Guidance for Industry 

 
Q11 Development and 

Manufacture of Drug 

Substances 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 

 
November 2012 

ICH 

   
Guidance for Industry 

 
Q11 Development and 

Manufacture of Drug 

Substances 

 
 
Additional copies are available from: 

 
Office of Communications 
 
Division of  Drug Information, WO51, Room  2201 
 
Center for Drug Evaluation  and Research  

Food and  Drug Administration 

10903 New Hampshire Ave., Silver Spring, MD 20993-0002 
  
Phone: 301-796-3400;  Fax: 301-847-8714 
 
druginfo@fda.hhs.gov 
  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
 
and/or 

 
 Office of Communication, Outreach  and  

Development, HFM-40 
 
Center for Biologics Evaluation and Research 

 Food and Drug  Administration 

1401 Rockville Pike, Rockville, MD  20852-1448  

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
ocod@fda.hhs.gov
    
(Tel)  800-835-4709 or 301-827-1800 
 
 
 
 
 
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) 

 
November 2012 

ICH 

     
Contains Nonbinding Recommendations  
 
 
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION (1)....................................................................................................... 1 
 
II.   SCOPE (2).......................................................................................................................... 2 
 
III.   MANUFACTURING PROCESS DEVELOPMENT (3) .............................................. 2 
 
A.   General Principles (3.1).................................................................................................................2
  
1.  Drug Substance Quality Link to Drug Product (3.1.1)....................................................................2
  
2.  Process Development Tools (3.1.2).................................................................................................3
  
3.  Approaches to Development (3.1.3).................................................................................................3
  
4.  Drug Substance Critical Quality Attributes (3.1.4).........................................................................4 
 
5.  Linking Material Attributes and Process Parameters to Drug Substance CQAs (3.1.5).................5
  
6.  Design Space (3.1.6)........................................................................................................................6
  
B.   Submission of Manufacturing Process Development Information (3.2)...................................7
  
1.  Overall Process Development Summary (3.2.1)..............................................................................7
  
2.  Drug Substance CQAs (3.2.2)..........................................................................................................8
  
3.  Manufacturing Process History (3.2.3)...........................................................................................8
  
4.  Manufacturing Development Studies (3.2.4) ...................................................................................8 
 
IV. 	  DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS 

CONTROLS (4) ................................................................................................................ 9 
 
V. 	  SELECTION OF STARTING MATERIALS AND SOURCE MATERIALS (5) ..... 9 
 
A.   General Principles (5.1).................................................................................................................9
  
1.  Selection of Starting Materials for Synthetic Drug Substances (5.1.1) ...........................................9
  
2.  Selection of Starting Materials for Semi-synthetic Drug Substances (5.1.2).................................11 
 
3.  Selection of Source and Starting Materials for Biotechnological/Biological Drug Substances 

(5.1.3).............................................................................................................................................11
  
B.   Submission of Information for Starting Material or Source Materials (5.2) .........................11
  
1.  Justification of Starting Material Selection for Synthetic Drug Substances (5.2.1)......................11 
 
2.  Justification of Starting Material Selection for Semi-synthetic Drug Substances (5.2.2)..............12
  
3.  Qualification of Source or Starting Materials for Biotechnological/Biological Drug Substances
  
(5.2.3).............................................................................................................................................13
  
VI.   CONTROL STRATEGY (6).......................................................................................... 13 
 
A.   General Principles (6.1)...............................................................................................................13
  
1.  Approaches to Developing a Control Strategy (6.1.l) ...................................................................13 
 
2.  Consideration in Developing a Control Strategy (6.1.2)...............................................................14 
 
B.   Submission of Control Strategy Information (6.2) ...................................................................14
  
VII.   PROCESS VALIDATION/EVALUATION (7) ........................................................... 15 
 
A.   General Principles (7.1)...............................................................................................................15
  
B.   Principles Specific to Biotechnological/Biological Drug Substance (7.2)................................15
  
VIII.   SUBMISSION OF MANUFACTURING PROCESS DEVELOPMENT AND 

RELATED INFORMATION IN CTD FORMAT (8) ................................................. 16 
 
   
Contains Nonbinding Recommendations  
 
A. 	  Quality Risk Management and Process Development (8.1).....................................................16
  
B. 	  Critical Quality Attributes (CQAs) (8.2) ...................................................................................17 
 
C. 	  Design Space (8.3) ........................................................................................................................17 
 
D.  	 Control Strategy (8.4)..................................................................................................................17
  
IX.   LIFECYCLE MANAGEMENT (9) .............................................................................. 17 
 
X.   ILLUSTRATIVE EXAMPLES (10) ............................................................................. 18 
 
A. 	  Example 1: Linking Material Attributes and Process Parameters to Drug Substance CQAs 
 Chemical Entity (10.1)..............................................................................................................19
  
B. 	  Example 2:  Use of Quality Risk Management to Support Lifecycle Management of Process 

Parameters (10.2).........................................................................................................................22
  
C. 	  Example 3: Presentation of a Design Space for a Biotechnological Drug Substance Unit
  
Operation (10.3)...........................................................................................................................24
  
D. 	  Example 4: Selecting an Appropriate Starting Material (10.4)..............................................26 
 
E. 	  Example 5: Summary of Control Elements for Select CQAs (10.5).......................................27 
 
XI.   GLOSSARY (11)............................................................................................................. 32
  
 
   
Contains Nonbinding Recommendations  
 
1
 
Guidance for Industry  
 
Q11 Development and Manufacture of Drug Substances 

 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 (1)2  
 
This guidance describes approaches to developing and understanding the manufacturing process 
of the drug substance, and also provides guidance on what information should be provided in 
Module 3 of the Common Technical Document (CTD) sections 3.2.S.2.2  3.2.S.2.6 (see the 
ICH guidance M4Q: The CTD  Quality3 (ICH M4Q)). It addresses aspects of development and 
manufacture that pertain to drug substance, including the presence of steps designed to reduce 
impurities.  In addition, this guidance provides further clarification on the principles and 
concepts described in the ICH guidances, Q8 Pharmaceutical Development (ICH Q8), Q9 
Quality Risk Management (ICH Q9), and Q10 Pharmaceutical Quality System (ICH Q10), as 
they pertain to the development and manufacture of drug substance. 
 
A company can choose to follow different approaches in developing a drug substance.  For the 
purpose of this guidance, the terms traditional and enhanced are used to differentiate two 
possible approaches.  In a traditional approach, set points and operating ranges for process 
parameters are defined and the drug substance control strategy is typically based on 
demonstration of process reproducibility and testing to meet established acceptance criteria.  In 
                                                 
1  This guidance  was developed within  the Q11  Expert Working Group  of the International  Conference on  
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been  
subject to consultation by the  regulatory  parties, in accordance with the ICH process.  This document has been  
endorsed by the ICH Steering Committee at Step 4  of the ICH process, April 2012.  At  Step 4 of the process, the  
final draft is recommended for adoption to the regulatory bodies of the European  Union, Japan, and the United  
States. 
2 Arabic numbers reflect the organizational breakdown of the document endorsed  by the ICH Steering Committee at 
Step 4 of  the ICH process, April 2012. 
 
3 The guidances referenced in this document are available on the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update 
guidances  periodically.  To make sure you  have the most recent version of a guidance, check the FDA Drugs 
guidance Web page  or  CBER guidance Web page  at  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm. 
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Contains Nonbinding Recommendations  
 
an enhanced approach, risk management and scientific knowledge are used more extensively to 
identify and understand process parameters and unit operations that have an impact on critical 
quality attributes (CQAs) and develop appropriate control strategies applicable over the lifecycle 
of the drug substance, which might include the establishment of design space(s). As discussed in 
ICH Q8 for drug product, a greater understanding of the drug substance and its manufacturing 
process can create the basis for more flexible regulatory approaches. The degree of regulatory 
flexibility is generally predicated on the level of relevant scientific knowledge provided in the 
application for marketing authorization.  
 
