Q11 Development and Manufacture of 
Drug Substances (Chemical Entities and 
Biotechnological/Biological  Entities) 
Questions and Answers 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
February 2018 
ICH 
 
   
Q11 Development and Manufacture of 
Drug Substances (Chemical Entities and 
Biotechnological/Biological  Entities) 
Questions and Answers 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
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or 
 
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Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm    
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
 
February 2018 
ICH 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION (1)................................................................................................. 1 
II.  SCOPE (2) .................................................................................................................. 2 
III.  MANUFACTURING PROCESS DEVLOPMENT (3) .............................................. 2 
IV.  DESCRIPTION OF THE MANUFACTURING PROCESS AND PROCESS 
CONTROLS (4).......................................................................................................... 2 
V.  SELECTION OF STARTING MATERIALS AND SOURCE MATERIALS (5) ..... 2 
VI.  CONTROL STRATEGY (6) .................................................................................... 12 
VII.  PROCESS VALIDATION/EVALUATION (7) ....................................................... 12 
VIII.  SUBMISSION OF MANUFACTURING PROCESS DEVEOPMENT AND 
RELATED INFORMATION IN THE COMMON TECHNCICAL DOCUMENT 
(CTD) FORMAT (8)................................................................................................. 12 
IX.  LIFECYCLE MANAGEMENT (9) ......................................................................... 12 
X.  ILLUSTRATIVE EXAMPLES (10)......................................................................... 12 
XI.  GLOSSARY (11) ...................................................................................................... 12 
 
  Contains Nonbinding Recommendations 
 
Q11 Development and Manufacture of Drug Substances 
(Chemical Entities and Biotechnological/Biological  Entities) 
Questions and Answers 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this 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 (1)2 
 
Since the ICH guidance Q11 Development and Manufacture of Drug Substances (ICH Q11) was 
finalized,3  worldwide experience with implementation  of the recommendations  on the 
development and manufacture of drug substances has given rise to requests for clarification 
relating to the selection and justification  of starting materials. 
This question-and-answer (Q&A) document is intended to provide additional  clarification  and to 
promote convergence and improve harmonization  of the considerations  for the selection and 
justification  of starting materials and of the information  that should be provided in marketing 
authorization  applications  and/or Master Files.  The focus of the Q&A document is on chemical 
entity drug substances.  
The scope of this Q&A document follows that of ICH Q11.  ICH Q11 is applicable  to drug 
substances as defined in the Scope sections of the ICH Q6A and Q6B guidances, but might also 
be appropriate for other types of products following  consultation  with the appropriate regulatory 
authorities.  ICH Q11 does not apply to contents of submissions  during the clinical  research 
stages of drug development.  Nevertheless, the development principles  presented in ICH Q11 
and this supporting  Q&A document are important to consider during the investigational  stages.   
                                              
1 This guidance was developed within the Expert Working Group (Quality) of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use), and 
has been subject to consultation by the regulatory parties, in accordance with the ICH process.  This document was 
endorsed by the ICH Assembly at Step 4 of the ICH process, August 2017.  At Step 4 of the process, the final draft 
is recommended for adoption to the regulatory bodies of the ICH regions. 
2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Assembly at Step 4 of 
the ICH process, August 2017. 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  1  Contains Nonbinding Recommendations 
 
Generally,  it is anticipated that active pharmaceutical ingredient  (API) starting materials that 
have already been accepted by regulatory authorities (e.g., for use in authorized medicinal 
products) would not need to be rejustified  against the ICH Q11 general principles  or the 
recommendations included  in this Q&A document, unless significant  changes are made to the 
manufacturing processes and controls.  However, a starting material accepted for one 
manufacturers process may not be considered acceptable for a different manufacturers process, 
if the proposal does not comply with the ICH Q11 guidance.   
Applicant is used throughout  the Q&A document and should be interpreted broadly to refer to 
the marketing authorization  holder, the filing  applicant, the drug product manufacturer, and/or 
the drug substance manufacturer.  Designation of starting materials should be based on process 
knowledge of the intended commercial process.  A decision tree is available in Annex 1 to serve 
as a pictorial exemplification  to apply all ICH Q11 general principles for the selection and 
justification  of a starting material.   
 
In general, FDAs guidance documents 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.   
 
 
II.  SCOPE (2) 
 
There was no Q&A drafted on this section. 
 
