ICH Q12: Implementation Considerations for FDA-Regulated Products: Draft Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

ICH Q12: Implementation
Considerations for
FDA-Regulated Products
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) Ashley Boam 301-796-6341,
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010,
or (CDRH) CDRH product jurisdiction officer at CDRHProductJurisdiction@fda.hhs.gov.
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)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products (OCP)
May 2021
Pharmaceutical Quality/CMC

ICH Q12: Implementation
Considerations for
FDA-Regulated Products
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4 th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
and/or
Office of Policy
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 66, Room 5431
Silver Spring, MD 20993-0002
Email: CDRH-Guidance@fda.hhs.gov
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products
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)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products (OCP)
May 2021
Pharmaceutical Quality/CMC

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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	CONSIDERATIONS FOR IMPLEMENTATION ....................................................... 2
A. 	Introduction .................................................................................................................................... 2
B. 	Categorization of Postapproval CMC Changes .......................................................................... 2
C. 	Established Conditions .................................................................................................................. 2
1. Submission of ECs ........................................................................................................................... 3
2. Identification of ECs ........................................................................................................................ 4
3. Identification of ECs for a Drug Substance or Drug Product in a Drug Master File ..................... 5
4. Identification of ECs for Device Constituent Parts of Combination Products ................................ 6
5. Changes to Approved ECs ............................................................................................................... 7
6. Postapproval Submissions in Accordance With Approved ECs ...................................................... 7
7. Maintenance of the Application ....................................................................................................... 7
D. 	Postapproval Change Management Protocol .............................................................................. 8
E. 	Product Lifecycle Management Document.................................................................................. 8
F. 	Pharmaceutical Quality System and Change Management ....................................................... 9
G. 	Relationship Between Regulatory Assessment and Inspection .................................................. 9
H. 	Structured Approaches for Frequent CMC Postapproval Changes and Stability Data
Approaches To Support the Evaluation of CMC Changes ............................................................... 10
APPENDIX A. ESTABLISHED CONDITIONS FOR COMBINATION PRODUCTS
WITH DEVICE CONSTITUENT PARTS .............................................................................. 11
APPENDIX B. DECISION TREE FOR IDENTIFYING ESTABLISHED CONDITIONS
AND REPORTING CATEGORIES FOR DEVICE CONSTITUENT PARTS ................... 12
APPENDIX C. PRODUCT LIFECYCLE MANAGEMENT DOCUMENT EXAMPLE ... 13

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ICH Q12: Implementation Considerations for	1
FDA-Regulated Products	2
Guidance for Industry1
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
14
I. 	INTRODUCTION	15
16
The International Council for Harmonisation (ICH) guidance for industry Q12 Technical and	17
Regulatory Considerations for Pharmaceutical Product Lifecycle Management and its Annexes	18
(ICH Q12, May 2021) provide a framework to facilitate the management of postapproval	19
chemistry, manufacturing, and controls (CMC) changes in a more predictable and efficient	20
manner.2 ICH Q12 includes regulatory tools and enablers with associated guiding principles that	21
should enhance industry’s ability to manage postapproval changes and increase transparency	22
between industry and regulatory authorities, supporting innovation and continual improvement.	23
24
This guidance should be read in conjunction with ICH Q12, which this guidance complements	25
by clarifying how the ICH Q12 tools and enablers can be implemented within the U.S. regulatory	26
system. These guidances apply to drug substances and drug products3 that are the subject of new	27
drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug	28
applications (ANDAs), and supplements to these applications regulated by the Center for Drug	29
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research	30
(CBER). They also apply to combination products4 with device constituent parts that are the	31
subject of NDAs, BLAs, ANDAs, and supplements to these applications regulated by CDER and	32
CBER.	33
34
The contents of this document do not have the force and effect of law and are not meant to bind	35
the public in any way, unless specifically incorporated into a contract. This document is intended	36
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Research in cooperation with the Center for Biologics Evaluation and Research, Center for Devices and
Radiological Health, and Office of Combination Products at the Food and Drug Administration.
2 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 For the purposes of this guidance, drug substance and drug product include biological drug substances and drug
products.
4 See 21 CFR 3.2(e).