Traditional and enhanced approaches are not mutually exclusive. A company can use either a 
traditional approach or an enhanced approach to drug substance development, or a combination 
of both. 
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
II.  SCOPE (2) 
 
This guidance is applicable to drug substances as defined in the Scope sections of the ICH 
guidances, Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug 
Substances and New Drug Products: Chemical Substances (ICH Q6A) 
and Q6B Specifications: Test Procedures and Acceptance Criteria for 
Biotechnological/Biological Products (ICH Q6B), but might also be appropriate for other types 
of products following consultation with the appropriate regulatory authorities.  It is particularly 
relevant to the preparation and organization of the contents of sections 3.2.S.2.2  3.2.S.2.6 of 
Module 3 of the Common Technical Document (ICH M4Q).  The guidance does not apply to 
contents of submissions during the clinical research stages of drug development.  Nevertheless, 
the development principles presented in this guidance are important to consider during the 
investigational stages. 
 
Regional requirements for postapproval changes are not covered by this guidance. 
 
III.  MANUFACTURING PROCESS DEVELOPMENT (3) 
 
A.   General Principles (3.1) 
 
The goal of manufacturing process development for the drug substance is to establish a 
commercial manufacturing process capable of consistently producing drug substance of the 
intended quality. 
 
1.   Drug Substance Quality Link to Drug Product (3.1.1)  
 
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Contains Nonbinding Recommendations  
 
The intended quality of the drug substance should be determined through consideration of its use 
in the drug product as well as from knowledge and understanding of its physical, chemical, 
biological, and microbiological properties or characteristics, which can influence the 
development of the drug product (e.g., the solubility of the drug substance can affect the choice 
of dosage form).  The Quality Target Product Profile (QTPP), potential CQAs of the drug 
product (as defined in ICH Q8) and previous experience from related products can help identify 
potential CQAs of the drug substance.  Knowledge and understanding of the CQAs can evolve 
during the course of development. 
 
2.  Process Development Tools (3.1.2)  
 
Quality Risk Management (QRM, as described in ICH Q9) can be used in a variety of activities, 
including assessing options for the design of the manufacturing process, assessing quality 
attributes and manufacturing process parameters, and increasing the assurance of routinely 
producing batches of the intended quality. Risk assessments can be carried out early in the 
development process and repeated as greater knowledge and understanding become available. 
Either formal or informal risk management tools, such as recognized tools or internal procedures, 
can be used. 
 
Knowledge management (as described in ICH Q10) can also facilitate manufacturing process 
development.  In this context, potential sources of information can include prior knowledge and 
development studies.  Prior knowledge can include established biological, chemical, and 
engineering principles; technical literature; and applied manufacturing experience.  Data derived 
from relevant prior knowledge, including platform manufacturing (see glossary), can be 
leveraged to support development of the commercial process and expedite scientific 
understanding. 
 
3.  Approaches to Development (3.1.3)  
 
ICH Q8 recognizes that Strategies for product development vary from company to company 
and from product to product.  The approach to, and extent of, development can also vary and 
should be outlined in the submission.  These concepts apply equally to the development of the 
drug substance manufacturing process.  An applicant can choose either a traditional approach or 
an enhanced approach to drug substance development, or a combination of both.  
 
Manufacturing process development should include, at a minimum, the following elements: 
  
	   Identifying potential CQAs associated with the drug substance so that those 
characteristics having an impact on drug product quality can be studied and controlled 
 
	   Defining an appropriate manufacturing process 
 
	   Defining a control strategy to ensure process performance and drug substance quality 
 
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Contains Nonbinding Recommendations  
 
An enhanced approach to manufacturing process development would additionally include the 
following elements: 
  
	   A systematic approach to evaluating, understanding, and refining the manufacturing 
process, including: 
 
o	   Identifying (through e.g., prior knowledge, experimentation, and risk assessment) 
the material attributes (e.g., of raw materials, starting materials, reagents, solvents, 
process aids, intermediates) and process parameters that can have an effect on drug 
substance CQAs; and 
 
o	   Determining the functional relationships that link material attributes and process 
parameters to drug substance CQAs.  
 
   Using the enhanced approach in combination with QRM to establish an appropriate 
control strategy, which can, for example, include a proposal for a design space(s). 
 
The increased knowledge and understanding obtained from taking an enhanced approach could 
facilitate continual improvement and innovation throughout the product lifecycle (see ICH Q10). 
 
4.  Drug Substance Critical Quality Attributes (3.1.4) 
 
A CQA is a physical, chemical, biological, or microbiological property or characteristic that 
should be within an appropriate limit, range, or distribution to ensure the desired product quality. 
Potential drug substance CQAs are used to guide process development.  The list of potential 
CQAs can be modified as drug substance knowledge and process understanding increase.  
 
Drug substance CQAs typically include those properties or characteristics that affect identity, 
purity, biological activity, and stability.  When physical properties are important with respect to 
drug product manufacture or performance, these can be designated as CQAs.  In the case of 
biotechnological/biological products, most of the CQAs of the drug product are associated with 
the drug substance and thus are a direct result of the design of the drug substance or its 
manufacturing process.  
 
Impurities are an important class of potential drug substance CQAs because of their potential 
impact on drug product safety.  For chemical entities, impurities can include organic impurities 
(including potentially mutagenic impurities), inorganic impurities (e.g., metal residues) and 
residual solvents (see the ICH guidances, Q3A Impurities in New Drug Substances (ICH Q3A) 
and Q3C Impurities: Residual Solvents (ICH Q3C)). For biotechnological/biological products, 
impurities can be process-related or product-related (see ICH Q6B).  Process-related impurities 
include cell substrate-derived impurities (e.g., Host Cell Proteins and DNA), cell culture-derived 
impurities (e.g., media components), and downstream-derived impurities (e.g., column  
leachables).  Determining CQAs for biotechnological/biological products should also include 
consideration of contaminants, as defined in ICH Q6B, including all adventitiously introduced 
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Contains Nonbinding Recommendations  
 
materials not intended to be part of the manufacturing process (e.g., adventitious viral, bacterial, 
or mycoplasma contamination). 
 
The identification of CQAs for complex products can be challenging. 
Biotechnological/biological products, for example, typically possess such a large number of 
quality attributes that it might not be possible to fully evaluate the impact on safety and efficacy 
of each one. Risk assessments can be performed to rank or prioritize quality attributes. Prior 
knowledge can be used at the beginning of development, and assessments can be iteratively 
updated with development data (including data from nonclinical and clinical studies) during the 
lifecycle. Knowledge regarding mechanism of action and biological characterization, such as 
studies evaluating structure-function relationships, can contribute to the assessment of risk for 
some product attributes.  
 
5.  Linking Material Attributes and Process Parameters to Drug Substance CQAs 
(3.1.5)  
 
The manufacturing process development program should identify which material attributes (e.g., 
of raw materials, starting materials, reagents, solvents, process aids, intermediates) and process 
parameters should be controlled.  Risk assessment can help identify the material attributes and 
process parameters with the potential for having an effect on drug substance CQAs.  Those 
material attributes and process parameters that are found to be important to drug substance 
quality should be addressed by the control strategy. 
 
The risk assessment used to help define the elements of the control strategy that pertain to 
materials upstream from the drug substance can include an assessment of manufacturing process 
capability, attribute detectability, and severity of impact as they relate to drug substance quality. 
For example, when assessing the link between an impurity in a raw material or intermediate and 
drug substance CQAs, the ability of the drug substance manufacturing process to remove that 
impurity or its derivatives should be considered in the assessment. The risk related to impurities 
can usually be controlled by specifications for raw material/intermediates and/or robust 
purification capability in downstream steps. The  risk assessment can also identify CQAs for 
which there are inherent limitations in detectability in the drug substance (e.g., viral safety).  In 
these cases, such CQAs should be controlled at an appropriate point upstream in the process.  
 
For chemical entity development, a major focus is knowledge and control of impurities.  It is 
important to understand the formation, fate (whether the impurity reacts and changes its chemical 
structure), and purge (whether the impurity is removed by, for example, crystallization, 
extraction), as well as their relationship to the resulting impurities that end up in the drug 
substance as CQAs. The process should be evaluated to establish appropriate controls for 
impurities as they progress through multiple process operations. 
 
Using a traditional approach, material specifications and process parameter ranges can be based 
primarily on batch process history and univariate experiments.  An enhanced approach can lead 
to a more thorough understanding of the relationship of material attributes and process 
parameters to CQAs and the effect of interactions.  Example 1 illustrates the development of  
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Contains Nonbinding Recommendations  
 
process parameters using prior knowledge and chemistry-first principles (see section X.A (10.1) 
of this guidance). 
 
