Q12 Technical and Regulatory
Considerations for Pharmaceutical
Product Lifecycle Management
Core Guideline

This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not establish any rights for any person andis not binding on FDA or the public. You can use an alternative approach if it satisfies therequirements of the applicable statutes and regulations. To discuss an alternative approach,contact the FDA staff responsible for this guidance as listed on the title page.

For questions regarding this draft document contact (CDER) Mahesh Ramanadham 301796-3272 or (CBER) Ingrid Markovic 240-402-8115.

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICALREQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINETechnical and Regulatory Considerations for Pharmaceutical
Product Lifecycle Management
Core Guideline

Q12
Draft version
Endorsed on 16 November 2017
Currently under public consultation

At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate
ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory
authorities of the ICH regions for internal and external consultation, according to nationalor regional procedures.

TABLE OF CONTENTS
1.

INTRODUCTION ...................................................................................................... 1
1.1.
Objectives ..................................................................................................... 1
1.2.
Scope ........................................................................................................... 1
1.3.
ICH Q12 Regulatory Tools and Enablers ...................................................... 1

2.

CATEGORISATION OF POST-APPROVAL CMC CHANGES ................................. 3

3.

ESTABLISHED CONDITIONS (ECs) ....................................................................... 5
3.1.
Introduction ................................................................................................... 5
3.2.
Definition of ECs and Their Role in the Regulatory Submission .................... 5
3.2.1.
ECs Definition ................................................................................ 5
3.2.2.
ECs in a Regulatory Submission .................................................... 5
3.2.3.
Identification of ECs ....................................................................... 6
3.2.3.1.
Identification of ECs for the Manufacturing
Processes .................................................................... 6
3.2.3.2.
Identification of ECs for Analytical Procedures ............. 8
3.2.4.
Revision of ECs ............................................................................. 9
3.3.
Roles and Responsibilities ............................................................................ 9

4.

POST-APPROVAL CHANGE MANAGEMENT PROTOCOL (PACMP) .................. 10
4.1.
Definition of a PACMP ................................................................................ 10
4.2.
Application of a PACMP.............................................................................. 11
4.3.
Elements of a PACMP ................................................................................ 11
4.4.
Modification to an Approved PACMP .......................................................... 12
4.5.
Types of PACMPs ...................................................................................... 12

5.

PRODUCT LIFECYCLE MANAGEMENT (PLCM) .................................................. 13
5.1.
PLCM Document: Scope ........................................................................... 13
5.2.
Submitting the PLCM Document ................................................................. 14
5.3.
Maintenance of the PLCM Document ......................................................... 14
5.4.
Format and Location of PLCM Document ................................................... 146.

PHARMACEUTICAL QUALITY SYSTEM (PQS) AND CHANGE
MANAGEMENT ..................................................................................................... 14
6.1.
General Considerations .............................................................................. 14
6.2.
Management of Manufacturing Changes in the Supply Chain ..................... 147.

RELATIONSHIP BETWEEN REGULATORY ASSESSMENT AND
INSPECTION ......................................................................................................... 15

8.

POST-APPROVAL CHANGES FOR MARKETED PRODUCTS ............................. 15
8.1.
Structured Approach to Analytical Procedure Changes............................... 15
8.1.1.
Principles ..................................................................................... 16
8.1.2.
Structured Approach .................................................................... 17
8.2.
Data Requirements to Support CMC Changes ........................................... 19
8.2.1.
Stability Data Approaches to Support the Evaluation of
CMC Change ............................................................................... 199.

GLOSSARY ........................................................................................................... 20

10. REFERENCES ....................................................................................................... 21
APPENDIX 1: COMMON TECHNICAL DOCIMENT SECTIONS THATCONTAIN ECs ....................................................................................................... 22
APPENDIX 2: PRINCIPLES OF CHANGE MANAGEMENT ......................................... 28

1

1.

INTRODUCTION 1

2

1.1.

Objectives

3
4
5
6
7
8
9
10
11

The concepts outlined in prior ICH Quality Guidelines (ICH Q8, Q9, Q10 and Q11) provide
opportunities for science and risk-based approaches for drug development and risk-based
regulatory decisions. These guidelines are valuable in the assessment of Chemistry,
Manufacturing and Controls (CMC) changes across the product lifecycle. ICH Q8 and Q11
guidelines focus mostly on early stage aspects of the product lifecycle (i.e., product development,
registration, and launch). Experience with implementation of recent ICH guidelines has revealed
technical and regulatory gaps that limit the full realisation of more flexible regulatory approaches
to post-approval CMC changes as described in ICH Q8 (R2) and Q10 Annex I. This guideline
addresses the commercial phase of the product lifecycle (as described in ICH Q10).

12
13
14
15

A harmonised approach regarding technical and regulatory considerations for lifecycle
management will benefit patients, industry, and regulatory authorities by promoting innovationand continual improvement in the biopharmaceutical sector, strengthening quality assurance andimproving supply of medicinal products.

16
17
18
19
20
21
22
23
24

This guideline provides a framework to facilitate the management of post-approval CMC changes
in a more predictable and efficient manner. It is also intended to demonstrate how increased
product and process knowledge can contribute to a reduction in the number of regulatory
submissions. Effective implementation of the tools and enablers described in this guideline should
enhance industry’s ability to manage many CMC changes effectively under the firm’s
Pharmaceutical Quality System (PQS) with less need for extensive regulatory oversight prior to
implementation. The extent of operational and regulatory flexibility is subject to product andprocess understanding (ICH Q8 and Q11), application of risk management principles (ICH Q9),
and an effective pharmaceutical quality system (ICH Q10).

25
26
27
28
29
30

In certain ICH regions, the current ICH Q12 guideline is not fully compatible with the establishedlegal framework with regard to the use of explicit Established Conditions (ECs) referred to in
Chapter 3 and with the Product Lifecycle Management (PLCM) referred to in Chapter 5 as outlinedin this guideline. These concepts will, however, be considered when the legal frameworks will be
reviewed and, in the interim, to the extent possible under the existing regulation in these ICH
regions. 2

31
32

1.2.

33
34
35

This guideline applies to pharmaceutical drug substances (i.e., active pharmaceutical ingredients)
and pharmaceutical drug products, including marketed chemical, and biotechnological/biologicalproducts. The guideline also applies to drug-device combination products that meet the definition

Scope

1

This guidance is intended to be considered in conjunction with the ICH Q12 Annex document being
simultaneously published for comment.
2
Note: In the United States, the ICH Q12 guidance is fully compatible with the established legal
framework. Therefore, the concept of Established Conditions and supporting Product Lifecycle
Management document are fully supported by the U.S. FDA as described in this guidance.

36
37

of a pharmaceutical or biotechnological/biological product. Changes needed to comply withrevisions to pharmacopeial monographs are not in scope of this guideline.

