126 
 
Guidance for Industry 
 
 
BACPAC I: Intermediates in  
Drug Substance Synthesis 
Bulk Actives Postapproval Changes: 
Chemistry, Manufacturing, and Controls 
Documentation 
 
Note:  This guidance replaces the version dated February 2001.  The document has been revised 
to reflect that the information provided on the chemistry, manufacturing, and controls of drug 
substances is now only applicable to animal drugs.   
 
Comments and suggestions regarding this document should be sent to Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, 
MD 20852.  Submit electronic comments to http://www.regulations.gov.  All comments should be 
identified with the exact title of the document. 
For questions regarding this document, contact Dennis Bensley, Center for Veterinary Medicine 
(HFV-143), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, (240) 276-
8268, E-mail: dennis.bensley@fda.hhs.gov. 
 
Additional copies of this guidance document may be requested from the Communications Staff 
(HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, 
Rockville, MD  20855, and may be viewed on the Internet at 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/d
efault.htm.  
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
June 1, 2006   
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................3 
II.  BACKGROUND...............................................................................................................4 
III.  GENERAL CONSIDERATIONS...................................................................................6 
IV.  ASSESSMENT OF CHANGE.........................................................................................6 
A.  Equivalence of Impurity Profiles..................................................................................................7 
B.  Equivalence of Physical Properties..............................................................................................9 
V.  TYPES OF CHANGE.....................................................................................................10 
A.  Site, Scale, and Equipment Changes..........................................................................................10 
B.  Specification Changes..................................................................................................................12 
C.  Manufacturing Process Changes................................................................................................15 
D.  Multiple Changes.........................................................................................................................19 
ATTACHMENT A:  BACPAC I DECISION TREE..............................................................20 
ATTACHMENT B:  GLOSSARY............................................................................................21 
 
 
  Contains Nonbinding Recommendations 
1
GUIDANCE FOR INDUSTRY  
 
BACPAC I:  Intermediates in Drug Substance Synthesis 
 
Bulk Actives Postapproval Changes:  Chemistry, Manufacturing, 
and Controls Documentation
 
 
 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 
 You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance. 
 
 
 
 
I.  INTRODUCTION 
 
This guidance provides recommendations to holders of new animal drug applications (NADAs), 
abbreviated new animal drug applications (ANADAs), or veterinary master files (VMFs) who 
intend, during the postapproval period, to change the (1) site of manufacture, (2) scale of 
manufacture, (3) equipment, (4) specification(s),2 and/or (5) manufacturing process of 
intermediates in the synthetic pathway leading to the drug substance.3 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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. 
 
                                                 
1  This guidance has been prepared by the Bulk Actives Postapproval Changes (BACPAC) Working Group of the 
Drug Substance Technical Committee operating under the Chemistry, Manufacturing, and Controls Coordinating 
Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER), with participation by the Center for 
Veterinary Medicine (CVM), at the Food and Drug Administration (FDA).   
2  Terms in bold italics are defined in the glossary. 
3  The FDA solicited early input on this topic through a public meeting sponsored by the American Association of 
Pharmaceutical Scientists in conjunction with the FDA.  The meeting, held March 25-27, 1997, provided a forum for 
FDA to hear public opinion on postapproval changes in the manufacture of drug substances. 
3 of 22   
II.  BACKGROUND 
 
Under section 506A of the Federal Food, Drug, and Cosmetic Act (the Act), the holder of an 
NADA or ANADA must notify FDA about each change in each condition established in an 
approved application beyond the variations already provided for in the application.  The Act 
provides for four reporting categories:  (1)  Prior Approval Supplement, (2) Supplement  
Changes Being Effected in 30 days, (3)  Supplement  Changes Being Effected, and (4) Annual 
Report.  The reporting category for a change is based on the potential for the change to have an 
adverse effect on the identity, strength, quality, purity, or potency of the drug product as these 
factors may relate to the safety or effectiveness of the drug product.  This guidance provides 
recommendations on reporting categories for postapproval changes relating to intermediates in 
drug substance synthesis based on a determination by the Center for Veterinary Medicine 
(CVM) of the potential for a specified change to have an adverse effect on the drug product.  It 
also provides recommendations on the information that should be provided to CVM to ensure 
continued drug substance quality and drug product quality and performance characteristics. 
 
This guidance describes chemistry, manufacturing, and controls information and documentation 
in support of each change and provides recommendations on reporting categories.  The guidance 
applies to synthetic drug substances and the synthetic steps involved in the preparation of 
semisynthetic drug substances.  It is limited to structurally well-characterized drug substances 
for which impurities can be monitored at the levels recommended.  The guidance covers:  (1) 
site, scale, and equipment changes involving the synthetic steps up to and including the step that 
produces the final intermediate, (2) specification changes for raw materials, starting materials, 
and intermediates, except the final intermediate, and (3) manufacturing process changes 
involving the synthetic steps up to and including the final intermediate.4   
 
Postapproval changes affecting the following are not addressed in this document: 
 
  Synthetic peptides 
  Oligonucleotides 
  Radiopharmaceuticals 
  Drug substances derived exclusively by isolation from natural sources or produced by 
procedures involving biotechnology 
  Nonsynthetic steps for semisynthetic drug substances 
  
