Postapproval Changes 
to Drug Substances 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Carolyn Cohran 240-402-8612; 
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010; 
or (CVM) Dennis Bensley 240-402-0696. 
 
 
 
 
 
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 Veterinary Medicine (CVM) 
 
September 2018 
Pharmaceutical Quality/CMC 
   
Postapproval Changes 
to Drug Substances 
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., 4th 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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
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/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
and/or 
Policy and Regulations Staff, HFV-6 
Center for Veterinary Medicine 
Food and Drug Administration 
7519 Standish Place, Rockville, MD 20855 
https://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm 
 
 
 
 
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 Veterinary Medicine (CVM) 
 
September 2018 
Pharmaceutical Quality/CMC
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Established Conditions and Reporting Categories ..................................................................... 2 
B.  Reporting Responsibilities............................................................................................................. 3 
III.  GENERAL CONSIDERATIONS ................................................................................... 4 
A.  Assessment of Risk ......................................................................................................................... 4 
B.  Other Relevant Guidances ............................................................................................................ 6 
IV.  ASSESSMENT OF CHANGE ......................................................................................... 6 
A.  Drug Substance .............................................................................................................................. 6 
1. Equivalence of Impurity Profiles ..................................................................................................... 7 
2. Equivalence of Physical Properties ................................................................................................. 9 
B.  Drug Product ................................................................................................................................ 13 
1. Drug Product Manufacturing and Release Data ........................................................................... 13 
2. Drug Product In Vitro Data ........................................................................................................... 14 
3. Stability Data ................................................................................................................................. 15 
V.   TYPES OF CHANGES AND DOCUMENTATION ................................................... 16 
VI.  FACILITY, SCALE, AND EQUIPMENT CHANGES .............................................. 16 
A.  Facility Changes ........................................................................................................................... 16 
B.  Scale Changes ............................................................................................................................... 17 
C.  Equipment Changes ..................................................................................................................... 18 
D.  Recommended Documentation for the Drug Substance in a Master File or an Approved 
Application ............................................................................................................................................ 18 
E.  Recommended Documentation for the Drug Product in an Approved Application .............. 20 
VII.  SPECIFICATION CHANGES ...................................................................................... 21 
A.  Specification Changes to Raw Materials and Intermediates ................................................... 21 
B.  Specification Changes to Drug Substances ................................................................................ 22 
C.  Recommended Documentation for the Drug Substance in a Master File or an Approved 
Application ............................................................................................................................................ 22 
1. Documentation for Specification Changes to Raw Materials and Intermediates .......................... 22 
2. Documentation for Specification Changes to Drug Substances .................................................... 23 
D.  Recommended Documentation for the Drug Product in an Approved Application .............. 24 
1. Documentation for Specification Changes to Raw Materials and Intermediates .......................... 24 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
2. Documentation for Specification Changes to Drug Substances .................................................... 24 
VIII.  MANUFACTURING PROCESS CHANGES .............................................................. 25 
A.  Changes That Do Not Involve the Route of Synthesis .............................................................. 25 
B.  Changes in Route of Synthesis in One or More Steps .............................................................. 26 
C.  Establishing a Reprocessing Procedure as Part of the Established Manufacturing Process 26 
D.  Recommended Documentation for the Drug Substance in a Master File or an Approved 
Application ............................................................................................................................................ 26 
E.  Recommended Documentation for the Drug Product in an Approved Application .............. 28 
IX.  STARTING MATERIAL CHANGES .......................................................................... 28 
A.  Recommended Documentation for the Drug Substance in a Master File or an Approved 
Application ............................................................................................................................................ 29 
B.  Recommended Documentation for the Drug Product in an Approved Application .............. 30 
X.    CONTAINER CLOSURE SYSTEM CHANGES........................................................ 31 
XI.  MULTIPLE CHANGES ................................................................................................ 31 
XII.  REPORTING CATEGORY .......................................................................................... 31 
XIII.  GLOSSARY..................................................................................................................... 32 
APPENDIX A. CHANGES TO DRUG SUBSTANCE MANUFACTURE ........................... 36 
APPENDIX B: REPORTING CATEGORIES FOR ADDITIONAL EXAMPLES OF 
CHANGES ................................................................................................................................... 37 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Postapproval Changes to Drug Substances  
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  This guidance provides recommendations to holders of approved new drug applications (NDAs), 
17  abbreviated new drug applications (ANDAs), new animal drug applications (NADAs), and 
18  abbreviated new animal drug applications (ANADAs) and holders of drug master files (DMFs) 
19  and veterinary master files (VMFs) who want to make a change to the drug substance 
20  manufacturing process during the drug product applications postapproval period.2 It does not 
21  address holders of biologics license applications (BLAs) or holders of any master files cross-
22  referenced in BLAs. 
23   
24  The guidance applies to synthetic drug substances and the synthetic steps involved in preparing 
25  semisynthetic drug substances. The guidance covers the following changes: 
26   
27    Facility, scale, and equipment changes associated with all steps of drug substance 
28  manufacturing. 
29   
30    Specification changes to starting materials, raw materials, intermediates, and the 
31  unfinished and final drug substance.  
32   
33    Synthetic manufacturing process changes.  
34   
35    Changes in the source of the drug substance. 
36   
37    Changes to the container closure system for the drug substance. 
38   
                                                 
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 and the Center for Veterinary 
Medicine at the Food and Drug Administration.  
2 In general, when this guidance refers to NDAs, ANDAs, and DMFs, we are also referring to NADAs, ANADAs, 
and VMFs, respectively. Further, the use of the term master files includes both DMFs and VMFs. 
 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
39  This guidance does not address postapproval changes to peptides,3 oligonucleotides, 
40  radiopharmaceuticals; or drug substances isolated from natural sources or produced by 
41  procedures involving biotechnology; or nonsynthetic steps (such as fermentation) for 
42  semisynthetic drug substances. This guidance also does not address complex active ingredients 
43  as defined in the Generic Drug User Fee Act Reauthorization Performance Goals and Program 
44  Enhancements Fiscal Years 2018-2022, known as the GDUFA II Commitment Letter.4    
45   
46  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
47  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
48  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
49  the word should in Agency guidances means that something is suggested or recommended, but 
50  not required. 
51   
52   
53  II.  BACKGROUND 
54   
55  As part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA II), FDA 
56  committed to issuing a guidance on postapproval changes to Type II API DMFs and submission 
57  mechanisms for ANDA holders who reference such DMFs.5 This guidance is intended to fulfill that 
58  commitment, and describes the recommended documentation for master file holders or drug 
59  substance manufacturers, as appropriate. The guidance also outlines the recommended 
60  documentation to be submitted by the approved application holder, as well as references the 
61  appropriate pathways for such submissions.  
62   
63  A.  Established Conditions and Reporting Categories 
64   
65  Under 21 CFR 314.70, 314.97, and 514.8, application holders must notify FDA about changes to 
66  conditions established in approved applications beyond the variations already provided for in 
67  their applications. FDAs regulations identify three broad reporting categories: major changes 
                                                 
3 See the guidance for industry Changes to an Approved Application for Specified Biotechnology and Specified 
Synthetic Biological Products. We update guidances periodically. To make sure you have the most recent version of 
a guidance, check the FDA Drugs or Biologics guidance web pages at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm. 
4See GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 20182022. All public 
documents cited in this guidance may be found on the FDA website (www.fda.gov). Complex Product generally 
includes: 1) Products with complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of 
active pharmaceutical ingredients (APIs), naturally sourced ingredients); complex formulations (e.g., liposomes, 
colloids); complex routes of delivery (e.g., locally acting drugs such as dermatological products and complex 
ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions or gels) or complex 
dosage forms (e.g., transdermals, metered dose inhalers, extended release injectables); 2) Complex drug-device 
combination products (e.g., auto injectors, metered dose inhalers); and 3) Other products where complexity or 
uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific 
engagement. 
5 See GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 20182022, page 19. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
68  (i.e., changes that require submission of a prior approval supplement (PAS));6 moderate changes 
69  (i.e., changes that require submission of a changes being effected in 30 days (CBE-30) 
70  supplement or a changes being effected (CBE-0) supplement);7 and changes that must be 
71  reported in an annual report.8 The reporting category for a change is based on the potential risk 
72  for the change to have an adverse effect on the identity, strength, quality, purity, or potency of 
73  the drug product as these factors may relate to its safety or effectiveness. This guidance provides 
74  recommendations on the information that should be provided to CDER, CBER, or CVM to 
75  ensure continued drug substance quality and drug product quality and performance 
76  characteristics. For the most up-to-date information on reporting categories for postapproval 
77  changes, see the referenced guidances in section XII, Reporting Category. 
78   
79  B.  Reporting Responsibilities 
80     
81  Where drug substance information is provided in a DMF, a letter(s) of authorization must be 
82  provided to allow the applicant to reference the DMF.9 Any addition, change, or deletion of 
83  information in the master file must be submitted to the master file10 in the form of an 
84  amendment. Further, the master file holder must notify each person authorized to reference the 
85  DMF of the nature of the changes,11 and should provide as much detail as is consistent with the 
86  confidentiality agreement between the master file holder and the authorized person, so that the 
87  authorized person can determine how to report the changes in the approved application. In turn, 
88  application holders must notify FDA of each change in each condition established in an approved 
89  application, excluding the variations already provided for in the application.12  
90   
91  When drug substance information is contained in an application, rather than in a referenced 
92  DMF, such changes must be submitted to FDA in the form of a supplement to the approved 
93  application or in an annual report, whichever is appropriate for the change being made.13 
94   
95  The responsibility for reporting the types of changes described in this guidance could lie with a 
96  single party or with several parties, depending on whether the drug substance synthesis or 
97  processing is described in an application or in one or more master files. The notification to FDA 
98  should include reference to the section of this guidance under which the change is made and all 
99  pertinent information to ensure the quality of the drug substance and drug product. For example, 
100  when a master file holder makes a manufacturing process change, the change should be 
101  described in an amendment to the master file, and the application holder should provide 
                                                 
