Q12 Technical and Regulatory 
Considerations for 
Pharmaceutical Product 
Lifecycle Management 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2021 
ICH 
 
    
Q12 Technical and Regulatory 
Considerations for 
Pharmaceutical Product 
Lifecycle Management 
 
Guidance for Industry 
 
 
 
Additional copies are available from: 
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Food and Drug Administration 
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U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2021 
ICH
  Contains Nonbinding Recommendations 
 
FOREWORD 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.  
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry.  
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1) ....................................................................................................... 1 
A.  Objectives (1.1) ............................................................................................................................... 1 
B.  Scope (1.2) ....................................................................................................................................... 2 
C.  ICH Q12 Regulatory Tools and Enablers (1.3) ........................................................................... 2 
II.  CATEGORIZATION OF POSTAPPROVAL CMC CHANGES (2) .......................... 4 
III.  ESTABLISHED CONDITIONS...................................................................................... 6 
A.  Introduction (3.1) ........................................................................................................................... 6 
B.  ECs in the Regulatory Submission (3.2)....................................................................................... 6 
1. ECs Definition (3.2.1) ...................................................................................................................... 6 
2. ECs in a Regulatory Dossier (3.2.2) ................................................................................................ 6 
3. Identification of ECs (3.3.3)............................................................................................................. 7 
4. Revision of ECs (3.2.4) .................................................................................................................. 10 
C.  Roles and Responsibilities (3.3) .................................................................................................. 11 
IV.  POSTAPPROVAL CHANGE MANAGEMENT PROTOCOL (4) .......................... 11 
A.  Definition of a PACMP (4.1) ....................................................................................................... 11 
B.  Application of a PACMP (4.2) .................................................................................................... 12 
C.  Elements of a PACMP (4.3) ........................................................................................................ 13 
D.  Modification of an Approved PACMP (4.4) .............................................................................. 14 
E.  Types of PACMPs (4.5) ............................................................................................................... 14 
V.  PRODUCT LIFECYCLE MANAGEMENT DOCUMENT (5) ................................. 14 
A.  PLCM Document: Scope (5.1) .................................................................................................... 15 
B.  Submitting the PLCM Document (5.2) ...................................................................................... 15 
C.  Maintenance of the PLCM Document (5.3) ............................................................................... 15 
D.  Format and Location of PLCM Document (5.4) ....................................................................... 15 
VI.  PHARMACEUTICAL QUALITY SYSTEM AND CHANGE MANAGEMENT (6)
  16 
A.  PQS General Considerations (6.1) .............................................................................................. 16 
B.  Change Management Across the Supply Chain and Product Lifecycle (6.2) ......................... 17 
VII.  RELATIONSHIP BETWEEN REGULATORY ASSESSMENT AND 
INSPECTION (7) ........................................................................................................................ 18 
VIII.  STRUCTURED APPROACHES FOR FREQUENT CMC POSTAPPROVAL 
CHANGES (8) ............................................................................................................................. 18 
i  Contains Nonbinding Recommendations 
 
IX.  STABILITY DATA APPROACHES TO SUPPORT THE EVALUATION OF CMC 
CHANGES (9) ............................................................................................................................. 19 
X.  GLOSSARY (10) ............................................................................................................. 20 
XI.  REFERENCES (11) ........................................................................................................ 21 
APPENDIX 1.  COMMON TECHNICAL DOCUMENT SECTIONS THAT CONTAIN 
ESTABLISHED CONDITIONS................................................................................................ 22 
APPENDIX 2.  PRINCIPLES OF CHANGE MANAGEMENT ........................................... 29 
ii  Contains Nonbinding Recommendations 
 
Q12 Technical and Regulatory Considerations for Pharmaceutical 
Product Lifecycle Management 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION (1)2, 3  
 
A.  Objectives (1.1) 
 
This guidance provides a framework to facilitate the management of postapproval chemistry, 
manufacturing, and controls (CMC) changes in a more predictable and efficient manner.  A 
harmonized approach regarding technical and regulatory considerations for lifecycle 
management will benefit patients, industry, and regulatory authorities by promoting innovation 
and continual improvement in the pharmaceutical sector, strengthening quality assurance, and 
improving supply of medicinal products. 
 
The concepts outlined in prior ICH Quality guidances for industry (ICH Q8(R2), Q9, Q10, and 
Q11) provide opportunities for science- and risk-based approaches for use in drug development 
and regulatory decisions.  These guidances are valuable in the assessment of CMC changes 
across the product lifecycle.  ICH Q8(R2) and Q11 guidances focus mostly on early stage aspects 
of the product lifecycle (i.e., product development, registration, and launch).  This guidance 
addresses the commercial phase of the product lifecycle (as described in ICH Q10) and it both 
 
1 This guidance was developed within the Expert Working Group (Quality) of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and has been subject to 
consultation by the regulatory parties, in accordance with the ICH process.  This document has been endorsed by the 
ICH Steering Committee at Step 4 of the ICH process, November 2019.  At Step 4 of the process, the final draft is 
recommended for adoption to the regulatory members of the ICH regions. 
 
2 This guidance is intended to be considered in conjunction with the ICH Q12 Annexes being simultaneously 
published as a final guidance (see Q12 Technical and Regulatory Considerations for Pharmaceutical Product 
Lifecycle Management  Annexes (May 2021).  We update guidances periodically.  For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
3 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering Committee at 
Step 4 of the ICH process, November 2019. 
 
  1  Contains Nonbinding Recommendations 
 
complements and adds to the flexible regulatory approaches to postapproval CMC changes 
described in ICH Q8(R2) and Q10 Annex 1. 
 
This guidance is also intended to demonstrate how increased product and process knowledge can 
contribute to a more precise and accurate understanding of which postapproval changes should 
result in a regulatory submission as well as the definition of the levels of reporting categories for 
such changes (i.e., a better understanding of risk to product quality).  Increased knowledge and 
effective implementation of the tools and enablers described in this guidance should enhance 
industrys ability to manage many CMC changes effectively under the companys 
Pharmaceutical Quality System (PQS) with less need for extensive regulatory oversight prior to 
implementation.  This approach can incentivize continual improvement by providing an 
opportunity for greater flexibility in making postapproval changes.  It could also result in fewer 
associated postapproval submissions to the Marketing Authorization Application (MAA) and 
less associated regulatory burden.  The extent of this operational and regulatory flexibility and its 
adequate implementation is subject to the regulatory framework in place, as well as product and 
process understanding (ICH Q8(R2) and Q11), application of quality risk management principles 
(ICH Q9), and an effective PQS (ICH Q10). 
 
Regulatory Members of ICH are encouraged to provide publicly available information, 
preferably on their website, about the implementation of ICH Q12 in their region, especially with 
regard to regulatory considerations. 
 
The contents of this document do not have the force and effect of law and are not meant to bind the 
public in any way, unless specifically incorporated into a contract. This document is intended only to 
provide clarity to the public regarding existing requirements under the law. FDA guidance 
documents, including this guidance, should be viewed only as recommendations, unless specific 
regulatory or statutory requirements are cited. The use of the word should in Agency guidances 
means that something is suggested or recommended, but not required.  
 
B.  Scope (1.2) 
 
This guidance applies to pharmaceutical drug substances4 and products (both chemical and 
biological) that require a marketing authorization and to drug-device combination products that 
meet the definition of a pharmaceutical or biological product.  Changes needed to comply with 
new or revised pharmacopoeial monographs are not within the scope of this guidance. 
 