 
III.  MANUFACTURING PROCESS DEVLOPMENT (3) 
 
There was no Q&A drafted on this section. 
 
 
IV.  DESCRIPTION OF THE MANUFACTURING PROCESS AND PROCESS 
CONTROLS (4) 
 
There was no Q&A drafted on this section. 
 
 
V.  SELECTION OF STARTING MATERIALS AND SOURCE MATERIALS (5) 
 
Q1.  Should all the general principles in section 5 of ICH Q11 be considered and met in 
selecting and justifying starting materials?  (5.1) 
 
Applicants should consider all the ICH Q11 general principles  in the selection and justification 
of proposed starting materials, together with the clarifications  in this Q&A document, rather than 
choosing just a few of the general principles  and using them to justify starting material selection.  
  2  Contains Nonbinding Recommendations 
 
If a proposed starting material does not meet all of the general principles,  a rationale should be 
provided explaining  why the starting material is considered appropriate. 
 
Q2.  Is a starting material as described in ICH Q11 the same as an API starting 
material as described in ICH Q7?  (5.2) 
 
Yes.  ICH Q11 states that the GMP provisions  described in ICH Q7 apply to each branch of the 
drug substance manufacturing  process beginning  with the first use of a starting material.  ICH 
Q7 states that appropriate GMP (as defined in that guidances) should be applied to the 
manufacturing steps immediately  after API starting materials are entered into the process (see 
ICH Q7 Q&A 1.1).  Because ICH Q11 sets the applicability  of ICH Q7 as beginning  with the 
starting material, and ICH Q7 sets the applicability  of ICH Q7 as beginning  with the API 
starting material, these two terms are intended to refer to the same material.   
 
ICH Q7 states that an API starting material is a raw material, intermediate, or an API that is 
used in the production of an API.  ICH Q7 provides guidance regarding good manufacturing 
practices for the drug substance, but does not provide specific guidance on the selection and 
justification  of starting materials.  When a chemical, including  one that is also an API, is 
proposed to be a starting material, all ICH Q11 general principles  still need to be considered.   
 
Q3.  Do the ICH Q11 general principles for selection of starting materials apply to the 
selection of starting materials for linear and convergent syntheses?  (5.3)   
 
Yes.  The ICH Q11 general principles  apply to the selection of starting materials for linear or 
convergent syntheses.  The ICH Q11 general principles  should be applied independently  to each 
branch of a convergent synthesis, unless the point of convergence of the branches occurs 
upstream of an appropriate starting material.   
 
Q4.  Do the ICH Q11 general principles for selection of starting materials apply to 
processes where multiple chemical transformations are run without isolation of 
intermediates?  (5.4)   
 
Yes.  The ICH Q11 general principles  apply to processes where multiple  chemical 
transformations are run without isolation  of intermediates.  In the absence of such isolations 
(e.g., crystallization,  precipitations),  design of the manufacturing process (e.g., kinetics) and/or 
unit operations (e.g., extraction, distillation,  the use of scavenging agents) should be in place to 
adequately control and/or purge impurities  and be described in the application.   The ICH Q11 
general principles  also apply to sequential chemical transformations run continuously.   Non-
isolated intermediates are generally not considered appropriate starting materials. 
 
Q5.  ICH Q11 states A starting material is incorporated as a significant structural 
fragment into the structure of the drug substance.  Why then are intermediates 
used late in the synthesis, which clearly contain significant structural fragments, 
often not acceptable as starting materials?  (5.5) 
 
  3  Contains Nonbinding Recommendations 
 
The selection principle  about significant  structural fragment has frequently been misinterpreted 
as meaning that the proposed starting material should be structurally similar to the drug 
substance.  However, as stated in ICH Q11, this general principle  is intended to help distinguish 
starting materials from reagents, catalysts, solvents, or other raw materials.  
 
The term significant  structural fragment is not intended to dictate the selection of either a very 
early or a very late intermediate as the starting material.  A proposed starting material may be 
defined downstream from a commercially  available chemical, provided that there are multiple 
chemical transformation steps between the proposed starting material and the drug substance, 
and provided the justification  addresses the ICH Q11 general principles.   The presence of a 
significant  structural fragment should not be the sole basis for starting material selection.  
Starting materials justified  solely on the basis that they are a significant  structural fragment 
probably will not be accepted by regulatory authorities,  as the other general principles  for the 
appropriate selection of a proposed starting material should also be considered.   
 