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only to provide clarity to the public regarding existing requirements under the law. FDA	37
guidance documents, including this guidance, should be viewed only as recommendations, unless	38
specific regulatory or statutory requirements are cited. The use of the word should in Agency	39
guidances means that something is suggested or recommended, but not required.	40
41
42
II. 	CONSIDERATIONS FOR IMPLEMENTATION	43
44
The considerations below follow the order of the sections in ICH Q12 and are specific to FDA’s	45
implementation.	46
47
A. 	Introduction	48
49
As stated above, ICH Q12 and this guidance apply to drug substances and drug products that are	50
the subject of NDAs, BLAs, ANDAs, and supplements to these applications regulated by CDER	51
and CBER. They also apply to combination products with device constituent parts that are the	52
subject of NDAs, BLAs, ANDAs, and supplements to these applications regulated by CDER and	53
CBER.	54
55
B. 	Categorization of Postapproval CMC Changes	56
57
ICH Q12 describes two categories for regulatory communications: prior approval and	58
notification. In the U.S. regulatory system, prior approval means a prior approval supplement	59
(PAS), notification moderate means a changes being effected-30 (CBE-30) supplement, and	60
notification low means a CBE-0 supplement or annual report.5 As indicated in ICH Q12, the	61
lowest risk changes are managed and documented within the pharmaceutical quality system	62
(PQS) and do not need to be reported, but they may be verified during a surveillance or other	63
inspection.	64
65
C. 	Established Conditions	66
67
ICH Q12 defines established conditions (ECs) as legally binding information considered	68
necessary to assure product quality. As a consequence, any change to ECs necessitates a	69
submission to the regulatory authority. This is consistent with FDA’s regulations at 21 CFR	70
314.70(a)(1)(i), 314.97(a), and 601.12(a)(1). Although these regulations do not explicitly specify	71
what constitutes an EC, they do set forth a risk-based paradigm for reporting changes. In	72
addition, existing FDA guidance documents describe a broad set of postapproval changes and	73
make recommendations for how they should be reported.6 The risk-based paradigm set forth in	74
the regulations and the recommendations in these associated guidance documents can help	75
5 See 21 CFR 314.70, 314.97, and 601.12.
6 See, e.g., FDA’s Scale-Up and Postapproval Changes (SUPAC) guidances and the guidances for industry Changes
to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (July 1997),
Changes to an Approved NDA or ANDA (April 2004), and CMC Postapproval Manufacturing Changes To Be
Documented in Annual Reports (March 2014). Insofar as a guidance adjusts reporting categories pursuant to section
506A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 314.70 and 601.12, these adjustments
do establish legally enforceable responsibilities and are not only recommendations.

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applicants determine which elements of an application that FDA would typically consider to be	76
ECs. ICH Q12 further helps applicants gain clarity around which elements of the product,	77
manufacturing process, facilities and equipment, and control strategy in their applications are	78
considered to be ECs and therefore require reporting if changed.	79
80
Proposing elements to be considered ECs that may differ from those FDA typically considers to	81
be ECs based on the risk-based paradigm set forth in the regulations and the recommendations	82
contained in guidance is voluntary. Applicants may propose ECs in their original applications or	83
in a PAS.7 If specific ECs are not proposed, ECs would be those that FDA typically considers to	84
be ECs based on the risk-based paradigm set forth in the regulations and the recommendations	85
contained in guidance regarding postapproval changes.	86
87
Applicants may also propose reporting categories for changes to ECs. The reporting categories	88
proposed may be consistent with the risk-based paradigm set forth in the regulations and the	89
recommendations contained in guidance. Alternatively, an increased understanding of the risk to	90
product quality posed by a change to an EC may support a proposal for reduced reporting	91
categories.	92
93
1. 	Submission of ECs	94
95
To ensure clarity regarding ECs when submitting an original NDA, BLA, or ANDA, applicants	96
should:	97
98
• 	Include one of the following statements in the cover letter:	99
100
o 	Specific ECs are proposed.	101
102
o 	Specific ECs are not proposed; postapproval changes will follow the regulations and	103
the recommendations in guidance.8	
104
105
• 	Include one of the following statements in eCTD section 3.2.R of the application9:	106
107
o 	Specific ECs are proposed. Specific reporting categories for changes to those ECs are	108
not proposed and therefore will follow the regulations and the recommendations in	109
guidance.	110
7 Plans to include specific ECs in an original application or PAS are an appropriate topic for presubmission meetings
with FDA, if available.
8 In this guidance, FDA recommends as an option that the applicant state that it intends to follow both the
regulations and the recommendations in guidance. In most cases, an applicant could choose to follow the regulations
while taking a different approach than recommended in guidance and explain how its deviations from the guidance
would satisfy the applicable legal requirements. However, if a guidance adjusts reporting categories pursuant to
section 506A of the FD&C Act and 21 CFR 314.70 and 601.12, these adjustments do establish legally enforceable
responsibilities and are not only recommendations.
9 eCTD=electronic common technical document, the standard format for submitting applications, supplements, and
other information to FDA. For more information, see https://www.fda.gov/drugs/electronic-regulatory-submission-
and-review/electronic-common-technical-document-ectd.