C.  ICH Q12 Regulatory Tools and Enablers (1.3) 
 
Use of the following harmonized regulatory tools and enablers with associated guiding 
principles, as described in this guidance, will enhance the management of postapproval changes 
 
4  For drug substance information incorporated by reference (e.g., a Master File) in an MAA, the holder of the 
referenced information may use Q12 tools where applicable.  Use of Q12 tools is not intended to change the 
responsibilities of the holder of the referenced information, the Marketing Authorization Holder (MAH), or the 
regulatory authority.  For example, the holder of the referenced information has a responsibility to report relevant 
drug substance changes to the MAH referencing their submission (21 CFR 314.420(c)) so that the MAH can 
assess the impact of the change and report any related changes to the approved MAA, as necessary and per 
regional requirements. 
  2  Contains Nonbinding Recommendations 
 
and transparency between industry and regulatory authorities, supporting innovation and 
continual improvement: 
 
  Categorization of Postapproval CMC Changes (section II)Describes a framework 
that encompasses a risk-based categorization for the type of communication expected 
of the Marketing Authorization Holder (MAH) with the regulatory authority 
regarding CMC changes. 
 
  Established Conditions (section III)The concept of Established Conditions (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 section 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 
to ECs. 
 
  Postapproval Change Management Protocol (section IV)The Postapproval Change 
Management Protocol (PACMP) is a 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.  Such a mechanism enables planning and implementation of future changes 
to ECs in an efficient and predictable manner. 
 
  Product Lifecycle Management Document (section V)The Product Lifecycle 
Management (PLCM) document serves as a central repository for ECs and the 
associated reporting category for changes made to ECs.  The document also captures 
how a product will be managed during the commercial phase of the lifecycle, 
including relevant postapproval CMC commitments and PACMPs. 
 
  Pharmaceutical Quality System and Change Management (section VI)An effective 
PQS as described in ICH Q10 and compliance with regional good manufacturing 
practices (GMPs) are necessary to gain full benefit from this guidance.  In particular, 
management of manufacturing changes across the supply chain is an essential part of 
an effective change management system.  This guidance provides recommendations 
for robust change management across single or multiple entities involved in the 
manufacture of a pharmaceutical product. 
 
  Relationship Between Regulatory Assessment and Inspection (section VII)This 
section outlines the complementary roles of regulatory assessment and inspection in 
the oversight of postapproval changes and how communication between assessors and 
inspectors facilitates the use of the tools included herein. 
 
  Structured Approaches for Frequent CMC Postapproval Changes (section VIII)In 
addition to other tools described above, this section describes a strategy for a 
structured approach applicable to frequent CMC changes and a discussion of data 
  3  Contains Nonbinding Recommendations 
 
expectations to enable the use of immediate or other post-implementation 
notification. 
 
  Stability Data Approaches to Support the Evaluation of CMC Changes (section IX)
This section provides additional science- and risk-based approaches that are relevant 
to strategies for confirmatory stability studies to enable more timely implementation 
of CMC changes. 
 
Tools and enablers described above are complementary and are intended to link different phases 
of the product lifecycle.  Pharmaceutical development activities result in an appropriate control 
strategy, elements of which are considered to be Established Conditions.  All CMC changes to 
an approved product are managed through a companys Pharmaceutical Quality System; 
changes to ECs must also be reported to the regulatory authority.5  Where the regulatory system 
provides for Categorization of Postapproval CMC Changes for reporting according to risk, 
the MAH may propose reporting categories for changes to ECs based on risk and knowledge 
gained through enhanced pharmaceutical development.  A system with risk-based reporting 
categories also facilitates the use of Postapproval Change Management Protocols, which 
provide predictability regarding planning for future changes to ECs.  The Product Lifecycle 
Management Document is a summary that transparently conveys to the regulatory authority 
how the MAH plans to manage postapproval CMC changes.  The tools and enablers in this 
guidance do not change the Relationship Between Regulatory Assessment and Inspection; 
however, collaboration and communication between assessors and inspectors are necessary for 
the implementation of this guidance by regulators.  This guidance provides Structured 
Approaches for Frequent CMC Postapproval Changes to enable the implementation of 
certain CMC changes for authorized products without the need for prior regulatory review and 
approval.  Finally, this guidance provides Stability Data Approaches to Support the 
Evaluation of CMC Changesi.e., where the stability study is undertaken to confirm 
previously approved storage conditions and shelf life. 
 
 
II.  CATEGORIZATION OF POSTAPPROVAL CMC CHANGES (2) 
 
Regulatory mechanisms that allow the timely and efficient introduction of CMC changes are 
important for drug quality, safety, and availability.  There is a range of potential CMC changes 
for which communication between a company and the regulatory authority is required.  CMC 
changes vary from low to high potential risk with respect to product quality, safety, and efficacy.  
A well-characterized, risk-based categorization of regulatory communication requirements is 
important to the efficient use of industry and regulatory resources. 
 
In such a regulatory system, the types of CMC changes that occur during the commercial phase 
of the pharmaceutical product lifecycle that invoke communication with regulatory authorities 
are classified with regard to the potential to have an adverse effect on product quality of the drug 
product.  The regulatory communication category, supporting information/documentation 
 
5 See 21 CFR 314.70(a) and 601.12(a). 
  4  Contains Nonbinding Recommendations 
 
requirements, and associated time frame for evaluation are commensurate with that potential 
risk.  Based on potential risk, an inspection may be needed. 
 
Regulatory authorities are encouraged to utilize a system that incorporates risk-based regulatory 
processes for (a) requesting prior approval from the regulatory authority, (b) notifying the 
regulatory authority, or (c) simply recording CMC changes, with associated information 
requirements and, where applicable, time frames for decision.  Such a system would include the 
following categories for regulatory communications, with one or more levels in each case:  
 
  Prior approvalCertain changes are considered to have sufficient risk to require 
regulatory authority review and approval prior to implementation and are requested by 
the MAH in a suitably detailed regulatory submission. 
 
  NotificationCertain moderate- to low-risk changes are judged to 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.  A mechanism for immediate notification is useful when prior approval is 
not required, but timely awareness of the change by the regulator is considered necessary. 
 
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 during routine or other inspection. 
 
Harmonization or convergence toward a system of risk-based categorization of postapproval 
changes is encouraged as an important step toward achieving the objectives of this guidance.  
Such a system provides inherent, valuable flexibility in regulatory approach and a framework 
that can support additional regulatory opportunities, such as: 
 
  Facilitating the use of tools and enablers described in this guidance by providing a range 
of request and notification categories available as a target for a lowering of regulatory 
submission requirements. 
 
  The use of a lower category for request/notification if certain criteria/conditions are met 
and the relevant supporting documentation is provided as described in regional regulatory 
guidance; the need for regulatory inspection associated with the change may preclude the 
ability to use a lower category. 
 
  Providing options for converging to the same or similar reporting category as in other 
jurisdictions.  
 
A risk-based categorization system may be accomplished by having the principles captured in 
regulations with further details in guidance, as appropriate, which can provide additional 
flexibility to modify expectations as science and technology evolve.  For examples of risk-based 
categorization systems, refer to the existing regulations and guidance of ICH members, and 
World Health Organization (WHO) guidelines and guidance on changes to authorized products. 
 
