#156 
 
Guidance for Industry 
 
Comparability Protocols - 
Chemistry, Manufacturing, and 
Controls Information 
for New Animal Drugs 
 
 
Submit comments on this guidance at any time. Submit electronic comments on the guidance to 
http://www.regulations.gov.  Submit written comments to the Division of Dockets Management 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 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.  (See comments on the draft guidance under 
legacy docket number 2003D-0061). 
 
For further information regarding this guidance document, contact Dennis Bensley, Center for 
Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 Standish Place, 
Rockville, MD 20855, 240-402-0696; email: dennis.bensley@fda.hhs.gov. 
 
Additional copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish 
Place, Rockville, MD 20855, and may be viewed on the Internet at either 
http://www.fda.gov/AnimalVeterinary/default.htm or http://www.regulations.gov. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
April 2016 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 4 
II.  BACKGROUND ............................................................................................................... 4 
A.  What is a Comparability Protocol? .............................................................................................. 6 
B.  What is the Benefit of Using a Comparability Protocol? ........................................................... 6 
C.  Why is a Guidance on Comparability Protocols Being Provided? ............................................ 6 
D.  Where Can More Information on Postapproval Changes and Demonstration of Equivalence 
Be Found? ............................................................................................................................................... 7 
III.   WHAT TO CONSIDER IN PLANNING A COMPARABILITY PROTOCOL....... 7 
A.  How Does a Comparability Protocol Affect the Reporting of CMC Changes? ....................... 7 
B.  When Might a Comparability Protocol Be Useful for a CMC Change? .................................. 7 
C.  When Might a Comparability Protocol Be Inappropriate? ....................................................... 8 
IV.  PROCEDURES FOR COMPARABILITY PROTOCOLS.......................................... 9 
A.  How Should a Comparability Protocol Be Submitted? .............................................................. 9 
B.  How Are Changes and Study Results Submitted After a Comparability Protocol is 
Approved? ............................................................................................................................................. 10 
C.  What If Study Results Do Not Meet the Criteria Specified in the Approved Comparability 
Protocol? ................................................................................................................................................ 10 
D.  When Does a Comparability Protocol Become Obsolete? ........................................................ 10 
E.  How is an Approved Comparability Protocol Modified? ......................................................... 11 
V.  CONTENT OF A COMPARABILITY PROTOCOL ................................................. 11 
A.  What are the Basic Elements of a Comparability Protocol? .................................................... 11 
B.  Does FDA Have Specific Concerns About Changes in the Manufacturing Process That 
Should Be Addressed in a Comparability Protocol? ......................................................................... 15 
C.  Does FDA Have Specific Concerns About Changes in Analytical Procedures That Should 
Be Addressed in a Comparability Protocol? ...................................................................................... 16 
D.  Does FDA Have Specific Concerns About Changes in Manufacturing Equipment That 
Should Be Addressed in a Comparability Protocol? ......................................................................... 16 
E.  Does FDA Have Specific Concerns About Changing Manufacturing Facilities That Should 
Be Addressed in a Comparability Protocol? ...................................................................................... 16 
F.  Can a Comparability Protocol Be Used for Container Closure System Changes? ................ 17 
G.  Can Implementation of or Changes in Process Analytical Technology (PAT) Be Addressed 
in a Comparability Protocol? .............................................................................................................. 17 
2  Contains Nonbinding Recommendations 
H.  Can a VMF Be Cross-Referenced in an Applicants Comparability Protocol? ..................... 17 
I.  Can a Comparability Protocol Be Included in a VMF? ........................................................... 18 
J.   Can a Comparability Protocol be Included in a (J)INAD? ...................................................... 18 
 
   
3  Contains Nonbinding Recommendations 
Guidance for Industry 
 
Comparability Protocols  
Chemistry, Manufacturing, and Controls Information 
for New Animal Drugs 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
the topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title 
page. 
 
I.  INTRODUCTION 
 
This guidance provides recommendations to applicants on preparing and using comparability 
protocols for postapproval changes in chemistry, manufacturing, and controls (CMC).  The 
guidance applies to comparability protocols that would be submitted in new animal drug 
applications (NADAs), abbreviated new animal drug applications (ANADAs), or supplements to 
these applications.  Well-characterized synthetic peptides submitted in these applications are 
included within the scope of this guidance.  This guidance also applies to comparability 
protocols submitted in investigational new animal drug (INAD), generic investigational new 
animal drug (JINAD) and veterinary master file (VMF) submissions that are referenced in 
applications.  The FDA is providing this guidance in response to requests from those interested 
in using comparability protocols. 
 