6 See 21 CFR 314.70(b), 314.97(a), and 514.8(b)(2). 
7 See 21 CFR 314.70(c), 314.70(c)(3), 314.70(c)(6), and 514.8(b)(3), 514.8(b)(3)(iv). 
8 See 21 CFR 314.70(d), 314.81(b)(2), and 514.8(b)(4). 
9 21 CFR 314.420(b). See FDAs DMF web page at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/
UCM2007046. 
10 See 21 CFR 314.420(c).  
11 Ibid. 
12 See 21 CFR 314.70 (supplements and other changes to an approved NDA), and 21 CFR 314.97, requiring that 
ANDA holders comply with the requirements of 21 CFR 314.70 regarding the submission of supplemental ANDAs 
and other changes to an approved ANDA. For animal drugs, see 21 CFR 514.8. 
13 See 21 CFR 314.70 and 514.8. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
102  notification of the change (citing section VIII of this guidance) in a supplement or annual report, 
103  as appropriate. The data to support the process change should be provided in an amendment to 
104  the master file or supplement to the approved NDA or ANDA when no master file is referenced.  
105   
106   
107  III.  GENERAL CONSIDERATIONS  
108   
109  A.  Assessment of Risk 
110   
111  Any modification to drug substance manufacturing carries some risk of causing an adverse 
112  impact on quality, either in the physical properties of the drug substance or in the level or nature 
113  of impurities present, and, in some cases, to the bioequivalence or safety profile of the drug. 
114  Certain kinds of modifications (e.g., equipment or facility changes) are viewed as less likely to 
115  result in an adverse impact than others (e.g., changes in the synthetic route). However, each drug 
116  substance manufacturer will need to assess the particular modification for their drug substance to 
117  determine the risk associated with the change.14 This guidance applies to changes made 
118  throughout the drug substance manufacturing process, i.e., from the starting material through the 
119  final drug substance. Late-stage changes in the drug substance manufacturing process are 
120  generally viewed as more likely to have an adverse impact on the quality of the drug substance 
121  and, consequently, on the drug product. Some late-stage changes should be evaluated not only by 
122  comparing pre- and post-modification drug substance, but also by comparing drug product 
123  prepared from pre- and post-modification drug substance. Finished drug product manufacturers 
124  should ensure that drug substances used in their products meet established specifications and, for 
125  compendial drug substances, meet United States Pharmacopeia (USP) standards. 
126   
127  Risk assessment principles are outlined in International Council for Harmonisation (ICH) 
128  guidance for industry Q9 Quality Risk Management (ICH Q9).15 As noted in ICH Q9, the level 
129  of effort, formality, and documentation of the quality risk management process should be 
130  commensurate with the level of risk. A risk assessment should be performed by the drug 
131  substance manufacturer to assess the effect of the change, as well as by the drug product 
132  manufacturer to evaluate the risks associated with drug substance manufacturing modifications. 
133  A reduction in the number of drug substance and/or drug product batches from the 
134  recommendations provided in this guidance (see sections VI  XI) may also be acceptable if an 
135  adequate justification is provided based on the risk assessment.  
136   
137  The following are examples of factors to consider when conducting a risk assessment on a 
138  change to the drug substance: 
139   
140    Experience of the manufacturing facility and/or personnel involved in the portion of the 
141  process that encompasses the proposed change. 
142   
                                                 
14 See 21 CFR 314.70(a)(2). 
15 ICH guidances can be found on FDA Drugs or Biologics guidance web pages at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  and 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
143    Changes implemented at the same facility with experienced personnel may pose less 
o
144  risk than a change implemented at a new facility with inexperienced personnel or 
145  involvement of a third-party vendor. 
146   
147    Complexity of the manufacturing steps involved in the change. 
148   
149    Changes implemented to homogeneous reactions using common chemistry and 
o
150  reaction conditions may pose less risk than a change implemented to heterogeneous 
151  reaction steps involving unusually complex or sensitive chemistry, and/or unusual 
152  equipment or reaction conditions. 
153   
154    Physical and chemical stability of the material (intermediate or drug substance) involved 
155  in the change. 
156   
157    Changes implemented for a molecule that is physically and chemically stable may 
o
158  pose less risk than a change implemented for a molecule that degrades easily or has 
159  multiple or unstable physical forms. 
160   
161    Complexity of the molecule. 
162   
163    Changes implemented for a small molecule with minimal structural or stereochemical 
o
164  isomerism may pose less risk than a change implemented for a large molecule with 
165  multiple structural or stereochemical isomers. 
166   
167    Equivalence of the entire impurity profile.16 
168   
169    Batches of post-modification material that have levels of identified impurities 
o
170  comparable to historical data may pose less risk than batches with higher levels of 
171  identified impurities and/or new identified impurities. 
172   
173    Batches of post-modification material that have a number and level of unidentified 
o
174  impurities comparable to historical data may pose less risk than batches with a larger 
175  number and/or levels of unidentified impurities. 
176   
177    Comparability of physical properties when they may impact drug product performance or 
178  manufacturability (typically changes made to the drug substance at or after the final 
179  solution step would be the most likely to impact physical properties). 
180   
181    Post-modification  material that has the same physical properties may pose less risk 
o
182  than post-modification material with different physical properties (e.g., solid state 
183  form, particle size, solubility, bulk/tapped density). 
184   
                                                 
16 See section IV.A. The impurity profile includes specified identified impurities, specified unidentified impurities, 
unspecified impurities, and total impurities. 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
185  B.  Other Relevant Guidances 
186   
187  This guidance aligns with existing FDA guidance, including the ICH guidances for industry Q7 
188  Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Q7 Good 
189  Manufacturing Practice Guidance for Active Pharmaceutical Ingredients Questions and 
190  Answers, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, Q10 
191  Pharmaceutical Quality System, Q11 Development and Manufacture of Drug Substances, Q11 
192  Development and Manufacture of Drug Substances (Chemical Entities and 
193  Biotechnological/Biological Entities)Questions and Answers, and M7 Assessment and Control 
194  of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic 
195  Risk. In addition to ICH Q10, which describes key systems that help establish and maintain a 
196  state of control for process performance and product quality, the FDA guidances for industry 
197  Quality Systems Approach to Pharmaceutical CGMP Regulations and Process Validation: 
198  General Principles and Practices address the current good manufacturing practice (CGMP) 
199  requirement for change control. Change control is generally understood to be the responsibility 
200  of the quality control unit.17 Effective change control activities are key components of any 
201  quality system. Although this guidance does not repeat the concepts and principles explained in 
202  those guidances, FDA encourages the use of modern pharmaceutical development concepts, 
203  quality risk management, and an effective pharmaceutical quality system at all stages of the 
204  manufacturing process life cycle.  
205   
206   
207  IV.  ASSESSMENT OF CHANGE 
208   
209  A.  Drug Substance 
210   
211  After making manufacturing changes, DMF holders or drug substance manufacturers should 
212  assess the effects of the changes to the drug substance.18 A central principle underlying this draft  
213  guidance is that a change in the drug substance manufacturing process can be adequately 
214  assessed by comparing three consecutive pilot or commercial scale batches of pre- and post-
215  modification material to determine if the quality of the post-modification material is equivalent 
216  to or better than the quality of the pre-change material.19,20 Evaluation of the manufacturing 
217  change may include but is not limited to: 
218   
219    A comparison of impurities in pre- and post-modification intermediates, the unfinished 
220  drug substance, and/or the drug substance. 
221    A comparison of the drug substances physical properties before and after modification. 
222    Drug substance stability data. 
                                                 
17 See guidance for industry Quality Systems Approach to Pharmaceutical CGMP Regulations. 
18 See 21 CFR 314.70(a)(2). 
19 Whenever possible, changes in site, equipment, or manufacturing process (including changes in the source of the 
drug substance) should be evaluated using data from commercial-scale batches.  
20 Such a comparison does not in and of itself constitute full process performance qualification as described in the 
guidance for industry Process Validation: General Principles and Practices. 
 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
223   
224  Some manufacturing changes can be made without this full set of data (see specific changes 
225  listed in sections VI-XI). In other cases, factors in addition to those listed above should be 
226  considered in evaluating equivalence. For example, if the drug substance is defined as a mixture 
227  of active isomers or analogs, the ratios after the change should be within the stated acceptance 
228  criteria, or if not stated, within the upper and lower statistical limits21 of historical data. There 
229  should be no structural changes to the drug substance, as supported by structural analysis data 
230  when appropriate. 
231   
232  1.  Equivalence of Impurity Profiles 
233   
234  The impact of manufacturing modifications on the impurity profile (including impurities 
235  addressed by ICH M7) is evaluated by determining levels of existing and new impurities. It is 
236  important to determine the stage in the manufacturing process at which impurities should be 
237  evaluated and to establish the adequacy of the analytical procedures used for this purpose. Levels 
238  of residual solvents and inorganic substances should also be considered during evaluation of the 
239  impurity profile. 
240   
241  If the impurity profile of an isolated material (i.e., isolated intermediate, unfinished drug 
242  substance, or drug substance) following the change is equivalent to that of pre-change material, 
243  the drug substances impurity profile will be considered unaffected by the modification. If the 
244  manufacturing modification occurs at an upstream step before the final intermediate is produced, 
245  and equivalence cannot be demonstrated for the intermediate isolated immediately following the 
246  change, the impurity search should be extended to the next downstream intermediate. The 
247  impurity search should also be expanded to include appropriate downstream impurities that may 
248  be formed during the manufacturing process. The evaluation process should be repeated on 
249  downstream intermediates up to and including the drug substance. Equivalence should not be 
250  established by mixing pre- and post-modification materials or materials from different batches 
251  during manufacturing operations.  
252   
253  The analytical procedures used to evaluate the change should be adequate for quantitating both 
254  existing and new impurities. The same analytical procedure should be used when comparing 
255  impurity levels in pre- and post-modification batches. When the same method cannot be used 
256  and new drug substance analytical procedures are developed for this purpose, a summary of 
257  validation data for the new procedures should be provided. 
258   
259  The level of impurities should generally be assessed by comparing three consecutive, pilot or 
260  commercial-scale, post-modification batches with the historical data from three or more 
261  consecutive, representative, pre-modification batches. The assessment of impurities should 
262  normally be carried out soon after manufacture. However, retained samples can be used for the 
263  comparison, provided such samples reveal no adverse trend in the level of any impurity.  
264   
                                                 
