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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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: 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
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and/or 
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 Food and Drug Administration 
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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 
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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
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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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1  ICH Q12: Implementation Considerations for  
2  FDA-Regulated Products 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
8  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.  
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  The International Council for Harmonisation (ICH) guidance for industry Q12 Technical and 
18  Regulatory Considerations for Pharmaceutical Product Lifecycle Management and its Annexes 
19  (ICH Q12, May 2021) provide a framework to facilitate the management of postapproval 
20  chemistry, manufacturing, and controls (CMC) changes in a more predictable and efficient 
21  manner.2 ICH Q12 includes regulatory tools and enablers with associated guiding principles that 
22  should enhance industrys ability to manage postapproval changes and increase transparency 
23  between industry and regulatory authorities, supporting innovation and continual improvement. 
24   
25  This guidance should be read in conjunction with ICH Q12, which this guidance complements 
26  by clarifying how the ICH Q12 tools and enablers can be implemented within the U.S. regulatory 
27  system. These guidances apply to drug substances and drug products3 that are the subject of new 
28  drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug 
29  applications (ANDAs), and supplements to these applications regulated by the Center for Drug 
30  Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research 
31  (CBER). They also apply to combination products4 with device constituent parts that are the 
32  subject of NDAs, BLAs, ANDAs, and supplements to these applications regulated by CDER and 
33  CBER. 
34   
35  The contents of this document do not have the force and effect of law and are not meant to bind 
36  the public in any way, unless specifically incorporated into a contract. This document is intended 
 
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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37  only to provide clarity to the public regarding existing requirements under the law. FDA 
38  guidance documents, including this guidance, should be viewed only as recommendations, unless 
39  specific regulatory or statutory requirements are cited. The use of the word should in Agency 
40  guidances means that something is suggested or recommended, but not required. 
41   
42   
43  II.  CONSIDERATIONS FOR IMPLEMENTATION  
44   
45  The considerations below follow the order of the sections in ICH Q12 and are specific to FDAs 
46  implementation. 
47   
48  A.  Introduction 
49   
50  As stated above, ICH Q12 and this guidance apply to drug substances and drug products that are 
51  the subject of NDAs, BLAs, ANDAs, and supplements to these applications regulated by CDER 
52  and CBER. They also apply to combination products with device constituent parts that are the 
53  subject of NDAs, BLAs, ANDAs, and supplements to these applications regulated by CDER and 
54  CBER. 
55   
56  B.  Categorization of Postapproval CMC Changes 
57   
58  ICH Q12 describes two categories for regulatory communications: prior approval and 
59  notification. In the U.S. regulatory system, prior approval means a prior approval supplement 
60  (PAS), notification moderate means a changes being effected-30 (CBE-30) supplement, and 
61  notification low means a CBE-0 supplement or annual report.5 As indicated in ICH Q12, the 
62  lowest risk changes are managed and documented within the pharmaceutical quality system 
63  (PQS) and do not need to be reported, but they may be verified during a surveillance or other 
64  inspection. 
65   
66  C.  Established Conditions 
67   
68  ICH Q12 defines established conditions (ECs) as legally binding information considered 
69  necessary to assure product quality. As a consequence, any change to ECs necessitates a 
70  submission to the regulatory authority. This is consistent with FDAs regulations at 21 CFR 
71  314.70(a)(1)(i), 314.97(a), and 601.12(a)(1). Although these regulations do not explicitly specify 
72  what constitutes an EC, they do set forth a risk-based paradigm for reporting changes. In 
73  addition, existing FDA guidance documents describe a broad set of postapproval changes and 
74  make recommendations for how they should be reported.6 The risk-based paradigm set forth in 
75  the regulations and the recommendations in these associated guidance documents can help 
 