Also excluded from BACPAC I are certain changes in (1) specification and process (e.g., virus or 
adventitious agent removal process) associated with the use of raw materials, starting materials, 
and intermediates derived from natural sources (e.g., plants, bovine serum) or biotechnology 
(e.g., enzymes, monoclonal antibody reagents) used in the synthetic and/or semisynthetic 
process, and (2) source material (e.g., plants, microorganisms) of substances derived from 
natural sources that are the intermediates that begin the synthetic part of a semisynthetic process. 
                                                 
4  Changes to the final intermediate and manufacturing changes after the final intermediate will be covered in a 
forthcoming BACPAC II guidance.  Also note the limited exceptions that follow for specification and process 
changes relating to the use of raw materials and starting materials derived from natural sources or biotechnology. 
4 of 22   
    Until the CVM guidance entitled Chemistry, Manufacturing and Control Changes to an 
Approved NADA or ANADA is finalized, applicants with questions about related issues are 
encouraged to contact CVM for advice.5   
 
The following changes are excluded from BACPAC I: 
 
  Any specification change for a raw material, starting material, or intermediate derived from a 
biotechnology process 
  Changes related to testing for viruses or adventitious agents:  (1) relaxing an acceptance 
criterion, (2) deleting a test, or (3) a change in the analytical procedure that does not provide 
the same or increased assurance of the identity, strength, quality, purity, or potency of the 
material being tested as the analytical procedure previously described 
  Changes in virus or adventitious agent removal or inactivation methods 
  Changes in source material, cell line, or supplier of raw materials, starting materials, or 
intermediates derived from a biotechnology process 
  Changes in source material (e.g., plant species, geographic location of plant harvesting, 
microorganism) or supplier of substances derived from natural sources that are the 
intermediates that begin the synthetic part of a semisynthetic process6 
 
This guidance does not comment on or otherwise affect compliance or inspection documentation 
that has been defined by the Office of Compliance or FDA's Office of Regulatory Affairs. 
 
In general, an applicant should use the following sources of information, in the listed order, for 
guidance on recommended reporting categories for postapproval changes that are within the 
scope of this guidance.  BACPAC I, which provides the most specific guidance, should be the 
first source of information. 
 
1.  BACPAC I (except as specified above for changes relating to naturally sourced or 
biotechnology derived materials) 
 
 
2.  21 CFR 514.8 (when the final rule publishes)7  
 
Applicants can contact the appropriate chemistry review teams for guidance on postapproval 
changes not addressed in these information sources. 
 
 
                                                 
5 A notice of availability of a draft version of this guidance was published in the Federal Register on October 1, 
1999 (64 FR 53393). 
 
6 This exclusion from BACPAC I is intended to focus on those substances derived from natural sources that are the 
intermediates that begin the synthetic part of a semisynthetic process.  The recommendations in BACPAC I can be 
used for widely available (i.e., used more than just to produce pharmaceuticals) starting materials derived from 
natural sources, such as glucose or tartaric acid, that may be used in a synthetic process. 
 
7  A proposed rule was published in the Federal Register on October 1, 1999 (64 FR 53281). 
5 of 22   
III.  GENERAL CONSIDERATIONS 
 
Any modification to the method of manufacture of a drug substance carries some risk of causing 
adverse impact, either in the physical properties of the drug substance or in the level or nature of 
impurities present.  The risk of adverse change is generally acknowledged to be greater when a 
modification occurs near the end of a drug substance manufacturing process rather than the 
beginning.  Also, certain kinds of modifications (e.g., equipment or site changes) are viewed as 
less likely to result in adverse change than others (e.g., changes in the synthetic route).  
However, there are no simple rules for determining how much risk is associated with any 
particular modification.  This guidance is limited to changes made up to and including the final 
intermediate because these early modifications are generally viewed as less likely to have an 
adverse impact on the drug substance and, consequently, on the drug product.  The final 
intermediate was chosen as the break point in this attempt to categorize risk because (1) it is 
typically the most well characterized material in the synthetic scheme, except for the drug 
substance itself, and (2) physical properties of the drug substance usually will not be affected by 
changes made up to that point. 
 
The responsibility for reporting changes of the type described in this guidance can lie with a 
single party or with several parties, depending on whether the drug substance synthesis is 
described in an application or in one or more master files.  If the holder of a master file makes a 
BACPAC I change, a description of the change should be submitted to the master file and all 
persons authorized to reference the master file who are affected by the change should be notified 
by the master file holder that the change has been made.  The notification should include 
reference to the section of this guidance under which the change is made and all pertinent 
information to ensure the quality of the drug product.  For example, when the holder of a master 
file makes a site change for an intermediate other than the final intermediate, the change should 
be described in an amendment to the master file, and the drug product applicant should file 
information describing the change in the next annual report (i.e., notification).  The data to 
support the site change can be provided in either the master file amendment or in the annual 
report to the drug product application. 
 