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111
o 	Specific ECs are proposed. Specific reporting categories for changes to those ECs are	112
proposed.	113
114
o 	Specific ECs are not proposed; postapproval changes will follow the regulations and	115
the recommendations in guidance.	116
117
When proposing ECs in a PAS, applicants should:	118
119
• 	State in the cover letter that ECs are proposed.	120
121
• 	Include one of the following statements in eCTD section 3.2.R:	122
123
o 	Specific ECs are proposed. Specific reporting categories for changes to those ECs are	124
not proposed and therefore will follow the regulations and the recommendations in	125
guidance.	126
127
o 	Specific ECs are proposed. Specific reporting categories for changes to those ECs are	128
proposed.	129
130
If applicants choose to propose specific ECs, they can propose them for the entire CMC section	131
of the application (module 3: Quality) or for a subset of information provided in module 3 (e.g.,	132
for eCTD section 3.2.S or for eCTD section 3.2.P.3.3). If a limited set of ECs is proposed, such	133
as for an individual unit operation in the manufacturing process, the applicant should list for the	134
applicable eCTD sections all of the ECs for that unit operation. Additionally, the applicant	135
should include a statement that, for the appropriate eCTD sections, changes to those unit	136
operations for which ECs are not proposed will be reported according to the regulations and the	137
recommendations in guidance.	138
139
A complete list of proposed ECs, their reporting categories (if proposed), and the eCTD locations	140
for their scientific justification should be included in the Product Lifecycle Management (PLCM)	141
document in eCTD section 3.2.R. See section II.E in this guidance for more information about	142
the PLCM document. See section II.C.2 for information about the justification for proposed ECs,	143
including where such justifications should reside in the application.	144
145
2. 	Identification of ECs	146
147
When proposing specific ECs, applicants should include a scientific justification for their	148
selection in the relevant parts of module 3 of the application. In this justification, applicants	149
should address both the identification of particular parameters or attributes as ECs and the	150
proposed reporting categories (if applicable).	151
152
a. 	Parameters and attributes identified as ECs	153
154
In the justification, applicants should explain how they identified the parameters or attributes that	155
are proposed to be ECs and why others that might typically be considered to be ECs (considering	156