Risk assessment can be used during development to identify those parts of the manufacturing 
process likely to have an impact on potential CQAs.  Further risk assessments can be used to 
focus development work on areas for which better understanding of the link between process and 
quality is needed. Using an enhanced approach, the determination of appropriate material 
specifications and process parameter ranges could follow a sequence such as the one shown 
below: 
 
 	  Identify potential sources of process variability. 
 
 	  Identify the material attributes and process parameters likely to have the greatest 
impact on drug substance quality.  This can be based on prior knowledge and risk 
assessment tools. 
 
 	  Design and conduct studies (e.g., mechanistic and/or kinetic evaluations, multivariate 
design of experiments, simulations, modelling) to identify and confirm the links and 
relationships of material attributes and process parameters to drug substance CQAs. 
 
 	  Analyze and assess the data to establish appropriate ranges, including establishment of 
a design space if desired. 
 
Small-scale models can be developed and used to support process development studies.  The 
development of a model should account for scale effects and be representative of the proposed 
commercial process. A scientifically justified model can enable a prediction of quality, and can 
be used to support the extrapolation of operating conditions across multiple scales and  
equipment. 
 
6.  Design Space (3.1.6)  
 
Design Space is the multidimensional combination and interaction of input variables (e.g., 
material attributes) and process parameters that have been demonstrated to provide assurance of 
quality. Working within the design space is not considered as a change.  Movement out of the 
design space is considered to be a change and would normally initiate a regulatory postapproval 
change process. Design space is proposed by the applicant and is subject to regulatory 
assessment and approval (ICH Q8). 
 
The considerations for design space addressed in ICH Q8 for an enhanced approach to the 
development of the drug product are applicable to drug substance.  The ability to accurately 
assess the significance and effect of the variability of material attributes and process parameters 
on drug substance CQAs, and hence the limits of a design space, depends on the extent of 
process and product understanding. 
 
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Contains Nonbinding Recommendations  
 
Design space can be developed based on a combination of prior knowledge, first principles, 
and/or empirical understanding of the process.  Models (e.g., qualitative, quantitative) can be 
used to support design spaces across multiple scales and equipment.  
 
A design space might be determined per unit operation (e.g. reaction, crystallization, distillation, 
purification), or a combination of selected unit operations.  The unit operations included in such 
a design space should generally be selected based on their impact on CQAs and do not 
necessarily need to be sequential. The linkages between process steps should be evaluated so 
that, for example, the cumulative generation and removal of impurities is controlled.  A design 
space that spans multiple unit operations can provide more operational flexibility. 
 
The development and approval of a design space for some biotechnological/biological drug 
substances can be challenging due to factors including process variability and drug substance 
complexity (e.g., post-translational modifications). These factors can affect residual risk (e.g., 
potential for unexpected changes to CQAs based on uncertainties related to scale sensitivity) that  
remains after approval of the Design Space.  Depending on the level of residual risk, it may be 
appropriate for an applicant to provide proposals on how movements within a Design Space will 
be managed postapproval.  These proposals should indicate how process knowledge, control 
strategy, and characterization methods can be deployed to assess product quality following 
movement within the approved design space. 
 
B.  Submission of Manufacturing Process Development Information (3.2) 
 
The information provided on the development of the drug substance manufacturing process 
(primarily in section 3.2.S.2.6 of the application) should identify significant changes during 
process development; link relevant drug substance batches with the developmental stage of the 
manufacturing process used to prepare them; and explain how prior knowledge, risk assessments, 
and other studies (e.g., experimental, modelling, simulations) were used to establish important 
aspects of the manufacturing process and control strategy.  Process development information 
should be logically organized and easy to understand.  Manufacturers can present process 
development information in a number of different ways, but some specific recommendations are 
provided below for consideration. 
 
1.   Overall Process Development Summary (3.2.1) 
 
It is recommended that the manufacturing process development section begin with a narrative 
summary that describes important milestones in the development of the process and explains 
how they are linked to assuring that the intended quality of the drug substance is achieved.  The 
following should be included in the summary: 
  
	   List of drug substance CQAs 
  
	   Brief description of the stages in the evolution of the manufacturing process and 
relevant changes to the control strategy 
  
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Contains Nonbinding Recommendations  
 
	   Brief description of the material attributes and process parameters identified as having 
an impact on drug substance CQAs 
  
	   Brief description of the development of any design spaces 
 
Following the Overall Process Development Summary, the manufacturing process development 
section should include more comprehensive information, as recommended below. 
 
2.  Drug Substance CQAs (3.2.2)  
 
The CQAs of the drug substance should be listed, and the rationale for designating these 
properties or characteristics as CQAs should be provided.  In some cases, it might be appropriate 
to explain why other properties or characteristics that might be considered potential CQAs are 
not included in the list of CQAs. Links or references should be provided to information 
submitted elsewhere in the submission (e.g., 3.2.S.3.1, Elucidation of Structure and other 
Characteristics) that supports the designation of these properties or characteristics as CQAs. 
Some discussion of drug substance CQAs as they relate to drug product CQAs can be 
appropriate in the pharmaceutical development section of the application (e.g., 3.2.P.2.1, 
Components of the Drug Product). 
 
3.  Manufacturing Process History (3.2.3)  
 
A description and discussion should be provided of significant changes made to the 
manufacturing process or site of manufacture of drug substance batches used in support of the 
marketing application (e.g., those used in nonclinical or clinical studies or stability studies in 
support of a marketing authorization) and, if available, production-scale batches.  The 
description should usually follow a chronological sequence ending with the proposed 
commercial process. Batch information (batch size or scale, site and date of manufacture, route 
and process used, and intended purpose (e.g., in a specified toxicology or clinical study)) and 
supporting data from comparative analytical testing on relevant drug substance batches should be 
provided or referenced (e.g., batch analyses section 3.2.S.4.4). 
 
For biotechnological/biological drug substances, the reason for each significant change should be 
explained, together with an assessment of its potential to have an impact on the quality of the 
drug substance (and/or intermediate, if appropriate).  The manufacturing process history section 
should include a discussion of comparability during development as described in the ICH 
guidance Q5E Comparability of Biotechnological/Biological Products Subject to Changes in 
Their Manufacturing Process (ICH Q5E). A discussion of the data, including a justification for 
selection of the tests and assessment of results, should be included.  Testing used to assess the 
impact of manufacturing changes on the drug substance and the corresponding drug product can 
also include nonclinical and clinical studies. Cross-reference to the location of these studies in 
other modules of the submission should be included.  
 
4.  Manufacturing Development Studies (3.2.4)  
 
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The studies and risk assessments used to establish important aspects of the commercial 
manufacturing process and control strategy cited in the application should be listed (e.g., in 
tabular form). The purpose or end use of each cited study or risk assessment should be provided.  
 
Each cited study or risk assessment should be summarized with a level of detail sufficient to 
convey an understanding of the purpose of the study, the data collected, how it was analyzed, the 
conclusions reached, and the impact of the study on the manufacturing process or further 
development of the manufacturing process.  The particular parameters and ranges studied should 
be described and discussed in relation to the proposed operating conditions or design space for 
the commercial manufacturing process (as described in 3.2.S.2.2).  The risk assessment tools and 
study results on which a design space is based should be adequately described.  Example 2 
shows a possible communication tool for presenting a risk ranking for parameters evaluated 
during development of a design space (see section X.B (10.2) of this guidance). Where 
development refers to specific prior knowledge, the relevant information and data should be 
provided and, where appropriate, the relevance to the particular drug substance should be 
justified.   
 
Small-scale models used to support development of the commercial manufacturing process 
should be described. 
 
IV. 	 DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS 
CONTROLS (4) 
 
The description of the drug substance manufacturing process represents the applicants  
commitment for the manufacture of the drug substance.  Information should be provided to 
adequately describe the manufacturing process and process controls (see ICH M4Q (3.2.S.2.2)). 
 