  5  Contains Nonbinding Recommendations 
 
 
III.  ESTABLISHED CONDITIONS (3) 
 
A.  Introduction (3.1) 
 
This guidance establishes a harmonized approach to defining which elements in an application 
are considered necessary to assure product quality and therefore would require a regulatory 
submission if changed postapproval.  These elements are being defined in this guidance as 
Established Conditions for Manufacturing and Control (referred to as ECs throughout this 
guidance).  
 
B.  ECs in the Regulatory Submission (3.2) 
 
1.  ECs Definition (3.2.1) 
 
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.   
 
2.  ECs in a Regulatory Dossier (3.2.2) 
 
This section describes scientific risk-based approaches which can be used when defining ECs 
and their reporting categories.  Regional legal frameworks, supplemented through regulation and 
guidance, may define ECs with their reporting categories and/or may allow the scientific risk-
based approaches described in this section to be considered. 
 
All regulatory dossiers contain a combination of ECs and supportive information.  Supportive 
information is not considered to be ECs but is provided to share with regulators the development 
and manufacturing information at an appropriate level of detail.  Knowledge gained throughout 
the product lifecycle (including pharmaceutical development and characterization of chemical 
and biological drug substance and drug product) is the basis for identifying the elements of CMC 
that are ECs and those elements which are supportive information. 
 
An MAH should clearly identify the elements of CMC which they consider to be ECs and those 
which they consider to be supportive information.  The rationales for the ECs are provided in the 
appropriate Common Technical Document (CTD) modules. 
 
Similarly, the rationales for the associated reporting categories for changes to the ECs should be 
provided in the appropriate CTD modules.  The regulator assesses the ECs with respect to 
established scientific guidelines.  Where appropriate, regulators approve the EC and associated 
reporting category in line with the principles outlined in section II.  
 
See Appendix 1 for more information regarding sections of the dossier that contain ECs and 
supportive information.  Unless otherwise specified by regulatory requirement, identifying ECs 
for a given product is not mandatory. 
 
  6  Contains Nonbinding Recommendations 
 
ECs should not be confused with CMC regulatory commitments (e.g., stability, postapproval 
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 guidance, is 
considered supportive information.  Changes to CMC regulatory commitments are managed 
according to existing regional regulations and guidance. 
 
3.  Identification of ECs (3.3.3) 
 
This section outlines approaches to define ECs for manufacturing processes and analytical 
procedures.  A similar approach can be used to define other types of ECs (e.g., performance of 
the container closure system, device elements of drug-device combination products) and should 
be justified by the applicant and approved by the regulatory agency. 
 
The extent of ECs may vary based on the companys development approach, product and process 
understanding, and the 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. 
 
a.  Identification of ECs for manufacturing processes (3.2.3.1) 
 
A control strategy is designed to ensure that a product of required quality will be produced 
consistently (ICH Q8(R2)).  It is a planned set of controls, derived from current product and 
process understanding, that assures process performance and product quality.  The controls can 
include parameters and attributes related to drug substance and drug 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). 
 
The ECs for a manufacturing process should be defined based on product and process 
understanding, taking into account all of the relevant elements of the control strategy.  In 
addition to the unit operation and the sequence of steps, and in considering the overall control 
strategy, ECs proposed and justified in a manufacturing process description should be those 
inputs (e.g., process parameters, material attributes) and outputs (that may include in-process 
controls) that are necessary to assure product quality. 
 
Process parameters that need to be controlled to ensure that a product of required quality will be 
produced should be considered ECs.  These ECs are identified through an initial risk assessment 
and application of knowledge gained from executed studies, prior knowledge, and a criticality 
assessment that determines the level of impact that a process parameter could have on product 
quality.  The criticality assessment should account for severity of harm and whether the ranges 
studied sufficiently account for the expected variability in the EC.  Critical process parameters 
(CPPs) and other process parameters where an impact on product quality cannot be reasonably 
excluded should be identified as ECs. 
 
Once ECs are identified, an updated assessment of the potential risk to product quality associated 
with changing the EC, taking into account the overall control strategy, informs the reporting 
category for the EC.  The assessment of potential risk is derived from risk management activities 
  7  Contains Nonbinding Recommendations 
 
as described in ICH Q9.  The output of the risk assessment can include changes to manufacturing 
process ECs that range from high to low risk to product quality.  The reporting category should 
be defined based on level of risk.  A justification of the potential risk associated with changing 
ECs and corresponding reporting categories should be provided. 
 
A decision tree which illustrates the above step-wise approach to identifying ECs and reporting 
categories for process parameters is shown in Figure 1.  The principles in the decision tree can be 
applied to identify ECs for other parts of the manufacturing process and control strategy (e.g., 
relevant elements of input material attributes, equipment, and in-process controls) and associated 
reporting categories. 
 
Figure 1: Decision Tree for Identification of ECs and Associated Reporting Categories for 
Manufacturing Process Parameters 
 
 
The details of ECs and the associated reporting category will depend on the extent to which the 
company can apply knowledge from product and process understanding (i.e., development and 
experience accumulated throughout the product lifecycle) to manage the risks to product quality.  
Different approaches can be used alone, or in combination, to identify ECs for manufacturing 
processes; these include, but are not limited to, the following: 
 
  Parameter-based approaches, including: 
 
  8  Contains Nonbinding Recommendations 
 
  A minimal approach,6 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). 
 
  An 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 appropriate. 
 
  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).  This is enabled by knowledge gained 
from an enhanced approach, a data-rich environment, and an enhanced control strategy 
(e.g., models, Process Analytical Technology (PAT)).  For example, a performance-based 
approach could be considered for manufacturing process steps with in-line monitoring of 
relevant attributes or with feedback controls or optimization algorithms to achieve the 
relevant targets for that process step.  When considering this approach, it is important to 
ensure that all relevant parameters and material attributes that have a potential to impact 
product quality are monitored and the equipment used remains qualified in order to 
assure a stable process.  It should be noted that not all elements of the decision tree in 
Figure 1 apply because the enhanced control strategy used may remove the need for 
certain process parameters to be ECs. 
 
Use of this guidance should not lead to providing a less detailed manufacturing process 
description in the MAA.  A suitably detailed description of the manufacturing process in Module 
3 is expected to provide a clear understanding regardless of the approach used to identify ECs for 
manufacturing process parameters.  Manufacturing process descriptions include supportive 
information as well as identified ECs.  Information regarding product-specific postapproval 
change activities, such as post-change monitoring, may be provided as supporting information to 
aid in the determination of ECs and associated reporting categories.  Criticality and risk should 
be periodically reviewed (as expected by ICH Q10) during the lifecycle of the product and the 
ECs and reporting categories should be updated based on acquired knowledge.  
 
When implementing the change, and consistent with Appendix 2, an MAH should consider the 
impact of the planned change, whether concurrent changes are planned, and whether the 
originally proposed reporting category should be revised. 
 
This guidance does not impose additional regulatory filing expectations for process ECs due to 
non-conformance during routine operations.  Non-conformance to process-related ECs should be 
handled in accordance with GMP regulations (i.e., deviation/non-conformance handling 
process). 
 