21 For information on statistical limits, see historical data in the glossary.  
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
265  The impurity profile will be considered equivalent if the post-modification batches of an isolated 
266  intermediate, unfinished drug substance, or drug substance are evaluated and the test data for 
267  each batch demonstrate that: 
268   
269    At an intermediate level, any new impurityincluding any unspecified impurity
270  observed above the reporting threshold is evaluated and the control strategy for it and its 
271  downstream impurities are justified.  
272   
273    At the drug substance level, no new impurity is observed above the identification 
274  threshold of impurities as described in the ICH guidance for industry Q3A Impurities in 
275  New Drug Substances.22 
276   
277    Total impurities are within the stated limit or, if not stated, are at or below the upper 
278  statistical limit of historical data. 
279   
280    Each existing residual solvent is within its acceptance criterion or, if not previously 
281  specified, is at or below the limit in ICH guidance for industry Q3C Impurities: Residual 
282  Solvents or VICH guidance for industry GL18(R), Impurities: Residual Solvents in New 
283  Veterinary Medicinal Products, Active Substances and Excipients. Limits on solvents not 
284  covered under ICH Q3C or VICH GL18(R) should be established based on safety 
285  considerations. 
286   
287  If a new solvent is introduced during drug substance manufacturing, the solvents residual 
288  concentration in the drug substance should be evaluated. An appropriate test and acceptance 
289  criterion should be added to the drug substance specification; if such a test is not added, 
290  justification should be provided. Limits on new residual solvents should be established based on 
291  safety considerations and USP General Chapter <467> Residual Solvents, ICH Q3C, or VICH 
292  GL18(R) as applicable.23 
293   
294  Other principles regarding equivalence of impurity profiles are outlined below: 
295   
296    Non-isolated materials (e.g., solutions containing either intermediates or unfinished drug 
297  substances) are generally not appropriate for demonstrating equivalence. 
298   
299    When a manufacturing change is made to an outsourced operation, either the vendor or 
300  the customer can establish equivalence. 
301   
302    Scale changes should be evaluated using data from pre- and post-modification material, 
303  which should be at commercial-scale.  
                                                 
22Although these criteria (i.e., identification thresholds) are based on ICH Q3A and ICH guidance for industry 
Q3B(R2) Impurities in New Drug Products, which are not intended to apply to drug substances used in existing 
marketed drug products, they are considered appropriate for evaluating the equivalence of impurity profiles. For 
animal drugs, these criteria are described in VICH guidances for industry GL10(R), Impurities in New Veterinary 
Drug Substances, and GL11(R), Impurities in New Veterinary Medicinal Products. VICH=International 
Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products. 
23 USP references in this guidance refer to USP 40NF 35. 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
304   
305    Additional purification procedures (or routine repetition of an existing procedure) to 
306  achieve equivalence with pre-change material should be fully described. Such a change in 
307  purification procedure, in combination with the change that created a need for additional 
308  purification, should be submitted together as a multiple change (see section XI). 
309   
310  2.  Equivalence of Physical Properties 
311   
312  Two physical properties of the drug substancesolid state form24 and particle sizeare 
313  considered critical for evaluation when a manufacturing change is made, but other 
314  physiochemical characteristics also may be identified as critical in individual cases. The 
315  manufacturing changes most likely to affect the physical properties of a drug substance are those 
316  that involve the final solution step or processing operations that fall after the final solution step. 
317  Examples include changes to the following: 
318   
319    Process for the final precipitation of the drug substance.  
320    Operations in which a drug substance is slurried in a solvent in which it is partly soluble.  
321    How a drug substance is isolated from a suspension.  
322    How a drug substance is dried. 
323    Operations that manipulate particle size (e.g., micronization).  
324    Mixing operations for solids. 
325   
326  Changes in physical properties can also result from facility, scale, equipment, and other process 
327  changes. Testing of physical properties, when they are relevant to finished dosage form 
328  performance or manufacturability, is usually appropriate when a change is made to or after the 
329  final solution step. 
330   
331  When new impurities or higher levels of existing impurities are carried over into the final 
332  solution step, the physical properties can be affected. Although minor differences in the impurity 
333  profile at this stage are unlikely to cause physical property modifications to the drug substance, 
334  the possibility of such changes should be considered when the physical properties are relevant to 
335  finished dosage form performance or manufacturability.  
336   
337  a.  Equivalence of solid state form 
338   
339  Establishing equivalence with regard to the solid state form of drug substances is usually 
340  possible through testing of the drug substance. For dosage forms that fall under Category Two in 
341  Table 1 below, testing should be conducted when the manufacturing change has a moderate or 
342  high potential to adversely affect the physical properties of the drug substance.  
343   
344  The solid state form of the drug substance will be considered equivalent after a given change if 
345  the post-modification batches of the finished drug substance conform to established acceptance 
                                                 
24 For purposes of this guidance, solid state form includes hydrates, solvates, cocrystals, polymorphic crystalline, 
and amorphous states. 
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346  criteria for the solid state form. If acceptance criteria do not exist, the isolation of the same form 
347  or a mixture of forms within the range of historical data (as determined from three or more 
348  consecutive, representative, pre-modification batches) will serve to demonstrate equivalence. If 
349  equivalence is demonstrated, refer to section XII. Reporting Category.   
350   
351  For dosage forms that fall under Category One in Table 1, testing of the solid state form is also 
352  recommended when the drug substance manufacturing change has a moderate or high potential 
353  to adversely affect the physical properties of the drug substance, and when the drug substance 
354  physical properties can have an impact on the manufacturing and performance of the drug 
355  product. For these dosage forms found in Category One of Table 1, it is usually not necessary for 
356  the solid state form to remain the same. If a new solid state form is found, the drug product 
357  manufacturer should evaluate whether it is appropriate for use in making the dosage form, and 
358  the relevant properties of the form should be reported (e.g., solubility, stability).  
359   
360  b.  Equivalence of particle size distribution 
361   
362  Establishing equivalence of pre- and post-modification drug substance particle size distribution 
363  can be challenging for a number of reasons, including the influence of particle shape on different 
364  measurement techniques, incomplete knowledge about the effect of changes in particle size 
365  distribution or particle shape on specific drug substances and drug products, and the absence of 
366  standardized benchmarks for equivalence. Because of these difficulties, particle size data alone 
367  may be insufficient to establish equivalence for certain kinds of changes made to the process up 
368  to or after the production of the final intermediate. These include changes that could affect the 
369  physicochemical properties or bioavailability of the drug product and changes that could affect 
370  its content uniformity. 
371   
372  Three approaches to the evaluation of particle size data are possible:  
373   
374  1)  No comparison of particle size distribution data need be performed. 
375   
376  2)  Particle size distribution data should generally be obtained for three consecutive post-
377  modification batches of the drug substance and compared to three or more consecutive, 
378  representative, pre-modification batches.  
 379 
380  3)  Particle size distribution data should be obtained as described in 2). In addition, the drug 
381  product should be manufactured and tested to more fully evaluate equivalence. 
382   
383  The approach that is most appropriate for a given change will depend on the type of dosage form 
384  the drug substance will be used to manufacture, the nature of the change in the drug substance 
385  manufacturing process, and the drug products manufacturing method. 
386   
387  c.  Effect of particle size on physicochemical properties or bioavailability 
388   
389  If, based on the risk assessment, the application holder determines that a comparison of data 
390  from both the drug substance and drug product is needed, equivalence should be demonstrated 
391  for both, and such data should be provided. If a drug product has a history of performance 
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392  problems indicative of a sensitivity to changes in particle size or shape (e.g., dissolution failures 
393  at release or during stability studies), and if the drug substance manufacturing change has a high 
394  potential to adversely affect the drug substances particle size or shape, equivalence of the data 
395  from both the drug substance and drug product should be demonstrated.  
396   
397  d.  Effect of particle size on content uniformity 
398   
399  For some drug products, a change in particle size or shape may affect the content uniformity of 
400  the drug product irrespective of the risk that its physicochemical properties or bioavailability 
401  could be affected. Content uniformity is more likely to be an issue when the drug substance 
402  makes up only a small percentage of the total formulation weight, the drug substance is 
403  formulated as a solid, and the drug product is manufactured by a process that can be sensitive to 
404  changes in particle size or shape (e.g., dry granulation). If it is likely that the dosage forms 
405  content uniformity will be affected by a change in particle size or shape, and if the drug 
406  substance manufacturing change has a high potential to adversely affect the drug substances 
407  particle size or shape, then comparison of the data from both the drug substance and drug 
408  product should be used to evaluate the change. The drug product should meet the appropriate 
409  acceptance criteria for uniformity of dosage units as outlined in USP <905>.  
410   
411  e.   Drug substance physical properties considerations 
412    
413  The following tables summarize the factors to consider in evaluating the equivalence of physical 
414  properties. The amount of data submitted by the drug product manufacturer should be 
415  commensurate with criticality and risk as outlined in Table 1. Table 1 categorizes dosage forms 
416  based on their potential to be affected by a change in the drug substances physical properties 
417  (including particle size). Table 2 summarizes the potential for various changes to adversely affect 
418  the drug substances physical properties.  
419   
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420  Table 1: Relevance of Physical Properties to Dosage Form Performance  
421   
Category One: Physical Properties Are 
Category Two: Physical Properties May Be Critical 
Unlikely To Be Critical 
  Dosage forms in which the drug substance    Solid oral dosage forms containing drug substances 
is in solution when administered  that are not highly soluble* 
  Dosage forms in which the drug substance    Oral suspensions containing drug substances that 
is completely dissolved during the  are not highly soluble* 
manufacture of the dosage form    Non-oral dosage forms in which the drug substance 
  Oral dosage forms containing a highly  is a solid when administered (e.g., suspension 
soluble drug substance*  injection, powder for inhalation, some transdermal 
systems) 
  Dosage forms whose manufacturability is affected 
by changes in the drug substances physical 
properties (e.g., particle size, flowability, tapped 
density) 
  Suppositories in which the drug substance particles 
are designed to remain undissolved 
  Powders, sprinkles, and granules for oral use (e.g., 
some anti-infectives) 
  Powders for topical application (typically 
antibacterials, antifungals) 
  Some modified-release products 
* As defined in the guidance for industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for 
Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. 
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422   
423  Table 2: Potential for Postapproval Changes To Adversely Affect the Physical Properties of 
424  a Drug Substance  
425   
Low Potential  Moderate Potential  High Potential 
  Manufacturing process,    Facility changes that include    Most manufacturing process 
equipment, scale, or  the final solution step with  changes after the final solution 
facility change before the  no significant concurrent  step 
final solution step   changes in scale, equipment,    Equipment changes after the 
  Changes in DS* drying  or manufacturing process  final solution step  
equipment within the    Scale changes after the final    Changes to a new source of 
same operating principle  solution step with no 
DS** 
  Changes in DS isolation  significant concurrent    Change in DS particle size 
changes in equipment or 
equipment within the 
reduction equipment to 
manufacturing process 
same operating principle 
equipment of a different 
  Establishment of a    Change in DS particle size  operating principle and different 
reduction equipment to 
reprocessing operation as  design 
equipment of the same 
part of the manufacturing    Redesignation of a starting 
operating principle but a 
process 
material with a change in the DS 
different design  
  Redefinition of a starting  impurity profile 
  Changes in DS drying 
material with no change 
equipment involving a 
in the DS impurity profile 
change in operating 
principle 
  Changes in DS isolation 
equipment involving a 
change in operating 
principle 
  Changes to the equipment 
operating parameters during 
or after the final solution 
step 
 