38

1.3.

39
40
41
42

Use of the following harmonised regulatory tools and enablers with associated guiding principles,as described in this guideline, will enhance the management of post-approval changes, andtransparency between industry and regulatory authorities, leading to innovation and continual
improvement.

43

ICH Q12 Regulatory Tools and Enablers

•

44
45
46
47

Categorisation of Post-Approval CMC Changes is a framework that encompasses arisk-based categorisation for the type of communication expected of the Marketing
Authorisation Holder (MAH) with the regulatory authority regarding CMC changes.
•

48
49
50
51
52
53
54

•

66
67
68
69
70
71

Post-Approval Change Management Protocol (PACMP) (Chapter 4)
The 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 prioragreement between the MAH and regulatory authority. Such a mechanism enables
planning and implementation of future changes to ECs in an efficient and predictablemanner.

•

61
62
63
64
65

Established Conditions (ECs) (Chapter 3)
The concept of ECs provides a clear understanding between the MAH and regulatory
authorities regarding the necessary elements to assure product quality and identify theelements that require a regulatory submission, if changed. This guideline describes
how ECs are identified as well as what information can be designated as supportive
information that would not require a regulatory submission, if changed. In addition,
guidance is included for managing revisions of the ECs over a product’s lifecycle.

55
56
57
58
59
60

Categorisation of Post-Approval CMC Changes (Chapter 2)

Product Lifecycle Management (PLCM) (Chapter 5)
The PLCM document serves as a central repository for the ECs and the associatedreporting 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 post-approval CMC commitments and PACMPs.

•

Pharmaceutical Quality System (PQS) and Change Management (Chapter 6)
An effective PQS as described in ICH Q10 and compliance with regional GMPs arenecessary for implementation of this guideline. In particular, management of
manufacturing changes across the supply chain is an essential part of an effective
change management system. This guideline provides recommendations for robustchange management across multiple entities involved in the manufacture of apharmaceutical product.

2

•

72
73
74
75

Relationship Between Regulatory Assessment and Inspection (Chapter 7)
This guideline outlines the complementary roles of regulatory assessment andinspection, and how communication between assessors and inspectors facilitates theuse of the tools included herein.

•76

Post-Approval Changes for Marketed Products (Chapter 8)

77
78
79
80
81

Approaches to facilitate changes to marketed products are outlined. This guideline
provides detailed guidance to enable changes to analytical methods to be made withimmediate or other post-implementation notification. Science- and risk-based
approaches for stability studies in support of the evaluation of CMC changes are also
described.

82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98

The 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 changes toan approved product are managed through a firm’s Pharmaceutical Quality System; changes to
ECs must also be reported to the regulatory authority. Where the regulatory system provides for
Categorisation of Post-approval CMC Changes for reporting according to risk, the MAH may
propose reporting categories for changes to ECs based on risk and knowledge gained throughenhanced pharmaceutical development. A system with risk-based reporting categories also
facilitates the use of Post-Approval 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 post-approval CMC changes. The tools and enablers in this guideline do not change
the Relationship Between Regulatory Assessment and Inspection; however, collaboration andcommunication between assessors and inspectors are necessary for the implementation of thisguideline. Finally, this guideline proposes approaches to facilitate Post-Approval Changes toMarketed Products without the need for regulatory review and approval prior to implementationof certain CMC changes.

99

2.

100
101
102
103
104
105

Regulatory mechanisms that allow the timely and efficient introduction of CMC changes areimportant to drug quality, safety, and availability. There is a range of potential CMC changes forwhich communication between a firm and the regulatory authority is required. CMC changes varyfrom low to high potential risk with respect to product quality. A well-characterised, risk-based
categorisation of regulatory communication requirements is important to the efficient use ofindustry and regulatory resources.

106
107
108
109
110
111

In such a regulatory system, the types of changes in the drug substance, drug product, production
process, quality controls, equipment, and facility that invoke communication with regulatory
authorities are classified with regard to the potential to have an adverse effect on product qualityof the drug product.
The regulatory communication category, supporting
information/documentation requirements, and associated time frame for evaluation arecommensurate with that potential risk.

CATEGORISATION OF POST-APPROVAL CMC CHANGES

3

112
113
114
115
116

Regulatory authorities are encouraged to utilise a system that incorporates risk-based regulatory
processes for (a) requesting approval from the regulatory authority, (b) notifying the regulatory
authority, or (c) simply recording CMC changes, with associated information requirements and,
where applicable, timeframes for decision. Such a system would include the following categories
for regulatory communications with one or more levels in each case:

117
118
119
120

•

Prior-approval: Certain 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. An inspection may be associated withsuch changes.

121
122
123
124
125
126

•

Notification: Certain moderate- to low-risk changes are judged to not require priorapproval and generally require less information to support the change. These changes arecommunicated to the regulatory authority as a formal notification that takes place within adefined period of time before or after implementation, according to regional requirements.
A mechanism for immediate notification is useful when prior approval is not required, buttimely awareness of the change by the regulator is considered necessary.

127
128

In addition, the lowest risk changes are only managed and documented within the PQS and notreported to regulators, but may be verified on routine inspection.

129
130
131
132

Harmonisation or convergence toward a system of risk-based categorisation of post-approvalchanges is encouraged as an important step toward achieving the objectives of this guideline. Sucha system provides inherent, valuable flexibility in regulatory approach and a framework that can
support additional regulatory opportunities such as:

133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150

•

Facilitating the use of tools and enablers described in this guideline by providing a rangeof 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 theability to use a lower category.

•

Options for possible regulatory convergence regarding the association of a certain type ofchange with a particular category when reasons for being different from other regulatory
authorities are not clearly established.

A risk-based categorisation system may be accomplished by having the principles captured inregulations with further details in guidance, which can provide additional flexibility to modify
expectations as science and technology evolve. For examples of risk-based categorisation systems,
refer to existing regulations and guidance of ICH members, and WHO guidelines and guidance onchanges to approved products.

4

151

3.

ESTABLISHED CONDITIONS (ECS)

152

3.1.

Introduction

153
154
155
156
157
158

Although the Common Technical Document (CTD) format has been defined for a marketing
application, there are no previously harmonised approaches to defining which elements in an
application are considered necessary to assure product quality and therefore would require aregulatory submission if changed post-approval. These elements are being defined in thisguideline as “Established Conditions for Manufacturing and Control” (referred to as ECs
throughout this guideline).

159

3.2.

Definition of ECs and Their Role in the Regulatory Submission

160
161
162
163

3.2.1.

ECs Definition

164
165
166
167
168

3.2.2.

All regulatory submissions contain a combination of ECs and supportive information (refer toAppendix 1). Supportive information is not considered to be ECs, but is provided to share withregulators the development and manufacturing information at an appropriate level of detail, and tojustify the initial selection of ECs and their reporting category.