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the regulations and the recommendations in guidance as described above) were not. For example,	157
in a manufacturing unit operation for which three of five process parameters are proposed to be	158
ECs (in a parameter-based approach), the applicant should explain how the three parameters	159
were identified as being ECs and why the other two were not. A description of the applicant’s	160
risk assessment process (including tools) used to identify particular parameters or attributes as	161
ECs, the criticality assessment conducted to determine the level of impact of each parameter on	162
product quality, and the supporting information for each (e.g., fundamental knowledge, empirical	163
investigation, prior knowledge from experience with other products, commercial experience)	164
should be provided. See also sections 3.2.3.1 “Identification of ECs for Manufacturing	165
Processes” and 3.2.3.2 “Identification of ECs for Analytical Procedures” in ICH Q12. Applicants	166
should not propose to manage attributes as ECs if changes to those attributes would require	167
submission of a new original application (e.g., change in dosage form for an NDA).	168
169
For parameters or attributes identified as ECs that have associated acceptable ranges, applicants	170
should include a justification for the proposed ranges.	171
172
b. 	Reporting categories	173
174
For each proposed EC, the applicant may identify a proposed reporting category: PAS, CBE-30,	175
CBE-0, or annual report. If this reporting category differs from that recommended in existing	176
guidance, the applicant should provide a justification in the relevant section of module 3. This	177
justification can be part of or complementary to the justification provided to support	178
identification of the EC. If the applicant chooses not to propose reporting categories, the	179
applicant should include a statement that reporting categories for changes to those ECs will	180
follow the regulations and the recommendations in guidance.	181
182
3. 	Identification of ECs for a Drug Substance or Drug Product in a Drug Master	183
File	184
185
If information about the drug substance or drug product is incorporated in an application by	186
reference to a Type II drug master file (DMF),10 ECs associated with that drug substance or drug	187
product can be proposed, but they should only be proposed as part of the application.11 In such	188
cases, the DMF holder will need to share sufficient information with the applicant12 so that	189
proposed ECs and their associated reporting categories can be specified in and approved as part	190
of the application. The justification in support of the identification of ECs can be located in the	191
DMF, as long as the application refers to the specific location of the justification in the DMF.	192
The applicant should provide a justification for proposed reporting categories in the application	193
because the justification will generally be specific to the final drug product and its conditions of	194
approval (e.g., dosing, route of administration) rather than generalizable across different products	195
10 FDA has proposed rulemaking to codify the expectation that BLA applicants submit drug substance, drug
substance intermediate, and drug product information directly to the BLA rather than incorporating it by reference to
a master file. See 84 FR 30968.
11 The same approach applies to information incorporated by reference from other types of DMFs (e.g., Types III,
IV, or V, where applicable).
12 See guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements (November
2016).

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incorporating the same drug substance or drug product. When ECs are approved for an	196
application that incorporates by reference information from a DMF, the applicant maintains	197
responsibility for reporting changes to ECs; however, the applicant should share the relevant	198
approved ECs with the DMF holder to ensure that the DMF holder is aware of how changes to	199
the referenced drug substance or drug product will be managed by the applicant.	200
201
4. 	Identification of ECs for Device Constituent Parts of Combination Products	202
203
Applicants may propose ECs for the device constituent part of a combination product in an	204
NDA, BLA, or ANDA. The combination product as a whole, including the roles and interactions	205
of the constituent parts, should be considered in proposing ECs and reporting categories for the	206
product, including in relation to each constituent part. The focus of this section is identifying	207
ECs for device constituent parts in particular. One approach is to assess the “characteristics of	208
the product that are essential for its safe and proper use”13 (primary characteristics) relating to	209
the device constituent part and to identify the associated ECs. The primary characteristics for the	210
device constituent part of a combination product generally include:	211
212
• 	Functions essential for safe use based on risk management principles (see, e.g., ICH	213
guidance for industry Q9 Quality Risk Management (June 2006); ISO 14971:2019,	214
Medical devices—Application of risk management to medical devices).	215
216
• 	Design features essential to achieve delivery of the labeled dose to a specific body site	217
(e.g., for a device constituent part that provides drug delivery).	218
219
• 	Characteristics that impact the drug constituent part’s critical quality attributes.	220
221
Applicants should consider the following as potential ECs:	222
223
• 	Design features that are primary characteristics.	224
225
• 	Manufacturing process elements for the device constituent part that need to be controlled	226
to ensure a primary characteristic.	227
228
• 	Other control strategy elements for the device constituent part that ensure a primary	229
characteristic.	230
231
See appendix A for a description of elements that are generally considered to be ECs for device	232
constituent parts. As with identifying ECs for drug constituent parts, whether it may be	233
appropriate to propose ECs for device constituent parts or a lesser reporting category for them	234
will vary based on extent of product and process understanding, knowledge gained from design	235
and development to manage the risks, and evidence to support designation and justification of	236
the primary characteristics. Similarly, the level of risk associated with a change to an EC will	237
13 See ISO 13485:2016, Medical devices—Quality management systems—Requirements for regulatory purposes,
Section 7.3.4 Product realization—Design and development—Design and development outputs. ISO=International
Organization for Standardization.