 
IV.  ASSESSMENT OF CHANGE 
 
A holder of an approved application must assess the effects of the change before distributing a 
drug product made with a manufacturing change (section 506A(b) of the Act).  A central tenet of 
this guidance is that a given change in the drug substance manufacturing process can be 
adequately assessed by comparing pre- and postchange materials and demonstrating that the 
postchange material is equivalent to the prechange material (i.e., of the same or better quality, as 
described below).  When equivalence cannot be demonstrated, applicants should submit a prior 
approval supplement and should consider appropriate tests for qualification of impurities, 
demonstration of bioequivalence, and assessment of stability.  This document does not call for 
the submission of stability data or routine stability commitments.  However, the stability of some 
drug products can be affected by small changes in impurities (e.g., increases in the trace levels of 
heavy metals).  For drug products with a potential for stability problems, the first production 
6 of 22   
batch of drug product made with postchange drug substance should be included in the 
applicants stability testing program. 
 
Two major factors for determining equivalence in the drug substance are the impurity profile 
and physical properties.  For the purposes of this guidance, only these factors will be discussed.  
However, other factors that can be important in individual cases should be evaluated to 
demonstrate equivalence.  For example, if the drug substance is defined as a mixture of active 
isomers or analogs, the ratios after the change should be within the stated acceptance criteria, or 
if not stated, within the upper and lower statistical limits8 of historical data.  There should be no 
structural changes to the final intermediate or to the drug substance, as supported by structural 
analysis data when appropriate. 
 
A.  Equivalence of Impurity Profiles 
 
The impact of manufacturing modifications on the impurity profile is evaluated by determining 
levels of existing impurities and new impurities.  It is important to determine the stage in the 
manufacturing process at which impurities should be evaluated and to establish the adequacy of 
the analytical procedures used for this purpose.  Levels of residual solvents and inorganic 
substances should also be considered during evaluation of the impurity profile. 
 
Ideally, impurities should be evaluated in isolated intermediates immediately following the 
process step in which the manufacturing modification is made.  If it can be shown that the 
impurity profile of an isolated intermediate following the modified step is equivalent (as defined 
below), the impurity profile of the drug substance will be considered unaffected by the 
modification.  If equivalence cannot be demonstrated at the isolated intermediate immediately 
following the change, the impurity search can be extended to the next downstream intermediate 
and the evaluation process repeated until the final intermediate is reached.  The Agency 
recognizes that it may not always be possible to establish equivalence prior to or at the final 
intermediate.  For example, adequate analytical procedures may not be available, cannot be 
developed, or, in some cases, historical data may not exist.  When it is not feasible to evaluate 
impurities in intermediates, or when equivalence cannot be demonstrated at these stages, the 
testing can be carried out on the drug substance itself.  Equivalence can be demonstrated on any 
single intermediate or on the drug substance.  Equivalence should not be established by 
combining results from multiple intermediates. 
 
The analytical procedures used to evaluate the change should be adequate for quantitating both 
existing and new impurities at the recommended levels.  Development of new analytical 
procedures may be called for.  When new analytical procedures are developed for this purpose, a 
summary of validation data should be provided.  The same analytical procedure should be used 
when comparing impurity levels in pre- and postmodification batches.   
 
The level of impurities should be assessed by comparing three consecutive postmodification 
batches to the historical data from three or more consecutive representative premodification 
                                                 
8  See information on statistical limits included in the definition of historical data in the glossary. 
7 of 22   
batches.  For the purposes of BACPAC I, representative premodification batches are production 
scale batches of drug substance that meet all acceptance criteria in the specification, or 
production scale batches of an intermediate that have been successfully used in a subsequent 
process.  The assessment of impurities should normally be carried out soon after manufacture.  
However, retained samples can be used for the comparison, provided there is no trend toward the 
level of any impurity increasing over time.   
 
The impurity profile will be considered equivalent after a given change if three consecutive 
postmodification batches of either an isolated intermediate or the drug substance are evaluated 
and the test data for each batch demonstrate that: 
 
  For evaluation at an intermediate, no new impurity is observed above 0.1% (or above 0.2% 
in an intermediate with only veterinary use). 
 
For evaluation at the drug substance, no new impurity is observed above the qualification 
threshold of impurities as described in the Veterinary International Conference on 
Harmonisation (VICH) guidance GL10 Impurities in New Veterinary Drug Substances.9  
 
  Each existing impurity is within its stated limit or, if not stated, is at or below the upper 
statistical limit of historical data. 
 
  Total impurities are within the stated limit or, if not stated, are at or below the upper 
statistical limit of historical data. 
 
  Each existing residual solvent is within its stated limit or, if not stated, is at or below the 
upper statistical limit of historical data. 
 
  New residual solvents, in either an intermediate or the drug substance, are at or below the 
levels recommended10 in the VICH guidance GL18 Impurities: Residual Solvents, when 
finalized.11 
 
Additional principles regarding equivalence of impurity profiles are outlined below. 
 
                                                 
9 Although these criteria (i.e., 0.1%, 0.2%, qualification threshold) are based on ICH guidances that are intended for 
registration applications of new drug substances, they are considered appropriate for the purpose of evaluating the 
equivalence of impurity profiles under BACPAC I. 
10  Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent 
possible to meet product specifications, good manufacturing practices, or other quality-based requirements.  This 
should be considered when proposing limits for new residual solvents in the drug substance.   
  
11  A notice of availability of the September 1999 draft version of this guidance was published in the Federal 
Register on October 12, 1999 (64 FR 55296).  Until this guidance is finalized, applicants with questions about levels 
of new residual solvents are encouraged to contact CVM for advice. 
8 of 22   
  Equivalence of the impurity profile can be established by testing any isolated intermediate 
following the change, including the final intermediate or the drug substance.  Equivalence 
should not be established by combining results from multiple intermediates. 
 