The description of the manufacturing process should be provided in the form of a flow diagram  
and sequential procedural narrative. The in-process controls for each step or stage of the process 
should be indicated in the description.  Scaling factors should be included for manufacturing 
steps intended to span multiple operational scales when the process step is scale dependent.  Any 
design spaces in the manufacturing process should be included as part of the manufacturing 
process description. Example 3 gives an example of the presentation of a design space for a 
biotechnological product (see section X.C (10.3) of this guidance). 
 
Many biotechnological/biological products have complex upstream processes and use splitting 
and pooling to create a drug substance batch. An explanation of how batches of drug substance 
are defined by the manufacturer (e.g., splitting and pooling of harvests or intermediates) should 
be provided. Details of batch size or scale and batch numbering should be included.  
 
V. 	 SELECTION OF STARTING MATERIALS AND SOURCE MATERIALS (5) 
 
A. 	  General Principles (5.1) 
 
1. 	 Selection of Starting Materials for Synthetic Drug Substances (5.1.1)  
 
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The following general principles should be considered in determining where the drug substance 
manufacturing process begins (i.e., in selecting starting materials). 
 
	   In general, changes in material attributes or operating conditions that occur near the 
beginning of the manufacturing process have lower potential to have an impact on the 
quality of the drug substance. 
 
o	   The relationship between risk and number of steps from the end of the 
manufacturing process is the result of two factors, one concerning the physical 
properties of the drug substance and the other concerning the formation, fate, and 
purge of impurities. The physical properties of a drug substance are determined 
during the final crystallization step and subsequent operations (e.g., milling, 
micronizing), all of which occur at the end of the manufacturing process.  
Impurities introduced or created early in the manufacturing process typically have  
more opportunities to be removed in purification operations (e.g., washing, 
crystallization of isolated intermediates) than impurities generated late in the 
manufacturing process, and are therefore less likely to be carried into the drug 
substance. However, in some cases (e.g., when peptides or oligonucleotides are 
synthesized on a solid support), there is a more limited relationship between risk 
and number of steps from the end of the manufacturing process. 
  
	   Regulatory authorities assess whether the controls on the drug substance and drug 
substance manufacturing process can be considered adequate, including whether there 
are appropriate controls for impurities.  To conduct this assessment, enough of the 
drug substance manufacturing process should be described in the application for 
regulatory authorities to understand how impurities are formed in the process; how 
changes in the process could affect the formation, fate, and purge of impurities; and 
why the proposed control strategy is suitable for the drug substance manufacturing 
process. This will typically include a description of multiple chemical transformation 
steps. 
 
 	  Manufacturing steps that have an impact on 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. 
 
 	  Each branch of a convergent drug substance manufacturing process begins with one or 
more starting materials.  The Good Manufacturing Practice (GMP) provisions 
described in the ICH guidance Q7 Good Manufacturing Practice Guidance for Active 
Pharmaceutical Ingredients (ICH Q7) apply to each branch beginning with the first 
use of a starting material.  Performing manufacturing steps under GMP together with 
an appropriate control strategy provides assurance of quality of the drug substance. 
 
 	  A starting material should be a substance of defined chemical properties and structure. 
Non-isolated intermediates are usually not considered appropriate starting materials.  
 
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	   A starting material is incorporated as a significant structural fragment into the 
structure of the drug substance. Significant structural fragment in this context is 
intended to distinguish starting materials from reagents, solvents, or other raw 
materials.  Commonly available chemicals used to create salts, esters, or other simple 
derivatives should be considered reagents. 
 
All the general principles above should be considered in selecting Starting Material(s), rather 
than strictly applying each general principle in isolation (see Example 4 in section X.D (10.4) of 
this guidance). 
 
2.  Selection of Starting Materials for Semi-synthetic Drug Substances (5.1.2) 
 
For purposes of this guidance, a semi-synthetic drug substance is one in which the structural 
constituents have been introduced by a combination of chemical synthesis and elements of 
biological origin (e.g., obtained from fermentation or by extraction from botanical material).  In 
some cases, it might be appropriate for the applicant to describe the manufacturing process 
starting from the source material (microorganism or botanical material).  However, if it can be 
demonstrated that one of the isolated intermediates in the synthetic process complies with the 
principles outlined above for the selection of starting materials for synthetic drug substances, that  
isolated intermediate can be proposed as the starting material.  The applicant should specifically 
evaluate whether it is possible to analytically characterize the proposed starting material, 
including its impurity profile, and whether the fermentation or botanical material and extraction 
process have an impact on the impurity profile of the drug substance.  Risks from microbial and 
other contamination should also be addressed. 
 
3. 	 Selection of Source and Starting Materials for Biotechnological/Biological Drug 
Substances (5.1.3)  
 
Cell banks are the starting point for manufacture of biotechnological drug substances and some  
biological drug substances. In some regions, these are referred to as source materials  in others, 
starting materials. Guidance is contained in the ICH guidances, Q5A Viral Safety Evaluation of 
Biotechnology Products Derived From Cell Lines of Human or Animal Origin (ICH Q5A), Q5B 
Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for 
Production of r-DNA Derived Protein Products (ICH Q5B), and Q5D Quality of 
Biotechnological/Biological Products:  Derivation and Characterization of Cell Substrates Used 
for Production of Biotechnological/Biological Products (ICH Q5D). 
 
B.  Submission of Information for Starting Material or Source Materials (5.2) 
 
Applicants should identify all proposed starting materials or source materials and provide 
appropriate specifications. Proposed starting materials for synthetic and semi-synthetic drug 
substances should be justified. 
 
1. 	 Justification of Starting Material Selection for Synthetic Drug Substances (5.2.1)  
 
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The applicant should provide a justification for how each proposed starting material is 
appropriate in light of the general principles for the selection of starting materials outlined above 
in section V.A.1 (5.1.1). This can include information on: 
 
	   The ability of analytical procedures to detect impurities in the starting material; 
  
	   The fate and purge of those impurities and their derivatives in subsequent processing 
steps; and 
 
	   How the proposed specification for each starting material will contribute to the control 
strategy. 
  
The applicant should provide, as part of the justification, a flow diagram outlining the current  
synthetic route(s) for the manufacture of the drug substance, with the proposed starting materials  
clearly indicated.  Changes to the starting material specification and to the synthetic route from  
the starting material to final drug substance are subject to regional, postapproval change 
requirements.  In addition, regional requirements concerning starting material suppliers might 
also be applicable. 
 
An applicant generally need not justify the use of a commercially available chemical as a starting 
material.  A commercially available chemical is usually one that is sold as a commodity in a 
preexisting, non-pharmaceutical market in addition to its proposed use as starting material.  
Chemicals produced by custom syntheses are not considered to be commercially available.  If a 
chemical from a custom synthesis is proposed as a starting material, it should be justified in 
accordance with the general principles for the selection of starting materials outlined above in 
section V.A.1 (5.1.1). 
 
In some instances, additional purification steps by the drug substance manufacturer might be 
called for to ensure the consistent quality of a commercially available starting material.  In these 
instances, the additional purification steps should be included as part of the description of the 
drug substance manufacturing process.  Specifications should normally be provided for both 
incoming and purified starting material. 
 
2.  Justification of Starting Material Selection for Semi-synthetic Drug Substances 
(5.2.2)  
 
If an isolated intermediate is proposed as the starting material for a semi-synthetic drug 
substance, the applicant should provide a justification that explains how the proposed starting 
material complies with the general principles for the selection of starting materials outlined 
above in section V.A.1 (5.1.1). Otherwise, the applicant should describe the manufacturing 
process starting from the microorganism or botanical material, as appropriate, and these 
materials should be qualified. 
 
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3. 	 Qualification of Source or Starting Materials for Biotechnological/Biological 
Drug Substances (5.2.3) 
 
Guidance is contained in ICH Q5A, ICH Q5B, and ICH Q5D.   
 
VI. 	 CONTROL STRATEGY (6) 
 
A. 	 General Principles (6.1) 
 
A control strategy is a planned set of controls, derived from current product and process 
understanding, that assures process performance and product quality (ICH Q10). Every drug 
substance manufacturing process, whether developed through a traditional or an enhanced 
approach (or some combination thereof), has an associated control strategy. 
  