Q6.  What is the difference between a commercially available chemical and a custom 
synthesized chemical?  (5.6) 
 
ICH Q11 states that a commercially  available chemical is usually one that is sold as a 
commodity  in a pre-existing,  non-pharmaceutical  market in addition  to its proposed use as 
starting material.  A definition  of custom synthesized chemical was not provided in ICH Q11, 
but a custom synthesized chemical is generally understood to be one that is made specifically  to 
a drug substance manufacturers requirement, either in-house or externally, or available for 
purchase but where the only use is for pharmaceutical manufacture.  The reference to non-
pharmaceutical market in the ICH Q11 description of commercially  available chemicals is 
intended to preclude purchased intermediates from being claimed as commercially  available 
chemicals.   
 
ICH Q11 makes an important distinction  between commercially  available chemicals and custom 
synthesized chemicals.  An applicant generally need not justify the use of a commercially 
available chemical as a starting material, whereas a custom synthesized chemical proposed as a 
starting material should be justified  in accordance with the ICH Q11 general principles.    
 
The availability  of a chemical from multiple  suppliers should not be the sole basis for the 
designation  of a chemical as a commercially  available starting material.  This includes situations 
where a custom synthesized chemical has become available over time from multiple  suppliers.   
Such chemicals should still be justified  according to the ICH Q11 general principles  for selection 
of starting materials.  It can be acceptable for a starting material that is demonstrated to be a 
commercially  available chemical to enter late in the synthesis, e.g., in the last chemical 
transformation prior to the drug substance.  
 
A chemical manufactured on a small scale can be suitable as a commercially  available starting 
material, provided that the scale is sufficient for the manufacture of the drug substance and that 
the chemical is also used in a pre-existing,  non-pharmaceutical  market.   
 
  4  Contains Nonbinding Recommendations 
 
In some cases, a chemical that does not meet the definition  of a commercially  available chemical 
(e.g., it does not have a non-pharmaceutical  use) but is simple enough in structure may be 
accepted as a starting material (e.g., protected natural amino acids).  However, in such cases, a 
rationale should be provided explaining  why the starting material is considered appropriate (see 
Q&A 5.1) and why the proposed control strategy is appropriate to control impurities  in the drug 
substance.   
 
Q7.  Q11 recommends that manufacturing steps that impact the impurity profile of the 
drug substance should normally be included in the manufacturing process described 
in section 3.2.S.2.2 of the application.  At what level would a related substance or 
mutagenic impurity be considered to impact the impurity profile of the drug 
substance?  (5.7) 
 
For non-mutagenic related substances, the ICH Q3A identification  threshold serves to identify 
the level above which a related substance is considered to have an impact on the impurity  profile 
of the drug substance.  A related substance with an acceptance criterion above the ICH Q3A 
identification  threshold is considered to impact the drug substance impurity  profile.   
 
For mutagenic impurities,  the 30 percent threshold of the ICH M7 acceptable limit  serves to 
identify the level above which a mutagenic impurity  is considered to have an impact on the 
impurity  profile of the drug substance.  In this situation,  the control strategy will generally 
include a test for the impurity  at the acceptable limit  (see section 8 of ICH M7).  Any of the 
approaches described in section 8 of ICH M7 can be used to determine which impurities  are 
likely  to be present in the drug substance above the 30 percent threshold.   
 
In line with ICH M7 and ICH S9, there are situations (e.g., when the drug substance is itself 
genotoxic,  and other circumstances as described in these guidances) when the selection of the 
starting material for a drug substance does not need to specifically  consider the mutagenic 
impurity  profile at the levels described above.  In such cases, mutagenic impurities  are not 
considered to impact the impurity  profile of the drug substance unless they are above the ICH 
Q3A identification  threshold.  Impurities that persist through multiple  steps of the manufacturing 
process should be considered in conjunction  with Q&A 5.8. 
 
Q8.  What is meant by impurities that persist in ICH Q11 Example 4?  (5.8) 
 
ICH Q11 recommends that manufacturing  steps that impact the impurity  profile of the drug 
substance should normally  be included in the manufacturing process described in section 
3.2.S.2.2 of the application.   However, as described in ICH Q11 Example 4, this principle  does 
not necessarily apply when impurities  originate early and persist across multiple  steps to the 
drug substance.  It is normally  expected that the justification  for an impurity  that persists will be 
based on it being carried across one or more manufacturing steps upstream of the proposed 
starting material, when these steps do not otherwise impact the impurity  profile of the drug 
substance (for impact, see Q&A 5.7). 
 