426  * DS=drug substance. 
427  ** See section XI. 
428   
429  B.  Drug Product    
430   
431  1.  Drug Product Manufacturing and Release Data 
432   
433  The manufacture of a batch of drug product using the post-modification drug substance is not 
434  always required. However, when, as a result of the change, the drug substance equivalence 
435  cannot be established, and the drug substance physical properties can affect manufacturability or 
436  performance of the drug product, application holders must assess the drug product made with the 
437  post-modification drug substance before distributing the drug product.25 In such cases a batch of 
                                                 
25 Section 506A(b) of the FD&C Act. 
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438  drug product should be manufactured to fully evaluate the effect of a change in drug substance 
439  manufacturing. The drug product batch may be of reduced size, though usually not less than 10 
440  percent of a normal commercial-scale batch.26 Release testing and the results of in-process 
441  testing (e.g., in-process data collected during tablet compression, blend uniformity data) should 
442  be provided for the drug product batch.   
443   
444  Evaluation of the manufacturing change may include, but is not limited to: 
445   
446    Qualification of impurities, if appropriate. 
447   
448    Manufacturing and release data for one or more batches of the drug product made with 
449  the post-modification drug substance. 
450   
451    In vitro testing (e.g., dissolution, in vitro release) demonstrating the equivalence of the 
452  drug product made from the post-modification drug substance to the drug product made 
453  from the pre-modification drug substance. In some cases, in vivo bioequivalence studies 
454  may be needed. 
455   
456  When the drug product is available in multiple strengths (including different formulations), a 
457  batch of only one strength may be manufactured. The strength chosen for evaluation should be 
458  the strength most sensitive to changes in the drug substances physical properties. If there is no 
459  evidence of one strength being more sensitive than another, the lowest strength should be used 
460  for low-dose drug products; the highest strength should be used for all other products. A 
461  scientific rationale for the strength chosen should be provided in the submission to FDA. In the 
462  case of complex dosage forms with multiple strengths, such as modified release products, one 
463  batch per strength may be needed. 
464   
465  2.  Drug Product In Vitro Data 
466   
467  If a batch of drug product is manufactured because the change in drug substance manufacturing 
468  could affect the drug products physicochemical properties or bioavailability, the equivalence of 
469  this batch relative to the drug product made from the pre-modification drug substance should be 
470  determined using an appropriate in vitro test procedure. The type of testing that will be 
471  appropriate will vary with dosage form, route of administration, and solubility of the drug 
472  substance. Figure 1 contains a decision tree that provides further reference to additional 
473  guidances that cover this information. For dosage forms not listed in Figure 1, the appropriate 
474  chemistry and biopharmaceutics or bioequivalence teams should be consulted. Please contact the 
475  regulatory project manager or regulatory business project manager assigned to the application to 
476  facilitate this communication.  
477   
478   
                                                 
26 See the following SUPAC guidances for industry: Immediate Release Solid Oral Dosage Forms (SUPAC-IR), 
Modified Release Solid Oral Dosage Forms (SUPAC-MR), and Nonsterile Semisolid Dosage Forms (SUPAC-SS). 
SUPAC=Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution 
Testing, and In Vivo Bioequivalence Documentation.  
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479   
480  Figure 1: Decision Tree for In-Vitro Testing of Drug Products 
481   
Change in source or
physicochemical properties 
of DS*
Conduct comparative 
DS aqueous-
DS solubility  multipoint dissolution study 
No solubility pH  Yes
high**? using multi-pH media*** with 
dependent?
approved testing conditions
Yes
No
Conduct comparative 
multipoint dissolution study 
using application/compendial 
medium & approved testing 
conditions
Proposed change to DS 
Comparative 
Yes manufacture is 
dissolution similar?
supported
No
Lack of comparative dissolution similarity 
indicates possible need for bioequivalence 
study to support proposed change to DS 
manufacture
482   
483   
484  _____________________ 
485  * DS=drug substance. For changes in drug substance used in semisolid dosage forms, refer to SUPAC-SS for 
486  test documentation. 
487  ** For definitions of low and high solubility, refer to guidance for industry Waiver of In-Vivo Bioavailability and 
488  Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics 
489  Classification System. 
490  *** For multi-pH media conditions, refer to SUPAC-IR and SUPAC-MR. 
491   
492   
493   
494  3.  Stability Data 
495   
496  The need for and amount of stability data on the drug substance and drug product will depend on 
497  the type of change and its effect on the drug substance and the drug product dosage form. For 
498  specific details, see sections VI-XI.  
499     
500   
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501  V.   TYPES OF CHANGES AND DOCUMENTATION    
502   
503  The discussion of the change being reported should be accompanied by (1) a risk assessment for 
504  FDA review (see section III, General Considerations) and (2) recommended documentation as 
505  outlined in sections VIXI below. These sections contain general recommendations for the types 
506  of data that should be submitted to support a proposed change in facility, scale, and equipment; 
507  specification; manufacturing process; starting materials and container closure system as well as 
508  general recommendations to consider when making multiple changes.  
509   
510  The amount of data submitted to justify a change and the type of reporting category chosen 
511  should be fully supported by the outcome of the risk assessment. The risk assessment need not be 
512  a lengthy, complex document but should show how the risk was evaluated and explain how the 
513  accompanying data demonstrate the risk was addressed or mitigated to support the selected 
514  reporting category. 
515   
516  Recommended drug substance documentation should be submitted as an amendment to the 
517  referenced master file, or in the drug substance section (3.2.S) in a supplement to the approved 
518  application when no master file is referenced. Recommended drug product documentation should 
519  be submitted as an annual report or supplement to the approved application depending on the risk 
520  associated with the change. For more information on reporting categories, see section XII. 
521   
522   
523  VI.  FACILITY, SCALE, AND EQUIPMENT CHANGES 
524   
525  The manufacturing facility, scale, and equipment changes discussed in this section do not include 
526  modifications to the synthetic pathway (i.e., the same starting materials, intermediates, and 
527  unfinished drug substances are involved with only minor variations in solvents and reagents). 
528  Adjustments in process parameters should be limited to those needed to accommodate new 
529  equipment.  
530   
531  A.  Facility Changes 
532   
533  Facility changes involve changes in location of the site of manufacture of intermediates 
534  (including the final intermediate) and unfinished and final drug substances for both company-
535  owned and contract manufacturing facilities.  FDA must be notified when a drug substance 
536  manufacturer uses a manufacturing facility that differs from that which is specified in the 
537  approved application.27,28 The new facility, which may be in the same or different campus, 
538  should have similar environmental controls (e.g., temperature, humidity, cross contamination) as 
539  the previous facility. The applicant or DMF holder is responsible for ensuring that any new 
540  manufacturing facility is operating in accordance with CGMP regulations. Some types of facility 
541  changes include, but are not limited to: 
542   
                                                 
27 See 21 CFR 314.70(a) and 514.8(b)(1). 
28 If this change also includes a withdrawal of a facility, the Agency should be notified which facilities are being 
withdrawn in the submission, and which existing or new facility will take over the withdrawn facilitys operations. 
 
  16  Contains Nonbinding Recommendations 
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543    The addition of a new contract manufacturing facility for an intermediate by the drug 
544  substance manufacturer or an existing contract manufacturer.  
545   
546    The addition or relocation of an in-house intermediate manufacturing facility to a 
547  different campus. 
548   
549    Transfer of an additional manufacturing step to a facility already being used for other 
550  manufacturing steps.  
551   
552    Change of facility for the final purification or final manipulation of the drug substance. 
553   
554    Addition of an alternate manufacturing facility for the drug substance.  
555   
556  A change from one drug substance manufacturer to another is considered a change in the source 
557  of the drug substance, not a change of facility. If a facility change also involves changes in the 
558  manufacturing process, scale, or equipment, this should be considered a multiple change for 
559  purposes of data recommendations and reporting category (see section XII). 
560   
561  Since intermediates are to be manufactured in compliance with CGMP regulations, when there 
562  are multiple manufacturing facilities for an intermediate, it is recommended that the same 
563  specification and analytical procedure(s) be used at each facility to ensure equivalent quality. 
564   
565  For recommended documentation, see section VI.DE. 
566    
567  B.  Scale Changes 
568   
569  Scale changes refer to changes in the batch size outside the validated scale for intermediates, the 
570  unfinished drug substance, or the drug substance. This section is relevant to scale changes that 
571  use the same equipment as listed in the current master batch record (MBR), equipment that 
572  differs only in capacity from the equipment listed in the current MBR, or equipment of the same 
573  construction material, design, and operating principle as the equipment listed in the current 
574  MBR. Changes to equipment with a different construction material or design and operating 
575  principle should be considered equipment changes (see section VI.C). Adjustments in process 
576  parameters should be limited to those needed to accommodate changes in equipment. In general, 
577  scale changes before the final intermediate is produced are less likely to impact the impurity 
578  profile or physical characteristics of the final drug substance and less supporting data may be 
579  necessary to support the change. For reaction steps that are known to be sensitive to scale from 
580  previous experience (e.g., scale-up of pilot- to commercial-scale batches), the risk to product 
581  quality is higher and a greater amount of supporting data may be necessary. A change to new 
582  equipment, even if it uses the same construction material, design, and operating principle, could 
583  still affect the impurity profile or physical properties of the drug substance. For example, if the 
584  equipment is used during or after the final solution step to reduce the particle size, or to dry or 
585  isolate the drug substance (e.g., filtration), the impact on the impurity profile and physical 
586  properties of the drug substance could be greater. 
587   
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588  Some nonproportional changes may be appropriate in executing a change in batch scale; 
589  however, changes in batch size that alter the ratio of reactants, solvents, or other materials should 
590  be evaluated as a manufacturing process change and reported as a multiple change (see section 
591  XI). 
592   
593  Drug substances used to establish equivalence should be manufactured with materials 
594  manufactured at the new scale. A significant change in scale that results in the use of new 
595  equipment and changes in process parameters during or after the final synthetic step should be 
596  considered a multiple change (see section XI).  
597   
598  For recommended documentation, see section VI.DE. 
599   
600  C.  Equipment Changes 
601   
602  This section pertains to equipment changes involving new equipment that is of a different 
603  construction material, design, or operating principle than the equipment listed in the current 
604  MBR. Changes in equipment at an existing manufacturing facility should be reported. When a 
605  contract manufacturer is used, a quality agreement29 should ensure that changes in equipment 
606  that take place at the contract manufacturer are reported to the holder of the master file or 
607  application. A significant change in scale that results in the use of new equipment and changes in 
608  process parameters during or after the final synthetic step should be considered a multiple change 
609  (see section XI). 
610   
611  A change to new equipment with different construction material, design, or operating principle 
612  has the greatest potential to adversely affect the physical properties of the drug substance if the 
613  equipment is used during or after the final solution step or after subsequent processing 
614  procedures, such as: 
615   
616    Isolating the drug substance (e.g., changing from filtration to centrifugation). 
617   
618    Drying the drug substance (e.g., changing from vacuum tray dryer to fluid bed dryer). 
619   
620    Reducing the particle size of the drug substance (e.g., changing from dry milling to 
621  fluidized bed jet milling). 
622   
623  For recommended documentation, see section VI.DE. 
624   
625  D.  Recommended Documentation for the Drug Substance in a Master File or an 
626  Approved Application   
627   
628  Submissions to master files and the drug substance section in an approved application should 
629  include a description of the change. More specifically: 
630   
                                                 