FDA guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
II.  BACKGROUND 
 
As an applicant, you are responsible for assessing, prior to distribution of a product, the effect of 
any postapproval CMC changes on the identity, strength, quality, purity, and potency of the 
product as these factors relate to the safety or efficacy of the product (section 506A(b) of the 
Federal Food, Drug, and Cosmetic Act (the act)).  Such an assessment often includes 
demonstration that the pre- and postchange products (i.e., products manufactured prior to and 
subsequent to a change) are equivalent.  Postapproval CMC changes must be reported to FDA in 
one of four reporting categories (Section 506A of the Act): 
 
   
4  Contains Nonbinding Recommendations 
  Annual Report (AR)1 
 
The annual submission to the approved application reporting changes that FDA has identified 
as having minimal potential to adversely affect the identity, strength, quality, purity, or 
potency of a product as they may relate to the safety or effectiveness of the product. 
 
  Change-Being-Effected Supplement (CBE) 
 
A submission to an approved application reporting changes that FDA has identified as having 
moderate potential to adversely affect the identity, strength, quality, purity, or potency of a 
product as they may relate to the safety or effectiveness of the product.  A CBE supplement 
must be received by FDA before or concurrently with distribution of the product made using 
the change. 
 
  Change-Being-Effected-in-30-Days Supplement (CBE-30). 
 
A submission to an approved application reporting changes that FDA has identified as having 
moderate potential to adversely affect the identity, strength, quality, purity, or potency of a 
product as they may relate to the safety or effectiveness of the product.  A CBE-30 
supplement must be received by FDA at least 30 days before distribution of the product made 
using the change. 
 
  Prior Approval Supplement (PAS) 
 
A submission to an approved application reporting changes that FDA has identified as having 
a substantial potential to adversely affect the identity, strength, quality, purity, or potency of 
a product as they may relate to the safety or effectiveness of the product.  A PAS supplement 
must be received and approved by FDA prior to distribution of the product made using the 
change. 
 
In many cases, using a comparability protocol will facilitate the subsequent implementation and 
reporting of CMC changes, which could result in moving a product into distribution sooner than 
if a protocol was not used. 
 
This guidance describes the general principles and procedures associated with developing and 
submitting a comparability protocol to the FDA.  The guidance also describes the basic elements 
of a comparability protocol and specific issues to consider when developing comparability 
protocols for changes in: 
   
                                                 
1 The annual report is the Minor Changes and Stability Report (MCSR) according to 21 CFR 514.8(a)(2)(iii). 
 
5  Contains Nonbinding Recommendations 
  the manufacturing process 
  analytical procedures2 
  manufacturing equipment 
  manufacturing facilities 
  container closure systems 
  process analytical technology (PAT) 
 
The guidance also discusses submitting comparability protocols as investigational new animal 
drug submissions, generic investigational new animal drug submissions and veterinary master 
file submissions. 
 
A.  What is a Comparability Protocol? 
 
A comparability protocol is a well-defined, detailed, written plan for assessing the effect of 
specific CMC changes in the identity, strength, quality, purity, and potency of a specific drug 
product as these factors relate to the safety and effectiveness of the product.  A comparability 
protocol describes the changes that are covered under the protocol and specifies the tests and 
studies that will be performed, including the analytical procedures that will be used, and 
acceptance criteria that will be achieved to demonstrate that specified CMC changes do not 
adversely affect the product.  The submission of a comparability protocol is optional. 
 
B.  What is the Benefit of Using a Comparability Protocol? 
 
At the time the application containing the comparability protocol is approved, the FDA can 
designate,3 where appropriate, a reduced reporting category for future reporting of CMC changes 
covered by the approved comparability protocol (see III.A).  Furthermore, because a detailed 
plan will be provided in the comparability protocol, the FDA is less likely to request additional 
information to support changes made under the protocol (see IV.D for a potential exception).  
The use of a comparability protocol could allow an applicant to implement CMC changes and 
place a product in distribution sooner than without the use of a comparability protocol. 
 
C.  Why is a Guidance on Comparability Protocols Being Provided? 
 
For many years, applicants have used protocols to implement certain types of CMC changes, 
such as to extend an expiration dating period or to demonstrate the interchangeability of certain 
plastic containers.  More recently, there have been many improvements in the techniques for 
characterizing products, production methods, process controls, and release testing.  Because of 
these improvements and because we are able to better assess the potential effect of CMC changes 
on a product, protocols are now being used with other types of CMC changes (e.g., 
manufacturing process, analytical procedure).  We have received a number of requests for 
guidance from applicants interested in using comparability protocols for these other types of 
changes. 
                                                 
2 The term analytical procedure, as used in this guidance, includes chemical, physical, microbiological, and 
biological test procedures. 
3 The term designate, in this context, refers to the reporting category agreed to by the applicant and FDA during the 
review of the submission containing the comparability protocol.  See V.A.6. 
6  Contains Nonbinding Recommendations 
 
D.  Where Can More Information on Postapproval Changes and Demonstration 
of Equivalence Be Found? 
 
We recommend that applicants consult all relevant guidances for information relating to 
postapproval changes.  The following guidances provide especially relevant information on (1) 
demonstrating equivalence, (2) documentation to be provided to support postapproval changes, 
and (3) the recommended reporting categories. 
 