 
6 Also referred to as traditional approach in ICH Q11. 
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b.  Identification of ECs for analytical procedures (3.2.3.2) 
 
Similar to the principles described for manufacturing process, ECs related to analytical 
procedures should include elements which assure performance of the procedure.  The extent of 
ECs and their reporting categories could vary based on the degree of understanding of the 
relationship between method parameters and method performance, the method complexity, and 
control strategy.  A justification to support the identification of ECs and corresponding reporting 
categories for changes to ECs based on risk management should be provided. 
 
Different approaches can be used to identify ECs for analytical proceduresfor example as 
analytical technology and development approaches advance; these approaches include, but are 
not limited to, the following: 
 
  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 parameter acceptable ranges rather than set points, performance criteria).  
 
Use of this guidance should not lead to providing a less detailed description of analytical 
procedures in the MAA.  A suitably detailed description of the analytical procedures in Module 3 
is expected to provide a clear understanding regardless of the approach used to identify ECs for 
analytical procedures.  Description of analytical procedures includes supportive information as 
well as identified ECs. 
 
4.  Revision of ECs (3.2.4) 
 
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). 
 
Options available for the MAH to change approved ECs and to revise the associated reporting 
category for approved ECs include: 
 
  Submission of an appropriate postapproval regulatory submission describing and 
justifying the proposed revision to the approved ECs.  Justification may include 
information such as validation data and batch analyses. 
 
  Submission of a PACMP, in the original MAA or as part of a postapproval submission, 
describing a revision to ECs or reporting categories and how the change will be justified 
and reported. 
 
  Use of an approved postapproval regulatory commitment, as appropriate. 
 
  10  Contains Nonbinding Recommendations 
 
C.  Roles and Responsibilities (3.3) 
 
The management of all changes to, and maintenance of, the approved marketing authorization is 
the responsibility of the MAH.  There is a joint responsibility to share and utilize information 
between the MAH and any manufacturing organizations to assure that the marketing 
authorization is maintained and reflects current operations, and that changes are implemented 
appropriately across relevant sites.  Maintenance of the marketing authorization should follow 
regional expectations.  See section VI for information related to interactions between an MAH 
and any manufacturing organizations. 
 
For any referenced submission (e.g., Type II Drug Master File, Active Substance Master File) in 
an MAA, the holder of the referenced submission has a responsibility to communicate changes to 
their ECs to the MAH referencing their submission (21 CFR 314.420(c)) so that the MAH can 
assess the impact of the change and report any related change to the ECs found in the approved 
MAA, as necessary and per regional requirements. 
 
The approval of ECs and subsequent changes to ECs is the responsibility of the regulatory 
authorities. 
 
 
IV.  POSTAPPROVAL CHANGE MANAGEMENT PROTOCOL (4) 
 
A.  Definition of a PACMP (4.1) 
 
A PACMP is a regulatory tool that provides predictability and transparency in terms of the 
requirements and studies needed to implement a change as the approved protocol provides an 
agreement between the MAH and the regulatory authority.  A protocol describes the CMC 
change an MAH intends to implement during the commercial phase of a product lifecycle; how 
the change would be prepared and verified, including assessment of the impact of the proposed 
change; and the suggested reporting category in line with regional regulations and guidance
i.e., a lower reporting category and/or shortened review period as compared to similar change 
procedures without an approved PACMP.  The PACMP also identifies specific conditions and 
acceptance criteria to be met.  A PACMP can address one or more changes for a single product 
or may address one or more changes to be applied to multiple products (see section IV.E).  The 
PACMP may be submitted with the original MAA or subsequently as a stand-alone submission 
and can be proposed independent of any prior identification of ECs.  The PACMP requires 
approval by the regulatory authority, and the conditions and acceptance criteria outlined in the 
protocol must be met and results communicated to the regulatory authority in the manner 
previously agreed upon, in order to implement the change(s).7 
 
A PACMP should describe changes with a level of detail commensurate with the complexity of 
the change.  Once approved, there is an expectation that the validity of the proposed approach 
and control strategy be confirmed prior to implementation of the change(s).  For example, if new 
information becomes available following approval of the protocol, the risk assessment provided 
 
7 See 21 CFR 314.70(e) and 601.12(e). 
  11  Contains Nonbinding Recommendations 
 
in the initial PACMP submission should be reviewed by the MAH before implementing the 
change(s) to ensure that the outcomes of that risk assessment as they pertain to the planned 
change(s) are still valid.  If the review of the initial risk assessment indicates an increased level 
of risk associated with execution of the change, the previously approved reporting category 
should no longer be considered appropriate; instead, existing regional regulation or guidance 
should be followed or the relevant regulatory authority consulted. 
 
The MAH is responsible for ensuring that whenever a CMC change is to be introduced under a 
PACMP, the facility meets the regulatory requirements of the regulatory jurisdiction where the 
PACMP was approved with respect to GMP compliance, and inspection or licensing status.  
 
B.  Application of a PACMP (4.2) 
 
The application of a PACMP process typically involves the following two steps: 
 
  Step 1:  Submission of a written protocol that describes the proposed change(s), its 
rationale(s), risk management activities, proposed studies and acceptance criteria to 
assess the impact of the change(s), other conditions to be met (e.g., confirmation that 
there is no change to the approved specification), the proposed reporting category for the 
change(s), and any other supportive information (see also below).  The 
PACMP document can be located in CTD Module 3.2.R.8  This protocol is reviewed and 
approved by the regulatory authority in advance of execution of the protocol. 
 
  Step 2:  The tests and studies outlined in the protocol are performed.  If the results/data 
generated meet the acceptance criteria in the protocol and any other conditions are met, 
the MAH submits this information to the regulatory authority according to the 
categorization (classification) in the approved protocol for review by the regulatory 
authority as appropriate.  Depending on the reporting category, approval by the 
regulatory authority may or may not be required prior to implementation of the change.  
If the acceptance criteria and/or other conditions in the protocol (see step 1) are not met, 
the change cannot be implemented using this approach and should instead follow existing 
regulation or guidance and the associated reporting category. 
 
Significant changes to the manufacturing process or controls that were not anticipated in 
PACMP step 1 (e.g., change of order of unit operations) cannot be implemented as part of step 2 
and should be the subject of a regulatory submission as governed by regional regulation or 
guidance.  However, minor unanticipated modifications of the process or controls related to the 
intended change and not affecting the technical principles of the protocol are normally 
considered within scope, if appropriately justified. 
 
No change outlined in a PACMP should introduce any additional risks to patient safety, product 
quality, or efficacy.  A CMC change that would require supportive efficacy, safety (clinical or 
nonclinical), or human pharmacokinetic/pharmacodynamic (PK/PD) data to evaluate the effect 
 
8 In some regions, the PACMP may be included in other modules. 
  12  Contains Nonbinding Recommendations 
 
of the change (e.g., certain formulation changes, clinical or nonclinical studies to evaluate new 
impurities, assessment of immunogenicity/antigenicity) is not suitable for inclusion in a PACMP. 
 
C.  Elements of a PACMP (4.3) 
 
The development of the PACMP is informed by the application of process and product 
understanding gained from product development and/or manufacturing experience.  A PACMP 
would typically include the following, for example:  
 
  A detailed description of the proposed change(s), including a rationale.  The differences 
before and after the proposed change(s) should be clearly highlighted (e.g., in a tabular 
format). 
 
  Based on an initial risk assessment, a list of specific tests and studies to be performed to 
evaluate the potential impact of the proposed change(s), such as:  characterization, batch 
release, stability (as appropriatesee section IX), in-process controls.  The PACMP 
should include an appropriate description of the analytical procedures and proposed 
acceptance criteria for each test or study. 
 