5 See 21 CFR 314.70, 314.97, and 601.12. 
6 See, e.g., FDAs 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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76  applicants determine which elements of an application that FDA would typically consider to be 
77  ECs. ICH Q12 further helps applicants gain clarity around which elements of the product, 
78  manufacturing process, facilities and equipment, and control strategy in their applications are 
79  considered to be ECs and therefore require reporting if changed. 
80   
81  Proposing elements to be considered ECs that may differ from those FDA typically considers to 
82  be ECs based on the risk-based paradigm set forth in the regulations and the recommendations 
83  contained in guidance is voluntary. Applicants may propose ECs in their original applications or 
84  in a PAS.7 If specific ECs are not proposed, ECs would be those that FDA typically considers to 
85  be ECs based on the risk-based paradigm set forth in the regulations and the recommendations 
86  contained in guidance regarding postapproval changes. 
87   
88  Applicants may also propose reporting categories for changes to ECs. The reporting categories 
89  proposed may be consistent with the risk-based paradigm set forth in the regulations and the 
90  recommendations contained in guidance. Alternatively, an increased understanding of the risk to 
91  product quality posed by a change to an EC may support a proposal for reduced reporting 
92  categories. 
93   
94  1.  Submission of ECs 
95   
96  To ensure clarity regarding ECs when submitting an original NDA, BLA, or ANDA, applicants 
97  should: 
98   
99    Include one of the following statements in the cover letter: 
100   
101    Specific ECs are proposed. 
o
102   
103    Specific ECs are not proposed; postapproval changes will follow the regulations and 
o
104  the recommendations in guidance.8 
105   
106    Include one of the following statements in eCTD section 3.2.R of the application9: 
107   
108    Specific ECs are proposed. Specific reporting categories for changes to those ECs are 
o
109  not proposed and therefore will follow the regulations and the recommendations in 
110  guidance. 
 
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   
112    Specific ECs are proposed. Specific reporting categories for changes to those ECs are 
o
113  proposed. 
114   
115    Specific ECs are not proposed; postapproval changes will follow the regulations and 
o
116  the recommendations in guidance. 
117   
118  When proposing ECs in a PAS, applicants should: 
119   
120    State in the cover letter that ECs are proposed. 
121   
122    Include one of the following statements in eCTD section 3.2.R:  
123   
124    Specific ECs are proposed. Specific reporting categories for changes to those ECs are 
o
125  not proposed and therefore will follow the regulations and the recommendations in 
126  guidance. 
127   
128    Specific ECs are proposed. Specific reporting categories for changes to those ECs are 
o
129  proposed. 
130   
131  If applicants choose to propose specific ECs, they can propose them for the entire CMC section 
132  of the application (module 3: Quality) or for a subset of information provided in module 3 (e.g., 
133  for eCTD section 3.2.S or for eCTD section 3.2.P.3.3). If a limited set of ECs is proposed, such 
134  as for an individual unit operation in the manufacturing process, the applicant should list for the 
135  applicable eCTD sections all of the ECs for that unit operation. Additionally, the applicant 
136  should include a statement that, for the appropriate eCTD sections, changes to those unit 
137  operations for which ECs are not proposed will be reported according to the regulations and the 
138  recommendations in guidance.  
139   
140  A complete list of proposed ECs, their reporting categories (if proposed), and the eCTD locations 
141  for their scientific justification should be included in the Product Lifecycle Management (PLCM) 
142  document in eCTD section 3.2.R. See section II.E in this guidance for more information about 
143  the PLCM document. See section II.C.2 for information about the justification for proposed ECs, 
144  including where such justifications should reside in the application. 
145   
146  2.  Identification of ECs  
147   
148  When proposing specific ECs, applicants should include a scientific justification for their 
149  selection in the relevant parts of module 3 of the application. In this justification, applicants 
150  should address both the identification of particular parameters or attributes as ECs and the 
151  proposed reporting categories (if applicable). 
152   
153  a.  Parameters and attributes identified as ECs 
154   
155  In the justification, applicants should explain how they identified the parameters or attributes that 
156  are proposed to be ECs and why others that might typically be considered to be ECs (considering 
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157  the regulations and the recommendations in guidance as described above) were not. For example, 
158  in a manufacturing unit operation for which three of five process parameters are proposed to be 
159  ECs (in a parameter-based approach), the applicant should explain how the three parameters 
160  were identified as being ECs and why the other two were not. A description of the applicants 
161  risk assessment process (including tools) used to identify particular parameters or attributes as 
162  ECs, the criticality assessment conducted to determine the level of impact of each parameter on 
163  product quality, and the supporting information for each (e.g., fundamental knowledge, empirical 
164  investigation, prior knowledge from experience with other products, commercial experience) 
165  should be provided. See also sections 3.2.3.1 Identification of ECs for Manufacturing 
166  Processes and 3.2.3.2 Identification of ECs for Analytical Procedures in ICH Q12. Applicants 
167  should not propose to manage attributes as ECs if changes to those attributes would require 
168  submission of a new original application (e.g., change in dosage form for an NDA). 
169   
170  For parameters or attributes identified as ECs that have associated acceptable ranges, applicants 
171  should include a justification for the proposed ranges. 
172   
173  b.  Reporting categories 
174   
175  For each proposed EC, the applicant may identify a proposed reporting category: PAS, CBE-30, 
176  CBE-0, or annual report. If this reporting category differs from that recommended in existing 
177  guidance, the applicant should provide a justification in the relevant section of module 3. This 
178  justification can be part of or complementary to the justification provided to support 
179  identification of the EC. If the applicant chooses not to propose reporting categories, the 
180  applicant should include a statement that reporting categories for changes to those ECs will 
181  follow the regulations and the recommendations in guidance. 
182   
183  3.  Identification of ECs for a Drug Substance or Drug Product in a Drug Master 
184  File 
185   
186  If information about the drug substance or drug product is incorporated in an application by 
187  reference to a Type II drug master file (DMF),10 ECs associated with that drug substance or drug 
188  product can be proposed, but they should only be proposed as part of the application.11 In such 
189  cases, the DMF holder will need to share sufficient information with the applicant12 so that 
190  proposed ECs and their associated reporting categories can be specified in and approved as part 
191  of the application. The justification in support of the identification of ECs can be located in the 
192  DMF, as long as the application refers to the specific location of the justification in the DMF. 
193  The applicant should provide a justification for proposed reporting categories in the application 
194  because the justification will generally be specific to the final drug product and its conditions of 
195  approval (e.g., dosing, route of administration) rather than generalizable across different products 
 