169
170
171
172
173

ECs should not be confused with CMC regulatory commitments (e.g., stability and othercommitments) made by an MAH to provide data or information to the regulatory agency in amarketing authorisation application (MAA). Such information, in the context of this guideline, isconsidered supportive information. Changes to CMC regulatory commitments are not addressedin this guideline, but are managed according to existing regional regulations and guidance.

174

ECs in a submission are either implicit or explicit:

ECs are legally binding information (or approved matters) considered necessary to assure productquality. As a consequence, any change to ECs necessitates a submission to the regulatory
authority.
ECs in a Regulatory Submission

175
176
177

•

Implicit ECs are elements that are not specifically proposed by the MAH but are derived
from and revised according to regional regulation or guidance related to post-approvalchanges.

178
179
180
181
182

•

Explicit ECs are specifically identified and proposed by the MAH together with their
proposed reporting category as part of a regulatory submission (see Chapter 3.2.3). This
guideline provides the opportunity to identify explicit ECs and associated reporting
categories. Unless otherwise specified by regional requirement, identifying explicit ECs
for a given product is not mandatory.

183
184
185

An MAH may use one or both approaches as described above to define ECs and their associatedreporting categories. If the MAH wishes to propose a different reporting category than provided
in regional regulation and guidance for an implicit EC, the explicit EC approach should be used.

186
187

The MAH should provide rationales for the ECs and associated reporting categories in theappropriate CTD sections in Module 3.

5

188
189

See Appendix 1 for more information regarding sections of the marketing application that may
contain ECs and supportive information.

190
191
192
193
194

3.2.3.

195
196

The extent of ECs may vary based on the firm’s development approach and potential risk to
product quality.

197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216

3.2.3.1.

Identification of ECs

This chapter outlines approaches to define ECs for manufacturing processes and analyticalmethods. A similar approach can be used to define other types of ECs (e.g., performance of thecontainer closure system) and should be justified by the applicant and approved by the regulatory
agency.

Identification of ECs for the Manufacturing Processes

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. These should include critical process parameters(CPPs, as defined in ICH Q8(R2)), as well as key process parameters (KPPs), which are parametersof the manufacturing process that may not be directly linked to critical product quality attributes,
but need to be tightly controlled to assure process consistency as it relates to product quality.
The details of ECs and the associated reporting category will depend on the extent to which thefirm can apply knowledge from product and process understanding (i.e., their development
approach) to manage the risks to product quality. Appropriate justification should be provided tosupport the identification of ECs and proposed reporting categories. Different approaches can beused alone, or in combination, to identify ECs for manufacturing processes; these include, but are
not limited to the following:•

A parameter based approach, in which product development prior to regulatory
submission provides a limited understanding of the relationship between inputs andresulting quality attributes, will include a large number of inputs (e.g., process parametersand material attributes) along with outputs (including in-process controls).

217
218
219
220

•

An enhanced approach with increased understanding of interaction between inputs andproduct 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.

221
222
223
224
225
226

•

In certain cases, applying knowledge from a data-rich environment enables a performancebased approach in which ECs could be primarily focused on control of unit operation
outputs rather than process inputs (e.g., process parameters and material attributes). For
example, a performance-based approach could be considered for manufacturing process
steps with in-line continuous monitoring (e.g., using appropriate process analyticaltechnologies such as NIR for the control of a blending process).

227
228

When considering this approach, it is important to ensure that all relevant parameters andmaterial attributes that have a potential to impact product quality are monitored and

6

229
230
231
232

equipment used remains qualified in order to assure a stable process. In certain cases, suchas a path-dependent process where a specific outcome cannot be defined (e.g., fluid bed
granulation and drying), select parameters or attributes may need to be specified as ECs(e.g., differences in granular properties can affect the final product quality).

233
234
235

A suitably detailed description of the manufacturing process is important to provide a clear
understanding of what is and is not necessary to assure product quality. Use of this guidanceshould not lead to a less detailed description of the manufacturing process in Module 3 of the CTD.

236
237
238
239
240
241
242
243

A decision tree to identify ECs and associated reporting categories for manufacturing processparameters is shown in Figure 1. This decision tree is intended to guide the identification of ECs
based on an assessment of criticality (i.e., CPPs) or impact on the process consistency as it relates
to product quality (i.e., KPPs). The corresponding reporting category is dependent on the potential
risk to quality. Risk assessment activities should follow approaches described in ICH Q9. In
assessing the risk and subsequent reporting category, an MAH should consider the overall control
strategy and any possible concurrent changes. Appropriate justification should be provided insupport of the identification of ECs and those aspects that are not ECs.

244

7

245
246

Figure 1. Decision Tree for Identification of ECs and Associated Reporting Categories for
Manufacturing Process Parameters 3

247
248

4567

249
250
251

Information regarding product-specific post-approval change activities, such as post-changemonitoring, may be provided as supporting information to aid in the determination of ECs andassociated reporting categories.

252
253

Criticality and risk should be evaluated periodically during the lifecycle of the product and, using
the decision tree, the ECs should be updated based on acquired knowledge.

254
255

Additionally, an MAH should consider the impact of concurrent changes when assessing theappropriate reporting category.

256
257
258

3.2.3.2.

Identification of ECs for Analytical Procedures

ECs related to analytical procedures should include elements which assure performance of theprocedure. Appropriate justification should be provided to support the identification of ECs for3This diagram does not apply as is for the performance-based approach.
Appropriate justification is expected for ECs and non-ECs
5
Assessment of risk to quality using tools and concepts found in ICH Q96
In some cases, moderate risk changes may require prior approval.
7
See Chapter 2 for further guidance on reporting categories and see Chapter 3.3 regarding roles and responsibilities
related to managing changes and maintaining an approved application.
4

8

259
260

analytical procedures. The extent of ECs could vary based on the method complexity,
development and control approaches.

261
262
263

•

Where the relationship between method parameters and method performance has not been
fully studied at the time of submission, ECs will incorporate the details of operationalparameters including system suitability.

264
265
266
267
268

•

When there is an increased understanding of the relationship between method parametersand method performance defined by a systematic development approach including
robustness studies, ECs are focused on method-specific performance criteria (e.g.,
specificity, accuracy, precision) rather than a detailed description of the analyticalprocedure.

269
270
271
272

A suitably detailed description of the analytical procedures in Module 3 is expected to provide aclear understanding regardless of the approach used to identify ECs for analytical procedures. Useof this guideline should not lead to providing a less detailed description of analytical proceduresin the MAA.

273
274
275
276

3.2.4.

It may be necessary to change approved ECs as a result of knowledge gained during the productlifecycle (e.g., manufacturing experience, introduction of new technologies or changes in thecontrol strategy).