In Example 4, an impurity  in Compound B impacts the impurity  profile of the drug substance.  
Steps 2 and 3 (from Compound B to Compound D) do not introduce other impurities  that impact 
  5  Contains Nonbinding Recommendations 
 
the drug substance impurity  profile.  If impurities  generated in Steps 2 or 3 do impact the drug 
substance impurity  profile,  these steps should also be considered for inclusion  in 3.2.S.2.2 of the 
application.    
 
Impurities that persist may or may not react in subsequent steps, but are not removed to the 
extent that they would no longer be considered to impact the drug substance impurity  profile.  
For example, an impurity  that persists might have physico-chemical  properties (e.g., solubility) 
similar to other intermediates or the drug substance, like the enantiomer in Example 4, which 
could make its removal intrinsically  difficult.   
 
ICH Q11 Example 4 illustrates  that when the synthetic route contains an impurity  that persists, it 
can be acceptable to control the impurity  in the starting material specification even though it 
impacts the impurity  profile of the drug substance.  Therefore, it is not always necessary to 
include steps that form such an impurity  in section 3.2.S.2.2, provided that the other ICH Q11 
general principles  are addressed (ICH Q11 section 5.1.1). Example 4 is not exclusive to 
stereoisomers and can be applied to other types of impurities  that persist.   
 
In Example 4, there are 3 chemical transformation steps between the starting material D and the 
drug substance.  The 3 steps in Example 4 are not intended to imply  that 3 chemical 
transformation steps are considered enough (see Q&A 5.11) in all cases, nor that 3 chemical 
transformation steps are mandatory.  
 
In the case of Example 4, application  of the ICH Q11 principles  includes control of the 
enantiomer in the specification of the proposed starting material D, in combination  with the 
understanding  that the steps immediately  prior to D do not introduce other impurities  that impact 
the impurity  profile of the drug substance.  The applicant should provide information  in the 
application  on the upstream process to justify the proposed starting material including  control 
strategy of the impurity  that persists. 
 
In Example 4, there are 3 chemical transformation steps between the starting material D and the 
drug substance.  The 3 steps in Example 4 are not intended to imply  that 3 chemical 
transformation steps are considered enough (see Q&A 5.11) in all cases, nor that 3 chemical 
transformation steps are mandatory.  
 
In the case of Example 4, application  of the ICH Q11 principles  includes control of the 
enantiomer in the specification of the proposed starting material D, in combination  with the 
understanding  that the steps immediately  prior to D do not introduce other impurities  that impact 
the impurity  profile of the drug substance.  The applicant should provide information  in the 
application  on the upstream process to justify the proposed starting material including  control 
strategy of the impurity  that persists. 
 
Q9.  What should an applicant consider when determining which manufacturing  steps 
impact the mutagenic impurity profile of the drug substance, as part of the selection 
and justification of starting materials?  (5.9)   
 
  6  Contains Nonbinding Recommendations 
 
As part of determining  which manufacturing  steps impact the impurity  profile of the drug 
substance, the applicant should identify  mutagenic materials that are likely  to be formed or are 
introduced in the manufacturing  process.  The applicant should also determine which steps 
contribute mutagenic impurities  to the drug substance at a level considered to impact the 
impurity  profile (see Q&A 5.7).  The Hazard Assessment Elements from ICH M7 can be used to 
determine which of the actual and potential  impurities  are considered to be mutagenic.   
 
For the selection and justification  of starting materials, the following  approaches are 
recommended:  
 
  Impurities that have been identified  in the drug substance (actual impurities)  should be 
assessed for mutagenicity.   
 
  Reagents and intermediates used in the synthesis from commercially  available chemicals 
to the drug substance should be assessed for mutagenicity  if they are likely  to impact the 
impurity  profile of the drug substance.  Note that this may include assessment of the 
mutagenicity  of some reagents and intermediates used in steps before the starting material 
that is eventually proposed.  
 