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determine the appropriate reporting category for that change. See appendix B for an approach	238
that can be followed for device constituent parts when identifying ECs and their associated	239
reporting categories.	240
241
5. 	Changes to Approved ECs	242
243
As indicated in ICH Q12, applicants may propose to add, eliminate, or make changes to	244
approved ECs or revisions to their associated reporting categories through:	245
246
• 	Submission of a supplement.	247
248
o 	Addition of an EC that provides increased assurance of the quality of the drug	249
substance or product with a reporting category provided for in the regulations or	250
recommended in guidance should be submitted as a CBE-0 (see § 314.70(c)(6)).	251
252
o 	All other changes should be submitted as a PAS.	253
254
• 	Submission of a postapproval change management protocol (PACMP; see section II.D in	255
this guidance).	256
257
• 	Fulfillment of a previously approved postapproval commitment submitted in a	258
supplement or annual report. For example, this may be done if an EC was approved with	259
an allowance for a modification pending the availability—and submission, where	260
specified—of certain information.	261
262
6. 	Postapproval Submissions in Accordance With Approved ECs	263
264
When submitting postapproval supplements and annual reports to report CMC changes in	265
accordance with approved ECs, applicants should state in the cover letter that the submission	266
contains changes made in accordance with previously approved ECs. These submissions should	267
also include an updated PLCM (see section II.E in this guidance).	268
269
7. 	Maintenance of the Application	270
271
As indicated in ICH Q12, maintenance of the application is subject to regional requirements. To	272
ensure that FDA has access to up-to-date analytical procedures, applicants should include in the	273
annual report a copy of all analytical procedures that have been appropriately modified during	274
the reporting period without a submission (i.e., managed only through the PQS as changes did	275
not relate to ECs). This information is intended to be for information only and typically is not	276
subject to review unless it is determined that changes to ECs for the procedure were in fact made.	277
Applicants should include this information in eCTD section 1.13.5 or 1.13.7 with a statement	278
such as “For information only: Changes made to analytical methods, including those not	279
requiring submission.”	280
281

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D. 	Postapproval Change Management Protocol	282
283
In the U.S. regulatory system, PACMPs are referred to as comparability protocols and are	284
voluntary. These protocols differ from the use of ECs in one important respect. Both	285
comparability protocols and the use of ECs address the element to be reported if changed and the	286
reporting mechanism, but a comparability protocol requires the tests and studies to support a	287
future change to an EC to be specified at the time of the protocol submission (21 CFR	288
314.70(e)).	289
290
FDA recommends that comparability protocols be submitted in eCTD section 3.2.R. For a	291
comparability protocol that includes one or more changes that apply to more than one product,	292
see draft guidance for industry Comparability Protocols for Human Drugs and Biologics:	293
Chemistry, Manufacturing, and Controls Information (April 2016)14 for information on the	294
appropriate content and format of the submission and the circumstances in which a comparability	295
protocol might be useful.	296
297
E. 	Product Lifecycle Management Document	298
299
As described in ICH Q12, the PLCM document should include proposed ECs, reporting	300
categories for making changes to approved ECs, a list of comparability protocols (if submitted),	301
and postapproval CMC commitments, if applicable. FDA recommends that the PLCM document	302
be provided in tabular format in eCTD section 3.2.R, with specific references to the submission	303
sequence, eCTD section number, and page number where each EC’s scientific justification can	304
be found. FDA further recommends that the PLCM indicate the manufacturing sites (preferably	305
by facility establishment identifier (FEI) number) where an EC will be implemented.15 For	306
example, if there are two drug product manufacturing sites named in the application, but the	307
manufacturing process-related ECs will only be associated with the manufacturing at one of	308
those two sites, the FEI number of this site should be specified in the PLCM for those process-	309
related ECs. It is then assumed that ECs for operations at the other facility will follow the	310
regulations and the recommendations in guidance. If the ECs will be implemented at both sites,	311
both FEI numbers should be listed. Applicants should attribute FEIs to ECs in the PLCM at the	312
most inclusive level (e.g., one FEI listed at the beginning of 3.2.P if all subsequent ECs in the	313
section are associated with one drug product facility). See appendix C in this guidance for an	314
example of a PLCM document.	315
316
Applicants should provide an updated PLCM document with each supplement or annual report	317
that reports changes to approved ECs. If no specific ECs are proposed, submission of a PLCM	318
document is not necessary.	319
320
14 More specifically, see the appendix, section A, question 6. When final, this guidance will represent FDA’s current
thinking on this topic.
15 Such facilities may include facilities responsible for design control for a combination product. See guidance for
industry Current Good Manufacturing Practice Requirements for Combination Products (January 2017).