  Discussion regarding the suitability of the approved control strategy or any changes 
needed to the control strategy associated with the planned change(s). 
 
  Any other conditions to be met, such as confirmation that certain process qualification 
steps will be completed before implementation. 
 
  Where applicable, supportive data from previous experience with the same or similar 
products related to development, manufacturing, characterization, batch release, and 
stability to allow for risk mitigation. 
 
  Proposed reporting category for step 2 of the PACMP. 
 
  Confirmation, as appropriate, that ongoing verification will be performed under the PQS 
to continue to evaluate and ensure that there is no adverse effect of the change(s) on 
product quality.  In cases where monitoring of the impact on product quality following 
implementation of the change(s) is required, a summary of the quality risk management 
activities should be provided to support the proposed PACMP.  If multiple changes are to 
be implemented, these activities should address the potential risk from the cumulative 
effect of multiple changes and how they are linked. 
 
The MAH should demonstrate in the PACMP suitable scientific knowledge and understanding of 
aspects impacted by the proposed change in order to conduct an appropriate risk assessment of 
the proposed change(s).  Typically, more complex changes would require enhanced 
product/process understanding. 
 
 
  13  Contains Nonbinding Recommendations 
 
D.  Modification of an Approved PACMP (4.4) 
 
A modification to an approved PACMP, such as replacement or revision of a test, study, or 
acceptance criterion, should provide the same or greater capability to assess the effect of the 
proposed change on the product quality and would normally involve a notification type of 
communication with the regulatory authority.  A modification that more significantly alters the 
content of the protocol may require either prior approval of a protocol amendment or submission 
of a new protocol, as agreed upon with the regulatory authority. 
 
E.  Types of PACMPs (4.5) 
 
There are different types of PACMPs: 
 
  One or more change(s) associated with a single productSee above and sections I.D and 
I.E of the ICH Q12 Annexes for content and implementation.  A PACMP can also be 
designed to be used repeatedly to make a specified type of CMC change over the 
lifecycle of a product, applying the same principles.  If the protocol describes several 
changes for a particular product, a justification should be added showing how the changes 
are related and that inclusion in a single protocol is appropriate. 
 
  Broader protocolsThe general principles outlined above apply.  The risk of the 
proposed change(s) should be similar across products; additional considerations should 
be taken into account depending on the approach.  For example: 
 
  One or more changes to be implemented across multiple products (e.g., change in 
stopper across multiple products that use the same container closure system)The 
same risk mitigation strategy should be applicable across all impacted products 
 
  One or more changes to be implemented across multiple products and at multiple 
sites (e.g., change in analytical method across multiple sites, change in manufacturing 
site(s) across multiple products)The same risk mitigation strategy should be 
applicable across all impacted products and/or sites (see section I.E of the ICH Q12 
Annexes) 
 
 
V.  PRODUCT LIFECYCLE MANAGEMENT DOCUMENT (5) 
 
The PLCM document outlines the specific plan for product lifecycle management that includes 
the ECs, reporting categories for changes to ECs, PACMPs (if used), and any postapproval CMC 
commitments.  Its purpose is to encourage prospective lifecycle management planning by the 
MAH and to facilitate regulatory assessment and inspection.  The PLCM document should be 
updated throughout the product lifecycle as needed. 
 
 
 
  14  Contains Nonbinding Recommendations 
 
A.  PLCM Document: Scope (5.1) 
 
The PLCM document serves as a central repository in the MAA for ECs and reporting categories 
for making changes to ECs.  It includes the key elements described below and references to 
related information located elsewhere in the MAA (see section I.F of the ICH Q12 Annexes).  
Submission of the PLCM document is critical when the MAH proposes ECs in line with the risk-
based approaches in section III of this ICH Q12 guidance. 
 
The elements of the PLCM document are summarized below:  
 
  ECs (refer to section III)The ECs for the product should be listed in the PLCM 
document.  The identification and justification of ECs are located in the relevant sections 
of the CTD. 
 
  Reporting category for making changes to approved ECs (refer to section III)The 
reporting categories when making a change to an EC should be listed in the PLCM 
document.  The detailed justification of the reporting categories is located in the relevant 
sections of the CTD. 
 
  PACMPs (refer to section IV)PACMPs that are submitted to prospectively manage 
and implement one or more postapproval changes should be listed. 
 
  Postapproval CMC commitmentsSpecified CMC development activities, agreed 
upon between the MAH and regulatory authority at the time of approval (e.g., specific 
process monitoring, additional testing), that will be performed during the commercial 
phase should be listed in the PLCM document. 
 
B.  Submitting the PLCM Document (5.2) 
 
The PLCM document is submitted in the original MAA or in a supplement/variation for 
marketed products when defining ECs (section III).   
 
C.  Maintenance of the PLCM Document (5.3) 
 
An updated PLCM document should be included in postapproval submissions for CMC changes.  
The updated PLCM document will capture the change in ECs and other associated elements 
(reporting category, commitments, PACMP).  The MAH should follow regional expectations for 
maintaining a revision history for the PLCM document.   
 
D.  Format and Location of PLCM Document (5.4) 
 
A tabular format is recommended to capture certain elements of PLCM described in section 
IV.A, but other appropriate formats can be used. See section I.F of the ICH Q12 Annexes for an 
example PLCM table. 
 
  15  Contains Nonbinding Recommendations 
 
The PLCM document can be located in CTD Module 3.2.R.9 
 
 
VI.  PHARMACEUTICAL QUALITY SYSTEM AND CHANGE MANAGEMENT (6) 
 
A.  PQS General Considerations (6.1) 
 
An effective PQS as described in ICH Q10 and in compliance with regional GMP requirements 
where the application is filed10 is necessary across the entire supply chain and product lifecycle 
to support the use of the tools described in this guidance.  The PQS includes appropriate change 
management, enabled by knowledge management, and management review.  The principles are 
further elaborated on in Appendix 2.  The relationship among knowledge management, change 
management, and the regulatory process for ECs is illustrated in Figure 2. 
 
 
Figure 2: Connection Between Knowledge Management and Change Management Process 
 
 
Maintaining an effective PQS is the responsibility of a company (manufacturing sites and MAH 
where relevant).  It is not the intent of this guidance to require a specific inspection assessing the 
state of the PQS before the company can use the principles in this guidance.  The conduct of 
 
9 In some regions, the PLCM may be included in Module 1. 
10 In the U.S., GMP requirements are established by 501(a)(2)(B) of the FD&C Act (U.S.C. 351(a)(2)(B)) and 21 
CFR parts 210 and 211. 
  16  Contains Nonbinding Recommendations 
 
inspections in connection with submitted MAAs and surveillance will nevertheless continue as 
foreseen by regional regulatory requirements. 
 
It is understood that a manufacturing site can be considered to be in general GMP compliance 
while resolving deficiencies that do not require regulatory action.  In the event that such 
deficiencies have an impact on the effectiveness of change management in the PQS, they may 
result in restrictions on the ability to utilize flexibility in this guidance. 
 
B.  Change Management Across the Supply Chain and Product Lifecycle (6.2) 
 
Supply chains involve multiple stakeholders (e.g., MAHs, research and development (R&D) 
organizations, manufacturers, Contract Manufacturing Organizations (CMOs), suppliers).  It is 
important that these stakeholders interact to effectively use knowledge and manage changes 
during the product lifecycle. 
 