  GFI #83  Chemistry, Manufacturing, and Controls Changes to an Approved NADA or 
ANADA 
 
  Various SUPAC documents4 
 
III.   WHAT TO CONSIDER IN PLANNING A COMPARABILITY PROTOCOL 
 
A.  How Does a Comparability Protocol Affect the Reporting of CMC Changes? 
 
A comparability protocol prospectively specifies the tests and studies that will be performed, 
analytical procedures that will be used, and acceptance criteria that will be achieved to assess the 
effect of CMC changes.  A well-planned protocol provides sufficient information for FDA to 
determine whether the potential for an adverse effect on the product can be adequately evaluated.  
With a comparability protocol, the FDA can determine if a specified change can be reported in a 
category lower than the category for the same change, were the change to be implemented 
without an approved comparability protocol.  Typically, categories designated for reporting 
changes under an approved comparability protocol are one category lower than normally would 
be the case (e.g., from PAS to CBE-30, CBE, or AR).  In some cases, a reduction of more than 
one reporting category may be possible (e.g., PAS to AR). 
 
B.  When Might a Comparability Protocol Be Useful for a CMC Change? 
 
A comparability protocol could be useful for a variety of CMC changes, but there are some 
exceptions (see Section III.C).  In addition, a comparability protocol can describe a single CMC 
change or multiple related changes.  However, we recommend that each change be discrete and 
specific.  A comparability protocol can be particularly useful for changes of a repetitive nature.  
We recommend that you have sufficient manufacturing information (e.g., developmental studies, 
manufacturing experience, demonstrated process capability, out-of-specification (OOS) 
investigations, stability data) with the particular product or process or similar products or 
processes so you can specify a priori the tests, studies, analytical procedures, and acceptance 
criteria appropriate for demonstrating that the CMC change or changes will not adversely affect 
the product.  We recommend that comparability protocols be considered for CMC changes that 
applicants anticipate will be made. 
 
                                                 
4 SUPAC (Scale-up and Post-Approval Changes).  See 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064979.htm. 
7  Contains Nonbinding Recommendations 
We recommend you consider product-specific and process-specific attributes when determining 
whether to develop a comparability protocol.  Attributes can include, but are not limited to, the 
following: 
 
  Complexity of the product structure 
  Ability to characterize the chemical, physical, microbiological, and biological 
properties of the product 
  Degree to which differences in product structure and physical properties (e.g., 
polymorph) can be detected 
  Degree of product heterogeneity if present 
  The effect on safety of changes in the impurities 
  The robustness of the product (i.e., the ability of product to remain unaffected by 
changes) 
  Rigorousness of the manufacturing process controls (i.e., the ability of the 
manufacturing process controls to ensure that the product remains unaffected by 
changes) 
 
In general, we recommend that a comparability protocol be considered only if the product 
resulting from the changes is expected to meet the approved drug substance and/or drug product 
specifications and appropriate and sensitive analytical procedures have been established and 
validated or qualified (i.e., for nonroutine tests such as characterization studies) to detect the 
effect of the change on the approved product. 
 
C.  When Might a Comparability Protocol Be Inappropriate? 
 
A comparability protocol would be inappropriate for some CMC changes.  In some cases, it may 
be impossible for the changes and/or plan for evaluating the effect of the CMC changes on the 
product to be fully described a priori.  A change may also be too complex to evaluate its effect 
on the product without efficacy, safety (clinical or nonclinical), or pharmacodynamic or 
pharmacokinetic (PK/PD) information. 
 