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F. 	Pharmaceutical Quality System and Change Management	321
322
As indicated in ICH Q12, in addition to compliance with current good manufacturing practice	323
(CGMP) requirements,16 an effective PQS is necessary to support the use of the tools in that	324
guidance. However, also as noted in that guidance, FDA will not require a specific inspection	325
before an applicant can make use of the principles in the guidance. FDA’s assessment of the	326
effectiveness of the PQS will generally be informed by routine inspections conducted by FDA	327
and capable foreign regulators17 and other available information. Management should employ	328
the principles of ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009) to	329
ensure the continued capability of the PQS to support the management of ECs.	330
331
Because of the importance of the PQS in supporting the use of ICH Q12 tools, when an applicant	332
proposes to introduce a new manufacturing site after approval, the applicant should not assume	333
that the initially approved ECs will apply. Instead, if ECs are proposed, applicants should include	334
the following in supplements that propose a new site:	335
336
• 	Reassessment of the relevant ECs.	337
338
• 	Justification for proposed changes to ECs as a result of this reassessment in the relevant	339
parts of module 3 of the application.	340
341
FDA will also consider information included in a supplement that supports a determination that	342
the new site deserves the same level of regulatory flexibility regarding postapproval changes as	343
the site included in the original application. The determination of PQS capability will consider	344
factors such as whether the new site is operated under the same PQS as the original; the state of	345
regulatory compliance determined by FDA and other national drug regulatory authorities;	346
conformance with ICH Q10, especially as concerns change management practices; and	347
conformance with other applicable change management regulations and policies.	348
349
As indicated in ICH Q12, inspection observations that raise concern regarding the effectiveness	350
of the PQS, and change management in particular, may lead to a need to modify previously	351
approved ECs, reporting categories, or comparability protocols until such time as the PQS	352
effectiveness has returned to an acceptable state. In these cases, FDA intends to communicate the	353
impact of such findings on previously approved ECs, reporting categories, and comparability	354
protocols with facilities and applicants, as appropriate.	355
356
G. 	Relationship Between Regulatory Assessment and Inspection	357
358
The use of ICH Q12 tools, such as ECs, is not expected to change FDA’s processes for how	359
information is assessed as part of the application or from a facility inspection. Similarly, it does	360
16 See section 510(a)(2)(B) of the FD&C Act; 21 CFR parts 4, 210, 211, and 600; and guidance for industry Current
Good Manufacturing Practice Requirements for Combination Products.
17 Capability determinations are made in accordance with section 809 of the FD&C Act; see also
https://www.fda.gov/international-programs/international-arrangements/mutual-recognition-agreement-mra.

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not change the expectations regarding the type of information to be submitted in an application	361
or the information that is to be available for an inspection.	362
363
H. 	Structured Approaches for Frequent CMC Postapproval Changes and	364
Stability Data Approaches To Support the Evaluation of CMC Changes	365
366
Sections VIII and IX of ICH Q12 and section II of the ICH Q12 Annexes provide alternative	367
approaches for certain CMC postapproval changes. FDA supports the use of such approaches.	368
FDA also encourages applicants to gain its feedback before proposing or implementing novel	369
approaches.	370

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APPENDIX A. ESTABLISHED CONDITIONS FOR COMBINATION PRODUCTS	371
WITH DEVICE CONSTITUENT PARTS	372
373
The combination product as a whole, including the roles and interactions of the constituent parts,	374
should be considered in proposing established conditions (ECs) and reporting categories for the	375
product, including in relation to each constituent part. This appendix provides general guidance	376
about the elements that are generally considered ECs for the device constituent part of	377
combination products.1 It does not contain a complete list of ECs for a device constituent part;	378
each application should include a justification for the identification of proposed ECs.	379
380
The following are generally considered ECs for the device constituent part of combination	381
products:	382
383
• 	Identification of the device: If purchased from a third party, manufacturer identifiers for	384
the device (e.g., brand name); references to device clearance or approval (if applicable).	385
386
• 	Description and design features: Device description; principle (e.g., mechanical,	387
electrical) and mechanism (e.g., spray, mixing) of operation for delivery of the drug	388
product; design features that are primary characteristics; materials of construction in	389
direct or indirect contact with the drug product and patient.	390
391
• 	Manufacturers: Name, address, and responsibilities for sites that perform assembly,	392
packaging, and testing of the device constituent part.	393
394
• 	Manufacturing (e.g., assembly): Unit operations and sequence in the manufacturing	395
process; manufacturing process parameters, material attributes, and in-process controls,	396
where variability impacts primary characteristics.	397
398
• 	Release/expiry specification and associated test methods for attributes that ensure	399
primary characteristics.	400
1 Similar to appendix 1 in International Council for Harmonisation guidance for industry Q12 Technical and
Regulatory Considerations for Pharmaceutical Product Lifecycle Management (May 2021).