A control strategy can include, but is not limited to, the following: 
  
 	  Controls on material attributes (including, e.g., raw materials, starting materials, 
intermediates, reagents, primary packaging materials for the drug substance) 
 
 	  Controls implicit in the design of the manufacturing process (e.g., sequence of 
purification steps (Biotechnological/Biological drug substances), or order of addition 
of reagents (Chemical entities)) 
 
 	  In-process controls (including in-process tests and process parameters) 
 
 	  Controls on drug substance (e.g., release testing) 
 
1. 	 Approaches to Developing a Control Strategy (6.1.l)  
 
A control strategy can be developed through a combination of approaches, using the traditional 
approach for some CQAs, steps, or unit operations, and a more enhanced approach for others. 
 
In a traditional approach to developing a manufacturing process and control strategy, set points 
and operating ranges are typically set narrowly based on the observed data to ensure consistency 
of manufacture.  More emphasis is placed on assessment of CQAs at the stage of the drug 
substance (i.e., end-product testing).  The traditional approach provides limited flexibility in the 
operating ranges to address variability (e.g., in raw materials).  
 
An enhanced approach to manufacturing process development generates better process and 
product understanding than the traditional approach, so sources of variability can be identified in 
a more systematic way.  This allows for the development of more meaningful and efficient 
parametric, attribute, and procedural controls.  The control strategy might be developed through 
several iterations as the level of process understanding increases during the product lifecycle.  A 
control strategy based on an enhanced approach can provide for flexibility in the operating 
ranges for process parameters to address variability (e.g., in raw materials).  
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2.  Consideration in Developing a Control Strategy (6.1.2)  
 
A control strategy should ensure that each drug substance CQA is within the appropriate range, 
limit, or distribution to assure drug substance quality.  The drug substance specification is one 
part of a total control strategy and not all CQAs need to be included in the drug substance 
specification. CQAs can (1) be included on the specification and confirmed through testing the 
final drug substance, (2) be included on the specification and confirmed through upstream  
controls (e.g., as in Real Time Release Testing (RTRT)), or (3) not be included on the 
specification but ensured through upstream controls.  Examples of upstream controls can 
include:  
 
 	  in process testing; 
  
 	  use of measurements of process parameters and/or in process material attributes that 
are predictive of a drug substance CQA.  In some cases, Process Analytical 
Technology (PAT) can be used to enhance control of the process and maintain output 
quality. 
 
Regardless of whether a traditional or enhanced process development approach is taken, the use 
of upstream controls should be based on an evaluation and understanding of the sources of 
variability of a CQA.  Downstream factors that might have an impact on the quality of the drug 
substance, such as temperature changes, oxidative conditions, light, ionic content, and shear, 
should be taken into consideration. 
 
When developing a control strategy, a manufacturer can consider implementing controls for a 
specific CQA at single or multiple locations in the process, depending on the risk associated with  
the CQA and the ability of individual controls to detect a potential problem.  For example, with 
sterilized chemical entities or biotechnological/biological drug substances, there is an inherent  
limitation in the ability to detect low levels of bacterial or viral contamination.  In these cases, 
testing on the drug substance is considered to provide inadequate assurance of quality, so 
additional controls (e.g., attribute and in-process controls) are incorporated into the control 
strategy. 
 
The quality of each raw material used in the manufacturing process should be appropriate for its 
intended use.  Raw materials used in operations near the end of the manufacturing process have a 
greater potential to introduce impurities into the drug substance than raw materials used 
upstream.  Therefore, manufacturers should evaluate whether the quality of such materials 
should be more tightly controlled than similar materials used upstream.  
 
B.   Submission of Control Strategy Information (6.2) 
 
The information provided on the control strategy should include detailed descriptions of the 
individual elements of the control strategy plus, when appropriate, a summary of the overall drug 
substance control strategy. The summary of the overall control strategy can be presented in 
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either a tabular format or in a diagrammatic format, to aid visualization and understanding (see 
Example 5 for an example of a Control Strategy Summary in tabular form (in section X.E (10.5) 
of this guidance)). Ideally, the summary should explain how the individual elements of the 
control strategy work together to assure drug substance quality. 
 
ICH M4Q recommends that the individual elements of the control strategy reported in an 
application be provided in the appropriate sections of a submission, including: 
 
   Description of Manufacturing Process and Process Controls (3.2.S.2.2); 
   Control of Materials (3.2.S.2.3); 
   Controls of Critical Steps and Intermediates (3.2.S.2.4);  
   Control of Drug Substance (3.2.S.4); and 
   Container Closure System (3.2.S.6). 
 
VII.  PROCESS VALIDATION/EVALUATION (7) 
 
A.  General Principles (7.1) 
 
Process validation is the documented evidence that the process, operated within established 
parameters, can perform effectively and reproducibly to produce a drug substance or 
intermediate meeting its predetermined specifications and quality attributes (ICH Q7).  
 
Process validation can include the collection and evaluation of data, from the process design 
stage throughout production, that establish scientific evidence that a process is capable of 
consistently delivering a quality drug substance. 
 
The drug substance manufacturing process should be validated before commercial distribution of  
resulting drug product. For biotechnological processes, or for aseptic processing and sterilization 
process steps for drug substances, the data provided in support of process validation is included 
as part of the marketing application (3.2.S.2.5).  For non-sterile chemical entity drug substance 
processes, results of process validation studies are not normally included in the dossier.  
 
Generally, process validation includes the collection of data on an appropriate number of 
production batches (see ICH Q7, section XII.E (12.5)). The number of batches can depend on 
several factors, including but not limited to (1) the complexity of the process being validated, (2) 
the level of process variability, and (3) the amount of experimental data and/or process 
knowledge available on the specific process. 
 
As an alternative to the traditional process validation, continuous process verification (ICH Q8) 
can be used in process validation protocols for the initial commercial production and also for 
manufacturing process changes for the continual improvement throughout the remainder of the 
product lifecycle. 
 
B.  Principles Specific to Biotechnological/Biological Drug Substance (7.2) 
 
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For biotechnological/biological drug substances, the information provided in the dossier in 
support of process validation usually contains both commercial-scale process validation studies 
and small-scale studies.  Process validation batches should be representative of the commercial 
process, taking into account the batch definition as detailed in the process description. 
 
The contribution of data from small-scale studies to the overall validation package will depend 
upon demonstration that the small-scale model is an appropriate representation of the proposed 
commercial scale. Data should be provided demonstrating that the model is scalable and 
representative of the proposed commercial process.  Successful demonstration of the suitability 
of the small-scale model can enable manufacturers to propose process validation with reduced 
dependence on testing of commercial-scale batches.  Data derived from commercial-scale 
batches should confirm results obtained from small-scale studies used to generate data in support 
of process validation. Scientific grounds, or reference to guidelines that do not require or 
specifically exclude such studies, can be an appropriate justification to conduct certain studies 
only at small scale (e.g., viral removal). 
 
Studies should be conducted to demonstrate the ability of the process to remove product-related 
impurities, process-related impurities (ICH Q6B) and potential contaminants (such as viruses in 
processes  using material from human or animal origin, see ICH Q5A).  Studies carried out to 
demonstrate the lifetime of chromatography columns can include experimental studies carried 
out in small-scale models but should be confirmed during commercial-scale production. 
 
The limit of in vitro cell age for commercial production should be assessed.  ICH Q5B and Q5D 
provide further guidance for relevant products. 
 
When platform manufacturing experience is used, the suitability of the control strategy should be 
demonstrated and the drug substance manufacturing process should be appropriately validated at 
the time of marketing authorization application.  Usually, full scale validation studies should 
include data derived from the final manufacturing process and site(s) used to produce the product 
to be commercialized. 
 
VIII. 	 SUBMISSION OF MANUFACTURING PROCESS DEVELOPMENT AND 
RELATED INFORMATION IN CTD FORMAT (8) 
 
The use of an enhanced approach to process development generates information for which a 
location in the CTD is not defined. Process development information should usually be 
submitted in section 3.2.S.2.6 of the CTD.  Other information resulting from development 
studies could be accommodated by the CTD format in a number of different ways and some  
specific suggestions are provided below.  The applicant should clearly indicate where the 
different information is located.  In addition to what is submitted in the application, certain topics 
referenced in this guidance (e.g., lifecycle management, continual improvement) are handled 
under the applicants pharmaceutical quality system (see ICH Q10). 
 