In general, we do not recommend comparability protocols for: 
 
  Broad, nonspecific plans for CMC changes 
  A change whose adverse effect on the product cannot be definitively evaluated by 
prespecified tests, studies, analytical procedures, and acceptance criteria 
  Any CMC change that warrants the submission of a new original application. 
  A CMC change that requires efficacy, safety (clinical or nonclinical), or PK/PD data 
to evaluate the effect of the change (e.g., certain formulation changes, clinical or 
nonclinical studies to qualify new impurities) 
 
8  Contains Nonbinding Recommendations 
It may be possible to design a comparability protocol for some of these CMC changes, but FDA 
may be limited in its ability to designate a reporting category other than PAS for changes 
implemented under such a protocol.  Specific examples of changes that may be difficult to justify 
under a comparability protocol can include5: 
 
  A change in the drug substance or drug product specifications (for exceptions, see 
V.A.4 and V.C) 
  A change in the qualitative or quantitative formulation of the drug product.6 
  A change in the type of delivery system 
  A change from plant, animal, or multicellular (e.g., algae, macroscopic fungi) source 
material to a different one (e.g., different plant species, different tissue and/or plant 
part, plant to animal) 
  A change from synthesis-derived to naturally sourced material and vice versa 
  A change from solid phase to liquid phase peptide synthesis and vice versa 
  A move to a manufacturing site, facility, or area when a prior approval supplement is 
recommended because a current good manufacturing practice (CGMP) inspection is 
warranted (e.g., see examples in guidances listed in II.D.) 
 
IV.  PROCEDURES FOR COMPARABILITY PROTOCOLS 
 
A.  How Should a Comparability Protocol Be Submitted? 
 
You can submit a comparability protocol in a prior approval supplement or as part of the original 
application.  We recommend that you indicate clearly in the cover letter that you are submitting a 
comparability protocol. 
 
The submission can consist of the proposed comparability protocol in 
 
  A prior approval supplement that is reviewed and approved prior to generating data 
supporting the change. 
  A prior approval supplement that includes the proposed comparability protocol and 
test and study results as specified in the proposed comparability protocol and any 
other pertinent information to support a change covered under the protocol.  The 
product already manufactured with the change can be distributed only after approval 
of the supplement. 
  An original application that is reviewed and approved prior to generating data 
supporting the change. 
                                                 
5 In some situations, these changes could warrant the submission of a new application. 
6 A comparability protocol might be useful in certain cases for quantitative changes in excipients, and FDA might 
designate a reduced reporting category for certain types of products and changes if you have sufficient information 
to assess the potential effect of the change (e.g., quantitative changes in an excipient beyond the ranges specified in 
the SUPAC guidances). 
9  Contains Nonbinding Recommendations 
 
In all cases, a comparability protocol would be reviewed and approved by FDA prior to an 
applicant implementing a change under the protocol.  Furthermore, an applicant who is using an 
approved comparability protocol to implement postapproval CMC changes must assess the effect 
of the changes on the identity, strength, quality, purity, and potency of the product as these 
factors relate to the safety or efficacy of the product prior to distributing product made with the 
change. (Section 506A(b) of the act)). 
 
B.  How Are Changes and Study Results Submitted After a Comparability 
Protocol is Approved? 
 
After a protocol is approved, you should document and submit each implemented change within 
the scope of the protocol using the reporting category designated by FDA.  The submission 
would include (1) the results of all tests and studies specified in your comparability protocol, (2) 
discussions of any deviations that occurred during the tests or studies, (3) a summary of any 
investigations performed, and (4) any other pertinent information.  To ensure prompt and 
accurate review, we recommend that you indicate in the cover letter to the submission that it 
includes data from a change covered under a comparability protocol and provide a reference to 
the submission in which the comparability protocol was approved. 
 
C.  What If Study Results Do Not Meet the Criteria Specified in the Approved 
Comparability Protocol? 
 
In certain instances, the tests and studies specified in an approved comparability protocol can 
lead to an unpredicted or unwanted outcome (e.g., test results do not meet predefined acceptance 
criteria).  If this occurs, you can elect not to implement the change.  If you decide to pursue the 
change, you should submit a prior approval supplement that provides the supporting data to 
justify why the change will not adversely affect the identity, strength, quality, purity, and 
potency of the specific drug product as these factors relate to the safety and effectiveness of the 
product. 
 
D.  When Does a Comparability Protocol Become Obsolete? 
 
New regulatory requirements, identification of a safety issue (e.g., screening for new infectious 
agents in materials from a biological source), identification of a new scientific issue, or 
technological advancement after the comparability protocol has been approved can render a 
protocol obsolete.  We recommend you review the tests, studies, analytical procedures, and 
acceptance criteria in your approved comparability protocol to ensure they remain current and 
consistent with the approved application and current FDA policy.  We recommend you 
determine whether the tests, studies, analytical procedures, and acceptance criteria described in 
your comparability protocol are still appropriate prior to implementing and submitting a change 
under the protocol.  If you find the comparability protocol is no longer correct or adequate, the 
current protocol should be modified or withdrawn.  FDA can request additional information to 
support a change that is implemented using an obsolete protocol. 
 
