more
predictable and efficient manner
 Presents a number of harmonized regulatory tools
and enablers with associated guiding principles
 ICH Q12 - Step 4
Demonstrates how increased product and process
knowledge can contribute to a more precise and
accurate understanding of which post-approval
changes require regulatory submission.

 Emphasizes the importance of an effective

pharmaceutical
quality systems in the management of changes
during the
product lifecycle.
 ICH Q12 - Step 4
Table of Contents –Core Guideline:
1. Introduction
- Objectives, Scope, Regulatory Tools and Enablers
2. Categorization of Post-Approval CMC Changes
3. Established Conditions
4. Post-Approval Change Management Protocol
5. Product Life-cycle Management Document
6. Pharmaceutical Quality System and Change
Management
7. Relationship Between Regulatory Assessment and
Inspection
 ICH Q12 - Step 4
Table of Contents –Core Guideline:
8. Structured Approaches for Frequent CMC Post-
Approval Changes
9. Stability Data Approaches to Support the Evaluation
of CMC Changes
10. Glossary
11. References
Appendix 1: CTD Sections that Contain ECs
Appendix 2: Principles of Change Management
 ICH Q12 - Step 4
Table of Contents – Annexure
 Annexure I – Illustrative Examples
 Identification of Established Conditions for the
Manufacturing
Process - Chemical Medicinal Product
 Identification of Established Conditions for the
Manufacturing
Process - Biological Medicinal Product
 Identification of Established Conditions for Analytical
Procedures
 PACMP Example 1
 PACMP Example 2
 Product Life-cycle Management Document -
 ICH Q12 - Step 4
Selected Acronyms and Definitions*:
Critical Process Parameter (CPP) – process
parameter whose variability has an impact on a
critical quality attribute and therefore should be
monitored or controlled to assure the process
produces the desired product quality. (ICH Q8(R2))
 Critical Quality Attribute (CQA) – a physical,
chemical, biological or microbiological property or
characteristic that should be within an appropriate
limit, range, or distribution to assure the desired
product quality. (ICH Q8(R2))
 ICH Q12 - Step 4
Selected Acronyms and Definitions*:
 Post-approval CMC commitment – commitment by
the MAH to undertake specific CMC activities to be
implemented during the commercial phase
 EC – Established Condition
 MAA – Marketing Authorisation Application
 MAH – Marketing Authorisation Holder
 PACMP – Post-approval Change Management
Protocol
 PLCM – Product Lifecycle Management
 PQS – Pharmaceutical Quality System
 ICH Q12 - Step 4
Introduction Chapter 1:- :
Objectives:
Harmonize management of post-approval CMC
changes…in a more transparent and efficient
manner…across ICH regions
Facilitate risk-based regulatory oversight
 Emphasize…control strategy as a key component of
the dossier
 Support continual improvement and facilitate
introduction of
innovation
Enhance use of regulatory tools for prospective
change
management…enabling strategic management of
 ICH Q12 - Step 4
Potential Benefits:-
Reduce unnecessary cost and time burdens on industry
and regulators, while assuring that patients have reliable
access to high quality medicinal products
 Support continual improvement, which can result in
decreased product variability and increased manufacturing
efficiency
 Help to mitigate drug shortages related to manufacturing
and quality issues
 Facilitate the introduction of innovations in manufacturing
 ICH Q12 - Step 4
Scope:
Pharmaceutical drug substances and products (both
chemical and biological) that require a marketing
authorisation
Drug-device combination products that meet the
definition
of a pharmaceutical or biological product
Does not include changes needed to comply with
Pharmacopoeial monographs
 ICH Q12 - Step 4
Categorisation of Post-Approval CMC
Changes -Chapter 2:-
Convergence toward risk-based categorization of
post-approval changes is encouraged as an
important step toward achieving the objectives of
Q12
CMC changes vary from low to high potential risk with
respect to product quality, safety, and efficacy
Guideline describes a framework that encompasses a
risk-based categorization for the type of
communication expected of the MAH with the
regulatory authority regarding CMC changes
 ICH Q12 - Step 4
 Prior-approval: Changes with sufficient risk to require
regulatory authority review and approval prior to
implementation
 Notification: Moderate- to low-risk changes that do not
require prior approval and generally require less information
to support the change
 These changes are communicated to the regulatory
authority as a formal notification that takes place within a
defined period of time before or after implementation,
according to regional requirements.