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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196  incorporating the same drug substance or drug product. When ECs are approved for an 
197  application that incorporates by reference information from a DMF, the applicant maintains 
198  responsibility for reporting changes to ECs; however, the applicant should share the relevant 
199  approved ECs with the DMF holder to ensure that the DMF holder is aware of how changes to 
200  the referenced drug substance or drug product will be managed by the applicant.  
201   
202  4.  Identification of ECs for Device Constituent Parts of Combination Products 
203   
204  Applicants may propose ECs for the device constituent part of a combination product in an 
205  NDA, BLA, or ANDA. The combination product as a whole, including the roles and interactions 
206  of the constituent parts, should be considered in proposing ECs and reporting categories for the 
207  product, including in relation to each constituent part. The focus of this section is identifying 
208  ECs for device constituent parts in particular. One approach is to assess the characteristics of 
209  the product that are essential for its safe and proper use13 (primary characteristics) relating to 
210  the device constituent part and to identify the associated ECs. The primary characteristics for the 
211  device constituent part of a combination product generally include: 
212   
213    Functions essential for safe use based on risk management principles (see, e.g., ICH 
214  guidance for industry Q9 Quality Risk Management (June 2006); ISO 14971:2019, 
215  Medical devicesApplication of risk management to medical devices). 
216   
217    Design features essential to achieve delivery of the labeled dose to a specific body site 
218  (e.g., for a device constituent part that provides drug delivery).  
219   
220    Characteristics that impact the drug constituent parts critical quality attributes. 
221   
222  Applicants should consider the following as potential ECs:  
223   
224    Design features that are primary characteristics. 
225   
226    Manufacturing process elements for the device constituent part that need to be controlled 
227  to ensure a primary characteristic. 
228   
229    Other control strategy elements for the device constituent part that ensure a primary 
230  characteristic. 
231   
232  See appendix A for a description of elements that are generally considered to be ECs for device 
233  constituent parts. As with identifying ECs for drug constituent parts, whether it may be 
234  appropriate to propose ECs for device constituent parts or a lesser reporting category for them 
235  will vary based on extent of product and process understanding, knowledge gained from design 
236  and development to manage the risks, and evidence to support designation and justification of 
237  the primary characteristics. Similarly, the level of risk associated with a change to an EC will 
 