10  Contains Nonbinding Recommendations 
E.  How is an Approved Comparability Protocol Modified? 
 
You can submit a revised protocol at any time.  Like an original protocol, a revised protocol 
should be submitted as a PAS or (J)INAD protocol (see V.J.) to your application following the 
recommended submission procedures summarized in section IV.A.  To ensure prompt and 
accurate review, we recommend that you indicate in the cover letter to the submission that it 
includes a revision to an approved comparability protocol and identify all modifications. 
 
A comparability protocol would be modified to reflect relevant changes in the application.  For 
example, an applicant could request a change in an analytical procedure that is used for release 
testing but is also cited in an approved comparability protocol.  As part of the request to make 
such a change, FDA recommends that the applicant indicate up front all comparability protocols 
that will be affected.  The specified comparability protocols can be updated as part of this 
submission using the appropriate reporting category for the change, rather than submitting a 
separate submission requesting a modification of the comparability protocol. 
 
Editorial changes can also be made.  Notification of editorial changes to a comparability protocol 
can be provided in the AR. 
 
V.  CONTENT OF A COMPARABILITY PROTOCOL 
 
We recommend that a comparability protocol be developed and used within the context of 
existing change control procedures.  Such procedures ensure that specified changes do not 
adversely affect the identity, strength, quality, purity, or potency of the product. 
 
The comparability protocol can describe a single CMC change or multiple changes.  Each 
change should be specified and the acceptance criteria for evaluating the effect of the changes 
should be well defined.  If multiple changes are included in a protocol, we recommend that the 
multiple changes be interrelated (i.e., one change cannot be made without the others).  For 
example, a change in a fermentation medium component used to produce an antibiotic can result 
in more rapid cell growth, which, in turn, causes a higher production rate of antibiotic.  Changes 
related to this change in culture medium could include modification in the length of cell 
fermentation, increase in harvesting time, and/or changes to purification columns.  We 
recommend that you submit separate comparability protocols for unrelated changes. 
 
A.  What are the Basic Elements of a Comparability Protocol? 
 
1.  Description of the Planned Changes 
 
A comparability protocol should provide a detailed description of the proposed changes clearly 
identifying all differences from the conditions approved in the application.  A table, diagram, 
and/or flow chart can be included to help illustrate the differences. 
 
   
11  Contains Nonbinding Recommendations 
2.  Specific Tests and Studies to Be Performed 
 
A list should be included of the specific tests (e.g., release, in-process) and studies (e.g., 
characterization, stability, removal of impurities, laboratory-scale adventitious agent removal or 
inactivation) you will perform to assess the effect of the change on the drug substance, drug 
product, and/or, if appropriate, the intermediate, in-process material, or component (e.g., 
container closure system) directly affected by the change.  Include the rationale for selecting the 
particular battery of tests and studies.  For example, the use of nonroutine studies (e.g., 
characterization) can be warranted in cases where in-process or release specifications are not 
sufficiently discriminatory to evaluate the change. 
 
A protocol should include a plan to compare results from routine batch release testing and, as 
appropriate, nonroutine testing (e.g., characterization studies) on pre- and postchange products or 
other material, if appropriate.  The protocol should specify the number and type (e.g., pilot, 
production) of pre- and postchange batches and/or samples that will be compared.  The number 
and type of batches and/or samples to be compared can vary depending on the extent of the 
proposed change, type of product or process, and available manufacturing information.  Retained 
samples of prechange material can be used for comparison, provided there is no significant 
change in material on storage (e.g., level of degradants increasing over time).  A plan would 
specify whether retained samples are going to be used and the maximum age of the retained 
samples, and include information to support the appropriateness of the use of retained samples.  
In general, the results from postchange material should fall within the normal batch-to-batch 
variation observed for prechange material. 
 
A comparability protocol should include a plan for the stability studies that will be performed to 
demonstrate the equivalence of pre- and postchange product.  The comparability protocol would 
provide (1) information that is typically provided in a stability protocol, such as the number and 
type of batches that will be studied, test conditions, and test time points or (2) a reference to the 
currently approved stability protocol.  The amount of stability data that will be generated before 
the product made with the change is distributed would be specified.  The plan for evaluating 
stability could vary depending on the extent of the proposed change, type of product, and 
available manufacturing information.  In some cases, no stability studies may be warranted or a 
commitment to report results from stability studies in an AR can be sufficient.  If no stability 
studies are planned, we recommend that this be stated clearly. 
 
The differences, if any, in the tests and studies from those previously reported in the approved 
application or subsequent updates (i.e., supplements, annual reports) would be described.  We 
recommend you identify the location in your application of any referenced tests or studies. 
 
3.  Analytical Procedures to be Used 
 
A protocol should specify the analytical procedures that you intend to use to assess the effect of 
the CMC changes on the product or intermediate material.  Analytical procedures would be 
chosen capable of detecting new impurities or other changes in a product that can result from the 
change. 
 