 In addition, the changes that are not required to be
reported to regulators are only managed and documented
within the PQS, but may be verified on routine inspection by
regulators
 ICH Q12 - Step 4
Established Conditions – Chapter 3
The concept of ECs provides a clear understanding
between the MAH and regulatory authorities
regarding the elements to assure product quality and
that involve a regulatory communication, if changed
This guideline describes how ECs are identified as
well as what information can be designated as
supportive information that would not involve a
regulatory communication, if changed. In addition,
guidance is included for managing revisions of the
ECs
 ICH Q12 - Step 4
Established Conditions – Chapter 3
ECs should not be confused with CMC regulatory
commitments (e.g., stability, post approval CMC
commitment, and other commitments) made by an
MAH to provide data or information to the regulatory
agency in an MAA.
 Such information, in the context of this guideline, is
considered supportive information
 Changes to CMC regulatory commitments are
managed according to existing regional regulations
and guidance
 ICH Q12 - Step 4
ECs are legally binding information considered
necessary to assure product quality
 As a consequence, any change to ECs necessitates
a submission to the regulatory authority
 All regulatory submissions contain a combination of
Ecs and supportive information
 Supportive information is not considered to be an
EC
 Appendix 1 provides an overview of CTD sections
that
generally contain ECs
 ICH Q12 - Step 4
Identifying ECs and the role of risk:
 The number of ECs and how they are defined will
vary based on a number of factors, including:
 product and process understanding
 characterization
 the company’s development approach, and
 potential risk to product quality
 Appropriate justification should be provided in
support of
the identification of ECs, the proposed reporting
categories for ECs, and those aspects that are not
ECs
 ICH Q12 - Step 4
ECs for manufacturing processes:
 Include individual unit operations and their sequence
in the manufacturing process
Comprise those inputs (e.g., process parameters,
material
attributes) and outputs (may include in-process
controls)
necessary to assure product quality
 Should consider the overall control strategy
 ICH Q12 - Step 4
ECs for manufacturing processes (cont.):
Process parameters that need to be controlled to
ensure that a product of required quality will be
produced should be considered ECs
 CPPs and other process parameters where an impact
on product quality cannot be reasonably excluded
should be identified as Ecs.
 ICH Q12 - Step 4
Identification of ECs draws upon:
 An initial risk assessment
 Prior knowledge
 Application of knowledge gained from executed
studies
 A criticality assessment that determines the level of
impact that a process parameter could have on
product quality
 Should account for severity of harm and whether the
ranges studied sufficiently account for the expected
variability in the EC.
 ICH Q12 - Step 4
Figure 1 : Decision Tree for Identification of ECs and
Associated Reporting Categories for Manufacturing
Process Parameters
 ICH Q12 - Step 4
Established Conditions – Chapter 3 (6)
ECs for manufacturing processes can vary based
on extent of knowledge:
 Parameter-based approaches
 Minimal approach, with a limited understanding of the
relationship between inputs and resulting quality
attributes, will include a large number of inputs (e.g.,
process parameters and material attributes) along
with outputs (including in-process tests)
 Enhanced approach with increased understanding of
interaction between inputs and product quality
attributes together with a corresponding control
strategy can lead to
identification of ECs that are focused on the most
important input parameters along with outputs, as
 ICH Q12 - Step 4
Established Conditions – Chapter 3 (6)
ECs for manufacturing processes can vary
based on extent of knowledge:
In a performance-based approach, ECs could be
primarily focused on control of process outputs
(e.g., attributes, measurements, responses) rather
than process inputs (e.g., process parameters and
material attributes)
 Enabled by knowledge gained from an enhanced
approach, a data-rich environment,
and an enhanced control strategy (e.g., models,
Process Analytical Technology (PAT))
 Different approaches can be used alone or in
combination
 ICH Q12 - Step 4
Established Conditions – Chapter 3 (7)
ECs for analytical procedures
 Include elements which assure performance of the
procedure
 Extent of ECs and reporting categories can vary
based on the degree of understanding of the
relationship between method parameters and method
performance, method complexity, and control
strategy.
 ICH Q12 - Step 4
Different approaches can be used to identify ECs:
 When more limited development studies have
been conducted this may result in a narrow
operating window to ensure method performance.
In such cases ECs may be more extensive with
fixed and/or tight conditions
 Enhanced understanding can lead to a wider
operating window that ensures method
performance, where ECs can be reduced and
focused on method performance (e.g., method
parameters acceptable ranges rather than set
points, performance criteria)
 ICH Q12 - Step 4
Established Conditions – Chapter 3 (8)
Reporting categories for post-approval changes:
Reporting category should consider:
 An assessment of the potential risk to product quality
associated with changing the EC
 The overall control strategy
 Risk assessment activities
 Should follow approaches described in ICH Q9 (Risk
Management)
 Output can include changes that range from high to
low risk to product quality
 Reporting category should be defined based on level
of potential risk; justification for the risk and proposed
reporting category should be provided in the MAA.