13 See ISO 13485:2016, Medical devicesQuality management systemsRequirements for regulatory purposes, 
Section 7.3.4 Product realizationDesign and developmentDesign and development outputs. ISO=International 
Organization for Standardization. 
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238  determine the appropriate reporting category for that change. See appendix B for an approach 
239  that can be followed for device constituent parts when identifying ECs and their associated 
240  reporting categories. 
241   
242  5.  Changes to Approved ECs 
243   
244  As indicated in ICH Q12, applicants may propose to add, eliminate, or make changes to 
245  approved ECs or revisions to their associated reporting categories through: 
246   
247    Submission of a supplement. 
248   
249    Addition of an EC that provides increased assurance of the quality of the drug 
o
250  substance or product with a reporting category provided for in the regulations or 
251  recommended in guidance should be submitted as a CBE-0 (see  314.70(c)(6)). 
252   
253    All other changes should be submitted as a PAS.  
o
254   
255    Submission of a postapproval change management protocol (PACMP; see section II.D in 
256  this guidance). 
257   
258    Fulfillment of a previously approved postapproval commitment submitted in a 
259  supplement or annual report. For example, this may be done if an EC was approved with 
260  an allowance for a modification pending the availabilityand submission, where 
261  specifiedof certain information. 
262   
263  6.  Postapproval Submissions in Accordance With Approved ECs 
264   
265  When submitting postapproval supplements and annual reports to report CMC changes in 
266  accordance with approved ECs, applicants should state in the cover letter that the submission 
267  contains changes made in accordance with previously approved ECs. These submissions should 
268  also include an updated PLCM (see section II.E in this guidance). 
269   
270  7.  Maintenance of the Application  
271   
272  As indicated in ICH Q12, maintenance of the application is subject to regional requirements. To 
273  ensure that FDA has access to up-to-date analytical procedures, applicants should include in the 
274  annual report a copy of all analytical procedures that have been appropriately modified during 
275  the reporting period without a submission (i.e., managed only through the PQS as changes did 
276  not relate to ECs). This information is intended to be for information only and typically is not 
277  subject to review unless it is determined that changes to ECs for the procedure were in fact made. 
278  Applicants should include this information in eCTD section 1.13.5 or 1.13.7 with a statement 
279  such as For information only: Changes made to analytical methods, including those not 
280  requiring submission.  
281     
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282  D.  Postapproval Change Management Protocol 
283   
284  In the U.S. regulatory system, PACMPs are referred to as comparability protocols and are 
285  voluntary. These protocols differ from the use of ECs in one important respect. Both 
286  comparability protocols and the use of ECs address the element to be reported if changed and the 
287  reporting mechanism, but a comparability protocol requires the tests and studies to support a 
288  future change to an EC to be specified at the time of the protocol submission (21 CFR 
289  314.70(e)).  
290   
291  FDA recommends that comparability protocols be submitted in eCTD section 3.2.R. For a 
292  comparability protocol that includes one or more changes that apply to more than one product, 
293  see draft guidance for industry Comparability Protocols for Human Drugs and Biologics: 
294  Chemistry, Manufacturing, and Controls Information (April 2016)14 for information on the 
295  appropriate content and format of the submission and the circumstances in which a comparability 
296  protocol might be useful. 
297   
298  E.  Product Lifecycle Management Document  
299   
300  As described in ICH Q12, the PLCM document should include proposed ECs, reporting 
301  categories for making changes to approved ECs, a list of comparability protocols (if submitted), 
302  and postapproval CMC commitments, if applicable. FDA recommends that the PLCM document 
303  be provided in tabular format in eCTD section 3.2.R, with specific references to the submission 
304  sequence, eCTD section number, and page number where each ECs scientific justification can 
305  be found. FDA further recommends that the PLCM indicate the manufacturing sites (preferably 
306  by facility establishment identifier (FEI) number) where an EC will be implemented.15 For 
307  example, if there are two drug product manufacturing sites named in the application, but the 
308  manufacturing process-related ECs will only be associated with the manufacturing at one of 
309  those two sites, the FEI number of this site should be specified in the PLCM for those process-
310  related ECs. It is then assumed that ECs for operations at the other facility will follow the 
311  regulations and the recommendations in guidance. If the ECs will be implemented at both sites, 
312  both FEI numbers should be listed. Applicants should attribute FEIs to ECs in the PLCM at the 
313  most inclusive level (e.g., one FEI listed at the beginning of 3.2.P if all subsequent ECs in the 
314  section are associated with one drug product facility). See appendix C in this guidance for an 
315  example of a PLCM document.  
316   
317  Applicants should provide an updated PLCM document with each supplement or annual report 
318  that reports changes to approved ECs. If no specific ECs are proposed, submission of a PLCM 
319  document is not necessary. 
320   
 