12  Contains Nonbinding Recommendations 
Since the current approved analytical procedures are optimized for the approved product and 
process, modified or new procedures may be warranted.  For example, revised or new analytical 
procedures can be called for to monitor the removal of a new process impurity generated by a 
new manufacturing process.  In this situation, submission of results for pre- and postchange 
products using both the old and new analytical procedures may be warranted.  Studies performed 
to assess the feasibility of the proposed change can often be helpful in determining whether the 
current approved analytical procedures will be appropriate for assessing the effect of the change 
on the product (see V.A.5). Validation of new modified analytical procedures or revalidation of 
existing analytical procedures should be performed, as appropriate.  The protocol would specify 
that any new or revised analytical procedures and the appropriate validation or revalidation 
information would be provided when a postapproval CMC change implemented using the 
approved comparability protocol is reported to FDA. 
 
In some instances, analytical procedures are used in the characterization and/or assessment of the 
functionality of a product, but not for batch release or for process control (e.g., X-ray 
crystallography, plume geometry for metered dose inhalers).  If these analytical procedures are 
not routinely used for process or release testing, you do not have to report changes in these 
analytical procedures (e.g., when they are used only for drug development).  However, if these 
analytical procedures are specified in and provided as part of a comparability protocol, any new 
or revised analytical procedures and, as appropriate, results from validation or qualification 
studies for any modified procedure would be provided when a postapproval CMC change 
implemented using the approved comparability protocol is reported to FDA. 
 
In cases where changes in analytical procedures are intended to be implemented independent of 
other CMC changes, we recommend that a comparability protocol specific for analytical 
procedure changes be submitted (see V.C). 
 
4.  Acceptance Criteria 
 
You should include the acceptance criteria (numerical limits, ranges or other criteria) for each 
specified test and study that will be used to assess the effect of the CMC changes on the product 
or other material and/or demonstrate equivalence between pre- and postchange material.  In 
general, the drug substance and drug product specification would be identical to that in the 
approved application. Any statistical analyses that will be performed and the associated 
evaluation criteria would be identified. 
 
If implementing a change using a comparability protocol calls for a revision of the drug product 
or drug substance specification, we recommend you consider the recommended reporting 
category7 for the type of specification change as well as the designated reporting category for 
reporting a change using your comparability protocol.  When the recommended reporting 
category for the specification change is higher (e.g., PAS) than the reporting category for 
changes made under the comparability protocol (e.g., CBE-30), the change would be reported as 
recommended for the specification change.  If the recommended reporting category for the 
specification change is the same or lower than the designated reporting category for changes 
                                                 
7 For example, the recommended reporting categories for specification changes found in GFI #83  Chemistry, 
Manufacturing, and Controls Changes to an Approved NADA or NADA. 
13  Contains Nonbinding Recommendations 
made under the comparability protocol, the specification can be updated and provided when a 
postapproval CMC change implemented using the approved comparability protocol is reported to 
FDA. 
 
5.  Data to Be Reported Under or Included With the Comparability Protocol 
 
You should identify the type (e.g., release, long-term or accelerated stability data) and amount of 
data (e.g., 3-months accelerated stability data) that will be submitted at the time a postapproval 
CMC change implemented using the approved comparability protocol is reported to FDA and, 
when appropriate, generated prior to your distributing the product made with the change (e.g., 
when proposed reporting category is a CBE-30, CBE-0, or AR). 
 
If available, you can include any data from studies performed to assess the feasibility of the 
proposed change with the proposed comparability protocol.  Data obtained from a small-scale 
process or other studies incorporating the proposed change can provide preliminary evidence that 
the change is feasible, as well as preliminary information on the effect of the change on the 
product.  Development or feasibility studies can provide insight into the relevance and adequacy 
of the choice of the battery of tests you have identified to assess the product. 
 
6.  Proposed Reporting Category 
 
The use of an approved comparability protocol may justify a reduction in the reporting category 
for the particular CMC change when implemented (see III.A).  We recommend you include a 
proposal for the reporting category that you would use for changes implemented using the 
approved comparability protocol.  FDA will evaluate your proposed reporting category as part of 
its review of the comparability protocol and communicate any concerns about your proposal.  
Agreement by the applicant and FDA on the reporting category for the specified CMC changes 
will be part of the process of approving the comparability protocol. 
 
7.  Equivalence Not Demonstrated Using the Approved Comparability Protocol 
 
It is anticipated that some changes in the manufacturing process will result in a postchange 
product that cannot be demonstrated to be equivalent to the prechange product without more 
extensive physicochemical, biological, pharmacology, PK/PD, efficacy, or safety testing or in a 
product that does not meet the prespecified acceptance criteria in the protocol.  You should 
identify in the protocol the steps you will take in such circumstances. 
 