  Mutagenic substances that are impurities  in commercially  available chemicals or 
synthetic intermediates, or that are formed as the result of side reactions during the 
synthesis, could also be present in the drug substance at levels relevant to safety.  
However, such mutagenic impurities  and by-products are usually present at much lower 
concentrations than reagents, solvents, and intermediates.   Therefore, the risk that such 
impurities  will carry over significantly  into the drug substance from early reaction steps 
is lower than for reagents, solvents, or intermediates from the same steps.  The applicant 
should use risk-based reasoning to determine which steps to include in the hazard 
assessment for this category of potential impurity,  and include a discussion of the risk 
assessment when identifying  the point in the synthesis where these impurities  and by-
products are included  in the assessment. 
 
Information collected during the evaluation of potential mutagenic impurities  can be submitted in 
an application  and could be valuable for multiple  purposes.  For example, the justification  for a 
proposed starting material should include information  demonstrating that none of the steps 
immediately  upstream (i.e., earlier in the synthesis) of the proposed starting material impact the 
impurity  profile of the drug substance.  Also, the suitability  of the proposed control strategy can 
be supported with information  about any mutagenic impurities  formed or purged in the 
manufacturing steps between the proposed starting material and the drug substance, or that are 
controlled  in the specification of the proposed starting material.  The ICH Q11 exception for 
impurities  that persist is also applicable to mutagenic impurities  (see Q&A 5.8).  In addition, 
steps involving  mutagenic reagents or impurities  may be upstream of the starting material if they 
do not impact the impurity  profile of the drug substance (see Q&A 5.10). 
 
The approaches outlined  in this Q&A are consistent with the principles  in ICH M7 concerning 
hazard assessment, risk characterization of mutagenic impurities,  and their control.  However, 
ICH M7 does not provide specific guidance on how mutagenic impurity  assessment can be used 
  7  Contains Nonbinding Recommendations 
 
to justify  selection of appropriate starting materials.  This Q&A addresses the application  of the 
principles  in ICH M7 to the selection and justification  of starting materials, based on the ICH 
Q11 concept of impact to the impurity  profile of the drug substance.   
 
This Q&A is not intended for the types of drug substances and indications  for which ICH M7 
does not apply (e.g., genotoxic drug substances, advanced cancer indications  per ICH S9).   
 
Q10.  Do all steps that involve mutagenic reagents, impurities, or establish regio- or 
stereochemical configurations, need to be included in the process description in 
section 3.2.S.2.2 of the application?  (5.10)   
 
No.  The ICH Q11 general principles  for selection of starting materials do not include a 
recommendation  that all steps involving  mutagenic reagents or impurities  should be included in 
the process description in section 3.2.S.2.2.  Similarly,  the general principles  do not include a 
recommendation  that all steps that establish regio- or stereochemical configurations  (which can 
therefore result in regio- or stereoisomerism) should be included in section 3.2.S.2.2.  However, 
it is expected that the other ICH Q11 general principles  on impurities  (see Q&As 5.7, 5.8 and 
5.9) and inclusion  of enough of the manufacturing process (see Q&A 5.11) be applied when 
deciding whether steps that involve  mutagenic reagents, impurities,  or establish regio- or 
stereochemical configurations,  need to be included.  As an example, a mutagenic compound 
could be introduced prior to the starting material, or be the starting material itself, provided the 
ICH Q11 general principles  are addressed. 
 
Q11.  ICH Q11 states that enough of the drug substance manufacturing process should 
be described in the application . . ..  What considerations should an applicant apply 
in the selection of the proposed starting materials to assure that enough of the drug 
substance manufacturing process will be described in the process description in 
section 3.2.S.2.2 of the application?  (5.11)   
 
In deciding  whether enough of the drug substance manufacturing process is described in section 
3.2.S.2.2 of the application,  the following  considerations should be applied.   
 
The applicant should first evaluate which chemical transformation  steps in the manufacturing 
process impact the impurity  profile of the drug substance.  These steps should normally  be 
included in section 3.2.S.2.2 (see Q&As 5.7, 5.8 and 5.9).   
 
Next, the applicant should examine the steps immediately  upstream of those steps that impact the 
impurity  profile of the drug substance.  These steps should normally  also be included in section 
3.2.S.2.2 if:  
 
  They need to be carefully controlled  (e.g., within narrow parameter ranges) to prevent 
generation of impurities  that would otherwise impact the impurity  profile of the drug 
substance.   
 