29 See guidance for industry Contract Manufacturing Arrangements for Drugs: Quality Agreements. 
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631    For facility changes, provide: 
632   
633    The name, address, and contact persons information (name, phone number, email 
o
634  address) for the new facility, its DUNS number, and FEI number, if available.  
635   
636    A concise description of the manufacturing steps being transferred and a summary 
o
637  of variations in equipment or process parameters. 
638   
639    A statement that the synthetic pathway is identical at the new facility for a master 
o
640  file.30  
641   
642    For scale changes, provide a concise description of the change, including a comparison 
643  to the current/approved process and a summary with justification for variations in 
644  equipment or process controls. 
645    
646    For equipment changes, provide a concise description of the change, including a 
647  comparison to the equipment that is being replaced and a summary with justification for 
648  variations in process controls. 
649   
650  Regardless of the type of changefacility, scale, or equipmentsubmissions to master files and 
651  the drug substance section in an approved application should also include the following 
652  documentation:  
653   
654    A comparison of the impurity profile of pre- and post-modification material to establish 
655  equivalence per the guidelines in section IV, Assessment of Change. Comparative data 
656  and certificates of analysis (COA) from at least three consecutive batches of the material 
657  manufactured after implementation of the change should be provided. The data may be 
658  generated for an intermediate or the drug substance depending on which step of the 
659  manufacturing process is being performed as a result of the change. 
660   
661    If the impurity profile is demonstrated to be equivalent for an intermediate or for the drug 
662  substance: 
663   
664    An evaluation of the impurities in the pre- and post-modification material and a 
o
665  discussion of purging data or the results from spike/purge studies. 
666   
667    A statement of  commitment to put the first commercial-scale batch of the drug 
o
668  substance into the stability program.  
669   
670    If the equivalence of the impurity profile or physical properties is not demonstrated in the 
671  drug substance and a revised specification is proposed, see section VII, Specification 
672  Changes. In addition, provide: 
                                                 
30 Type II API DMFs intended for reference in a generic drug submission that are subject to the DMF fee under 
GDUFA I may only contain a single drug substance manufacturing process. See guidance for industry Completeness 
Assessments for Type II API DMFs Under GDUFA, pp. 45 and 9 (see note for item #1). 
  19  Contains Nonbinding Recommendations 
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673   
674    Three months of accelerated and 3 months of long-term stability data from three 
o
675  batches and a statement of commitment to continue the stability study through the 
676  retest/expiry date of the drug substance. 
677   
678    A description of any new analytical procedures used during batch analysis to evaluate 
o
679  the presence/absence of impurities. A summary of validation data should be provided 
680  for new test methods as well as for existing methods if the use is being extended 
681  beyond their original purpose.  
682   
683  For changes submitted to master files, method transfer data should be provided for analytical 
684  methods that are used for routine release or stability analysis of the drug substance at the new 
685  facility.  
686   
687  E.  Recommended Documentation for the Drug Product in an Approved 
688  Application  
689   
690  Submissions to approved applications should include the following documentation if not already 
691  provided in the drug substance section of the application:  
692   
693    A description of the change; for facility changes, provide the name, address, as well as 
694  FEI and DUNS numbers for the new facility/vendor.  
695   
696    The drug substance manufacturers COA for the drug substance made after 
697  implementation of the change or drug substance made with intermediates produced after 
698  implementation of the change.  
699   
700    The drug product manufacturers COA for drug substance confirming conformance to the 
701  application-approved specification and USP, if applicable. 
702   
703  If equivalence of the drug substance impurity profile and physical properties is not demonstrated 
704  and the physical properties are likely to affect the drug product manufacturability or performance 
705  (see Table 1), the submission should also include the following information: 
706   
707    A comparison of the COA for the pre-change drug product and the COA for the three 
708  batches post-modification drug product made with the drug substance manufactured after 
709  implementation of the change.   
710   
711    Dissolution data as described in section IV, Assessment of Change. 
712   
713    Analytical procedure data summary to ensure adequate quantitation and absence of co-
714  elution of chromatographic peaks for drug substance impurities for both the drug 
715  substance and drug product methods. 
716   
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717    Three months of accelerated and available long-term stability data for one batch of drug 
718  product using the post-modification drug substance, and a statement of commitment to 
719  submit long-term data in an annual report. 
720   
721   
722  VII.  SPECIFICATION CHANGES  
723   
724  This section addresses specification changes to raw materials (reagents and solvents), 
725  intermediates , and drug substances (including unfinished drug substances). Changes to controls 
726  for critical steps (e.g., tests for monitoring reaction progress or for control of reaction events) are 
727  also covered.  
728   
729  A.  Specification Changes to Raw Materials and Intermediates 
730   
731  Specification changes to raw materials and intermediates generally fall into one of the following 
732  categories:  
733   
734    Specification changes made to comply with compendial changes, including the 
735  following: 
736   
737    USP Monograph or other compendial monographs31 for a raw material become 
o
738  available. 
739   
740    USP Monograph or other compendial monographs for a raw material is updated. 
o
741   
742    Specification changes that provide greater assurance of quality, including the following: 
743   
744    Tightening acceptance criteria. 
o
745   
746    Adding a new impurity control. 
o
747   
748    Revising an existing analytical procedure with an improved procedure. 
o
749   
750    Revising specifications associated exclusively with improved analytical procedures. 
o
751   
752    Other specification changes, including the following: 
753   
754    Relaxing acceptance criteria. 
o
755   
756    Deleting a test. 
o
757   
                                                 