277
278

Options available for the MAH to change approved ECs, and to revise the associated reporting
category for approved ECs include:

Revision of ECs

279
280
281

•

Submission of an appropriate post-approval regulatory submission describing andjustifying the proposed revision to the approved ECs. Justification may include informationsuch as validation data and batch analyses.

282
283
284

•

Submitting a PACMP, in the original marketing application or as part of a post-approvalsubmission, describing a revision to ECs or reporting categories, and how the change will
be justified and reported.

285
286

•

Revisions to ECs could also be made utilizing an approved post-approval regulatorycommitment, as appropriate.

287

3.3.

288
289
290
291
292
293
294

The management of all changes to and maintenance of the approved marketing application is the
responsibility of the MAH. There is a joint responsibility to share and utilise information between
the MAH and any manufacturing organizations to assure the marketing application is maintained,reflects current operations, and that changes are implemented appropriately across relevant sites.
Maintenance of the marketing application (including aspects that are not identified as ECs) should
follow regional expectations. See Chapter 6 for information related to interactions between an
MAH and any manufacturing organizations.

Roles and Responsibilities

9

295
296
297
298
299

For any referenced submission (e.g., Type II Drug Master File, Active Substance Master File, etc.)
in a marketing application, the holder of the referenced submission has a responsibility to reportchanges to their ECs to the MAH referencing their submission, so that the MAH can assess theimpact of the change and report any related change to the ECs found in the approved MAA, as
necessary and per regional requirements.

300
301

The approval of ECs and subsequent changes to ECs is the responsibility of the regulatory
authorities.

302

4.

POST-APPROVAL CHANGE MANAGEMENT PROTOCOL (PACMP)

303

4.1.

Definition of a PACMP

304
305
306
307
308
309
310
311
312
313
314
315
316

A PACMP is a regulatory tool that provides predictability and transparency in terms of therequirements and studies needed to implement a change as the approved protocol provides anagreement 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, how the change would
be prepared and verified, including assessment of the impact of the proposed change, and thesuggested reporting category in line with regional requirements, i.e., a lower reporting category
and/or shortened review period as compared to similar change procedure 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 Chapter 4.5). The PACMP may be submitted with theoriginal MAA or subsequently as a stand-alone submission. The PACMP requires approval by
the regulatory authority, and the conditions and acceptance criteria outlined in the protocol must
be met in order to implement the change(s).

317
318
319
320
321
322
323
324
325
326
327
328

A PACMP should describe changes with a level of detail commensurate with the complexity of
the change. Once approved, in cases where implementation (see “step 2” below) is pending, there
is an assumption that the proposed approach is re-evaluated by the MAH on a regular basis and its
validity reconfirmed prior to implementation of the change(s). Specifically, before implementing
the change(s), the risk assessment provided in the initial PACMP submission should be reviewed
by the MAH to ensure that the outcomes of that risk assessment as they pertain to the plannedchange(s) are still valid. If the review of the initial risk assessment indicates an increased level ofrisk associated with execution of the change, the previously approved reporting category should
no longer be considered appropriate. In such cases, existing guidance should be followed or aconsultation with the relevant regulatory authority should be sought. In addition, the MAH should
confirm that the control strategy continues to ensure that the product will be produced consistently
following implementation of the change(s).

329
330
331
332
333
334

Finally, the use of a PACMP is enabled through an effective PQS that incorporates quality risk
management principles (ICH Q9) and an effective change management system (ICH Q10,
Appendix 2). 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.

10

335

4.2.

336

A PACMP typically involves two steps:

337
338
339
340
341
342

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 thechange(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). This protocol is reviewed and approved by the regulatory authority
in advance of execution of the protocol.

343
344
345
346
347
348
349
350

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 categorisation (classification) in theapproved protocol for review by the regulatory authority as appropriate. Depending on thereporting 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 follow
existing regulation or guidance instead.

351
352
353
354
355
356

Significant changes to the manufacturing process or controls that were not anticipated in the
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 theintended change and not affecting the technical principles of the protocol are normally consideredwithin scope, if appropriately justified.

357
358
359
360
361

No change outlined in a PACMP should introduce any additional risks to patient safety, productquality or efficacy. A CMC change that would require supportive efficacy, safety (clinical or nonclinical), or human PK/PD data to evaluate the effect of the change (e.g., certain formulation
changes, clinical or non-clinical studies to evaluate new impurities, assessment of
immunogenicity/antigenicity) is generally not suitable for inclusion in a PACMP.

362

4.3.

363
364
365

The development of the PACMP is informed by the application of process and productunderstanding gained from product development and/or manufacturing experience. A PACMP
includes some, if not all, of the following elements:

Application of a PACMP

Elements of a PACMP

366
367
368

•

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 tabularformat).

369
370
371
372
373

•

Based on an initial risk assessment, a list of specific tests and studies to be performed toevaluate the potential impact of the proposed change(s), such as characterisation, batch
release, stability (as appropriate, see Chapter 8.2.1), and in-process controls. The PACMP
should include an appropriate description of the analytical procedures and proposed
acceptance criteria for each test or study.

11

374
375

•

Discussion regarding the suitability of the approved control strategy or any changes needed
to the control strategy associated with the planned change(s).

376
377

•

Any other conditions to be met, such as confirmation that certain process qualification steps
will be completed before implementation.

378
379
380

•

Where applicable, supportive data from previous experience with the same or similar
products related to: development, manufacturing, characterisation, batch release, andstability to allow for risk mitigation.

381•

Proposed reporting category for the implementation of step 2 of the PACMP.

382
383
384
385
386
387
388

•

Confirmation that ongoing verification will be performed under the PQS to continue toevaluate 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 thechange(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 multiplechanges and how they are linked.

389
390
391
392

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.

393

4.4.

394
395
396
397
398
399

A modification to an already 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. Such changes would normally require a notification typeof communication with the regulatory authority. A modification that more significantly alters thecontent of the protocol may require either prior approval of a protocol amendment or submissionof a new protocol, as agreed upon with the regulatory authority.

400

4.5.

401

There are different types of PACMPs:

402
403
404

Modification to an Approved PACMP

Types of PACMPs

•

405
406
407
408
409
410

One or more changes to a single product – see above and Annex IIA, for content andimplementation. 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 isappropriate.

•

Broader protocols – the general principles outlined above apply. The risk of the proposedchange(s) should be similar across products; additional considerations should be taken into
account depending on the approach, for example:

12

411
412
413

o 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): thesame risk mitigation strategy should be applicable across all impacted products;

414
415
416
417

o One or more changes to be implemented across multiple products and at multiple
sites (e.g., change in analytical method across multiple sites, change inmanufacturing site(s) across multiple products): the same risk mitigation strategy
should be applicable across all impacted products and/or sites (see Annex IIB).

418

5.