  In situ intermediates are generally not appropriate for demonstrating equivalence. 
 
  The batches of the intermediate or drug substance used for testing should be synthesized 
using exclusively the material that has been subjected to the change(s) (i.e., without blending 
with prechange material). 
 
  When a manufacturing change is made to an outsourced intermediate, either the vendor or 
the customer can establish equivalence.  However, in addition to assessing equivalence of the 
impurity profile, release testing by the vendor or acceptance testing by the customer, as 
appropriate, should be conducted. 
 
  Changes can be evaluated using data from pilot scale batches.  If equivalence is 
demonstrated by using pilot batches, the first production batch should also be evaluated for 
equivalence.  The production batch equivalence data should be kept on file at the 
manufacturing site.   
 
If equivalence cannot be demonstrated on the production batch, this would be considered 
evidence of an adverse effect on the identity, strength, quality, purity, and/or potency of the drug 
product, and the change should not be implemented (i.e., the drug product affected by the change 
should not be distributed).  An applicant still wishing to institute such a change can contact the 
appropriate chemistry review teams for guidance on any additional information that should be 
provided in support of the change and reporting of the change. 
 
  Additional purification procedures (or repetition of an existing procedure on a routine basis) 
to achieve equivalence with prechange material after the final intermediate are not covered 
under BACPAC I.  However, modified purification procedures prior to the final intermediate 
can be submitted under BACPAC I (see section V.C for process changes and section V.D for 
multiple changes). 
 
B.  Equivalence of Physical Properties 
 
In general, physical properties of the drug substance are not likely to be affected by changes 
made before the final intermediate because most synthetic schemes involve dissolution of the 
crude drug substance in a suitable solvent before the drug substance is isolated by crystallization 
or precipitation.  This final solution step, and not a preceding step, usually determines the 
physical properties of the drug substance.  Generally, the only way changes before the final 
intermediate can affect the physical properties of the drug substance is by carryover of new 
impurities or higher levels of existing impurities into the final solution step.  Although minor 
differences in the impurity profile at this stage are unlikely to cause physical property 
modifications to the drug substance, the possibility of such changes in physical properties should 
be considered.  Consequently, physical properties of the drug substance, when they are relevant 
to finished dosage form performance, should be evaluated unless equivalence of the impurity 
9 of 22   
profile can be demonstrated prior to the final solution step (e.g., on the crude drug substance or 
an earlier intermediate).  
 
Generally, only two physical properties of the drug substance, morphic form12 and particle size, 
are considered critical for evaluation of equivalence.  However, other physical properties can be 
important in individual cases.  The physical properties of the drug substance will be considered 
equivalent after a given change if three consecutive postmodification batches of the finished 
drug substance are compared to three or more consecutive representative premodification 
batches and the test data for each batch demonstrate: 
 
  Conformance to established acceptance criteria for morphic form or, where acceptance 
criteria do not exist, the isolation of the same form or mixture of forms within the range of 
historical data 
 
  Conformance to historical particle size distribution profile 
 
The BACPAC I Decision Tree (Attachment A) incorporates the approaches described above for 
the evaluation of impurity profiles and physical properties and is a general guide for the 
assessment of changes. 
  
 
V.  TYPES OF CHANGE 
 
A.  Site, Scale, and Equipment Changes 
 
The manufacturing site, scale of manufacture, and manufacturing equipment changes discussed 
in this section do not include any modifications to the synthetic pathway (i.e., the same starting 
materials, intermediates, solvents, and reagents are involved).  Adjustments in operating 
conditions (e.g., temperature, pressure) should be limited to those that accommodate new 
equipment.  Under these constraints, the changes in this category should not usually give rise to 
different impurity profiles for either the intermediates following the change or the drug 
substance. 
 
1.  Site Changes 
 
Site changes include changes in location of the site of manufacture of intermediates, 
including the final intermediate, for both company-owned and contract manufacturing 
facilities.  Site changes can involve the addition of new contract manufacturing facilities 
or the relocation of manufacturing facilities approved in the referenced application(s).  
Transfer of an existing manufacturing step to a facility approved for other manufacturing 
steps should be considered a site change.   
 
Changes to a different manufacturing site should be reported.  Changes within the same 
manufacturing site need not be submitted to the Agency, and equivalence testing as 
                                                 
12 For purposes of this guidance, morphic form also includes hydrates, solvates, and amorphous materials. 
10 of 22   
described in this document need not be carried out.13   Changes in supplier of starting 
materials need not be submitted to the Agency except for those situations described in 
section I or when a firm has made a commitment to the Agency to do so. 
 
The new site should have similar environmental controls (e.g., temperature, humidity, 
cross contamination).  Manufacturing facilities should operate in accordance with the 
principles of current good manufacturing practice. 
 
Test documentation (submitted as amendments to master files and/or in annual reports or 
supplements to the applications, as appropriate) should include: 
 
  The name and address of the new facility 
  A concise description of the manufacturing steps being transferred, a summary of any 
variation in equipment or operating conditions, and a statement that the synthetic 
pathway is identical at the new site 
  Evaluation of the impurity profile and physical properties.  This evaluation should 
include: 
 
  A report on changes in impurities with a description of analytical procedures 
  Data on three consecutive batches made at the new site 
  Historical data for comparison 
  A description of the source of the historical data. 
 