A. 	 Quality Risk Management and Process Development (8.1) 
 
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Quality risk management can be used at different stages during process development and 
manufacturing implementation.  The assessments used to guide and justify development 
decisions (e.g., risk assessment and functional relationships linking material attributes and 
process parameters to drug substance CQAs) can be summarized in section 3.2.S.2.6.  
 
B.  Critical Quality Attributes (CQAs) (8.2) 
 
The CQAs of the drug substance should be listed, and the rationale for designating these 
properties or characteristics as CQAs should be provided in the manufacturing process 
development section of the application (3.2.S.2.6).  However, detailed information about 
structural characterization studies that supports the designation of these properties or 
characteristics as CQAs should be provided in the appropriate CTD format sections (e.g., 
3.2.S.3.1 Elucidation of Structure and other Characteristics, 3.2.S.7 Stability).  Some discussion 
of drug substance CQAs as they relate to drug product CQAs can be appropriate in the 
pharmaceutical development section of the application (3.2.P.2.1, Components of the Drug 
Product). 
 
C.  Design Space (8.3) 
 
As an element of the proposed manufacturing process, the design space(s) can be described in 
the section of the application that includes the description of the manufacturing process and 
process controls (3.2.S.2.2). If appropriate, additional information can be provided in the section 
of the application that addresses the controls of critical steps and intermediates (3.2.S.2.4).  The 
manufacturing process development section of the application (3.2.S.2.6) is the appropriate place 
to summarize and describe process development studies that provide the basis for the design 
space(s). The relationship of the design space(s) to the overall control strategy can be discussed 
in the section of the application that includes the justification of the drug substance specification 
(3.2.S.4.5). 
 
D.  Control Strategy (8.4) 
 
Although the drug substance specification is only one part of the total control strategy, the 
section of the application that includes the justification of the drug substance specification 
(3.2.S.4.5) is a good place to summarize the overall drug substance control strategy. However, 
detailed information about input material controls, process controls, and control of drug 
substance should still be provided in the appropriate CTD format sections (e.g., description of 
manufacturing process and process controls (3.2.S.2.2), control of materials (3.2.S.2.3), controls 
of critical steps and intermediates (3.2.S.2.4), drug substance specification (3.2.S.4.1)).  A brief 
description of relevant changes to the control strategy during the evolution of the manufacturing 
process should be provided in section 3.2.S.2.6 of the application. 
 
IX.  LIFECYCLE MANAGEMENT (9) 
 
The quality system elements and management responsibilities described in ICH Q10 are intended 
to encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby 
promoting continual improvement across the entire product lifecycle.  Product and process 
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knowledge should be managed from development through the commercial life of the product up 
to and including product discontinuation. 
 
The development and improvement of a drug substance manufacturing process usually continues 
over its lifecycle. Manufacturing process performance, including the effectiveness of the control 
strategy, should be periodically evaluated. Knowledge gained from commercial manufacturing 
can be used to further improve process understanding and process performance and to adjust the 
control strategy to ensure drug substance quality.  Knowledge gained from other products, or 
from new innovative technologies, can also contribute to these goals.  Continual improvement 
and successful process validation, or continuous process verification, call for an appropriate and 
effective control strategy.   
 
There should be a systematic approach to managing knowledge related to both drug substance 
and its manufacturing process throughout the lifecycle.  This knowledge management should 
include but not be limited to process development activities, technology transfer activities to 
internal sites and contract manufacturers, process validation studies over the lifecycle of the drug 
substance, and change management activities.  The knowledge and process understanding should 
be shared as needed to perform the manufacturing process and implement the control strategy 
across sites involved in manufacturing the drug substance. 
 
An applicant can include in the original submission a proposal for how specific future changes 
will be managed during the product lifecycle, including changes to the control strategy.  As an 
example of lifecycle management of process parameters for a biotechnological product, see 
Example 2 (in section X.B (10.2)). 
 
Any proposed change to the manufacturing process should be evaluated for the impact on the 
quality of drug substance and, when appropriate, drug product.  This evaluation should be based 
on scientific understanding of the manufacturing process and should determine appropriate 
testing to analyze the impact of the proposed change.  For chemical entities, the appropriate 
testing to analyze the impact of the proposed change could include, but is not limited to, an 
assessment of current and potential new impurities and an assessment of the test procedures 
abilities to detect any new impurities.  This testing should be performed at an appropriate point  
in the process (e.g., on an intermediate or drug substance) after the proposed change.  For 
process changes for biotechnological/biological drug substances, see also ICH Q5E. 
 
All changes should be subject to internal change management processes as part of the Quality 
System (ICH Q7 and ICH Q10).  This includes movements within the Design Space, which do 
not require approval by regional regulatory authorities.   
 
Changes to information filed and approved in a dossier should be reported to regulatory 
authorities in accordance with regional regulations and guidances. 
 
X.  ILLUSTRATIVE EXAMPLES (10)  
 
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The examples in this section are provided for illustrative purposes and only suggest potential 
uses. This section is not intended to create any new expectations beyond the current regulatory 
requirements. 
 
A. 	 Example 1: Linking Material Attributes and Process Parameters to Drug 
Substance CQAs  Chemical Entity (10.1) 
 
This example illustrates development of a design space using prior knowledge and chemistry-
first principles.  It depicts both a traditional and an enhanced approach to determination of the 
ranges for parameters controlling  the formation of a hydrolysis impurity during Step 5 of the 
following reaction scheme (also used in Example 4 (see section X.D (10.4)). 
 
R
Step 1  1  Step 2  Step 3 
A   C  D 
R
R   2 
3 
(B) 
Step 4 
R1   Purification   R1 Step 6  Step 5
F  E 
R   R
R   4  R   4 
3  3 
Final Drug  Crude 
  
Substance   Drug Substance 
  
 
 
After the formation of intermediate F in Step 5, the mixture is heated to reflux.  During reflux, an 
impurity is formed through hydrolysis of intermediate F. 
 
For the purpose of this simplified example, this is the only reaction of intermediate F that occurs 
during this reflux. The following assumptions were used in the design of the process: 
 
	   The concentration of intermediate F remains approximately constant. 
	   Temperature remains constant. 
	   The acceptance criterion for the hydrolysis impurity in Intermediate F is 0.30%. 
(This is based on the CQA in the drug substance and the demonstrated capacity of the 
subsequent steps to purge the impurity.) 
	   The initial amount of water in the reflux mixture depends on the amount of water in 
Intermediate  E, which can be controlled by drying. 
The time of reflux and the water concentration were identified as the most important parameters 
affecting the hydrolysis of intermediate F. Other potential factors were determined to be 
insignificant based on prior knowledge and risk assessment. 
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The reaction was expected to follow second-order kinetics according to the equation below: 
 
  
d hydrolysis _ impurity
   
 k H O F  
dt  2
 
Where  F  refers to the concentration of intermediate  F.
 
Through simple experimentation, the following graph linking the extent of hydrolysis to time and 
the water content of intermediate E can be generated: 
 
Hydrolysis Degradation at Reflux 
0.60 
F 
e 
t
a
i
d 0.50 
e
m
r 2.0% 
e
Int 0.40  1.5% 
n  1.0% 
i
) 
% 0.5% 
( 0.30 
y  4.0%
t
ri 2.0%
u
p
m 0.20  1.0%
s I 0.5%
i
s
y
ol 0.10 
r
d
y
H
0.00 
0.0  1.0  2.0  3.0  4.0  5.0 
Reflux Time (hours) 
 
Traditional Approach: 
 
In a traditional approach, this information would be used to set a proven acceptable range for 
percentage of water and time that achieves the acceptance criteria for the hydrolysis impurity of 
0.30% in intermediate F.  This is typically done by setting a target value and maximum such as: 
 
   Dry Intermediate E to a maximum water content of 1.0%; and 
   Target reflux time of 1 hour and a maximum reflux time of 3 hours. 
Enhanced Approach:  
 
The second-order rate equation can be integrated and solved explicitly.4  
                                                 
4 Levenspiel, O., Chemical Reaction Engineering, 2nd  Edition, John  Wiley and Sons, 1972. 
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  M  X 
ln  F   H O  F  kt 
M 1 X  2  o o 
  
F 
 
Where: 
F    refers to the initial concentration of intermediate F,
o 
   
H O   refers to the initial concentration of water, 
2 o 
   
M H O F   refers to the ratio of the initial concentration of water to the 
2  o  o 
initial concentration of intermediate F, and 
   
X X  F   refers to the time-dependent concentration of the hydrolysis 
F  o 
degradant of intermediate F divided by the initial 
concentration of intermediate F. 
 