419
420
421
422
423
424

The PLCM document outlines the specific plan for product lifecycle management that is proposedby the MAH, includes key elements of the control strategy, the ECs, proposed reporting categories
for changes to ECs, PACMPs (if used) and any post-approval CMC commitments. This willencourage prospective lifecycle management planning by the MAH and facilitate regulatory
assessment and inspection. The PLCM document should be updated throughout the productlifecycle as needed.

425

5.1.

426
427
428
429
430

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 in Chapter 5.2 below andreferences to the related information located elsewhere in the MAA (see Annex III). Submissionof the PLCM document is encouraged; however, the document is expected when the MAH
proposes explicit ECs.

431

The elements of the PLCM document are summarised below:

432
433
434

•

Summary of Product Control Strategy: A high level summary of the product control
strategy should be included in the PLCM document to clarify and highlight which elementsof the control strategy should be considered ECs.

435
436
437

•

ECs (refer to Chapter 3): The proposed 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.

438
439
440
441
442

•

Reporting category for making changes to approved ECs (refer to Chapter 3): The
proposed 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. The reporting category may be based on regional regulations or
guidance, or MAH justification.

443
444
445
446
447

•

PACMPs (refer to Chapter 4): PACMPs that are submitted to prospectively manage andimplement one or more post-approval changes should be listed along with the corresponding
ECs to be changed. The approval date of the PACMP should be noted in subsequent
submissions. If the PACMP is submitted and approved after approval of the original MAA,
an updated PLCM document should accompany the PACMP.

PRODUCT LIFECYCLE MANAGEMENT (PLCM)

PLCM Document: Scope

13

448
449
450

•

451

5.2.

452
453
454
455

The initial PLCM document is submitted with the original MAA or with a supplement/variation
for marketed products where defining ECs (Chapter 3.2.3) may facilitate regulatory change
management. Following regulatory review and approval of the MAA, the PLCM document willcontain ECs and associated reporting categories.

456

5.3.

457
458
459
460

An updated PLCM document should be included in post-approval 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 formaintaining a revision history for the PLCM document.

461

5.4.

462
463

A tabular format is recommended to capture certain elements of PLCM described in Chapter 5.2,
but other appropriate formats can be used. See Annex III for an example PLCM table.

464
465

The PLCM document can be located in either the CTD Module 1, 2, or 3 based on regional
recommendations.

466

6.

PHARMACEUTICAL QUALITY SYSTEM (PQS) AND CHANGE MANAGEMENT

467

6.1.

General Considerations

468
469
470
471
472
473

An effective PQS as established in ICH Q10 and in compliance with regional GMPs is the
responsibility of a firm (manufacturing sites and MAH where relevant) and it is not the intent of
this guideline to require a specific inspection assessing the state of the PQS before the firm canuse the principles in this guideline. The conduct of routine inspections in connection withsubmitted marketing applications and surveillance will nevertheless continue as foreseen byregional regulatory requirements.

474
475

In the event that the PQS is found not to be compliant, it may result in restrictions on the ability toutilise flexibility in this guideline.

476
477
478

Consistent with the basic requirements of ICH Q10, an effective change management system isnecessaryfor
implementationof
thisguidelineandissummarisedinAppendix 2.

479

6.2.

480
481
482
483
484

In many cases, a firm 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 beconsidered to support the approaches defined in this guideline:

Post-approval CMC commitments: CMC commitments (e.g., specific process monitoring,
revisions to ECs) that will be implemented during the commercial phase should be listed in
the PLCM document.
Submitting the PLCM Document

Maintenance of the PLCM Document

Format and Location of PLCM Document

Management of Manufacturing Changes in the Supply Chain

14

485
486

•

Changes to ECs should be communicated in a timely fashion between the MAH and theregulators, and between the MAH and the manufacturing chain (and vice versa).

487
488
489

•

The timeliness of communication is driven by the impact of any change related to ECs andshould be targeted to those entities in the chain that need to be aware of or to implement
the change over the lifecycle of the product.

490
491
492
493
494
495

•

Process knowledge and continual improvement are drivers for change. For example, aContract Manufacturing Organization (CMO) may be in a position to propose process
improvements which significantly improve control and product consistency. These data
can be utilised 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.

496
497

•

The communication mechanisms regarding MAA changes and GMP issues should be
defined in relevant documentation, including contracts with CMOs.

498

7.

RELATIONSHIP BETWEEN REGULATORY ASSESSMENT AND INSPECTION

499
500
501
502
503
504
505
506
507
508

Regulatory assessment and inspection are complementary activities and their fundamental roles
remain unchanged by this guideline. Facility-related information obtained on inspection should
be available to assessors and the most recent PLCM document, when applicable, should beavailable to inspectors.

509

8.

510
511
512
513
514
515

Marketed products can benefit from the application of ECs and PACMPs as described in thisguideline. Specifically, ECs and reporting categories can be proposed for a marketed product via
a post-approval regulatory submission; a PACMP can also be proposed for planned change(s) to amarketed product. In addition, such products would also benefit from additional approaches tofacilitate changes. This chapter describes a strategy for a structured approach for frequent CMC
changes (e.g., analytical methods) and data requirements for CMC changes (e.g., stability).

516

8.1.

517
518
519
520
521
522
523

Marketed products have existing analytical procedures that may benefit from advances made inanalytical sciences. The intent of this chapter is to incentivize structured implementation ofequivalent analytical procedures that are fit for purpose. An approach wherein specific criteria aredefined for changes to analytical procedures used to test marketed products is described below. If
this approach is followed and all criteria are met, the analytical procedure change can be madewith immediate or other post-implementation notification, as appropriate, to the relevant
regulatory authorities.

Communication between assessors and inspectors can facilitate regulatory review of a specificproduct submission. When required, information relating to GMP and marketing authorization
compliance may be communicated from inspectors to assessors, and vice-versa, via establishedmechanisms. The communications can also occur between regulators across regions in accordancewith appropriate bilateral/multilateral arrangements.
POST-APPROVAL CHANGES FOR MARKETED PRODUCTS

Structured Approach to Analytical Procedure Changes

15

524
525
526
527
528
529
530
531
532
533
534

The following situations are out of scope of this chapter:•••

Procedures where the specification does not adequately reflect the complex information
provided by the method. In particular, procedures for which only a subset of the peaks are
identified and specified (e.g., assay for identity by peptide map, assay for complex drug
substances), or where the specification acceptance criteria include a general comparison toa reference standard beyond specified peaks (e.g., “comparable to reference standard” suchas for naturally derived products, biotechnology products made in living systems).
Change(s) to a test method based on a biological/immunological/immunochemical
principle or a method using a biological reagent (e.g., bioassay, binding assay, ELISA,
testing for viral adventitious agents).
Changes to predictive models used with multivariate methods.

535
536

It is important to note that with the exception of the above exclusion criteria, all other methods arein scope including those used for biotechnological/biological products.