A summary of validation data should be provided for any new analytical procedures and 
also for existing procedures if their use is being extended beyond their original purpose.  
 
If equivalence of the impurity profile is established at any intermediate following the 
change, no testing of the drug substance is necessary.  
 
If testing is performed on the drug substance, equivalence should be established for (1) 
the impurity profile and (2) the physical properties, if relevant to the finished dosage 
form performance.  If either the impurity profile or physical properties are not equivalent 
in the drug substance, applicants still wishing to make the change should submit a prior 
approval supplement.  When equivalence is not established, applicants should consider 
conducting an assessment of the effect of the change on the safety and effectiveness of 
the drug product (e.g., qualification of impurities, bioequivalence studies).  The 
additional data that should be submitted will depend on the individual case, and the 
appropriate chemistry teams can be contacted for guidance. 
                                                 
13 Here and in several other places in BACPAC I, it is stated that a change need not be submitted to the Agency, 
and/or equivalence testing as defined in BACPAC I need not be conducted.  These statements do not relieve the 
responsible party from the obligation to have compliance or inspection documentation, which has been defined by 
the Office of Compliance or FDAs Office of Regulatory Affairs, available on site, nor does it relieve a holder of an 
approved application from assessing the effects of the change before distributing a drug product made with a 
manufacturing change (506A(b) of the Act).  In the rare instance there is evidence that such a change results in 
nonequivalence of production batches, the drug product affected by the change should not be placed into distribution 
(see section IV.A under additional principles  bullet 5).  
11 of 22   
 
2.  Reporting Category: 
 
  Annual Report if the site change does not involve the final intermediate 
  Supplement :Changes Being Effected if the site change involves the final 
intermediate 
 
3.  Scale Changes 
 
Scale changes include increases and decreases in the batch size of intermediates, 
including the final intermediate, beyond those approved in the original application. No 
attempt is made to classify scale changes according to the magnitude of the change.  
Scale changes need not be submitted to the Agency. 
 
4.  Equipment Changes 
 
A change to new equipment need not be submitted to the Agency, even where equipment 
is specified in the approved application. 
 
B.  Specification Changes  
 
Specification changes for release of an intermediate for further processing, raw materials (e.g., 
solvents and reagents), and starting materials are covered in this section.  Changes to controls of 
critical steps (e.g., tests for monitoring reaction progress or for control of reaction events) are 
also covered in this section.  Changes to operating conditions are covered under Manufacturing 
Changes (section V.C). 
 
Specification changes for the final intermediate are not included in this guidance, nor are certain 
specification changes for raw materials, starting materials, and intermediates derived from 
natural sources or biotechnology (see section I). 
 
1.  Specification Changes Made to Comply with Compendial Changes 
 
Test documentation (submitted in amendments to master files and/or in annual reports to 
the applications, as appropriate) should include: 
 
  A description of the change 
  Updated specifications   
 
Reporting Category: 
 
  Annual Report. 
 
2.  Specification Changes That Provide Greater Assurance of Quality 
 
Examples: 
12 of 22   
 
  Tightening of acceptance criteria 
  Replacing an existing analytical procedure with an improved procedure 
  Revised specifications associated exclusively with improved analytical procedures 
 
Test documentation (submitted as amendments to master files and/or in annual reports to 
the applications, as appropriate) should include: 
 
  Rationale for the proposed change and a brief description of any new analytical 
procedures, including a discussion of improvements over existing procedures.   
  Updated specifications.  
 
Reporting Category: 
 
  Annual Report. 
 
3.  Other Specification Changes 
 
Examples: 
 
  Relaxing acceptance criteria 
  Deleting a test 
  Replacing an existing analytical procedure with a new procedure that does not qualify 
as an improvement 
  Revised specifications associated with changes in supplier/grade of starting materials, 
reagents, or solvents 
 
Generally, if there is a specification change that falls under this category, the effect of 
the change on the impurity profile of a later intermediate or on the impurity profile 
and/or physical properties of the drug substance should be evaluated.  For example, if 
the stereochemistry at a position in an intermediate is induced through the use of a chiral 
reagent, a change in the acceptance criterion for the enantiomeric purity of the reagent 
from NLT 95% to NLT 90% should be evaluated.  The evaluation should be conducted 
using material that challenges the specification change.  For example, if an assay 
acceptance criterion for a starting material has been relaxed from a 98-102% range to a 
90-102% range, the equivalence of an intermediate or drug substance should be 
demonstrated for batches made using starting material with an assay value near the new 
lower limit (i.e., 90%).   
 
Some specification changes that fall within the scope of section V.B.3 would clearly not 
affect the quality of downstream intermediates or the drug substance and therefore no 
evaluation of equivalence would be needed.  Examples include: 
 
  Elimination of a redundant test (e.g., deletion of a boiling point test for a solvent 
where a chromatographic assay test is routinely performed) 
13 of 22   
 
  Elimination of a test that is no longer necessary (e.g., testing for an impurity that is no 
longer present due to a change in the supplier of a starting material) 
 
  Inconsequential quality changes (e.g., change in the concentration of a reagent which 
would subsequently be diluted prior to use) 
 
The common factor in these examples is that the ability to assess the chemical purity of 
the material is not being negatively altered by the change.  Evaluation is not needed for 
such changes.  
 
