Guidance for Industry 

 
 
Q8(R2) Pharmaceutical 

Development 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 2009 

ICH 

 
Revision 2 

   
Guidance for Industry 

 
 
Q8(R2) Pharmaceutical 

Development
 
  
 
 
 
 
 
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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  

 
 
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 Food and Drug  Administration 

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http://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) 

 
November 2009 

ICH 

 
Revision 2
 
   
TABLE OF CONTENTS 
 
PHARMACEUTICAL DEVELOPMENT  PARENT GUIDANCE 
 
I.   INTRODUCTION (1, 1.1)................................................................................................ 1 
 
II.   PHARMACEUTICAL DEVELOPMENT (2) ............................................................... 2 
 
A.   Components of the Drug Product (2.1)........................................................................................4
  
1.  Drug Substance (2.1.1)....................................................................................................................4
  
2.  Excipients (2.1.2) .............................................................................................................................4
  
B.   Drug Product (2.2).........................................................................................................................5
  
1.  Formulation Development (2.2.1)....................................................................................................5
  
2.  Overages (2.2.2) ..............................................................................................................................5
  
3.  Physicochemical and Biological Properties (2.2.3) ........................................................................6
  
C.   Manufacturing Process Development (2.3)..................................................................................6 
 
D.   Container Closure System (2.4)....................................................................................................7
  
E.   Microbiological Attributes (2.5) ...................................................................................................7
  
F.   Compatibility (2.6) .........................................................................................................................8
  
III.   GLOSSARY (3)................................................................................................................. 9 

 
PHARMACEUTICAL DEVELOPMENT  ANNEX 
 
1.   INTRODUCTION (1)..................................................................................................... 10 
 
II.	   ELEMENTS OF PHARMACEUTICAL DEVELOPMENT (2)................................ 11 
 
A. 	  Quality Target Product Profile (2.1)..........................................................................................11
  
B. 	  Critical Quality Attributes (2.2) .................................................................................................12
  
C. 	  Risk Assessment: Linking Material Attributes and Process Parameters to Drug Product 

CQAs (2.3) ....................................................................................................................................12 
 
D. 	  Design Space (2.4) ........................................................................................................................13 
 
1.  Selection of Variables (2.4.1).........................................................................................................13 
 
2.  Describing a Design Space in a Submission (2.4.2)......................................................................13 
 
3.  Unit Operation Design Space(s) (2.4.3)........................................................................................13
  
4.  Relationship of Design Space to Scale and Equipment (2.4.4)......................................................14
  
5.  Design Space Versus Proven Acceptable Ranges (2.4.5)..............................................................14
  
6.  Design Space and Edge of Failure (2.4.6).....................................................................................14 
 
E.   Control Strategy (2.5)..................................................................................................................14
  
F.   Product Lifecycle Management and Continual Improvement (2.6)........................................15
  
III. 	  SUBMISSION OF PHARMACEUTICAL DEVELOPMENT AND RELATED 
INFORMATION IN COMMON TECHNICAL DOCUMENT (CTD)  
FORMAT (3) ................................................................................................................... 16 
 
   
A.   Quality Risk Management and Product and Process Development (3.1)...............................16 
 
B.   Design Space (3.2) ........................................................................................................................16
  
C.   Control Strategy (3.3)..................................................................................................................16
  
D.   Drug Substance Related Information (3.4)................................................................................17 
 
IV. 	  GLOSSARY (4)............................................................................................................... 18
  
Appendix 1.  Differing Approaches to Pharmaceutical Development..........................................19
  
Appendix 2.   Illustrative Examples...................................................................................................20 
 
  Contains Nonbinding Recommendations  
 
1
 
Guidance for Industry  
 
Q8(R2) Pharmaceutical Development 

 
 
 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
This guidance is a revision of the ICH guidance Q8 Pharmaceutical Development (Q8 parent 
guidance) that published in May 2006. In June 2009, the Q8 parent guidance was revised to add 
an annex, which provides further clarification of the key concepts outlined in the May 2006 
guidance and describes the principles of quality by design (QbD).  The Q8(R1) document issued  
in June 2009 includes the Q8 parent guidance and the annex.  This second revision, Q8(R2), 
provides corrected captions for figures 2a and 2b in Appendix 2, section C. 
 