537
538
539
540

Making use of Chapter 8.1 is dependent on the regional implementation of ICH guidelines (e.g.,
ICH Q2, Q9 and Q10) and routine application of these guidelines by industry. The flexibility
provided in Chapter 8.1 may not be available in all regions and in all situations; some specificchanges may require prior approval as defined in regional guidance.

541
542

8.1.1.

543
544•

The high-level description of the original method and the revised method should be thesame (e.g., chromatography with spectroscopic detection).

545
546

•

Validation results should demonstrate that the revised method is equivalent to or better thanthe original method.

547
548
549
550
551
552

•

Test results obtained using the original method and revised method should be equivalent
to each other. This should be assessed in two ways: First, the revised method should givean equivalent outcome, i.e., the same quality decision will be made regardless of whether
the data was obtained by the original or the revised method. Second, the validation protocol
should contain explicit criteria that compare results obtained using the new and revised
method. See step 2 below for further details.

553
554

•

System suitability requirements should be established for the revised method. System
suitability ensures the day-to-day performance of the method during routine use.

555
556
557
558
559
560

•

Specification changes (e.g., total impurities, potency) cannot be introduced using thismechanism unless allowed by existing regional regulations.

•This approach may not be used if toxicological or clinical data are required as a result of
the method change.

Principles

In order for this approach to be used, the following should be met:

16

561
562

If these criteria are met, the methods are equivalent and changes can be made with immediate orother post-implementation notification, as appropriate, to regulatory authorities.

563
564

8.1.2.

•

Structured Approach

Step 1: Evaluate the high-level method description. Examples include:565

o Gravimetric analysis

566

o Volumetric analysis

567

o Atomic absorption

568

o Microscopy

569

o Thermal analysis

570

o Electrochemical analysis

571

o Column chromatography (e.g., HPLC, UPLC)

572
573

o Plate chromatography (e.g., TLC); if used as an ID test or limit test a change to anothertype of method description may be made if the criteria in this chapter are met.

574

o Electrophoresis

575
576

o Changes to spectroscopic procedures should remain within same specific technology, e.g.,
UV to UV, NMR to NMR.

577
578
579
580
581
582
583

When two techniques are used together (e.g., HPLC with UV detection), both would be part of themethod description (i.e., column chromatography with spectroscopic detection).

584
585
586

o The principles of ICH Q2 should be followed to validate the change. All validation
characteristics relevant to the type of method being validated should be executed as
described in ICH Q2.

587
588
589
590
591
592
593
594

o The validation protocol should include, at minimum, the tests used to validate the existing
method and all other relevant tests in ICH Q2. For example, if specificity, linearity,
precision, and accuracy were assessed during validation of the original method, thenspecificity, linearity, precision, and accuracy should also be included in the validation of
the revised method. The protocol acceptance criteria should reflect appropriate
expectations for method performance and be justified scientifically. They should also be
developed in the context of the validation acceptance criteria for the original method toassure that the revised method is fit for purpose.

•

Step 2: A prospective analytical validation protocol should be prepared and approved
internally by the firm. It should be based on a comparison of the current and proposed method
and knowledge of the original validation protocol. The validation should assure that therevised method will be fit for its intended purpose and should contain at least the following:

17

595
596
597
598
599
600

o The validation should assess equivalency of the results of the revised method to those of
the original method using parallel testing of an adequate number of samples of appropriate
concentration based on the intended use of the method. The assessment of equivalency
should include the requirement that the new method does not lose any meaningful
information provided by the old method. Also the same quality decision should result
when assessing data from the same samples tested using the original and revised methods.

601
602

o

603
604
605

o The protocol should also contain the detailed operating conditions of both the original
method and the revised method to assure the changes being made are clear. The descriptionof the method may be included by attachment.

If there is a switch from manual to automated methods, the validation should also assess
the impact of any related changes in critical reagents, reference standards or software.

606
607
608
609
610

•

Step 3: Consider the system suitability criteria that exist in the current method, if any, anddetermine, based on method development data and any additional knowledge gained fromcommercial production, the system suitability criteria aspects that should be part of the new
method. System suitability in this context includes all criteria used to evaluate the day-to-day
performance of the method when used for routine testing.

611
612
613
614

•

Step 4: Execute the validation protocol and compare the results to the predetermined
acceptance criteria. If any criterion is not met, an assessment should be performed to evaluate
the impact of the failure to meet the criterion on the validity of the method. If all criteria aremet, the method is considered acceptable for its intended use.

615
616
617
618
619
620
621

•

Step 5: Consider new product information, if any, identified as a result of a change in thecontext of the current regulatory filing. If new or revised specifications (e.g., total impurities,
potency) are required based on results obtained during method validation, this structured
approach may not be used unless allowed by existing regional regulations. In addition, thisapproach may not be used if toxicological or clinical data are required as a result of the methodchange. Thus, the method change should have no impact on safety, efficacy, purity, strength,
identity, or potency of the product.

622
623

•

Step 6: Prepare a written summary report documenting the outcome of the validation versus
the protocol criteria.

624
625

•

Step 7: Follow the internal change process as defined within the firm’s PQS to implement thechange.

626
627
628
629

•

Step 8: Unless new information is identified as a result of this process (see step 5), provide a
post-implementation notification of the method change to the regulatory authority after thechange is implemented as per regional reporting requirements. This may include the updated
method description, the protocol, and the summary report of the validation.

630
631

•

Step 9: Complete post-change monitoring. The firm’s change control system (refer toAppendix 2) should explicitly identify and document a mechanism to assure the change was

18

632
633
634
635
636

effective with no unintended consequences. The outcome of the assessment should be
documented with a conclusion indicating the acceptability of the change.
•

Step 10: All information related to the method change should be available for verification
during routine regulatory inspection.

637

8.2.

638
639
640
641
642

The data needed for submission to the regulatory authority in support of a post-approval change isestablished by regional regulations and guidance. This guideline provides science- and risk-based
approaches that can be used to develop strategies for confirmatory stability studies supporting
post-approval changes to enable more timely filing, approval, and implementation of the changes.
Such approaches could be proposed in a PACMP (see Annex IIB).

643
644
645
646
647
648
649
650

Stability Data Approaches to Support the Evaluation of CMC Change
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, never-marketed drug substance/drug product,
the purpose of stability studies, if needed, to support a post-approval 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 acquired for the drug product and drug
substance. Approaches to the design of such studies should be appropriately justified and may
include:Data Requirements to Support CMC Changes

8.2.1.