14 More specifically, see the appendix, section A, question 6. When final, this guidance will represent FDAs 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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321  F.  Pharmaceutical Quality System and Change Management 
322   
323  As indicated in ICH Q12, in addition to compliance with current good manufacturing practice 
324  (CGMP) requirements,16 an effective PQS is necessary to support the use of the tools in that 
325  guidance. However, also as noted in that guidance, FDA will not require a specific inspection 
326  before an applicant can make use of the principles in the guidance. FDAs assessment of the 
327  effectiveness of the PQS will generally be informed by routine inspections conducted by FDA 
328  and capable foreign regulators17 and other available information. Management should employ 
329  the principles of ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009) to 
330  ensure the continued capability of the PQS to support the management of ECs. 
331   
332  Because of the importance of the PQS in supporting the use of ICH Q12 tools, when an applicant 
333  proposes to introduce a new manufacturing site after approval, the applicant should not assume 
334  that the initially approved ECs will apply. Instead, if ECs are proposed, applicants should include 
335  the following in supplements that propose a new site: 
336   
337    Reassessment of the relevant ECs. 
338   
339    Justification for proposed changes to ECs as a result of this reassessment in the relevant 
340  parts of module 3 of the application. 
341   
342  FDA will also consider information included in a supplement that supports a determination that 
343  the new site deserves the same level of regulatory flexibility regarding postapproval changes as 
344  the site included in the original application. The determination of PQS capability will consider 
345  factors such as whether the new site is operated under the same PQS as the original; the state of 
346  regulatory compliance determined by FDA and other national drug regulatory authorities; 
347  conformance with ICH Q10, especially as concerns change management practices; and 
348  conformance with other applicable change management regulations and policies. 
349   
350  As indicated in ICH Q12, inspection observations that raise concern regarding the effectiveness 
351  of the PQS, and change management in particular, may lead to a need to modify previously 
352  approved ECs, reporting categories, or comparability protocols until such time as the PQS 
353  effectiveness has returned to an acceptable state. In these cases, FDA intends to communicate the 
354  impact of such findings on previously approved ECs, reporting categories, and comparability 
355  protocols with facilities and applicants, as appropriate. 
356   
357  G.  Relationship Between Regulatory Assessment and Inspection 
358   
359  The use of ICH Q12 tools, such as ECs, is not expected to change FDAs processes for how 
360  information is assessed as part of the application or from a facility inspection. Similarly, it does 
 
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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Draft  Not for Implementation 
361  not change the expectations regarding the type of information to be submitted in an application 
362  or the information that is to be available for an inspection.  
363   
364  H.  Structured Approaches for Frequent CMC Postapproval Changes and 
365  Stability Data Approaches To Support the Evaluation of CMC Changes 
366   
367  Sections VIII and IX of ICH Q12 and section II of the ICH Q12 Annexes provide alternative 
368  approaches for certain CMC postapproval changes. FDA supports the use of such approaches. 
369  FDA also encourages applicants to gain its feedback before proposing or implementing novel 
370  approaches.
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
371  APPENDIX A. ESTABLISHED CONDITIONS FOR COMBINATION PRODUCTS 
372  WITH DEVICE CONSTITUENT PARTS 
373   
374  The combination product as a whole, including the roles and interactions of the constituent parts, 
375  should be considered in proposing established conditions (ECs) and reporting categories for the 
376  product, including in relation to each constituent part. This appendix provides general guidance 
377  about the elements that are generally considered ECs for the device constituent part of 
378  combination products.1 It does not contain a complete list of ECs for a device constituent part; 
379  each application should include a justification for the identification of proposed ECs.  
380   
381  The following are generally considered ECs for the device constituent part of combination 
382  products: 
383   
384    Identification of the device: If purchased from a third party, manufacturer identifiers for 
385  the device (e.g., brand name); references to device clearance or approval (if applicable). 
386   
387    Description and design features: Device description; principle (e.g., mechanical, 
388  electrical) and mechanism (e.g., spray, mixing) of operation for delivery of the drug 
389  product; design features that are primary characteristics; materials of construction in 
390  direct or indirect contact with the drug product and patient. 
391   
392    Manufacturers: Name, address, and responsibilities for sites that perform assembly, 
393  packaging, and testing of the device constituent part. 
394   
395    Manufacturing (e.g., assembly): Unit operations and sequence in the manufacturing 
396  process; manufacturing process parameters, material attributes, and in-process controls, 
397  where variability impacts primary characteristics. 
398   
399    Release/expiry specification and associated test methods for attributes that ensure 
400  primary characteristics.
 