31 Refer to MAPP 5310.7 Acceptability of Standards from Alternative Compendia (BP/EPJP) for information on 
British Pharmacopoeia (BP), European Pharmacopoeia (EP), and Japanese Pharmacopoeia (JP). To make sure you 
have the most recent version of a MAPP, check the CDER MAPPs web page at 
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProc
edures/default.htm. 
  21  Contains Nonbinding Recommendations 
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758    Replacing an existing analytical procedure with a new procedure. 
o
759   
760    Revising specifications associated with changes in supplier/grade of reagents or 
o
761  solvents, including the use of recycled solvents. 
762   
763  Some specification changes would not be expected to affect the quality of downstream 
764  intermediates or the drug substance and therefore no evaluation of equivalence would be needed. 
765  Examples include the following: 
766   
767    Elimination of redundant testing (e.g., deletion of a boiling point test for a solvent if a 
768  chromatographic assay test is routinely performed). 
769   
770    Elimination of testing that is no longer required (e.g., testing for an impurity that is no 
771  longer present because of a change in the supplier of a starting material). 
772   
773    Minor specification changes (e.g., change in the concentration of a reagent that would 
774  subsequently be diluted before use). 
775   
776  The common factor in these three examples is that the ability to assess the chemical purity of the 
777  material is not adversely affected by the change and therefore evaluation is not needed. 
778   
779  B.  Specification Changes to Drug Substances 
780   
781  Specification changes to the drug substance or unfinished drug substance, including additions, 
782  deletions, or changes to analytical procedures, are covered in this section.  
783   
784  When a USP monograph becomes available or is updated, the drug substances specifications 
785  should be updated to comply with the compendial standards as appropriate. Deleting an existing 
786  test or changing from the routine test to a skip test should be justified. Relaxing an acceptance 
787  criterion in final drug substance specifications should be justified as appropriate. Impurities that 
788  are listed in the compendium but cannot be formed in the manufacturing process do not need to 
789  be included in the specification; however, a footnote should be added to the specification and 
790  COA of the final drug substance that states that the impurity cannot be formed. If compendial 
791  impurities are controlled upstream or as unknown impurities in the drug substance, a footnote 
792  should also be added to the specification and COA of the final drug substance.  
793   
794  C.  Recommended Documentation for the Drug Substance in a Master File or an 
795  Approved Application   
796   
797  1.  Documentation for Specification Changes to Raw Materials and Intermediates 
798   
799  For specification changes involving raw materials and intermediates, submissions to master files 
800  or to the drug substance section of approved applications should include the following 
801  documentation: 
802   
803    A description of and rationale for the proposed change. 
  22  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
804   
805    A brief description of new or revised analytical procedures and method 
806  validation/verification, as appropriate. 
807   
808    An updated COA with the revised specification for raw materials or intermediates. 
809   
810    Evaluation of the impurity profile (for intermediates or drug substance) and physical 
811  properties (for drug substance), including: 
812   
813    A report on the evaluation of changes in impurities with a description of the new or 
o
814  revised analytical procedures, with appropriate method validation/verification.  
815   
816    COAs for the three pilot or commercial scale batches made using the material with 
o
817  the revised specification, historical data for comparison, and a description of the 
818  source of the historical data.  
819   
820    Data to justify changes in intermediate specifications or to illustrate when 
o
821  manufacturing steps have been shown to remove or reduce the level of impurities to a 
822  specified level. In this case, spike/purge study data should be submitted. The 
823  additional data that should be submitted will depend on the individual case. Contact 
824  the regulatory project manager or regulatory business project manager assigned to the 
825  application for guidance. 
826   
827    Rationale for not providing an evaluation of intermediate or drug substance 
o
828  equivalence, if appropriate. 
829   
830  If impurity equivalence is demonstrated in an intermediate or in the drug substance, the 
831  submission should also include a commitment to put, at a minimum, the first commercial-scale 
832  batch of drug substance into the stability program.  
833   
834  If impurity equivalence is not demonstrated in an intermediate or at the drug substance, the 
835  submission should also include 3 months of accelerated and 3 months of long-term stability data 
836  from three batches. A commitment to continue the stability study through the retest/expiry date 
837  of the drug substance should also be included.  
838   
839  2.  Documentation for Specification Changes to Drug Substances  
840   
841  For specification changes involving drug substances, submissions to master files and the drug 
842  substance section of approved applications should include the following documentation: 
843   
844    A description of and rationale for the proposed specification change. 
845   
846    A brief description of new or revised analytical procedures and method 
847  validation/verification package, as appropriate. 
848   
  23  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
849    If the original analytical procedures are changed to compendial methods for assay 
o
850  and/or related substances, the method verification for the compendial methods should 
851  be provided. If an impurity is included in the original specification but not in the 
852  compendial impurity profile, it should be demonstrated that this impurity is controlled 
853  appropriately. A method validation report showing that the analytical procedure is 
854  appropriate for the noncompendial impurity should be provided.  
855   
856    If in-house methods are used for assay and/or related substances, method equivalency 
o
857  should be established between the in-house and compendial methods. All 
858  compendial-specified impurities should be included in the method equivalency study 
859  or justify its exclusion, if appropriate.  
860   
861    If a test is deleted or changed from a routine test to a skip test, the rationale for the 
862  proposed change, historical data, and a description of the source of the historical data.  
863   
864    An updated COA with a revised drug substance specification. 
865   
866    Justification for new or revised acceptance criteria with supporting data. 
867   
868    Evaluation of physical properties, if appropriate. 
869   
870    If such changes involve stability-indicating tests or methods, stability data using the new 
871  specification to support the retest/expiry period of the drug substance.  
872   
873  D.  Recommended Documentation for the Drug Product in an Approved 
874  Application  
875   
876  This information would be submitted by the applicant only if the specification change requires 
877  the submission of a supplement or inclusion in an annual report. 
878   
879  1.  Documentation for Specification Changes to Raw Materials and Intermediates 
880   
881  For specification changes involving raw materials and intermediates, submissions for 
882  applications should include the following documentation: 
883   
884    A general description of the specification change. 
885   
886    The drug substance manufacturers COA for the drug substance made with the 
887  intermediate that was manufactured in accordance with the proposed specification 
888  change, if available. 
889   
890  2.  Documentation for Specification Changes to Drug Substances 
891   
892  For specification changes involving drug substances, submissions for applications should include 
893  the following documentation: 
894   
  24  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
895    A description of the specification changes. 
896   
897    The drug substance manufacturers COA for the drug substance tested according to the 
898  proposed specification changes.  
899   
900    An updated COA from the drug product manufacturer for the drug substance using the 
901  revised specification. 
902   
903    Method description and transfer report for a drug substance manufacturers analytical 
904  procedure adopted by the drug product manufacturer. 
905   
906    The updated drug product specification and COAs, if the new or revised drug substance 
907  acceptance criteria impacts the drug product specification. 
908   
909   
910  VIII.  MANUFACTURING PROCESS CHANGES 
911   
912  This category encompasses a wide range of process-related changes, such as a change in the 
913  route of synthesis or an addition of a reprocessing procedure. Changes to the manufacturing 
914  process at or after the final solution step are considered to have a high potential to adversely 
915  affect the impurity profile and physical properties of the drug substance.  
916   
917  New specifications may be needed when new solvents, reagents, starting materials, or 
918  intermediates are involved in a change to the manufacturing process. (See also section VII). 
919  When the process changes involve concurrent facility, scale, or equipment changes (e.g., 
920  changing the method of isolating the drug substance from filtration to centrifugation, changing 
921  from tray to fluid bed drying), the changes are considered a multiple change (see section XI).  
922   
923  A.  Changes That Do Not Involve the Route of Synthesis  
924   
925  Examples include the following types of changes that might be made in one or more steps of the 
926  synthetic procedure, in purification processes, or in reprocessing operations: 
927   
928    Changes in unit operations (e.g., addition, deletion, change in the order, or repetition of 
929  an existing unit operation on a routine basis). 
930   
931    Addition or deletion of raw materials (e.g., solvents, reagents) or ancillary materials (e.g., 
932  resins, processing aids). 
933   
934    Changes in solvent composition (other than for an analytical procedure, which is covered 
935  in section VII, Specification Changes). 
936   
937    Changes to process parameters (e.g., temperature, pH, reagent stoichiometry, time). See 
938  section VI for changes to operating conditions that are scale or equipment related.  
939   
  25  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
940  Documentation of equivalence is recommended for most, but not all, cases. For example, if the 
941  amount of charcoal used in a process increases, equivalence testing may not be warranted. 
942  However, if the amount of charcoal decreases, there is the possibility of an increase in 
943  impurities; therefore, equivalence testing should be performed.  
944   
945  B.  Changes in Route of Synthesis in One or More Steps  
946   
947  In general, changes in route of synthesis are considered to have a moderate to high potential to 
948  adversely affect the impurity profile of the drug substance. The manufacturing process should be 
949  validated using the new route of synthesis. Impurity carryover studies and spike/purge studies 
950  should be conducted as appropriate. Control of mutagenic impurities in or expected to be in the 
951  final drug substance should be evaluated according to ICH M7 (section 4.1).  
952   
953  C.  Establishing a Reprocessing Procedure as Part of the Established 
954  Manufacturing Process 
955   
956  Reprocessing is not considered a routine event. If frequent reprocessing is expected, the 
957  procedures should be included as part of the established manufacturing process described in an 
958  application. If an application is approved without reprocessing procedures in the manufacturing 
959  process, the procedures can be added postapproval as an amendment to the DMF or as a 
960  supplement to the NDA or ANDA. Establishing a reprocessing operation as part of the 
961  manufacturing process has a low potential to adversely affect the physical properties of the drug 
962  substance. This category does not cover the addition of new steps beyond the established 
963  manufacturing process, which is considered reworking. Reworking increases the potential to 
964  affect the drug substance properties and needs more evaluation and testing according to ICH Q7.  
965   
966  D.  Recommended Documentation for the Drug Substance in a Master File or 
967  an Approved Application  
968   
969  For changes involving the manufacturing process, submissions to master files and the drug 
970  substance section of approved applications should include the following documentation: 
971   
972    A description of and rationale for the proposed change. 
973   
974    Specifications for new materials (e.g., starting materials, reagents, solvents, 
975  intermediates) as well as representative COAs. If new specifications are necessary in 
976  conjunction with a process change, this would be considered a multiple change (see 
977  section XI).  
978   
979    Executed batch records should be provided for master files referenced in support of an 
980  ANDA application. 
981   
982    Evaluation of the impurity profile (for intermediates or drug substance) and physical 
983  properties (for drug substance), including: 
984   
  26  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
985    A comparison of the impurity profile of pre- and post-modification material to 
o
986  establish equivalence as described in section IV, Assessment of Change. Historical 
987  data for comparison may be submitted, if applicable, along with a description of the 
988  source of the historical data. Data and COAs from at least three consecutive batches 
989  of the material manufactured using the alternate manufacturing process should be 
990  provided. These data may be for intermediates or drug substances depending on 
991  which part of the manufacturing process is being modified. 
992   
993    A description of new or revised analytical procedures that are used for the 
o
994  intermediate or drug substance analysis to evaluate the presence or absence of 
995  impurities. If the analytical procedure is used for drug substance testing, a summary 
996  of validation/verification data should be provided for new or revised methods and for 
997  existing methods if their use is being extended beyond their original purpose. 
998   
999    If an intermediate specification change is a result of the process change that 
o
1000  introduces the use of a new reagent, solvent, catalyst, or raw material, and such 
1001  change will not result in a change in drug substance specification, data to justify test 
1002  exclusion for new impurities as the result of the change.  
1003   
1004    Carryover studies that were conducted to justify upstream control of impurities 
o
1005  should be repeated if applicable to the portion of the process being changed. 
1006   
1007  If the impurity profile is demonstrated to be equivalent in an intermediate or in the drug 
1008  substance, the submission should include:  
1009   
1010    An evaluation of the impurities in the pre- and post-modification material and a 
1011  discussion of purging data or the results from spike/purge studies.  
1012   
1013    A commitment to put the first commercial-scale batch of the drug substance into the 
1014  stability program.  
1015   
1016  If impurity profile equivalence is not demonstrated in an intermediate or in the drug substance 
1017  and a revised or new in-process control or specification is proposed, see section VII, 
1018  Specification Changes. 
1019   
1020  If the drug substance impurity profile or physical properties are not equivalent, then 3 months of 
1021  accelerated and 3 months of long-term stability data from three batches should be provided in the 
1022  submission. A commitment to continue the stability study through the retest/expiry date of the 
1023  drug substance should also be included. 
1024   
1025  If the changes involve the route of synthesis, the submission should contain additional 
1026  information, which includes but is not limited to: 
1027   
1028    A detailed description of the new synthetic procedures, including the operating 
1029  conditions, controls of critical steps, and intermediates. 
1030    
  27  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1031    For master files, a summary of the process validation batch data for the new synthetic 
1032  procedure, including in-process controls, intermediate, and drug substance analysis, if the 
1033  process validation activities have been conducted. 
1034   
1035  E.  Recommended Documentation for the Drug Product in an Approved 
1036  Application 
1037   
1038  For changes involving the manufacturing process, submissions for applications should include 
1039  the following documentation: 
1040   
1041    The drug substance manufacturers COA for the drug substance made post-modification 
1042  or the drug substance made with intermediates produced after implementation of the 
1043  change.  
1044   
1045    The drug product manufacturers COA for the drug substance confirming conformance to 
1046  the application-approved specification and USP, if applicable. 
1047   
1048  In addition, if the drug substance impurity profile and physical properties equivalence are not 
1049  demonstrated and the physical properties are likely to influence the drug product 
1050  manufacturability or performance (see Table 1), the submission should include the following: 
1051   
1052    COAs for the pre-change drug product compared to the COAs for three batches of post-
1053  modification drug product made with the drug substance manufactured using the alternate 
1054  manufacturing process.   
1055   
1056    Dissolution data as described in section IV, Assessment of Change. 
1057   
1058    Analytical methods data summary to ensure adequate quantitation and absence of co-
1059  elution of chromatographic peaks for drug substance impurities for both the drug 
1060  substance and drug product methods. 
1061   
1062    Three months of accelerated and available long-term stability data for one batch of the 
1063  drug product using the post-modification drug substance and a commitment to submit 
1064  long-term data in an annual report. 
1065   
1066   
1067  IX.  STARTING MATERIAL CHANGES  
1068   
1069  With the introduction of the API starting material, good manufacturing practice as described in 
1070  ICH Q7 apply.32,33 Changes in vendor of the starting material may have a potential to adversely 
                                                 