  They include a unit operation that has been added to the manufacturing  process to control 
specific impurities  that would otherwise impact the impurity  profile of the drug 
  8  Contains Nonbinding Recommendations 
 
substance.  While starting material manufacturing processes typically  contain purification 
operations, addition  of purification  steps prior to a proposed starting material in order to 
avoid defining  an earlier, upstream compound as the starting material would not be 
considered appropriate.   
 
After these considerations,  if the evaluation would result in only a small number of chemical 
transformation steps, then it is generally appropriate to include one or more additional  chemical 
transformation steps in section 3.2.S.2.2.  This is to ensure that enough steps are conducted under 
GMP to appropriately mitigate risks associated with contamination  and future changes to the 
synthetic route or supplier of the starting material.  The following  paragraphs provide further 
clarification  on this risk mitigation  and should be considered together.   
 
  Although ICH Q11 does not specify how many steps should be performed under GMP, 
ICH Q11 recommends the inclusion  of multiple  chemical transformation steps in 
section 3.2.S.2.2 in order to reduce the risk of contamination  and support the effective 
implementation  of the control strategy throughout the product lifecycle.  When there 
would be a small number of steps, there is an increased risk of contamination  that needs 
to be addressed by the applicant in their starting material justification,  and will often be 
best mitigated by including  one or more additional  steps in section 3.2.S.2.2.   
 
  Potential risks from future changes to the starting material synthesis should also be 
considered (see Q&A 5.16).  There is an increased risk that impurities  generated as a 
result of a change to the manufacturing  process upstream of the starting material may not 
be detected or purged appropriately  if the starting material is only a small number of 
steps from the drug substance.  In order to determine how many additional  steps to 
include,  the applicant may also consider other approaches to risk mitigation;  for example, 
inclusion  of analytical methodologies  in the specification of the proposed starting 
material that are designed to detect a wide range of possible impurities  based on different 
physical and chemical separation and detection principles.   Appropriate acceptance 
criteria for unspecified impurities  should be included in the specification.    
 
The applicant should include in their justification  of the proposed starting material a 
comprehensive description as to what factors were considered in deciding  whether enough of the 
drug substance manufacturing  process is provided in section 3.2.S.2.2 of the application  to 
ensure that risks are appropriately  mitigated.   
 
Q12.  What considerations are important for a starting material specification?  (5.12)   
 
Applicants should provide and justify  a specification (which includes a list of tests, references to 
analytical procedures, and appropriate acceptance criteria) for all proposed starting materials as 
part of the drug substance control strategy.   
 
The specification of a starting material should include tests for identity  and purity (e.g., controls 
on impurities)  and, where applicable,  could include acceptance criteria for assay, specified, 
unspecified and total impurities,  residual solvents, reagents, elemental impurities  and mutagenic 
impurities.   The analytical procedures used should be suitably validated.  The tests and 
  9  Contains Nonbinding Recommendations 
 
acceptance criteria should be based on process knowledge and the drug substance control 
strategy.  The justification  of the specification should include an evaluation  of the risks and the 
ability  of the subsequent steps to adequately control and/or purge impurities.    
 
Q13.  For starting materials that are not commercially available chemicals, what 
information should be provided on the synthetic route?  (5.13)   
 
Information on how the proposed starting material is made (e.g., a flow chart of the starting 
material manufacturing process, showing all reagents, catalysts and solvents used) should be 
provided to help justify the controls applied to the starting material.  Information about the actual 
and potential  impurities  in the proposed starting material should be provided.   
 
Q14.  What information should be included in the application about a starting material 
that is a commercially available chemical?  (5.14)   
 
An applicant generally need not justify the use of a commercially  available chemical as a starting 
material (see ICH Q11 section 5.2.1).  However, the applicant should provide basic information 
on the starting material (chemical name, chemical formula, and molecular weight), information 
on the impurity  profile of the starting material,  and how the control strategy for the drug 
substance manufacturing process justifies the starting material specification.   
 
If the drug substance manufacturer needs to perform additional  purification  steps to ensure the 
consistent quality of a commercially  available starting material, ICH Q11 also recommends that 
these steps should be included in section 3.2.S.2.2 as part of the drug substance manufacturing 
process.   
 
The applicant should set appropriate controls and should justify the proposed specification  for 
the actual and potential impurities  that are reasonably expected in a proposed starting material, 
based on the scientific knowledge and available information.    
 