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). 
  11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
401  APPENDIX B. DECISION TREE FOR IDENTIFYING ESTABLISHED CONDITIONS 
402  AND REPORTING CATEGORIES FOR DEVICE CONSTITUENT PARTS 
403   
404  The decision tree below can be used to guide the identification of established conditions and 
405  associated reporting categories for the device constituent part of a combination product. 
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 products CQA?
Yes to any No to all
Primary characteristic:  Other characteristic: 
Essential for safe and  Not essential for 
proper use** safe and proper use
Define the design, process, and control strategy 
elements that are ECs
Manufacturing  Elements of 
process  Other control  design, 
Design 
elements that  strategy  process, and 
features that 
need to be  elements that  controls for 
are primary 
controlled to  ensure primary  other 
characteristics
ensure primary  characteristics characteristics 
characteristics are not ECs
What is the level of potential risk associated 
with the proposed change?
High Moderate to Low
PAS CBE-30 or CBE-0 Not Reported
*As determined using risk management principles in ICH guidance for industry Q9 Quality Risk 
Management (June 2006) or ISO 14971:2019, Medical devicesApplication of risk management to 
medical devices.
**See ISO 13485:2016, Medical devicesQuality management systemsRequirements for 
regulatory purposes, Section 7.3.4 Product realizationDesign and developmentDesign 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   
  12  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
407  APPENDIX C. PRODUCT LIFECYCLE MANAGEMENT DOCUMENT EXAMPLE 
408   
409  In this example,1 where the applicant proposes to follow FDA regulations and the 
410  recommendations in guidance for a change to a particular established condition, the reporting 
411  category has been left blank.  
412   
eCTD Section  Established Conditions   Reporting 
    Category When 
(Note that identification and justification of each EC is  Making a Change 
presented in the relevant eCTD section)  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,  The manufacturing process consists of the following  PAS 
p. 4  sequence of unit operations: 
   
1. Powder blending 
 
2. Roller compaction 
3. Tablet compression 
4. Film coating  
Seq 0001, 3.2.P.3.3,  1. Powder Blending    
p. 44 
The active substance and three excipients are mixed together.   
The following process parameters are defined as ECs. 
Seq 0003, 3.2.P.3.3,  Operating principle: Diffusion mixing  PAS 
p. 45 
Seq 0001, 3.2.P.3.3,  Equipment type: V-blender  Change to 
pp. 4547  equipment of same 
operating principle: 
AR 
Seq 0001, 3.2.P.3.2,  Scale: 200 kg  Increase up to 10x: 
p. 8, and 3.2.P.3.3,  AR 
pp. 4849 
Increase beyond 
10x: CBE-0 
Seq 0004, 3.2.P.3.4,  Design space for blending process parameters  CBE-30 
pp. 1015 
Blend speed: 10-20 rpm 
 
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). 
  13  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Blend time: 15-25 minutes 
  2. Roller Compaction    
  3. Tablet Compression    
  4. Film Coating    
413  Note: eCTD=electronic common technical document; EC=established condition; FEI=facility establishment 
414  identifier; PAS=prior approval supplement; AR=annual report; CBE=changes being effected. 
  14