A company has to manage communication of information and interactions of PQSs across 
multiple entities (internal and external).  Therefore, the implementation of robust change 
management across multiple sites (outsourced or not) is necessary.  In conjunction with change 
control principles in Appendix 2, the following change management activities should be 
considered to support the approaches defined in this guidance:  
 
  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). 
 
  The timeliness of communication is driven by the impact of any change related to ECs 
and should be targeted to those entities in the chain that need to be aware of or implement 
the change over the lifecycle of the product. 
 
  Process knowledge and continual improvement are drivers for change.  For example, a 
CMO may be in a position to propose process improvements which significantly improve 
control and product consistency.  These data can be used to revise the ECs and associated 
PLCM document.  The organization responsible for batch release should be aware of all 
relevant changes and, where applicable, be involved in the decision-making. 
 
  The communication mechanisms regarding MAA changes and GMP issues should be 
defined in relevant documentation, including contracts with CMOs. 
 
  A critical failure in a PQS anywhere in the supply chain may impact the ability to use the 
tools in this guidance; therefore, the company should communicate such failures to 
affected regulatory authorities. 
 
 
 
 
  17  Contains Nonbinding Recommendations 
 
VII.  RELATIONSHIP BETWEEN REGULATORY ASSESSMENT AND 
INSPECTION (7) 
 
Regulatory assessment and inspection are complementary activities and their fundamental roles 
remain unchanged by this guidance.  Nevertheless, effective communication between assessors 
and inspectors can facilitate regulatory oversight of PLCM. 
 
Appropriate mechanisms to share knowledge and information obtained through inspection or 
assessment activities can facilitate access to necessary information and mitigate increased 
submission burden on the MAH.  For example, the conclusions from inspections should be 
available to assessors to support ongoing oversight of PLCM, and the most recent PLCM 
document, when applicable, should be available to inspectors so they are aware of the currently 
approved status of the PLCM elements. 
 
Communication is encouraged between regulators across regions, in accordance with appropriate 
bilateral/multilateral arrangementsfor example, to communicate about critical failures in 
aspects of a companys PQS that may impact the use of tools described in this guidance. 
 
 
VIII.  STRUCTURED APPROACHES FOR FREQUENT CMC POSTAPPROVAL 
CHANGES (8) 
 
In addition to the other tools described in this guidance, a simplified approach to accomplishing 
certain CMC changes is needed for products whose marketing authorization did not involve the 
identification of ECs with associated reporting categories.  This section describes a strategy for a 
structured approach for frequent CMC changes. 
 
The strategy described for structured approaches to frequent CMC changes is exemplified with a 
description of an approach for analytical procedure changes in section II of the ICH Q12 
Annexes.  Similar structured approaches could be developed and applied for other frequent CMC 
changes, such as scale, packaging, etc.  These approaches may be applied when the following 
conditions exist: 
 
  The companys PQS change management process is effective and in compliance, as 
described in section VI, and incorporates an appropriate risk management system. 
 
  A structured approach can be found in section II of the ICH Q12 Annexes and describes 
the scope and the steps to be followed, including, where appropriate, data to be generated 
and criteria to be met.  Compliance with the requirements of relevant, internationally-
agreed-upon standards and/or regulatory guidelines may be specified as part of the 
structured approach. 
 
If the approach is followed and all criteria are met, the change can be made with immediate or 
other post-implementation notification, as appropriate, to the relevant regulatory authorities.  The 
flexibility provided in section II of the ICH Q12 Annexes may not be available in all regions and 
  18  Contains Nonbinding Recommendations 
 
in all situations; some specific changes may require prior approval, as defined in regional 
guidance. 
 
 
IX.  STABILITY DATA APPROACHES TO SUPPORT THE EVALUATION OF CMC 
CHANGES (9) 
 
The data needed for submission to the regulatory authority in support of a postapproval change is 
established by regional regulations and guidance.  This section provides additional science- and 
risk-based approaches that can be used to develop strategies for confirmatory stability studies 
supporting postapproval changes to enable more timely filing, approval, and implementation of 
the changes.  Such approaches could be included in a PACMP (see sections I.D and I.E of the 
ICH Q12 Annexes). 
 
Unlike the formal stability studies recommended in ICH Q1A(R2), whose objective is to 
establish a useful shelf life and storage conditions for a new, yet-to-be-marketed drug 
substance/drug product, the purpose of stability studies, if needed, to support a postapproval 
CMC change is to confirm the previously approved shelf life and storage conditions.  The scope 
and design of such stability studies are informed by the knowledge and experience of the drug 
product and drug substance acquired since authorization.  Approaches to the design of such 
studies should be appropriately justified and may include: 
 
  Identifying the stability-related quality attributes and shelf life-limiting attributes relative 
to the intended CMC changes, based on risk assessments and previously generated data. 
 
  Use of appropriate tools to evaluate the impact of the intended change.  These may 
include: 
 
  Drug substance and/or drug product accelerated and/or stress studies on 
representative material (which may be pilot- or laboratory-scale rather than full-scale) 
 
  Pre- and post-change comparability studies on representative material 
 
  Statistical evaluation of relevant data, including existing stability studies 
 
  Predictive degradation and other empirical or first-principle kinetic models 
 
  Utilization of prior knowledge, including relevant company knowledge and the 
scientific literature 
 
  Use of confirmatory stability studies post-change instead of submission of data as part of 
a regulatory change submission. 
 
Where applicable, a commitment to initiate or complete ongoing, long-term stability testing on 
post-change batches can assure that the approved shelf life and storage conditions continue to be 
applicable after the implementation of the CMC change. 
  19  Contains Nonbinding Recommendations 
 
X.  GLOSSARY (10) 
 
Table 1: Glossary 
Term  Definition 
Corrective Action  System that focuses on investigating, understanding, and correcting 
and Preventive  discrepancies while attempting to prevent their occurrence 
Action (CAPA) 
CMO  Contract Manufacturing Organization 
Process parameter whose variability has an impact on a critical 
Critical Process 
quality attribute and therefore should be monitored or controlled to 
Parameter (CPP) 
assure the process produces the desired product quality (Q8(R2)) 
A physical, chemical, biological, or microbiological property or 
Critical Quality 
characteristic that should be within an appropriate limit, range, or 
Attribute (CQA) 
distribution to assure the desired product quality (Q8(R2)) 
CTD  Common Technical Document 
Company  Manufacturing sites and MAH where relevant 
EC  Established Condition 
MAA  Marketing Authorization Application 
MAH  Marketing Authorization Holder 
A change to an approved EC that does not require approval prior to 
Notification 
implementation 
PACMP  Postapproval Change Management Protocol 
PLCM  Product Lifecycle Management 
Postapproval  Commitment by the MAH to undertake specific CMC activities to 
CMC  be implemented during the commercial phase 
Commitment 
Change to an approved EC that requires regulatory review and 
Prior-approval 
approval prior to implementation  
Regular periodic review of active pharmaceutical ingredients or 
Product Quality  drug products with the objective to verify process consistency, to 
Review (PQR)  highlight any trends, and to identify product and process 
improvements 
PQS  Pharmaceutical Quality System 
QRM  Quality Risk Management 
Communication to a regulatory authority regarding a change to an 
Submission 
EC that could be prior approval or notification  
  20  Contains Nonbinding Recommendations 
 
XI.  REFERENCES (11) 
 
ICH guidance for industry, M4: The CTD  Quality, August 2001 (available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents).  
 