Test documentation (submitted as amendments to master files and/or in annual reports or 
supplements to the applications, as appropriate) should include 
 
  Rationale for the proposed change and a brief description of any new analytical 
procedures 
  Evaluation of the impurity profile and physical properties, if appropriate (see above). 
 This evaluation should include: 
 
  A report on changes in impurities with a description of analytical procedures 
  Data on three consecutive batches made using material that justifies the 
revised specifications 
  Historical data for comparison 
  A description of the source of the historical data  
 
A summary of validation data should be provided for any new analytical procedures 
and also for existing procedures if their use is being extended beyond their original 
purpose.  
 
If equivalence of the impurity profile is established at any intermediate following the 
change, no testing of the drug substance is necessary. 
 
If testing is performed on the drug substance, equivalence should be established for 
(1) the impurity profile and (2) the physical properties, if relevant to the finished 
dosage form performance.  If either the impurity profile or physical properties are not 
equivalent in the drug substance, applicants still wishing to make the change should 
submit a prior approval supplement.  When equivalence is not established, applicants 
should consider conducting an assessment of the effect of the change on the safety 
and effectiveness of the drug product (e.g., qualification of impurities, bioequivalence 
studies).  The additional data that should be submitted will depend on the individual 
case, and the appropriate chemistry teams can be contacted for guidance. 
 
  Rationale for not providing an evaluation of equivalence, if applicable 
  Certificates of Analysis for raw materials and batch release data for intermediates, 
as appropriate 
14 of 22   
  Updated specifications  
 
Reporting Category: 
 
  Annual Report if an evaluation of the effect of the change on impurity profile 
and/or physical properties is not necessary 
  Supplement: Changes Being Effected if the effect of the change on impurity 
profile and/or physical properties should be demonstrated 
  
C.  Manufacturing Process Changes 
 
This category encompasses a wide range of process-related changes.  New specifications may be 
called for when different solvents, reagents, starting materials, or intermediates are involved (see 
also section V.B, Specification Changes).  Process changes that result in the formation of a 
different final intermediate are outside the scope of this guidance.  Also, certain process changes 
for raw materials, starting materials, and intermediates derived from natural sources or 
biotechnology are not included in this guidance (see section I). 
 
1.  Changes That Do Not Involve New Starting Materials14 or Intermediates 
 
Examples include the following types of changes that might be made in one or more steps 
of the synthetic process, purification processes, or reprocessing operations: 
 
  Changes in unit operations (e.g., addition, deletion, change in the order, repetition of 
an existing unit operation on a routine basis)  
  Addition or deletion of raw materials (e.g., solvents, reagents) or ancillary materials 
(e.g., resins, processing aids) 
  Changes in solvent composition (other than for an analytical procedure, which would 
be covered under Specification Changes) 
  Operating conditions (e.g., temperature, pH, reagent stoichiometry, time)15 
 
Documentation of equivalence is recommended for most, but not all, cases.  For example, 
if the amount of charcoal used in a process is increased, equivalence testing may not be 
warranted.  However, if the amount of charcoal is decreased, there is the possibility of an 
increase in impurities; therefore, equivalence testing should be performed.  If 
applicants/DMF holders have questions on whether equivalence testing should be 
conducted to support a change, the appropriate chemistry review teams can be consulted. 
 
Test documentation (submitted as amendments to master files and/or in annual reports or 
supplements to the applications, as appropriate) should include: 
                                                 
14 Changes in a supplier of starting materials need not be submitted to the Agency except for those situations 
described in section I or when a firm has made a commitment to the Agency to do so. 
 
15 Changes to operating conditions that are scale- or equipment-related or are within established or validated ranges 
need not be reported. 
15 of 22   
 
  Description of change 
  Specifications for new reagents and solvents and Certificates of Analysis from the 
suppliers, if applicable 
  Evaluation of the impurity profile and physical properties.  This evaluation should 
include: 
 
 A report on changes in impurities with a description of analytical procedures 
 Data on three consecutive batches made using material produced by the changed 
process 
 Historical data for comparison 
 A description of the source of the historical data   
 
A summary of validation data should be provided for any new analytical procedures and 
also for existing procedures if their use is being extended beyond their original purpose.  
 
If equivalence of the impurity profile is established at any intermediate following the 
change, no testing of the drug substance is necessary. 
 
When a new solvent is introduced into the synthetic process, the possibility of carryover 
into the drug substance should be assessed.  Tests and acceptance criteria should be 
established, as appropriate.  See section IV.A for additional guidance on evaluating 
equivalence when new residual solvents are present in an intermediate or the drug 
substance. 
 
If testing is performed on the drug substance, equivalence should be established for (1) 
the impurity profile and (2) the physical properties if relevant to the finished dosage form 
performance.  If either the impurity profile or physical properties are not equivalent in the 
drug substance, applicants still wishing to make the change should submit a prior 
approval supplement.  When equivalence is not established, applicants should consider 
conducting an assessment of the effect of the change on the safety and effectiveness of 
the drug product (e.g., qualification of impurities, bioequivalence studies).  The 
additional data that should be submitted will depend on the individual case, and the 
appropriate chemistry teams can be contacted for guidance. 
 