651•

Identifying the stability-related quality attributes and shelf-life limiting attributes

652
653

•

Stability risk assessments to determine what factors can affect stability relative to the
proposed CMC changes

654•

Use of appropriate tools to evaluate the impact of the proposed change. These may include:

655
656
657

o Drug substance and/or drug product accelerated and/or stress studies on
representative material (which may be pilot or laboratory scale rather than fullscale)

658

o Pre-and post-change comparability studies on representative material659

o Statistical evaluation of informal and formal stability studies or other relevant data660

o Predictive degradation and other empirical or first-principles kinetic modelling

661
662

o Application of relevant institutional knowledge and knowledge from the scientific
literature

663
664

o Use of confirmatory studies post-change instead of submission of data as part of aregulatory change submission

19

665
666
667

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 implementing the CMC change.

668

9.

GLOSSARY

Term

Definition

CAPA

Corrective Action and Preventive Action –System that focuses on investigating,understanding, and correcting discrepancies
while attempting to prevent theiroccurrence

CMO(s)

Contract Manufacturing Organization(s)CPPCritical Process Parameter – processparameter whose variability has an impact
on a critical quality attribute and therefore
should be monitored or controlled to assure
the process produces the desired productquality. (Q8R2)

CQA

Critical Quality Attribute – a physical,
chemical, biological, or microbiologicalproperty or characteristic that should bewithin an appropriate limit, range, or
distribution to assure the desired productquality. (Q8R2)

CTDCommon Technical Document

ECs

Established Conditions

Firm

Manufacturing sites and MAH where
relevant

KPP

Key Process Parameter – parameters of the
manufacturing process that may not bedirectly linked to critical product quality
attributes, but need to be tightly controlled
to assure process consistency as it relates to
product quality

MAA

Marketing Authorization Application

MAH

Marketing Authorization Holder

Notification

The submission of a change in ECs that
does not require approval prior to
implementation.

20

Term

Definition

PACMP

Post-Approval Change Management
Protocol

PLCM

Product Lifecycle Management

Post-approval CMC commitments

Commitment by the MAH to undertake
specific CMC activities to be implemented
during the commercial phase.

Prior-approval

Change to an approved establishedcondition that requires regulatory review
and approval prior to implementation

PQR

Periodic Quality Review – regular periodic
review of API or drug products with theobjective to verify process consistency, tohighlight any trends and to identify productand process improvements

PQS

Pharmaceutical Quality System

QRM

Quality Risk Management

669

10.

670

ICH M4: The CTD – Quality

671

ICH Q1A(R2) Stability Testing of New Drug Substances and Products

672

ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology

673
674

ICH Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their
Manufacturing Process

675

ICH Q8(R2) Pharmaceutical Development676

ICH Q9 Quality Risk Management

677

ICH Q10 Pharmaceutical Quality System

678

ICH Q11 Development and Manufacture of Drug Substances

679

ICH Q8, Q9, and Q10 Questions and Answers

680
681

ICH Q8, Q9, and Q10 Questions and Answers -- Appendix: Q&As from Training Sessions (Q8,Q9, and Q10 Points to Consider)

REFERENCES

21

682

APPENDIX 1: CTD SECTIONS THAT CONTAIN ECS

683

Notes:

684
685•

This table does not contain a complete list of ECs for a product. The intention of the table is to provide general guidance about theelements of manufacture and control that constitute ECs and their location within the CTD structure.

686
687

•

White rows indicate CTD sections where ECs are generally located. Grey rows indicate CTD sections where supportive
information is generally located.

688•

CTD sections containing ECs may contain elements of supportive information.

689•

B – applicable to biotechnological/biological products

690
691

•

For delivery system information, the location or the relevant content within the CTD structure may vary depending on the designof the particular product and region

CTD
SECTIONSECTION TITLEESTABLISHED CONDITIONS – General List with notes

3.2.S

DRUG SUBSTANCE

3.2.S.1

General Information

3.2.S.1.1

Nomenclature

3.2.S.1.2

Structure

3.2.S.1.3

General properties

3.2.S.2

Manufacture

3.2.S.2.1

Manufacturer(s)Drug Substance Manufacturing Site(s) (including testing)

3.2.S.2.2

Description of manufacturing
process and process controls

Individual unit operations and their sequence in the manufacturing process

Drug Substance Name, Structure
Supportive information

For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations,reference is made to Chapter 3.2.3.1 – Identification of ECs for the Manufacturing Processes

22

CTD
SECTIONSECTION TITLEESTABLISHED CONDITIONS – General List with notes

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. (B)

3.2.S.2.4

Control of critical steps andintermediates

Specifications (e.g., test, elements of analytical procedure and acceptance criteria) for critical steps and intermediates including
storage conditions of critical intermediates

3.2.S.2.5

Process validation and/or
evaluation

Supportive information

3.2.S.2.6

Manufacturing processdevelopment

Supportive information

3.2.S.3

Characterisation

Supportive information

3.2.S.3.1

Supportive information

3.2.S.3.2

Elucidation of structure andother characteristics
Impurities

3.2.S.4

Control of Drug Substance3.2.S.4.1

Specification

Drug Substance Specification
For each Quality Attribute on the specification••

3.2.S.4.2

Analytical Procedures

3.2.S.4.3

Validation of analyticalprocedure

Test Method
Acceptance Criteria

Reference is made to Chapter 3.2.3.2. –Identification of ECs for Analytical Procedures
Supportive information

23

CTD
SECTIONSECTION TITLE

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 qualification (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 andConclusions

3.2.S.7.2

Post-approval stability protocol
and stability commitments

3.2.S.7.3

Stability data

3.2.P

DRUG PRODUCT

3.2.P.1

Description and Composition ofDrug Product3.2.P.2

Pharmaceutical development

3.2.P.2.1

Components of the drug
product

3.2.P.2.2

Drug product3.2.P.2.3

Manufacturing processdevelopment

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

ESTABLISHED CONDITIONS – General List with notes

Drug Substance storage conditions and shelf-life (or Retest period for chemicals)

Supportive information (also see Chapter 3.2.2.)

Supportive information

Drug Product qualitative and quantitative composition

Supportive information

24

CTD
SECTIONSECTION TITLEESTABLISHED CONDITIONS – General List with notes

3.2.P.3.1

Manufacturer(s)Drug Product Manufacturing (including: testing, primary packaging, device assembly for drug product-device combination
products) sites

3.2.P.3.2

Batch Formula

Drug Product Batch Formula (Qualitative and Quantitative)

3.2.P.3.3

Description of manufacturing
process and process controls

Individual unit operations and their sequence in the manufacturing process
For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations,reference is made to Chapter 3.2.3.1 – Identification of ECs for the Manufacturing Processes

3.2.P.3.4

Controls of Critical Steps andIntermediates

Specifications (e.g., test, elements of analytical procedure and acceptance criteria) for critical steps and intermediates including
storage conditions of critical intermediates