ICH guidance for industry, Q1A(R2) Stability Testing of New Drug Substances and Products, 
November 2003 (available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents).  
 
ICH guideline, Q2(R1) Validation of Analytical Procedures: Text and Methodology, March 1995 
(available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q2-r1-
validation-analytical-procedures-text-and-methodology).    
 
ICH Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their 
Manufacturing Process, June 2005 (available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents). 
 
ICH guidance for industry, Q8(R2) Pharmaceutical Development, November 2009 (available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents). 
 
ICH guidance for industry, Q9 Quality Risk Management, June 2006 (available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents). 
 
ICH guidance for industry, Q10 Pharmaceutical Quality System, April 2009 (available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents). 
 
ICH guidance for industry, Q11 Development and Manufacture of Drug Substances, November 
2012 (available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents). 
 
ICH guidance for industry, Q8, Q9, and Q10 Questions and Answers (R4), November 2011 
(available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents). 
 
ICH guidance for industry, Q8, Q9, and Q10 Questions and Answers  Appendix Q&As from 
Training Sessions (Q8, Q9, and Q10 Points to Consider), July 2012 (available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents). 
   
  21  Contains Nonbinding Recommendations 
 
APPENDIX 1.  COMMON TECHNICAL DOCUMENT SECTIONS THAT CONTAIN ESTABLISHED CONDITIONS 
 
Notes:  
 
  This table does not contain a complete list of Established Conditions (ECs) for a product.  The intention of the table is to 
provide general guidance about the elements of manufacture and control that constitute ECs and their location within the 
Common Technical Document (CTD) structure. 
 
  White rows indicate CTD sections where ECs are generally located.  Grey rows indicate CTD sections where supportive 
information is generally located.  
 
  CTD sections containing ECs may also contain elements of supportive information.   
 
  For information related to the drug delivery system for a drug-device combination product, the location or the relevant content 
within the CTD structure may vary depending on the design of the particular product and region. 
 
Table A: CTD Sections That Contain ECs 
CTD 
SECTION TITLE  ESTABLISHED CONDITIONSGeneral List with Notes 
SECTION 
3.2.S  DRUG SUBSTANCE  
3.2.S.1  G  eneral Information  
3.2.S.1.1  Nomenclature    
Drug substance name, structure 
3.2.S.1.2  Structure 
 
3.2.S.1.3  General Properties  S upportive information 
3.2.S.2  Manufacture 
3.2.S.2.1  Manufacturer(s)  D  rug substance manufacturing site(s) (including testing) 
Continued 
 
 
 
  22  Contains Nonbinding Recommendations 
 
Table A continued: CTD Sections That Contain ECs 
CTD 
SECTION TITLE  ESTABLISHED CONDITIONSGeneral List with Notes 
SECTION 
3.2.S.2.2  Description of Manufacturing  Individual unit operations and their sequence in the manufacturing process  
Process and Process Controls   
For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations, 
reference is made to section III.B.3.a, Identification of ECs for the Manufacturing Processes. 
3.2.S.2.3  Control of Materials  Starting material specifications (test, elements of analytical procedure and acceptance criteria)  
 
Raw material/reagent/solvent critical controls 
   
Source of materials (e.g., cell and seed source, raw materials) and control of critical materials of biological origin 
 
Generation and control of Master  Working Cell Bank / Master  Working Seed Lot, etc. (applicable to 
biotechnological/biological products)  
3.2.S.2.4  Control of Critical Steps and  Specifications (e.g., test, elements of analytical procedure and acceptance criteria) for critical steps and intermediates, which 
Intermediates  m  ay include storage conditions of critical intermediates  
3.2.S.2.5  Process Validation and/or   
Evaluation  Supportive information 
 
3.2.S.2.6  Manufacturing Process 
Supportive information 
Development 
3.2.S.3  Characterization  Supportive information 
3.2.S.3.1  Elucidation of Structure and 
 
Other Characteristics 
Supportive information 
3.2.S.3.2  Impurities   
3.2.S.4  Control of Drug Substance 
3.2.S.4.1  Specification  Drug substance specification 
 
For each quality attribute on the specification: 
 
  Test method  
  Acceptance criteria 
Continued 
 
  23  Contains Nonbinding Recommendations 
 
Table A continued: CTD Sections That Contain ECs 
CTD 
SECTION TITLE  ESTABLISHED CONDITIONSGeneral List with Notes 
SECTION 
3.2.S.4.2  Analytical Procedures  Reference is made to section III.B.3.b, Identification of ECs for Analytical Procedures 
3.2.S.4.3  Validation of Analytical 
Supportive information 
Procedure 
3.2.S.4.4  Batch analyses  Supportive information 
3.2.S.4.5  Justification of Specification  Supportive information 
3.2.S.5  Reference Material   Reference material specification (e.g., test; elements of analytical procedure, where appropriate; and acceptance criteria) 
  
3.2.S.6  Container Closure  Material of construction and specification  
3.2.S.7  Stability  
3.2.S.7.1   Stability Summary and  Drug substance storage conditions and shelf life (or retest period for chemicals) 
Conclusions 
3.2.S.7.2  Postapproval Stability Protocol   
and Stability Commitments  Supportive information (also see section III.B.2) 
 
3.2.S.7.3  Stability Data  Supportive information 
3.2.P  DRUG PRODUCT 
Description and Composition of 
3.2.P.1  Drug product qualitative and quantitative composition 
Drug Product 
3.2.P.2  Pharmaceutical Development 
Continued 
 
 
 
 
 
 
 
  24  Contains Nonbinding Recommendations 
 
Table A continued: CTD Sections That Contain ECs 
CTD 
SECTION TITLE  ESTABLISHED CONDITIONSGeneral List with Notes 
SECTION 
3.2.P.2.1  Components of the Drug   
Product   
 
3.2.P.2.2   Drug Product 
 
 
3.2.P.2.3  Manufacturing Process 
Supportive information 
Development 
3.2.P.2.4  Container Closure System 
3.2.P.2.5  Microbiological Attributes 
3.3.P.2.6  Compatibility 
3.2.P.3  Manufacture 
3.2.P.3.1  Manufacturer(s)  Drug product manufacturing sites (including those for testing, primary and secondary packaging, device assembly for drug 
product-device combination products)  
3.2.P.3.2  Batch Formula  Drug product batch formula (qualitative and quantitative) 
3.2.P.3.3  Description of Manufacturing  Individual unit operations and their sequence in the manufacturing process 
Process and Process Controls   
For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations, 
reference is made to section III.B.3.a  
3.2.P.3.4  Controls of Critical Steps and  Specifications (e.g., test, elements of analytical procedure and acceptance criteria) for critical steps and intermediates, which 
Intermediates  may include storage conditions of critical intermediates  
3.2.P.3.5  Process Validation and/or 
Supportive information 
Evaluation 
3.2.P.4  Control of Excipients 
Continued 
 
 
 
 
 
 
 
  25  Contains Nonbinding Recommendations 
 
Table A continued: CTD Sections That Contain ECs 
CTD 
SECTION TITLE  ESTABLISHED CONDITIONSGeneral List with Notes 
SECTION 
3.2.P.4.1  Specifications  Excipient specification 
   