Reporting Category: 
 
  Annual Report if equivalence is demonstrated prior to the final intermediate. 
 
  Supplement:  Changes Being Effected if equivalence is demonstrated at the final 
intermediate or drug substance. 
 
16 of 22   
2.  Changes in the Route of Synthesis in One or More Steps Involving Different 
Starting Materials and/or Intermediates (except the final intermediate) 
 
Test documentation (submitted as amendments to master files and/or in supplements to 
the applications, as appropriate) should include: 
 
  Description of the change with details of the new synthetic procedure, the operating 
conditions, and controls of critical steps and intermediates 
  Appropriate structural characterization data for new intermediates 
  Specifications for any new starting materials and/or intermediates 
  Evaluation of the impurity profile and physical properties.  This evaluation should 
include: 
 
 A report on changes in impurities with a description of analytical procedures 
 Data on three consecutive batches made using material produced by the changed 
process 
 Historical data for comparison 
 A description of the source of the historical data.  
A summary of validation data should be provided for any new analytical procedures and 
also for existing procedures if their use is being extended beyond their original purpose.  
 
If equivalence of the impurity profile is established at any intermediate following the 
change, no testing of the drug substance is necessary. 
 
When a new solvent is introduced as a result of a change in the route of synthesis, the 
possibility of carryover into the drug substance should be assessed.  Tests and acceptance 
criteria should be established as appropriate.  See section IV.A for additional guidance on 
evaluating equivalence when new residual solvents are present in an intermediate or the 
drug substance. 
 
If testing is performed on the drug substance, equivalence should be established for (1) 
the impurity profile and (2) the physical properties, if relevant to the finished dosage 
form performance.  If either the impurity profile or physical properties are not equivalent 
in the drug substance, applicants still wishing to make the change should submit a prior 
approval supplement.  When equivalence is not established, applicants should consider 
conducting an assessment of the effect of the change on the safety and effectiveness of 
the drug product (e.g., qualification of impurities, bioequivalence studies).  The 
additional data that should be submitted will depend on the individual case, and the 
appropriate chemistry teams can be contacted for guidance. 
 
Reporting Category: 
 
  Supplement: Changes Being Effected in 30 Days if equivalence is demonstrated prior 
to the final intermediate. 
  Prior approval supplement if equivalence is demonstrated at the final intermediate or 
drug substance. 
17 of 22   
 
3.  Changes in Which an Intermediate Is Redefined as a Starting Material 
 
This change is often in response to an increase in commercial availability of the proposed 
starting material.  In general, the specification for the proposed starting material should 
be more comprehensive (e.g., additional tests and/or tighter acceptance criteria) than for 
the intermediate.  Redefinition of a final intermediate as a starting material is not covered 
under BACPAC I. 
 
Test documentation (submitted as amendments to master files and/or in supplements to 
the applications, as appropriate) should include: 
 
  Rationale for the proposed change and overview of current synthetic procedure 
  Evidence that the intermediate complies with the current definition and/or expected 
characteristics of a starting material. 
 
  A new or revised specification, a description of new or revised analytical procedures 
for the redefined starting material, and, if appropriate, additional tests and/or 
tightened acceptance criteria for downstream intermediates 
  A list of sources of the redefined starting material 
  A description of how the suitability of a new supplier or revised process from an 
existing supplier will be assessed  
  Evaluation of the impurity profile and physical properties.  This evaluation should 
include: 
 
 A report on changes in impurities with a description of analytical procedures 
 Data on three consecutive batches made using material that justifies the new or 
revised specifications 
 Historical data for comparison 
 A description of the source of the historical data.   
 
A summary of validation data should be provided for any new analytical procedures and 
also for existing procedures if their use is being extended beyond their original purpose.  
 
If equivalence of the impurity profile is established at any intermediate following the 
change, no testing of the drug substance is necessary. 
 
When a new solvent is introduced into the synthetic process, the possibility of carryover 
into the drug substance should be assessed.  Tests and acceptance criteria should be 
established, as appropriate.  See section IV.A for additional guidance on evaluating 
equivalence when new residual solvents are present in an intermediate or the drug 
substance. 
 
If testing is performed on the drug substance, equivalence should be established for (1) 
the impurity profile and (2) the physical properties, if relevant to the finished dosage 
form performance.  If either the impurity profile or physical properties are not equivalent 
18 of 22   
in the drug substance, applicants still wishing to make the change should submit a prior 
approval supplement.  When equivalence is not established, applicants should consider 
conducting an assessment of the effect of the change on the safety and effectiveness of 
the drug product (e.g., qualification of impurities, bioequivalence studies).  The 
additional data that should be submitted will depend on the individual case, and the 
appropriate chemistry teams can be contacted for guidance. 
 
  Certificates of Analysis from the suppliers for the proposed starting material. 
 
Reporting Category: 
 
  Supplement: Changes Being Effected in 30 Days. 
 