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APPENDIX B. DECISION TREE FOR IDENTIFYING ESTABLISHED CONDITIONS	401
AND REPORTING CATEGORIES FOR DEVICE CONSTITUENT PARTS	402
403
The decision tree below can be used to guide the identification of established conditions and	404
associated reporting categories for the device constituent part of a combination product.	405
Answer these questions about the characteristic:
• 	Is it essential for safe use based on risk management?*
• 	Is it essential to achieve delivery of the labeled dose?
• 	Does it impact the drug product’s CQA?
Primary characteristic:
Essential for safe and
proper use**
Other characteristic:
Not essential for
safe and proper use
Design
features that
are primary
characteristics
Manufacturing
process
elements that
need to be
controlled to
ensure primary
characteristics
Other control
strategy
elements that
ensure primary
characteristics
Define the design, process, and control strategy
elements that are ECs
Elements of
design,
process, and
controls for
other
characteristics
are not ECs
PAS 	CBE-30 or CBE-0 	Not Reported
What is the level of potential risk associated
with the proposed change?
“Yes” to any 	“No” to all
Moderate to Low	High
*As determined using risk management principles in ICH guidance for industry Q9 Quality Risk
Management (June 2006) or ISO 14971:2019, Medical devices—Application of risk management to
medical devices.
**See ISO 13485:2016, Medical devices—Quality management systems—Requirements for
regulatory purposes, Section 7.3.4 Product realization—Design and development—Design and
development outputs.
Note: CQA=critical quality attribute; EC=established condition; PAS=prior approval supplement;
CBE=changes being effected; ICH=International Council for Harmonisation; ISO=International
Organization for Standardization.
406

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APPENDIX C. PRODUCT LIFECYCLE MANAGEMENT DOCUMENT EXAMPLE	407
408
In this example,1 where the applicant proposes to follow FDA regulations and the	409
recommendations in guidance for a change to a particular established condition, the reporting	410
category has been left blank.	411
412
1 Adapted from annex IF in the International Council for Harmonisation guidance for industry Q12 Technical and
Regulatory Considerations for Pharmaceutical Product Lifecycle Management: Annexes (May 2021).
eCTD Section 	Established Conditions
(Note that identification and justification of each EC is
presented in the relevant eCTD section)
Reporting
Category When
Making a Change
to the EC
The ECs below are to be implemented at the following sites:
FEI xxxxxx
FEI yyyyyy
Seq 0001, 3.2.P.3.3,
p. 4
The manufacturing process consists of the following
sequence of unit operations:
1. Powder blending
2. Roller compaction
3. Tablet compression
4. Film coating
PAS
Seq 0001, 3.2.P.3.3,
p. 44
1. Powder Blending
The active substance and three excipients are mixed together.
The following process parameters are defined as ECs.
Seq 0003, 3.2.P.3.3,
p. 45
Operating principle: Diffusion mixing 	PAS
Seq 0001, 3.2.P.3.3,
pp. 45–47
Equipment type: V-blender 	Change to
equipment of same
operating principle:
AR
Seq 0001, 3.2.P.3.2,
p. 8, and 3.2.P.3.3,
pp. 48–49
Scale: 200 kg 	Increase up to 10x:
AR
Increase beyond
10x: CBE-0
Seq 0004, 3.2.P.3.4,
pp. 10–15
Design space for blending process parameters
Blend speed: 10-20 rpm
CBE-30

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Note: eCTD=electronic common technical document; EC=established condition; FEI=facility establishment	413 identifier; PAS=prior approval supplement; AR=annual report; CBE=changes being effected.	414
Blend time: 15-25 minutes
2. Roller Compaction
3. Tablet Compression
4. Film Coating