 
I.  INTRODUCTION (1, 1.1)2  
 
The Q8 parent guidance describes the suggested contents for the 3.2.P.2 (Pharmaceutical 
Development) section of a regulatory submission in the ICH M4 Common Technical Document 
(CTD) format. 
 
The Pharmaceutical Development section provides an opportunity to present the knowledge 
gained through the application of scientific approaches and quality risk management (for 
                                                 
1  This guidance was developed within  the Expert Working Group (Quality) 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 guidance includes an  
annex to Q8 Pharmaceutical Development  (the Q8 parent guidance).  The  annex has been endorsed  by the ICH  
Steering Committee at Step 4 of the ICH process, November 2008.  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.  Following  
the addition  of  the annex to the Q8  parent guidance, ICH recoded  the guidance Q8(R1). In  August 2009, ICH 
issued Q8(R2) with corrected captions for figures 2a and  2b  in Appendix 2, section C. 
2 Arabic numbers reflect the organizational  breakdown of the Q8  parent  guidance endorsed  by the ICH Steering 
Committee at Step 4 of the ICH process, November  2005. 
 
  1
  Contains Nonbinding Recommendations  
 
definition, see ICH Q9 Quality Risk Management)3 to the development of a product and its 
manufacturing process. It is first produced for the original marketing application and can be 
updated to support new knowledge gained over the lifecycle4 of a product. The Pharmaceutical 
Development section is intended to provide a comprehensive understanding of the product and 
manufacturing process for reviewers and inspectors. The guidance also indicates areas where the  
demonstration of greater understanding of pharmaceutical and manufacturing sciences can create 
a basis for flexible regulatory approaches. The degree of regulatory flexibility is predicated on 
the level of relevant scientific knowledge provided. 
 
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.  
 
Scope (1.2) 
 
This guidance is intended to provide guidance on the contents of section 3.2.P.2 (Pharmaceutical 
Development) for drug products as defined in the scope of Module 3 of the Common Technical 
Document (ICH M4:   Common Technical Document for the Registration of Pharmaceuticals for 
Human Use). The guidance does not apply to contents of submissions for drug products during 
the clinical research stages of drug development. However, the principles in this guidance are 
important to consider during those stages as well. This guidance might also be appropriate for 
other types of products. To determine the applicability of this guidance to a particular type of 
product, applicants can consult with the appropriate regulatory authorities. 
  
 
II.  PHARMACEUTICAL DEVELOPMENT (2) 
 
The aim of pharmaceutical development is to design a quality product and its manufacturing 
process to consistently deliver the intended performance of the product. The information and 
knowledge gained from pharmaceutical development studies and manufacturing experience 
provide scientific understanding to support the establishment of the design space, specifications, 
and manufacturing controls.    
 
Information from pharmaceutical development studies can be a basis for quality risk 
management. It is important to recognize that quality cannot be tested into products, i.e., quality 
should be built in by design. Changes in formulation and manufacturing processes during 
development and lifecycle management should be looked upon as opportunities to gain 
additional knowledge and further support establishment of the design space. Similarly, inclusion 
                                                 
3 Available on the Internet, on  the CDER guidance 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 CDER  guidance  
page. 
 
4  Terms that appear in  bold italic type in this guidance are defined in the glossary, section III (3). 
  2
  Contains Nonbinding Recommendations  
 
of relevant knowledge gained from experiments giving unexpected results can also be useful. 
Design space is proposed by the applicant and is subject to regulatory assessment and approval. 
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. 
 
The Pharmaceutical Development section should describe the knowledge that establishes that the 
type of dosage form selected and the formulation proposed are suitable for the intended use. This 
section should include sufficient information in each part to provide an understanding of the 
development of the drug product and its manufacturing process. Summary tables and graphs are 
encouraged where they add clarity and facilitate review. 
 
At a minimum, those aspects of drug substances, excipients, container closure systems, and 
manufacturing processes that are critical to product quality should be determined and control 
strategies justified. Critical formulation attributes and process parameters are generally identified 
through an assessment of the extent to which their variation can have impact on the quality of the 
drug product. 
 