32 However, there is an expectation that an appropriate level of controls suitable for the production of the API 
starting material should be applied. See guidance for industry Q7 Good Manufacturing Practice Guidance for Active 
Pharmaceutical Ingredients Questions and Answers. 
33 See guidance for industry 169 Drug Substance Chemistry, Manufacturing, and Controls Information available at 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm. 
  28  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1071  affect a drug substances impurity profile depending on the starting material and its proximity to 
1072  the drug substance. Changes to the route of synthesis or manufacturing process of the starting 
1073  material that result in changes to the starting material specification could have a higher level of 
1074  risk.  
1075   
1076  The drug substance manufacturer is responsible for managing changes to the manufacturing 
1077  process upstream of the starting material under its pharmaceutical quality system and for 
1078  selecting and qualifying additional vendors of the starting material (ICH Q11 Q&A 5.15 and 
1079  ICH Q7 Q&A 12.3). If there are changes to the vendor, the updated vendor list should be 
1080  reported in the DMF and/or application. The specifications and analytical procedures used at all 
1081  sites should ensure the same degree of quality, regardless of vendor, manufacturing process, or 
1082  site of use. The designation of a proposed starting material should be justified per the ICH Q11 
1083  general principles for selection of starting materials. 
1084   
1085  A.  Recommended Documentation for the Drug Substance in a Master File or an 
1086  Approved Application  
1087   
1088  For changes involving the starting material, submissions to master files and the drug substance 
1089  section of approved applications should include the following documentation: 
1090   
1091    The name, address, and contact persons information (name, phone number, email 
1092  address) for the new facility/vendor.  
1093   
1094    In-house and vendor COAs for the starting material, if applicable. 
1095   
1096    Additional documentation may be needed for a change in the synthetic route of a starting 
1097  material designated at a late stage in the manufacture of a drug substance.  
1098   
1099  Redesignated Starting Materials 
1100   
1101  The guidance ICH Q11 Development and Manufacture of Drug Substances  Questions and 
1102  Answers states that, Generally, it is anticipated that API starting materials that have already 
1103  been accepted by regulatory authorities (e.g., for use in authorized medicinal products) would not 
1104  need to be re-justified against the ICH Q11 general principles or the recommendations included 
1105  in this Q&A document, unless significant changes are made to the manufacturing processes and 
1106  controls. For FDA, this is understood to mean significant changes to the manufacturing process 
1107  and controls are those that are made between the introduction of the starting material and the 
1108  finished drug substance (e.g., when many unit operations that remove impurities are deleted from 
1109  the manufacturing process after introduction of the starting material). In such a situation, ICH 
1110  Q11, ICH Q11Q&A, and ICH Q7 should be consulted.   
1111   
1112  There is a potential relationship between the risk for adverse impact to drug substance quality 
1113  and the number of synthetic steps that occur between introduction of the starting material and the 
1114  end of drug substance synthesis. Factors such as the formation, fate, and purge of impurities near 
1115  the end of the synthetic pathway increase the risk for adverse impact to the drug substance 
1116  quality. If a starting material is re-designated such that the number of steps from the end of the 
  29  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1117  manufacturing process is reduced, the carryover of impurities into the drug substance is more 
1118  likely. FDA and the approved drug application holder(s) referenced in the master file should be 
1119  informed of the changes, and comparative batch analysis data for the drug substance should be 
1120  provided. 
1121   
1122  If the changes involve a re-designation of the starting material, the submission should contain at 
1123  a minimum the following information (not an exhaustive list) in addition to the documentation 
1124  described in section IX.A.: 
1125   
1126    The rationale for re-designating the starting material addressing ICH Q11 principles. 
1127    The list of sources of the re-designated starting material and the full name and address for 
1128  each source. 
1129    For non-commodity chemicals, the complete manufacturing process information from 
1130  each source, including the complete synthetic scheme and a brief process description 
1131  (such as when there is a new starting material specification). Reagents and solvents used 
1132  in the starting material process should be clearly indicated in these documents. 
1133    Updated specifications for the re-designated starting material, which include controls for 
1134  impurities and residual solvents. Justification and a discussion of the control strategy for 
1135  solvents and possible impurities should be included. Information from each source 
1136  regarding whether a class 1 solvent as described in ICH Q3C has been used or may be 
1137  present because of the manufacturing process should also be included. 
1138    A description of analytical procedures for the re-designated starting material. 
1139    The vendors COAs from each source of starting material. 
1140    Starting material COAs for the re-designated starting material generated by the drug 
1141  substance manufacturer using material obtained from each source. 
1142    When multiple sources are used, a comparison of batch data for re-designated starting 
1143  material generated from each source. 
1144    Comparative batch analysis data for downstream isolated materials, either the 
1145  intermediate or the drug substance. 
1146   
1147  B.  Recommended Documentation for the Drug Product in an Approved 
1148  Application 
1149   
1150  For changes in the vendor or manufacturing process of the starting material, no information need 
1151  be submitted by the applicant, unless the change triggers other changes addressed in this 
1152  guidance.    
1153   
1154  For redesignation of the starting material, the applicant should submit the drug substance 
1155  manufacturers COA for the drug substance manufactured with the new or changed starting 
1156  material. 
1157   
1158   
  30  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1159  X.    CONTAINER CLOSURE SYSTEM CHANGES 
1160   
1161  Please see the guidance for industry Container Closure Systems for Packaging Human Drugs 
1162  and Biologics.34 
1163   
1164  XI.  MULTIPLE CHANGES 
1165   
1166  Multiple changes are those that involve various combinations of the changes described in this 
1167  guidance. This includes changing to a new source of drug substance, which brings with it a 
1168  change in facility, and any number of changes in the manufacturing process, potentially 
1169  including an entirely different route of synthesis. The applicant should submit the drug substance 
1170  information as outlined in the Quality section of the CTD for the new drug substance source.35 
1171  Even if there is significant technology sharing or a common source of technology (e.g., if two 
1172  firms manufacture the drug substance via the same licensed process), significant differences may 
1173  exist in facilities, controls, and standard operating procedures. A change to a new source of the 
1174  drug substance is considered to have a high potential to have an adverse effect on the drug 
1175  substances impurity profile and physical properties. A new source of drug substance should be 
1176  supported by submission of three pilot or commercial scale batches of drug substance. Twelve 
1177  months of long-term and 6 months accelerated stability data for the drug substance should be 
1178  provided. If less than 12 months data are available at the time of submission, additional data 
1179  should be provided for review prior to approval. At least one batch of pilot or commercial scale 
1180  drug product should be manufactured; however, depending on the extent of drug product 
1181  understanding and complexity of the dosage form, up to three batches of drug product may be 
1182  requested. A minimum of 3 months long-term and 3 months accelerated drug product stability 
1183  data should be provided in the submission.   
1184   
1185  The recommended documentation for multiple changes should be the sum of the 
1186  recommendations for individual changes and the reporting category should be the most 
1187  restrictive of the categories recommended for the individual changes. 
1188   
1189   
1190  XII.  REPORTING CATEGORY 
1191   
1192  For manufacturing site, equipment, and process changes pertaining to non-commercially 
1193  available starting materials, drug substance intermediates, final intermediates, and drug 
1194  substance, the potential for an adverse effect to the drug product depends on the extent of 
1195  changes to the impurity profile and physical properties of the post-modification drug substance 
1196  and the type of dosage form it is used in. Therefore, the recommended reporting categories may 
1197  differ depending on these factors.  
1198   
1199  For guidance on reporting categories and examples, use the following sources of information, in 
1200  the listed order, for postapproval changes:  
                                                 
34 For the purpose of post-approval changes to the container/closure system of drug substances, the Container 
Closure Guidance also applies to animal drugs. 
35 See ICH guidance for industry M4Q: The CTD  Quality. 
  31  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1201  1.  21 CFR 314.70, 21 CFR 314.81, or 21 CFR 514.8, as appropriate. 
1202  2.  This guidance, which provides the most specific recommendations for the particular drug 
1203  substance manufacturing process change at issue.  
1204  3.  The guidance for industry Changes to an Approved NDA or ANDA or Chemistry, 
1205  Manufacturing, and Controls Changes to an Approved NADA or ANADA, as appropriate. 
1206  4.  The guidance for industry Changes to an Approved NDA or ANDA Questions and 
1207  Answers. 
1208  5.  The guidance for industry CMC Postapproval Manufacturing Changes to Be 
1209  Documented in Annual Reports.  
1210  6.  The draft guidance for industry Established Conditions: Reportable CMC Changes for 
1211  Approved Drug and Biologic Products.36 
1212   
1213  See appendix B for additional examples of changes not included in the above guidances. 
1214   
1215  If you have a question regarding a DMF,37 NDA, or ANDA for which you are the master file or 
1216  application holder, please contact the regulatory project manager or regulatory business project 
1217  manager assigned to the application.  
1218   
1219   
1220  XIII.  GLOSSARY 
1221   
1222  Acceptance Criteria: Numerical limits, ranges, or other criteria for the test described. 
1223   
1224  Batch: [A] specific quantity of [an intermediate or drug substance] that is intended to have 
1225  uniform character and quality, within specified limits, and is produced according to a single 
1226  manufacturing order during the same cycle of manufacture (21 CFR 210.3(b)(2)). A batch may 
1227  also mean a specific quantity of material or drug substance produced in one process or series of 
1228  processes so that it could be expected to be homogeneous. 
1229   
1230  Drug Product: [A] finished dosage form, e.g., tablet, capsule, or solution, that contains a drug 
1231  substance, generally, but not necessarily, in association with one or more other ingredients 
1232  (21 CFR 314.3(b)). 
1233   
1234  Drug Substance: [An] active ingredient that is intended to furnish pharmacological activity or 
1235  other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to 
1236  affect the structure or any function of the human body, but does not include intermediates used in 
1237  the synthesis of such ingredient ( 314.3(b)).  
1238   
                                                 