8.  Commitment 
 
You should include a commitment in your comparability protocol that you will update or 
withdraw your protocol when it becomes obsolete (see section IV.D.) 
 
   
14  Contains Nonbinding Recommendations 
B.  Does FDA Have Specific Concerns About Changes in the Manufacturing 
Process That Should Be Addressed in a Comparability Protocol? 
 
In addition to the general considerations provided in section V.A, we recommend that you 
consider the following issues for changes in the manufacturing process, where applicable: 
 
1.  Comparison of Physical Characteristics 
 
A comparability protocol would normally include a plan to compare the physical characteristics 
(e.g., polymorph forms, particle size distribution) of the product produced using the old and new 
processes when these characteristics are relevant to the safety and/or efficacy of the product. 
 
2.  Comparison of Impurity Profiles 
 
A comparability protocol would include a plan to determine the impurity profile of the product 
produced using the new process.  The studies would assess product-related impurities and 
process-related impurities, including, if applicable in-process reagents and catalysts.  We 
recommend that attention be given to demonstrating the absence of any new impurities or 
contaminants, or that they are removed or inactivated by downstream processing.  Any changes 
in the impurity profile would meet the predefined criteria (see section V.A.4).  The predefined 
criteria would indicate when qualification studies will be warranted to evaluate an increased 
level of an existing impurity or a new impurity (or an applicant could reference a relevant FDA 
guidance that recommends qualification levels). 
 
If during implementation of a change under an approved comparability protocol, the data 
indicate that nonclinical or clinical qualification studies for impurities are warranted, the change 
would not be appropriate for implementation under the approved comparability protocol (see 
III.C and V.A.7) 
 
3.  Effect on Downstream Processes 
 
We recommend that the effect of the change on downstream processes be examined. 
Downstream processes such as purification steps can be affected by higher product yields or 
shifts in impurity profiles when upstream processes are modified.  For example, adventitious 
agent removal or inactivation may have to be reassessed for processes involving materials or 
reagents derived from a biological source.  A comparability protocol would discuss how to 
ensure that the entire manufacturing process is adequately controlled. 
 
4.  Effect on Process Controls and Controls of Intermediates and/or In-process 
Materials 
 
We recommend you identify and justify implementation of new controls or variations from 
approved controls.  We recommend a statement be included that controls, including those that 
have been validated to inactivate and remove impurities or contaminants, will be revalidated for 
the new production process, if appropriate. 
 
15  Contains Nonbinding Recommendations 
C.  Does FDA Have Specific Concerns About Changes in Analytical Procedures 
That Should Be Addressed in a Comparability Protocol? 
 
A comparability protocol for changing an analytical procedure would provide the plan for 
validation of the changed analytical procedure and indicate whether the protocol will be used to 
modify the existing analytical procedure (i.e., retaining the same principle), or to change from 
one analytical procedure to another (e.g., normal to reverse phase HPLC).  The comparability 
protocol would be designed to demonstrate that the proposed changes in the analytical 
procedures improve or do not significantly change characteristics used in methods validation that 
are relevant to the type of analytical procedure (e.g., accuracy, precision, specificity, detection 
limit, quantitation limit, linearity, range).8 
 
Methods validation includes an assessment of the suitability of the analytical procedure.  A 
validation plan would have prespecified acceptance criteria for relevant validation parameters 
such as precision, range, accuracy, specificity, detection limit, and quantitation limit.  The 
proposed acceptance criteria for these parameters would ensure that the analytical procedure is 
appropriate for its intended use. The validation plan would assess whether a revised procedure is 
more susceptible than the original procedure to matrix effects by process buffers/media, product-
related contaminants, or other components present in the dosage form.  A plan would identify 
any statistical analyses that will be performed and whether product testing to compare the two 
procedures is intended.  The need and plan for providing product testing to compare the two 
procedures could vary depending on the extent of the proposed change, type of product, and type 
of test (e.g., chemical, biological). 
 
When used for release or process control, use of the new revised analytical procedure should not 
result in deletion of a test or relaxation of acceptance criteria that are described in the approved 
application. 
 
D.  Does FDA Have Specific Concerns About Changes in Manufacturing 
Equipment That Should Be Addressed in a Comparability Protocol? 
 
Comparability protocols may be most useful if applicants are planning to change to equipment 
with a different operating principal.  Equipment changes are often made in conjunction with 
changes to the manufacturing process.  We recommend that you evaluate this type of change 
with respect to its effect on the production process prior to deciding whether or not a 
comparability protocol would be appropriate. 
 
E.  Does FDA Have Specific Concerns About Changing Manufacturing Facilities 
That Should Be Addressed in a Comparability Protocol? 
 