 ICH Q12 - Step 4
Established Conditions – Chapter 3 (9)
Revision of Ecs
It may be necessary to change approved ECs as a
result of knowledge gained during the product
lifecycle (e.g., manufacturing experience,
introduction of new technologies, or changes in the
control strategy)
ECs may be revised through:
 Appropriate post-approval regulatory submission
describing and justifying the change
 Submission of a PACMP, in the original MAA or as part
of a post approval submission, describing and
justifying a revision to Ecs
 Use of an approved post-approval regulatory
 ICH Q12 - Step 4
Post-Approval Change Management Protocol –Chapter 4
Regulatory tool that provides predictability regarding
the information required to support a CMC change
and the type of regulatory submission based on prior
agreement between the MAH and regulatory
authority
Enables planning and implementation of future
changes to Ecs in an efficient and predictable manner
May address one or more changes for a single
product, or may address one or more changes to be
applied to multiple products
May be submitted with the original MAA or
subsequently as a stand-alone submission
(supplement/variation)
 ICH Q12 - Step 4
Post-Approval Change Management Protocol –
Chapter 4 (2)
Step 1
Submission of a written protocol
 Proposed change(s) with rationale(s)
 Risk management activities
 Proposed studies and acceptance criteria to assess
the impact of the change(s)
 Other conditions to be met, if any
 The proposed reporting category
 Other supportive information
 Approved by regulator in advance of execution
 ICH Q12 - Step 4
Post-Approval Change Management Protocol –
Chapter 4 (2)
Step 2
Carry out tests and studies outlined in the protocol
If results/data generated meet the acceptance
criteria in the protocol and any other conditions are
met, submit to the regulatory authority according to
the category in the approved protocol
Depending on the reporting category, approval by the
regulatory authority may or may not be required prior
to implementation of the change
 ICH Q12 - Step 4
Product Lifecycle Management Document – Chapter 5
Serves as a central repository for:
 Ecs
 Reporting category for making changes to approved
Ecs
 PACMPs (when proposed), and
 Any post-approval CMC commitments
Encourages prospective lifecycle management
planning MAH
 Facilitates regulatory assessment and inspection
 Intended to enable transparency and facilitate
continuous improvement.
 ICH Q12 - Step 4
DHT Study Product Lifecycle Management (PLCM)
Document – Chapter 5 (2)
Submitting the PLCM document
 Initial PLCM document is submitted with the original
MAA, or
 With a supplement/variation for marketed products
when defining ECs
 ICH Q12 - Step 4
DHT Study Product Lifecycle Management (PLCM)
Document – Chapter 5 (2)
Maintenance of the PLCM Document
 Updated PLCM document should be included in post-
approval submissions for CMC changes
 MAH should follow regional expectations for
maintaining a revision history for the PLCM document
Format and Location of PLCM Document
 Tabular format recommended, but not mandatory
 Located in Module 3.2R; may be Module 1 in some
regions
 ICH Q12 - Step 4
Pharmaceutical Quality System and Change
Management – Chapter 6
An effective PQS as described in ICH Q10
(Pharmaceutical
Quality System) and compliance with regional
GMP requirements are necessary to gain full
benefit from this guideline
 ICH Q10 describes principles for the effective
management of CMC changes under the PQS
 This guideline provides recommendations for robust
change
management across single or multiple entities
involved in the manufacture of a pharmaceutical
product
 ICH Q12 - Step 4
Pharmaceutical Quality System and Change
Management – Chapter 6 (2)
 Appendix 2 elaborates on ICH Q10 principles and
describes how the PQS can be utilized effectively in
the application of Q12 concepts
 If a manufacturing site has deficiencies that do not
require regulatory action, but have an impact on the
effectiveness of change management, it may result in
restrictions on the ability to utilise flexibility in this
guideline
 ICH Q12 - Step 4
Pharmaceutical Quality System and Change Management –
Chapter 6 (2)
Maintaining an effective PQS is the responsibility of a
company manufacturing sites and MAH where relevant)
 Not the intent to require a specific inspection assessing the
state of
the PQS before the company can use the principles in ICH
Q12.