Solving this equation for time (t) permits the calculation of the maximum allowable reflux time 
for any combination of initial water content and target level for the hydrolysis impurity.  (The 
initial concentration of intermediate F in the reflux mixture will essentially be constant from  
batch to batch.)  The following graph shows the combination of conditions required to ensure 
that the hydrolysis impurity remains below 0.30% in intermediate F. 
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Interdependence of  Reflux Time and Water Content in  
the Formation of Hydrolysis Impurity 
8.0 
7.0 
6.0 
)

s
r
u
o 5.0  Conditions that produce a level of 
h 0.30% of the hydrolysis impurity  
(
   
e
m 4.0  Operating above the line will produce 
i more than 0.30% of the hydrolysis 
T
  impurity  
x
3.0 
u
l
f
e
R
2.0 
1.0 
0.0 
0.0  1.0  2.0  3.0  4.0  5.0 
Water Content (%) in Intermediate E 
 
 
The area below the line in the plot above could be proposed as the design space. 
 
Summary: 
 
Although both the traditional and enhanced approaches provide ranges of water content and time  
to control the formation of the hydrolysis impurity, the enhanced approach allows more 
manufacturing flexibility. 
 
B. 	 Example 2:  Use of Quality Risk Management to Support Lifecycle 
Management of Process Parameters (10.2) 
 
This example illustrates how results from an iterative quality risk assessment can be used to 
communicate the rationale for classification and proposed future management of changes to 
process parameters.  Relevant parameters for establishment of a design space for a Q-anion 
exchange column are shown in this Risk Ranking Histogram.  The histogram showing the 
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ranking of parameters is intended for illustrative purposes only and is not all inclusive, nor is it 
meant to be applicable to all products that might use ion exchange chromatography.  
 
Initial Filing: 
 
A quality risk assessment using prior knowledge and development studies can be used to rank 
process parameters based on their relative potential to have an effect on product quality if 
parameter ranges were changed.  The histogram  shows the potential impact on quality for future 
changes to parameter ranges based on the knowledge and understanding at the time of 
submission.  Process development studies and interaction studies were conducted to establish 
design space boundaries for each of the higher risk parameters (parameters A-F) that had an 
impact on CQAs.  Parameters G, H, and I were also challenged in the development studies and 
shown not to have an impact on CQAs under the conditions studied.  Changes to the ranges of 
these parameters could still carry residual risk (based on prior knowledge/uncertainties, including 
potential scale sensitivity).  Parameters J-T were considered lower risk parameters based on 
documented prior knowledge, and therefore an impact on quality attributes is not anticipated.  
The ranking of parameters from the quality risk assessment can be used to communicate with 
regulators regarding a lifecycle management approach to assure continual improvement 
throughout the product lifecycle. 
 
Lifecycle Management Options: 
 
Risk should be reassessed throughout the lifecycle as process understanding increases.  
Recommendations regarding lifecycle management changes can be found in the Pharmaceutical 
Quality System (PQS) as described in ICH Q10.  
 
Working within the design space is not considered as a change.  Movement out of the design 
space is considered to be a change, and consequently, any extension of ranges for higher risk 
parameters (i.e., parameters A-F) outside the design space would normally initiate a regulatory 
postapproval change process. 
 
An applicant can include in the original submission a proposal for how specific future changes to 
parameters G, H, and I will be managed during the product lifecycle.  Extension of ranges for 
lower risk parameters (J-T) is addressed primarily via the PQS and does not require prior 
regulatory approval, although notification may be called for depending on regional regulatory 
requirements and guidance.  If it is determined subsequently to the filing that there is a change in 
the risk ranking, such that an extension of ranges for a parameter represents a higher risk, this 
change should be appropriately filed through the regional regulatory process. 
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C. 	 Example 3: Presentation of a Design Space for a Biotechnological Drug 
Substance Unit Operation (10.3) 
 
This example is based on a design space for a drug substance purification unit operation (Q
anion exchange column run for a monoclonal antibody in flow-through mode), determined from 
the common region of successful operating ranges for multiple CQAs.  The figure in this section 
illustrates a potential depiction of a design space based on successful operating ranges for three 
CQAs and the use of prior knowledge (platform  manufacturing) in developing a design space. 
The ranges represented here indicate areas of successful operation.  Operation beyond these 
ranges does not necessarily mean that drug substance of unacceptable quality will be produced, 
simply that these operating conditions have not been studied and therefore the quality of the drug 
substance is unknown. 
 
Viral clearance and host cell protein (HCP) ranges were derived from multivariate 
experimentation (see ICH Q8).  The successful operating range for DNA was derived from prior 
knowledge (platform manufacturing) which in turn was derived from results of multivariate 
studies performed on related products.  The successful operating range for HCP lies within the 
viral clearance and DNA successful operating ranges.  In this example, the diagrams below show 
how HCP limits the unit operation design space compared to viral safety and DNA. 
Consideration of additional input variables, process parameters, or CQAs could limit design 
space further. 
  
The design space is applicable only within specified conditions, including:  
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1.   Appropriately defined quality criteria for input materials; and 
2.   Appropriately selected CQAs and process parameters. 
 
 
 
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D.  Example 4: Selecting an Appropriate Starting Material (10.4) 
 
 
R
Step 1  1  Step 2  Step 3 
A   C  D 
R
R   2 
3 
(B) 
Step 4 
R1   Purification   R1 Step 6  Step 5
F  E 
R   R
R   4  R   4 
3  3 
Final Drug  Crude 
  
Substance   Drug Substance 
  
 
This example illustrates the importance of considering all general principles described in section 
V.A.1 (5.1.1) when selecting an appropriate starting material, rather than applying each general 
principle in isolation. The example is fictional, based on a linear synthesis for a relatively simple 
molecule, and is not intended to convey any particular meaning in relation to the number of 
steps. 
 
The desired stereochemical configuration in the drug substance results from the synthesis of 
compound B in step 1 from a commercially available achiral precursor  A and a stereo-selective 
reagent. A small amount of the opposite enantiomer of compound B is also formed in step 1.  
Once formed, both stereochemical configurations persist through the synthetic steps that follow, 
so the drug substance also contains a small amount of its undesired enantiomer as a specified 
impurity.  In accordance with the principle that manufacturing steps that have an impact on the 
drug substance impurity profile should normally be included in the manufacturing process 
described in section 3.2.S.2.2 of the application, it could be concluded that step 1 should be 
described in 3.2.S.2.2, and that A should be considered the starting material. 
 
However, for this manufacturing process, it is also known that all of the significant impurities in 
the drug substance (other than opposite enantiomer) arise from steps 4, 5, and 6.  Steps 2 and 3 
have no impact on the drug substance impurity profile, and the only impact from step 1 is with 
regard to the enantiomeric impurity.  Furthermore, it is also known that the stereocenter first 
formed in step 1 is stable to the manufacturing conditions in all of the steps that follow (i.e., no 
racemization occurs or is ever likely to occur), and that a suitable analytical procedure exists for 
measuring the amount of the opposite enantiomer in compound D. Therefore, provided 
compound D is in accordance with most of the other general principles described in section 
V.A.1 (5.1.1), it would be reasonable to propose D as the starting material instead of  A in 
accordance with the principle that early steps in the manufacturing process tend to have a lower 
potential to have an impact on drug substance quality than later steps.  In this example, the only 
impact of step 1 is on the amount of the enantiomeric impurity in the drug substance, and this 
could alternatively be controlled through an appropriate limit on the amount of the opposite 
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enantiomer in compound D. Information on steps 1-3 would be made available to regulatory 
authorities to justify such a proposal as per regional expectations. 
 
A similar argument could be made if the stereocenter in the drug substance originated in the 
commercially available precursor  A instead of being created in step 1. 
 
E.   Example 5: Summary of Control Elements for Select CQAs (10.5) 
 
This example illustrates how part of a drug substance control strategy might be summarized in 
tabular form. Tables 5a and 5b below show how an applicant can communicate information on 
multiple elements of a drug substance control strategy and guide the reviewer to sections of the 
CTD where detailed elements of the control strategy are described or justified.  Such control 
strategy summary tables should not contain the rationale or justification for the controls but 
should simply indicate where the information can be found in the application for marketing 
authorization.  
 