36 When final, this guidance will represent the FDAs current thinking on this topic. For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
37 See footnote 9.  
  32  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1239  Final Intermediate: In reference to synthetic and semisynthetic drug substances, the last 
1240  compound synthesized before the chemical reaction that produces the molecule or ion 
1241  responsible for the physiological or pharmacological action of the drug substance. The chemical 
1242  reaction that transforms the final intermediate into a form of the drug substance involves more 
1243  than a change in salt form (including a salt with hydrogen or coordination bonds) or other 
1244  noncovalent derivatives (such as complex chelates or clathrates).  
1245   
1246  Final Solution Step: The solution from which the drug substance is isolated in pure form.  
1247   
1248  Historical Data: For purposes of this guidance, data on impurities or physical attributes from 
1249  three or more consecutive representative pre-modification batches. The upper statistical limit of 
1250  an impurity should be based on the mean plus three times the standard deviation. A lower 
1251  statistical limit can be similarly defined, where appropriate (e.g., the level of an active 
1252  component, moisture content in a hydrate).  
1253   
1254  Impurity: Any component of the drug substance that is not the entity defined as the drug 
1255  substance (ICH Q3A or VICH GL10(R)). 
1256   
1257  Impurity Profile: A description of the identified and unidentified impurities present in a drug 
1258  substance (ICH Q3A or VICH GL10(R)) or drug product (ICH Q3B(R2) or VICH GL11(R)). 
1259   
1260  Intermediate: 
1261   
1262    For synthetic drug substances, a material produced during steps of the synthesis of a drug 
1263  substance that undergoes further molecular change or purification before it becomes a 
1264  drug substance. Intermediates may or may not be isolated (ICH Q7 and ICH Q3A or 
1265  VICH GL10(R)). 
1266   
1267    For drug substances derived from a biological source, a material produced during the 
1268  manufacturing process of a drug substance that undergoes further purification or 
1269  molecular modification before it becomes a drug substance.  
1270   
1271  Isolated Intermediate: An intermediate that is obtained after workup of a reaction step in the 
1272  synthetic scheme for the drug substance. The isolation or purification procedure should be part of 
1273  the validated process. An aliquot of a reaction product that is worked up or purified for purposes 
1274  of characterization does not constitute an isolated intermediate. 
1275   
1276  Method Validation: The process of proving that an analytical test procedure is suitable for its 
1277  intended use.  
1278   
1279  Operating Parameters: Conditions that can be adjusted to control the manufacturing process 
1280  (e.g., temperature, pressure, pH, time, mixing speed). 
1281   
1282  Particle Size Distribution: A measurement of the relative proportion of particles in a sample as 
1283  a function of size. 
1284   
  33  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1285  Person: Includes individual, partnership, corporation, and association. (Section 201(e) of the 
1286  FD&C Act). 
1287   
1288  Physical Properties: Attributes such as physical state, melting point, boiling point, solubility, 
1289  hygroscopicity, color, density, refractive index, partition coefficient, crystal shape, solid state 
1290  form, and particle size distribution. 
1291   
1292  Pilot Scale: The manufacture of a bulk drug substance or intermediate on a reduced scale by 
1293  processes representative of those to be applied on a larger, commercial manufacturing scale. 
1294   
1295  Polymorphism: The occurrence of different crystalline forms of the same drug substance 
1296  (ICH Q3A or VICH GL10(R)). 
1297   
1298  Process Validation: Establishing documented evidence that provides a high degree of assurance 
1299  that a specific process will consistently produce a product meeting its predetermined 
1300  specification and quality characteristics. 
1301   
1302  Representative Pre-modification Batches: Commercial-scale batches of a drug substance or 
1303  commercial-scale batches of an intermediate or unfinished drug substance that have been 
1304  successfully used to produce the drug substance.    
1305   
1306  Same Manufacturing Facility: Unbroken site or set of buildings in adjacent city blocks. 
1307   
1308  Semisynthetic Drug Substance: A drug substance produced by fermentation and synthesis or 
1309  synthesized from a precursor or structural element of natural origin (e.g., a product of natural or 
1310  plant origin). 
1311   
1312  Single Drug Substance Manufacturing Process: The same starting materials and intermediates 
1313  with minor variations being allowed in solvents and raw materials as long as the type of chemical 
1314  transformation in each step is unchanged. For example, palladium/carbon could be used at one 
1315  facility while platinum/carbon could be used at another. However, substitution of lithium 
1316  aluminum hydride at a facility would not be permissible as the chemical mechanism for that 
1317  transformation would be different and could generate a different impurity profile for the drug 
1318  substance.  
1319   
1320  Solid State Forms: Different crystalline forms of the same drug substance. These can include 
1321  solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms (ICH 
1322  guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New 
1323  Drug Substances and New Drug Products: Chemical Substances or VICH guidance for industry 
1324  GL39, Specifications: Test Procedures And Acceptance Criteria For New Veterinary Drug 
1325  Substances And New Medicinal Products: Chemical Substances; and ICH Q3A or VICH 
1326  GL10(R)). 
1327   
1328  Specification: The quality standard (i.e., tests, analytical procedures, and acceptance criteria) 
1329  provided in an application to confirm the quality of drug substances, drug products, 
1330  intermediates, raw materials, reagents, and other components, including the container closure 
  34  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1331  system and in-process materials. According to ICH Q6A, a specification includes the list of tests, 
1332  reference to analytical procedures, and acceptance criteria. 
1333   
1334  Starting Material: A material used in the synthesis of a drug substance that is incorporated as 
1335  an element into the structure of an intermediate or of the drug substance. A starting material can 
1336  be an article of commerce, a material purchased from one or more supplies under contract or 
1337  commercial agreement, or produced in-house. The chemical and physical properties, structure, 
1338  and impurity profile of a starting material are well-defined in the chemical literature.  
1339   
1340  Total Impurities: The sum of all impurities observed above the reporting limit. 
1341   
1342  Unfinished Drug Substance: A form of the drug substance that is further processed to produce 
1343  the form of the drug substance used to manufacture the drug product. The unfinished drug 
1344  substance can differ from the drug substance. For example, the solid state form of the unfinished 
1345  drug substance could be different from the finished drug substance or the counter ion for the 
1346  unfinished drug substance could be different from the actual drug substance. Although firms 
1347  have sometimes referred to such materials as intermediates, these materials do not meet the 
1348  definitions of intermediate and final intermediate provided in this guidance for synthetic or 
1349  semisynthetic drug substances.   
  35  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1350  APPENDIX A. CHANGES TO DRUG SUBSTANCE MANUFACTURE 
1351   
1352   
1353   
1354  _______________ 
1355  * DS=drug substance. Changes involve changes in facility, scale, equipment, specification, manufacturing process, 
1356  or starting materials. 
1357  **DP=drug product. 
  36  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1358   
1359  APPENDIX B: REPORTING CATEGORIES FOR ADDITIONAL EXAMPLES OF 
1360  CHANGES  
1361   
1362  Reporting Categories for Facility Changes 
1363   
1364  Change Being Effected in 30 Days (CBE-30) Supplement 
1365   
1366    A change to an alternate manufacturing facility within the same master file or within the 
1367  same corporate ownership (without a change in the existing manufacturing process), such 
1368  as a facility transfer for the last step in the manufacturing of the drug substance.  
1369   
1370    A change in the manufacturing facility for a drug substance intermediate, including the 
1371  final intermediate (CBE-30 at a minimum; see next entry for exception). 
1372   
1373  Prior Approval Supplement (PAS) 
1374   
1375    A change in the facility for manufacture of a drug substance intermediate, including the 
1376  final intermediate, if the change in manufacturing involves a new route of synthesis or the 
1377  proposed facility does not have an acceptable CGMP inspectional history. 
1378   
1379  Reporting Categories for Equipment Changes 
1380   
1381  CBE-30 
1382   
1383    A change from one type of drying process to another (e.g., oven tray to fluid bed or rotary 
1384  cone vacuum dryer) for a thermally stable intermediate or drug substance. 
1385   
1386    A change in drying process of the isolated wet crude final intermediate to using an 
1387  agitated nutsche filter dryer in place of a fluid bed drier or a centrifugation for a thermally 
1388  stable compound. 
1389   
1390    Changes to equipment used for particle size reduction in drug substances that are not 
1391  affected by particle size if the circumstances of the changes are such that an evaluation of 
1392  the drug substances physical properties is not required. 
1393   
1394  PAS 
1395   
1396    Changes in drug substance drying equipment to equipment of a different operating 
1397  principle and different design for a non-thermally stable intermediate or drug substance. 
1398   
1399    Changes to equipment used for particle size reduction to equipment of a different 
1400  operating principle and different design. 
1401   
1402    Equipment changes made during or after the final solution step. 
1403   
  37  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1404  Reporting Category for Manufacturing Process Changes  
1405   
1406  PAS 
1407   
1408    Changes that result in a change to the route of synthesis for the final intermediate or drug 
1409  substance. 
1410   
1411    Redefinition of a starting material resulting in a change in the impurity profile of the drug 
1412  substance. 
1413   
1414    Changes made after the formation of the final intermediate (e.g., new recrystallization 
1415  solvent). 
1416   
1417    Changes in the synthesis with adverse effect to the impurity profile (e.g., introduction of 
1418  genotoxic impurity). 
  38