The utility of a comparability protocol is often limited due to the scope of the change and the 
need, in some cases, for an inspection.  For example, a move to a new facility can involve many 
changes (e.g., new equipment, modified manufacturing process) that are difficult to 
                                                 
8 Guidance on validation of analytical procedures can be found in the CVM/VICH guidances GFI #63/GL1 
Validation of Analytical Procedures:  Definition and Terminology and GFI #64/GL2 Validation of Analytical 
Procedures:  Methodology. 
16  Contains Nonbinding Recommendations 
prospectively identify as part of a comparability protocol because the new facility is unknown or 
not constructed at the time the comparability protocol is being considered.  We recommend you 
consider carefully the appropriateness of a comparability protocol for a facility change that 
involves many other changes. 
 
We recommend a statement be included in the comparability protocol for changing 
manufacturing facilities saying that a move to a different drug substance or drug product 
manufacturing site will be implemented only when the site has a satisfactory CGMP inspection 
for the type of operation.  Furthermore, in the case of aseptically processed product, the 
statement would also indicate that a move to a different facility or area (e.g., room or building on 
a campus) will be made only when the specific facility or area has a satisfactory CGMP 
inspection (irrespective of the overall CGMP status for the campus).  For a move to another type 
of site (e.g., drug substance intermediate manufacturing site, testing laboratory), a statement 
would be included that the move to this site would not be implemented if there were an 
unsatisfactory CGMP inspection for the site.9 
 
F.  Can a Comparability Protocol Be Used for Container Closure System 
Changes? 
 
In the past, applicants have used protocols for container closure system changes, and they can 
continue to use them.  A comparability protocol can be particularly useful for repetitive container 
closure system changes. 
 
G.  Can Implementation of or Changes in Process Analytical Technology (PAT) 
Be Addressed in a Comparability Protocol? 
 
FDA anticipates that implementation of or changes in PAT could be addressed in a comparability 
protocol.  Early dialogue with FDA is encouraged.10 
 
H.  Can a VMF Be Cross-Referenced in an Applicants Comparability Protocol? 
 
A master file can be cross-referenced in a comparability protocol that provides for CMC changes 
(e.g., new manufacturer of drug substance, container resin).  The protocol would include a 
commitment to provide a letter authorizing the FDA to review the master file when a 
postapproval CMC change implemented using the approved comparability protocol is reported to 
FDA.  The comparability protocol would also indicate the type of information (e.g., 
manufacturing and formulation information for a plastic resin) that will be referenced in the 
master file and the information that you will provide such as the studies you will perform to 
demonstrate the suitability of the new material (e.g., conformance to approved specification, 
compatibility studies, stability studies). 
                                                 
9 A satisfactory CGMP inspection is an FDA inspection during which (1) no objectionable conditions or practices 
were found (No Action Indicated (NAI)) or (2) objectionable conditions were found, but corrective action is left to 
the firm to take voluntarily and the objectionable conditions will not be the subject of further administrative or 
regulatory actions (Voluntary Action Indicated (VAI)). 
10 See GFI titled PAT  A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality 
Assurance at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070305.pdf. 
17  Contains Nonbinding Recommendations 
 
I.  Can a Comparability Protocol Be Included in a VMF? 
 
A comparability protocol can be included in a master file.  The protocol can be cross-referenced 
for CMC changes.  Comparability protocols are product specific.  Therefore, the applicants 
submission would provide a comparability protocol that augments the information provided in 
the master file by specifying, for example, any additional studies that will be performed to 
demonstrate suitability of the postchange material (e.g., conformance to approved specification, 
compatibility studies, and stability studies).  The FDA ordinarily neither independently reviews 
master files nor approves or disapproves submissions to a master file. 
 
J.   Can a Comparability Protocol be Included in a (J)INAD? 
 
Comparability protocols may be submitted in a chemistry, manufacturing and controls (J)INAD 
technical data submission11 or a (J)INAD protocol without substantial data.12 
                                                 
11 Technical data submissions are described in GFI #132 -  Administrative Applications and the Phased Review 
Process at 
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052
532.pdf 
12 According to the performance goals and procedures for the ADUFA and AGDUFA reauthorizations for fiscal 
years 2014 through 2018, comparability protocols as described in 21 CFR 514.8(b)(2)(v) may be submitted as 
comparability protocols without substantial data in a (J)INAD file.  For more complex comparability protocols, for 
example sterile process validation protocols, the sponsor should discuss and have Agency concurrence regarding the 
appropriate filing strategy. See 
http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM343226.pdf and 
http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalGenericDrugUserFeeActAGDUFA/UCM343235.pdf 
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