D.  Multiple Changes 
 
Multiple changes are those that involve various combinations of the changes described in 
sections V.A, B, and C.  The test documentation should be the sum of the recommendations for 
individual changes and the reporting category should be the most restrictive.  For example, a 
change in the route of synthesis where equivalence is demonstrated at the final intermediate 
(prior approval supplement) and change in the manufacturing site of the final intermediate 
(Supplement: Changes Being Effected) should be submitted as a prior approval supplement, and 
the applicant should provide the listed test documentation for both changes.
19 of 22   
ATTACHMENT A:  BACPAC I DECISION TREE 
 
 
 
 
No
    Change within scope of BACPAC I1? Follow relevant guidances and/or regulations
 
 
  Yes
 
  BACPAC I
 
 
 
 
Yes  Equivalence No
   evaluated at
   intermediate?
 
 
  Equivalent impurity profile  No Equivalent impurity profile 
at any isolated intermediate  No
  and physical properties 
following change
(where relevant)
  including final intermediate?
in drug substance?
 
  Yes Yes
 
 
 
 
  Follow BACPAC I recommendations
  for test/filing documentation Prior Approval Supplement
 
 
1 Site, scale, and equipment changes involving the synthetic steps up to and including the step that produces the final 
intermediate; specification changes for raw materials, starting materials, and intermediates, except the final 
intermediate; manufacturing process changes involving the synthetic steps up to and including the step that produces 
the final intermediate
20 of 22   
ATTACHMENT B:  GLOSSARY  
 
Acceptance Criteria:  Numerical limits, ranges, or other criteria for the test described. 
 
Assess the Effects of the Change:  To evaluate the effects of a manufacturing change on the 
identity, strength, quality, purity, and potency of a drug product as these factors may relate to the 
safety or effectiveness of the drug product. 
 
Batch:  A specific quantity of an intermediate or drug substance intended to have uniform 
character and quality, within specified limits, and produced according to a single manufacturing 
order during the same cycle of manufacture.  A batch can also mean a specific quantity of 
material or drug substance produced in one process or series of processes so that it could be 
expected to be homogeneous (21 CFR 210.3(b)(2)). 
 
Drug Product:  A finished dosage form (e.g., tablet, capsule, or solution) that contains a drug 
substance generally, but not necessarily, in association with one or more other ingredients 
(21 CFR 314.3(b)(4)). 
 
Drug Substance:  An active ingredient that is intended to furnish pharmacological activity or 
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to 
affect the structure or any function of the human body, but does not include intermediates used in 
the synthesis of such ingredient (21 CFR 314.3(b)). 
 
Final Intermediate:  For the purposes of this guidance, the last compound synthesized before 
the reaction that produces the drug substance.  The final step forming the new drug substance 
involves covalent bond formation; ionic bond formation (i.e., making the salt of a compound) 
does not qualify.  Consequently, when the drug substance is a salt, the precursors to the organic 
acid or base, rather than the acid or base itself, should be considered the final intermediate. 
 
Final Solution Step:  The solution from which the drug substance is isolated in pure form by 
either crystallization or precipitation.  Where the purification procedure for the crude drug 
substance involves several crystallization or precipitation steps, final solution step refers only to 
the last of these steps.  
 
Historical Data:  For purposes of this guidance, data on impurities or physical attributes from 
three or more consecutive representative premodification batches.  The upper statistical limit of 
an impurity should be based on the mean plus three times the standard deviation.  A lower 
statistical limit can be similarly defined, where appropriate (e.g., the level of an active 
component, moisture content in a hydrate).   
 
Impurity:  Any component of the drug substance that is not the entity defined as the drug 
substance. 
 
Impurity profile:  A description of the identified and unidentified impurities present in a drug 
substance. 
 
21 of 22   
In Situ Intermediate:  An intermediate that is not isolated.  It is normally, but not necessarily, 
in solution (see the CDER guidance on Submitting Supporting Documentation in Drug 
Applications for the Manufacture of Drug Substances, February 1987).  
 
Intermediate:  A material produced during steps of the synthesis of a drug substance that 
undergoes further molecular change before it becomes a drug substance. 
 
Isolated Intermediate:  An intermediate that is obtained as the product after workup of a 
reaction step in the synthetic scheme for the drug substance.  The isolation or purification 
procedure should be part of the validated process.  An aliquot of a reaction product that is 
worked up and/or purified for purposes of characterization does not constitute an isolated 
intermediate. 
 
Pilot Scale:  The manufacture of a bulk drug substance or intermediate on a reduced scale by 
processes representative of and simulating that to be applied on a larger, production 
manufacturing scale. 
 
Same Manufacturing Site:  Continuous or unbroken site or a set of buildings in adjacent city 
blocks. 
 
Semisynthetic Drug Substance:  A drug substance produced by fermentation or biotechnology 
and synthesis or synthesized from a precursor or structural element of natural origin (e.g., from a 
plant). 
 
Specification:  The quality standard (i.e., tests, analytical procedures, and acceptance criteria) 
provided in the approved application to confirm the quality of drug substances, drug products, 
intermediates, raw material reagents, components, in-process material, container closure 
systems, and other materials used in the production of the drug substance or drug product. 
 
Starting Material:  A material used in the synthesis of a drug substance that is incorporated as 
an important element into the structure of the drug substance.  Starting materials are usually 
available from commercial sources.  See the CDER guidance on Submitting Supporting 
Documentation in Drug Applications for the Manufacture of Drug Substances (February 1987) 
(or current version of the drug substance guidance) for guidance on the factors that should be 
considered when evaluating whether a material can be classified as a starting material.   
 
Total Impurities:  The sum of all impurities observed. 
22 of 22