3.2.P.3.5

Process validation and/or
evaluation

3.2.P.4

Control of Excipients

3.2.P.4.1

Specifications

Supportive information

Excipient Specification
For each Quality Attribute on the specification••

Test Method
Acceptance Criteria

Or, if applicable,
Reference to Pharmacopeial monograph
3.2.P.4.2

Analytical Procedures

3.3.P.4.3

Validation of analyticalprocedures

3.3.P.4.4

Reference to Pharmacopeial monograph and if none exists, refer to Chapter 3.2.3.2 – Identification of ECs for Analytical
Procedures
Supportive information

Justification of specifications
Supportive information

25

CTD
SECTIONSECTION TITLEESTABLISHED CONDITIONS – General List with notes

3.2.P.4.5

Excipients of Human or Animal
OriginExcipient source and controls should be specified (for human- or animal-derived excipients only)

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••

3.2.P.5

Control of Drug Product3.2.P.5.1

Specification(s)Drug product specification
For each Quality Attribute on the specification••

3.2.P.5.2

Analytical Procedures

3.2.P.5.3

Validation of analyticalprocedures

Test Method
Acceptance Criteria

Test Method
Acceptance Criteria

Reference is made to Chapter 3.2.3.2 – Identification of Established Conditions for Analytical Procedures

Supportive information

3.3.P.5.4

Batch analyses

3.2.P.5.5

Characterisation of impurities

3.2.P.5.6

Justification of specification(s)3.2.P.6

Reference Materials

Reference material qualification (e.g., test, elements of analytical procedure, where appropriate, and acceptance criteria)

3.2.P.7

Container Closure System

Supplier/manufacturer of container closure

Supportive information

Material of construction and specification

26

CTD
SECTIONSECTION TITLE

3.2.P.8

Stability

3.2.P.8.1

Stability Summary andConclusion

3.2.P.8.2

Post-approval stability protocol
and stability commitment

ESTABLISHED CONDITIONS – General List with notes

Drug product storage conditions and shelf-life (or retest period for chemicals)
Where applicable, in-use storage conditions and shelf-life

Supportive information (also see Chapter 3.2.2.)

3.3 P.8.3

Stability data

3.2.A

APPENDICES

3.2.A.1

Facilities and equipment

Regional regulation and guidance apply

3.2.A.2

Adventitious agents safety
evaluation

Supportive information

3.2.A.3

Excipients

Supportive information

3.2.R

REGIONAL INFORMATION
Not Applicable

Supportive information

Regional regulation and guidance apply.
For EU, Medical Device information or CE mark confirmation

692

27

693

APPENDIX 2: PRINCIPLES OF CHANGE MANAGEMENT

694
695

Consistent with the basic requirements of ICH Q10, an effective change management
system supports the principles of this guideline and is described below:

696
697

1. Captures stimuli for change including those that can improve product performanceor process robustness;

698
699
700

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 authorisations;701

3. Leverages existing process performance and product quality knowledge;

702
703
704

4. Requires a science and data based risk assessment and risk categorisation of the
proposed change including the management of risk in the event the proposedchange is not implemented;

705
706
707
708

5. Determines data (existing and/or to be newly generated) needed to support thechange 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;

709
710

6. When required, ensures that a regulatory submission is developed (e.g.,
supplement/variation, PACMP) and submitted;

711
712
713

7. Uses a defined change control process to approve or reject the change and involve
appropriate stakeholders, including but not restricted to Manufacturing, Quality,
and Regulatory personnel;714

8. Ensures implementation of the change is based on:

715
716

a. Review that the change as implemented remains aligned with the relevant
protocols, any PLCM document and/or any PACMP;

717
718

b. Assessment of data generated to demonstrate that the change objective andacceptance criteria were met;

719
720

9. Ensures that risk-mitigating steps are developed in case of deviations fromacceptance criteria, or identification of unanticipated risks;

721
722

10. Captures new product/process knowledge gained during implementation of thechange;723
724

11. Verifies, post-implementation, that changes have been effective in achieving thedesired outcome with no unintended consequences;

725
726

a. If deviations associated with post-approval changes are detected, ensuresthat the issue is managed via the firm’s deviation management process and

28

727
728

appropriate corrective and/or preventive actions are identified andundertaken via the firm’s corrective and preventive action (CAPA) system

729
730
731

b. Where applicable, ensures that regulatory filings are updated and anassessment is made as to whether updates to the PLCM document areneeded

732
733
734

c. Requires a post-implementation lessons-learned exercise to build on the
product and process knowledge gained with a view to continual
improvement, including improvement of the PQS

735
736

d. Ensures that the change is included and assessed as part of the ProductQuality Review (PQR)

737
738

12. The change management system should be organised and available for review
during audit/inspection.

739

Management Review

740
741
742
743
744

Details of Management Review are extensively described in ICH Q10 including the use of
appropriate performance indicators as a means to assess the effectiveness of a PQS. Theseshould be meaningful, simple and data-driven. In addition to the requirements of ICH Q10
in the context of ensuring an effective change management system, the following could beconsidered in the Management Review:

745
746
747
748

•

Monitoring the timeliness of the change management system to assure that changes
are implemented in a timely manner commensurate with the urgency identified forthe change. When implementation is delayed, an assessment and mitigation of any
risks associated with the delay should be made;

749
750
751

•

Monitoring the performance of the change management system, such as assessing
the frequency of proposed changes that are not approved for implementation upon
first submission;

752
753
754

•

Ensuring that post-implementation verification occurs and reviewing the results ofthat verification as a measure of change management effectiveness (e.g., to identify
improvements to the change management system);

755

Use of Knowledge in Change Management

756
757
758
759

An effective change management system includes active knowledge management, inwhich 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 A1.

760
761
762
763

As indicated in ICH Q10 and shown in Figure A1, these sources can include, but are notlimited to, developmental studies, process understanding documents, product or process
trending, and product-specific CAPA outcomes. They should be comprehensive across the
product lifecycle, including all relevant stakeholders (R&D, manufacturing, CMOs,

29

764
765
766
767

suppliers, etc.). With respect to sharing knowledge between the firm and suppliers, andbetween the firm and CMOs, considerations for sharing knowledge that relates to productand process robustness or otherwise informs changes should be built into quality
agreements and/or contracts.

768
769
770
771
772
773

In addition to individual sources of information, there should be a mechanism to provide aholistic view of quality performance for a specific product or product family on a regularbasis, as captured in the PQR and shown in Figure A1. This should include steps taken to
identify and manage variability introduced from raw materials and the manufacturing
process that could impact on product quality during its lifecycle. This allows for theidentification of further need for change not apparent when the data are viewed in isolation.

774
775
776
777

Use of knowledge is the responsibility of the firm and should be described in the PQS (formore detailed information reference is made to ICH Q8, Q9, Q10, Q11, Q/IWG Q&A). As
described in ICH Q10, there is no added regulatory requirement for a formal knowledge
management system.

778
779

Figure A1

Connection Between Knowledge Management and Change Management
Process

780

30