Implementation of robust change management across
multiple
sites (outsourced or not) is necessary
Changes to ECs should be communicated in a timely
fashion between the MAH and the regulators, and between
the MAH and the manufacturing chain (and vice versa)
 ICH Q12 - Step 4
DHT study Relationship Between Regulatory
Assessment and Inspection – Chapter 7
This guideline outlines the complementary roles of
regulatory assessment and inspection in the
oversight of post-approval changes; and how
communication between assessors and inspectors
facilitates the use of the tools included herein
Roles of regulatory assessment and inspection are
unchanged
Effective assessor-inspector communication can
facilitate regulatory oversight of product lifecycle
management
Communication is encouraged between regulators
across regions, in accordance with appropriate
 ICH Q12 - Step 4
Structured Approaches for Frequent CMC Post-
Approval Changes – Chapter 8
This guideline describes a strategy for a structured
approach applicable to frequent CMC changes, and a
discussion of data expectations, to enable the use of
immediate or other post-implementation notification.
Simplified approach to accomplish certain CMC
changes for products
whose marketing authorization did not involve
identification of ECs and reporting categories
Structured approach may be applied when a
company’s PQS change management process is
effective, in compliance with regional GMPs, and
incorporates an appropriate risk management system
 ICH Q12 - Step 4
Structured Approaches for Frequent CMC Post-
Approval Changes – Chapter 8
Structured approach describes scope and steps to be
followed including, where appropriate, data to be
generated and criteria to be met
 An example of this approach for certain analytical
procedure changes is described in Annex II
If the approach is followed and all criteria met,
change can be made with immediate or other post-
implementation notification, as appropriate
 ICH Q12 - Step 4
Stability Data Approaches to Support the Evaluation
of CMC Changes – Chapter 9
Stability data needed for submission to the regulatory
authority in support of a post-approval change is
established by regional regulations and guidance
This guideline provides additional science- and risk-
based that are relevant to strategies for confirmatory
stability studies to enable more timely
implementation of CMC changes
Scope and design of stability studies are informed by
the knowledge of and experience with the drug
product and drug substance acquired since
authorisation
 ICH Q12 - Step 4
Annex I
 This Annex contains illustrative examples of:
 Identification of established conditions and proposed
reporting categories for the manufacturing process
 Identification of established conditions and proposed
reporting categories for analytical procedures
 PACMPs
 Product Life cycle Management Document
 ICH Q12 - Step 4
Considerations:
 Are mock examples that are provided for illustrative
purposes; only suggest how the tools described in
chapters 3, 4, and 5 could be applied
 Should not be used as a template or the sole basis for
a regulatory submission.
 Reporting categories may differ across regions
depending on regional legislation, the nature of the
product, and the MAH’s demonstrated understanding
of the product, process, and analytical procedure
 ICH Q12 - Step 4
Annex II
This Annex describes an approach wherein specific
criteria are defined for changes to analytical
procedures used to test marketed products
If this approach is followed and all criteria are met,
the analytical procedure change can be made with
immediate or other post-implementation notification,
as appropriate, to the relevant regulatory authorities
Intent of this approach is to incentivise structured
implementation of at least equivalent analytical
procedures that are fit for purpose
 ICH Q12 - Step 4
Results of Public Consultation
Significant revisions as a result of public
consultation included:
 Removal of the terms “implicit” and “explicit” as they
referred to Ecs
 Removal of the term “key process parameter (KPP)”
and revision of text to better explain the concept of
critical process parameter and identification of ECs
for manufacturing processes.
 ICH Q12 - Step 4
Results of Public Consultation
Significant revisions as a result of public
consultation included:
 Revision of the description for identification of ECs for
analytical methods and development of an illustrative
example
 Revisions to the recommended content of the PLCM
document and agreement regarding the
recommended location within the CTD
 Revisions to clarify the use of tools described in the
guideline for master files
 ICH Q12 - Step 4
Considerations:
The ICH Q12 guideline should be applied in
conjunction with other ICH “Q” guidelines, including
Q8(R2), Q9, Q10, and Q11
See Chapters 3, 4, and 5 of the Core Guideline for
recommendations regarding the appropriate location
for information to be submitted within a dossier
 ICH Q12 - Step 4
Guidelines for Implementation:
MAHs wishing to use the tools and enablers described
in ICH Q12 should consult publicly available
information provided by regulatory authorities (e.g.,
see regulators’ websites) about the implementation
of ICH Q12 in their region, especially with regard to
regulatory considerations.
 ICH Q12 - Step 4
Conclusions:
Use of the harmonized regulatory tools and enablers
with
associated guiding principles described in this
guideline will enhance the management of post-
approval CMC changes, and transparency between
industry and regulatory authorities, supporting
innovation and continual improvement.
Team Work

R. K. Dhiman
Cont. No.: +919319758159
Mail id: [email protected]

Thanks