There are multiple ways of presenting this information, and two are shown in Tables 5a and 5b 
below. One table shows more detail than the other to illustrate that there is a range of  
possibilities for presenting this information.  The amount of detail included in a control strategy 
summary table is up to the applicant and is not related to the type of drug substance.  CQAs and 
control elements shown in the tables below are only examples and are not intended to be a 
comprehensive representation of all elements of a drug substance control strategy.  The tables 
should not be considered templates.  The section of the application that includes the justification 
of the drug substance specification (3.2.S.4.5) is a good place to summarize the overall drug 
substance control strategy. 
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Contains Nonbinding Recommendations  
 
Table 5a.  Example of a Possible Control Strategy Summary  Biotechnological Products 
 
Section(s) in 
Drug  CTD where 
Control Strategy for drug substance CQA 
Substance  detailed 
 
CQA  information is 
located 
Contaminants  Summaries of viral safety information for  3.2.S.2.3 
in biologically  biologically sourced materials 
sourced   
materials   Detailed information, including for materials  3.2.A.2 
(Viral Safety)   of biological origin, testing at appropriate 
stages of production, and viral clearance 
studies 
 
Residual Host  Design Space for an individual unit operation  3.2.S.2.2 
Cell Proteins    (e.g., see Example 3)   
 
Target range for consistent removal assured  3.2.S.2.5 
by validation 
 
Analytical procedures and their validation  3.2.S.4.2 and 
3.2.S.4.3 
Specific  Controls implicit in the design of the  3.2.S.2.2 
Glycoforms   manufacturing process, including a summary 
of process control steps (e.g., cell culture 
conditions, downstream purification, holding 
conditions) 
 
Characterization to justify classification as  3.2.S.3.1 
CQA (cross-reference to nonclinical/clinical   
sections if relevant)   
  
Control of Critical Steps, Testing program and  3.2.S.2.4 and/or 
specifications   3.2.S.4.1 
 
Justification of specification  3.2.S.4.5 
  
Stability  3.2.S.7 
  
 
 
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Table 5b. Example of a Possible Control Strategy Summary  Chemical Entity. 
 
In process Controls  Controls on material   Impact of  Is CQA 
  Type of    (including In-process  attributes  Manufacturing  tested on 
  Control  testing and process  (raw   Process Design   drug 
Drug     parameters)  materials/starting  substance/  
Substance   materials  included in 
/intermediates)    Drug 
CQA (3.2.S.2.6) / 
Substance  
Limit in Drug 
specification  
Substance  
(3.2.S.4.1) 
Organic Purity          
-  Impurity X  Design space of  the reflux unit operation  Yes/Yes 
NMT* 0.15%  composed of a combination of  percentage of  
water in Intermediate E and the reflux time in step  
5 that delivers Intermediate F with Hydrolysis 
Impurity  0.30%  (3.2.S.2.2) 
-  Impurity Y  Process parameters      Yes/Yes 
NMT 0.20%  step 4 (3.2.S.2.2) 
p(H) 2 barg 
2
T <50C 
In-process test step 4 
(3.2.S.2.4) 
Impurity Y 0.50% 
-  Any individual    Spec for starting      Yes/Yes 
unspecified  material D (3.2.S.2.3) 
impurity  
NMT 0.10% 
-  Total impurities       Yes/Yes 
NMT 0.50% 
Enantiomeric purity     Spec for starting    Stereocenter is   No/No 
-  S-enantiomer  material D (3.2.S.2.3)  shown not to 
NMT 0.50%  - S-enantiomer  racemize 
0.50%  (3.2.S.2.6) 
Residual Solvent         
-  Ethanol  In-process test during    In-process  No/Yes 
NMT 5000 ppm  drying after final  results 
purification step   correlated to test  
(3.2.S.2.4)  results on drug  
LOD 0.40 %   substance 
(3.2.S.2.6) 
-  Toluene  In-process test step 4    Process steps  No/No1  
NMT 890 ppm  (3.2.S.2.4)  after step 4 are 
2000 ppm by G.C  shown to purge 
toluene to levels  
significantly  
below (less than 
10%) that 
indicated in 
ICH Q3C 
(3.2.S.2.6) 
* NMT: not more than 
1This approach could be acceptable as part of a control strategy  when justified by submission of relevant process data that  
confirm the adequacy of the process design and control.  The manufacturing process should be periodically evaluated under the 
firm's quality system to verify removal of the solvent. 
 
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Notes Concerning Table 5b: 
 
The above table is based on the route of synthesis presented in Example 1.  The Control for 
enantiomeric impurity is based on Decision Tree 5 from ICH Q6A, which allows for control of 
chiral quality to be established by applying limits to appropriate starting materials or 
intermediates when justified from development studies.  For this approach to be acceptable, data 
would need to be provided in 3.2.S.2.6 to demonstrate the stability of the stereocenter under the 
proposed manufacturing conditions. 
 
The table summarizes only a portion of the control strategy that would be presented at the time 
of initial submission and does not include all CQAs of the drug substance.  The example control 
strategy provides for control of some CQAs at stages in the process prior to the drug substance. 
The elements of the proposed control strategy described in the application would be justified by 
the applicant and subject to regulatory assessment and approval.  
 
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XI.  GLOSSARY (11)  

 
Chemical Transformation Step: For Chemical Entities, a step involved in the synthesis of the 
chemical structure of the drug substance from  precursor molecular fragments.  Typically, it 
involves C-X or C-C bond formation or breaking. 
 
Contaminants: Any adventitiously introduced materials (e.g., chemical, biochemical, or 
microbial species) not intended to be part of the manufacturing process of the drug substance or 
drug product. (ICH Q6B) 
 
Continuous Process Verification: An alternative approach to process validation in which 
manufacturing process performance is continuously monitored and evaluated. (ICH Q8) 
 
Control Strategy: A planned set of controls, derived from current product and process 
understanding, that assures process performance and product quality.  The controls can include 
parameters and attributes related to drug substance and drug product materials and components, 
facility and equipment operating conditions, in-process controls, finished product specifications, 
and the associated methods and frequency of monitoring and control. (ICH Q10) 
 
Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property 
or characteristic that should be within an appropriate limit, range, or distribution to ensure the 
desired product quality. (ICH Q8) 
 
Design Space: The multidimensional combination and interaction of input variables (e.g., 
material attributes) and process parameters that have been demonstrated to provide assurance of 
quality. Working within the design space is not considered as a change.  Movement out of the 
design space is considered to be a change and would normally initiate a regulatory postapproval 
change process. Design space is proposed by the applicant and is subject to regulatory 
assessment and approval. (ICH Q8) 
 
Intermediate: See ICH Q7, ICH Q3A, and ICH Q5C Quality of Biotechnological Products: 
Stability Testing of Biotechnological/Biological Products. 
 
Impurity:  See ICH Q3A, ICH Q6A, and ICH Q6B. 
 
Lifecycle: All phases in the life of a product from the initial development through marketing 
until the products discontinuation (ICH Q8). 
 
Platform Manufacturing: The approach of developing a production strategy for a new drug 
starting from manufacturing processes similar to those used by the same applicant to  
manufacture other drugs of the same type (e.g., as in the production of monoclonal antibodies 
using predefined host cell, cell culture, and purification processes, for which there already exists 
considerable experience). 
 
Process Robustness: Ability of a process to tolerate variability of materials and changes of the 
process and equipment without negative impact on quality. (ICH Q8) 
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Quality Risk Management (QRM): A systematic process for the assessment, control, 
communication, and review of risks to the quality of the drug (medicinal) product across the 
product lifecycle. (ICH Q9) 
 
Quality Target Product Profile (QTPP): A prospective summary of the quality characteristics of  
a drug product that ideally will be achieved to ensure the desired quality, taking into account 
safety and efficacy of the drug product. (ICH Q8) 
 
Real Time Release Testing: The ability to evaluate and ensure the quality of in-process and/or 
final product based on process data, which typically include a valid combination of measured 
material attributes and process controls. (ICH Q8) 
 
 
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