  For each quality attribute on the specification: 
 
  Test method 
  Acceptance criteria 
 
Or, if applicable: 
 
Reference to pharmacopoeial monograph 
3.2.P.4.2  Analytical Procedures  Reference to pharmacopoeial monograph; if none exists, refer to section III.B.3.b  
3.2.P.4.3  Validation of Analytical 
Supportive information 
Procedures 
 3.2.P.4.4  Justification of Specifications  Supportive information 
3.2.P.4.5  Excipients of Human or  Excipient source and controls  
Animal Origin  
 3.2.P.4.6  Novel Excipients  (If novel excipient specification is not described in 3.2.P.4.1) 
 
Novel Excipient Specification 
 
For each quality attribute on the specification: 
 
  Test method  
  Acceptance criteria 
3.2.P.5  Control of Drug Product 
Continued 
 
 
 
 
 
 
  26  Contains Nonbinding Recommendations 
 
Table A continued: CTD Sections That Contain ECs 
CTD 
SECTION TITLE  ESTABLISHED CONDITIONSGeneral List with Notes 
SECTION 
3.2.P.5.1  Specification(s)  Drug product specification 
 
For each quality attribute on the specification: 
  
  Test method   
  Acceptance criteria   
3.2.P.5.2  Analytical Procedures  Reference is made to section III.B.3.b 
3.2.P.5.3  Validation of Analytical 
Supportive information 
Procedures 
3.3.P.5.4  Batch Analyses 
3.2.P.5.5  Characterization of Impurities  S upportive information 
 3.2.P.5.6  Justification of Specification(s) 
3.2.P.6  Reference Materials  R  eference material specification (e.g., test; elements of analytical procedure, where appropriate; and acceptance criteria) 
3.2.P.7  Container Closure System  Material of construction and specification 
 
Where applicable, supplier/manufacturer of primary container closure system 
3.2.P.8  S tability  
3.2.P.8.1   Stability Summary and  Drug product storage conditions and shelf life  
Conclusion    
Where applicable, in-use storage conditions and shelf life 
3.2.P.8.2  Postapproval Stability Protocol   
and Stability Commitment   
Supportive information (also see section III.B.2) 
 
 
3.3 P.8.3  Stability Data  Supportive information 
3.2.A  APPENDICES 
Continued 
   
  27  Contains Nonbinding Recommendations 
 
Table A continued: CTD Sections That Contain ECs 
CTD 
SECTION TITLE  ESTABLISHED CONDITIONSGeneral List with Notes 
SECTION 
3.2.A.1  Facilities and Equipment  Regional regulation and guidance apply 
3.2.A.2  Adventitious Agents Safety 
Supportive information (applicable to biotechnological/biological products)  
Evaluation 
3.2.A.3  Excipients  Supportive information 
3.2.R  REGIONAL INFORMATION 
  Not applicable   Regional regulation and guidance apply 
   
 
 
 
 
  28  Contains Nonbinding Recommendations 
 
APPENDIX 2.  PRINCIPLES OF CHANGE MANAGEMENT 
 
Consistent with ICH Q10, an effective change management system supports the principles of this 
guidance and is described below: 
 
(1) Captures stimuli for change, including those that can improve product performance or 
process robustness 
 
(2) Ensures full understanding of the scope of the change and its implications for all aspects 
of the process and control strategy, including the impact on ECs and aspects that are not 
ECs in affected marketing authorizations 
 
(3) Leverages existing process performance and product quality knowledge 
 
(4) Requires science-based risk management and risk categorization of the intended change; 
considers the potential impact if the intended change is not implemented 
 
(5) Determines data (existing and/or to be newly generated) needed to support the change 
and accordingly develops study protocols describing the methods, prospective acceptance 
criteria, as well as additional post-implementation process performance and/or product 
quality monitoring as necessary 
 
(6) Ensures that an appropriate regulatory submission is filed when required 
 
(7) Uses a defined change control process to approve or reject the intended change and to 
involve appropriate stakeholders, including but not restricted to Manufacturing, Quality, 
and Regulatory Affairs personnel 
 
(8) Ensures implementation of the change is based on: 
 
a.  Review that the change as implemented remains aligned with the relevant study 
protocols, Product Lifecycle Management (PLCM) document, or Postapproval 
Change Management Protocol (PACMP) 
 
b.  Assessment of the data generated to demonstrate that the change objective and 
acceptance criteria were met 
 
(9) Ensures that risk-mitigating steps are developed in the case of deviations from acceptance 
criteria or identification of unanticipated risks 
 
(10) Verifies, post-implementation, that relevant changes have been effective in achieving 
the desired outcome with no unintended consequences for product quality  
 
If deviations associated with postapproval changes are detected, ensures that the issue is 
managed via the companys deviation management process and appropriate corrective 
  29  Contains Nonbinding Recommendations 
 
and/or preventive actions are identified and undertaken via the companys corrective 
action and preventive action (CAPA) system 
 
(11) Post-implementation: 
 
a.  Captures new product/process knowledge gained during implementation of the 
change 
 
b.  Where applicable, ensures that regulatory filings are updated, and an assessment is 
made as to whether updates to the PLCM document are needed 
 
c.  Where applicable, ensures that the change is included and assessed as part of the 
Product Quality Review (PQR) 
 
(12) Ensures that the change management system is available for review during 
audit/inspection 
 
Use of Knowledge in Change Management 
 
An effective change management system includes active knowledge management, in which 
information from multiple sources is integrated to identify stimuli for changes needed to improve 
product and/or process robustness.  The connection between knowledge management and change 
management is illustrated in Figure 2.  These sources can include, but are not limited to, 
developmental studies, process understanding documents, product or process trending, and 
product-specific CAPA outcomes.  Provisions should be made for sharing knowledge (e.g., in 
quality agreements and/or contracts) that relates to product and process robustness or otherwise 
informs changes between the Marketing Authorization Holder (MAH) and relevant 
manufacturing stakeholders (research and development organizations, manufacturers, Contract 
Manufacturing Organizations (CMOs), suppliers, etc.). 
 
In addition to individual sources of information, there should be a mechanism to provide a 
holistic view of quality performance for a specific product or product family on a regular basis, 
as captured in the Product Quality Review (PQR) and shown in Figure 2.  This should include 
steps taken to identify and manage sources of variability, which allow for the identification of 
further need for change not apparent when the data are viewed in isolation.  As described in the 
ICH Quality Implementation Working Group on Q8, Q9, and Q10 Questions and Answers (R4), 
there is no added regulatory requirement for a formal knowledge management system. 
 
Management Review 
 
In addition to the guidance provided in ICH Q10 regarding an effective change management 
system, the following should be considered in the management review: 
 
  Monitoring the timeliness of the change management system to assure that changes are 
implemented in a timely manner commensurate with the criticality/urgency identified for 
  30  Contains Nonbinding Recommendations 
 
the change.  When implementation is delayed, an assessment and mitigation of any risks 
associated with the delay should be made. 
 
  Monitoring the performance of the change management system, such as assessing the 
frequency of intended changes that are not approved for implementation by the quality 
unit.  
 
  Ensuring that post-implementation verification occurs and reviewing the results of that 
verification as a measure of change management effectiveness (e.g., to identify 
improvements to the change management system). 
  31