ICH M7 states: For starting materials that are introduced late in the synthesis of the drug 
substance (and where the synthetic route of the starting material is known) the final steps of the 
starting material synthesis should be evaluated for potential mutagenic impurities.   In the case 
where the starting material is a commercially  available chemical, then this evaluation would be 
used to determine the appropriate control strategy.   
 
For all starting materials, applicants should set appropriate controls and be able to justify the 
proposed specifications.   
 
Q15.  Can the Lifecycle Management section of ICH Q11 (section 9) apply to starting 
materials?  (5.15)   
 
Yes.  In addition  to what is submitted in the application,  changes upstream of the defined starting 
material should be managed under the applicant's Pharmaceutical Quality System (PQS), which 
should address residual risks to the drug substance quality.   
 
  10  Contains Nonbinding Recommendations 
 
The Lifecycle Management section of ICH Q11 reinforces managements responsibility 
described in Pharmaceutical Quality Systems (ICH Q10), which is applicable  to starting material 
lifecycle management.  ICH Q10 section 2.7 (Management of Outsourced Activities and 
Purchased Materials) recommends that  
 
The pharmaceutical quality system, including the management responsibilities described 
in this section, extends to the control and review of any outsourced activities and quality 
of purchased materials.  The pharmaceutical company is ultimately responsible to ensure 
processes are in place to assure the control of outsourced activities and quality of 
purchased materials.   
 
ICH Q7 sections 7 (Materials Management) and 13 (Change Control), ICH Q7 Q&A document 
sections 7 and 13, as well as ICH Q10 section 2.7 (Management of Outsourced Activities and 
Purchased Materials) provide guidance that can be applied to the management of starting 
materials and starting material suppliers.   
 
ICH Q9 and its Annexes provide guidance on the use of principles for quality risk management 
which can be applied to changes related to the starting materials (e.g., new starting material 
suppliers,  manufacturing processes, or specifications).   
 
Q16.  Does ICH Q11 include specific guidance for post-approval changes to steps 
upstream of the starting material (e.g., changes in synthetic route, reagents, 
solvents, starting material supplier)?  (5.16)   
 
No.  Post-approval changes to steps upstream of starting materials are not explicitly  covered in 
ICH Q11.  However, ICH Q11 does describe fundamental science and risk-based concepts that 
should be used to evaluate the impact of post-approval changes to the process after the starting 
material (ICH Q11 section 9  Lifecycle Management), and these same concepts should be 
applied to evaluate the impact of changes upstream of the starting material.   
 
For example, changes upstream of the starting material should be evaluated for their impact on 
the starting material (e.g., on current and potential new impurities,  including  potentially 
mutagenic and elemental impurities)  and, when appropriate, on the drug substance.  The 
evaluation could be based on risk assessment and scientific understanding of the proposed 
change and its proximity  to the starting material.  The evaluation should include an assessment of 
the control strategy (e.g., adequacy of the specification  for the starting material, including  the 
ability  of the analytical procedures to detect any new impurities).    
 
As stated in ICH Q7 Q&A document section 13.1, each party in the supply chain is responsible 
for transferring information  related to quality  or regulatory changes to the next customer in the 
supply chain so that the information  is transferred to the drug product manufacturer in a timely 
manner.   
 
Post-approval changes to information  on the starting material should be reported to regulatory 
authorities in accordance with regional regulations and guidances.   
 
 
  11  Contains Nonbinding Recommendations 
 
VI.  CONTROL STRATEGY (6)   
 
There was no Q&A drafted on this section.   
 
 
VII.  PROCESS VALIDATION/EVALUATION (7)   
 
There was no Q&A drafted on this section.   
 
 
VIII.  SUBMISSION OF MANUFACTURING PROCESS DEVEOPMENT AND 
RELATED INFORMATION IN THE COMMON TECHNCICAL DOCUMENT 
(CTD) FORMAT (8)   
 
There was no Q&A drafted on this section.   
 
 
IX.  LIFECYCLE MANAGEMENT (9)   
 
There was no Q&A drafted on this section.   
 
 
X.  ILLUSTRATIVE EXAMPLES (10)   
 
There was no Q&A drafted on this section.   
 
 
XI.  GLOSSARY (11)   
 
There was no Q&A drafted on this section.   
 
 
   
  12  Contains Nonbinding Recommendations 
 
 
  13  Contains Nonbinding Recommendations 
 
 
  14