In addition, the applicant can choose to conduct pharmaceutical development studies that can 
lead to an enhanced knowledge of product performance over a wider range of material attributes, 
processing options and process parameters. Inclusion of this additional information in the 
Pharmaceutical Development section provides an opportunity to demonstrate a higher degree of 
understanding of material attributes, manufacturing processes, and their controls. This scientific 
understanding facilitates establishment of an expanded design space. In these situations, 
opportunities exist to develop more flexible regulatory approaches, for example, to facilitate: 
 
 	  risk-based regulatory decisions (reviews and inspections) 
 	  manufacturing process improvements, within the approved design space described in the 
dossier, without further regulatory review 
 	  reduction of postapproval submissions 
 	  real-time quality control, leading to a reduction of end-product release testing 
 
To realize this flexibility, the applicant should demonstrate an enhanced knowledge of product 
performance over a range of material attributes, manufacturing process options and process 
parameters. This understanding can be gained by application of, for example, formal 
experimental designs, process analytical technology (PAT), and/or prior knowledge. 
Appropriate use of quality risk management principles can be helpful in prioritizing the 
additional pharmaceutical development studies to collect such knowledge. 
 
The design and conduct of pharmaceutical development studies should be consistent with their 
intended scientific purpose. It should be recognized that the level of knowledge gained, and not 
the volume of data, provides the basis for science-based submissions and their regulatory 
evaluation. 
 
  3
  Contains Nonbinding Recommendations  
 
A.  Components of the Drug Product (2.1) 
 
1.  Drug Substance (2.1.1)  
 
The physicochemical and biological properties of the drug substance that can influence the 
performance of the drug product and its manufacturability, or were specifically designed into the 
drug substance (e.g., solid state properties), should be identified and discussed.  Examples of 
physicochemical and biological properties that should be examined, as appropriate, include 
solubility, water content, particle size, crystal properties, biological activity, and permeability. 
These properties could be interrelated and, when appropriate, should be considered in 
combination.   
 
To evaluate the potential effect of drug substance physicochemical properties on the performance 
of the drug product, studies on drug product might be warranted. For example, ICH Q6A 
Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New 
Drug Products: Chemical Substances describes some of the circumstances in which drug product 
studies are recommended (e.g., Decision Trees #3 and #4 (Part 2)). This approach applies equally 
for ICH Q6B Specifications: Test Procedures and Acceptance Criteria for 
Biotechnology/Biological Products. The knowledge gained from the studies investigating the 
potential effect of drug substance properties on drug product performance can be used, as 
appropriate, to justify elements of the drug substance specification (3.2.S.4.5).  
 
The compatibility of the drug substance with excipients listed in 3.2.P.1 should be evaluated. For 
products that contain more than one drug substance, the compatibility of the drug substances 
with each other should also be evaluated. 
 
2.  Excipients (2.1.2)  
 
The excipients chosen, their concentration, and the characteristics that can influence the drug 
product performance (e.g., stability, bioavailability) or manufacturability should be discussed 
relative to the respective function of each excipient. This should include all substances used in 
the manufacture of the drug product, whether they appear in the finished product or not (e.g., 
processing aids). Compatibility of excipients with other excipients, where relevant (for example, 
combination of preservatives in a dual preservative system), should be established. The ability of 
excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling agents) to 
provide their intended functionality and to perform throughout the intended drug product shelf 
life should also be demonstrated. The information on excipient performance can be used, as 
appropriate, to justify the choice and quality attributes of the excipient and to support the 
justification of the drug product specification (3.2.P.5.6).  
 
Information to support the safety of excipients, when appropriate, should be cross-referenced 
(3.2.P.4.6). 
  4
  Contains Nonbinding Recommendations  
 
 
B.  Drug Product (2.2) 
 
1.  Formulation Development (2.2.1)  
 
A summary should be provided describing the development of the formulation, including 
identification of those attributes that are critical to the quality of the drug product, taking into 
consideration intended usage and route of administration. Information from formal experimental 
designs can be useful in identifying critical or interacting variables that might be important to 
ensure the quality of the drug product. 
 
The summary should highlight the evolution of the formulation design from initial concept up to 
the final design. This summary should also take into consideration the choice of drug product 
components (e.g., the properties of the drug substance, excipients, container closure system, any 
relevant dosing device), the manufacturing process, and, if appropriate, knowledge gained from  
the development of similar drug product(s). 
 
Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in the 
Pharmaceutical Development section of the application; this justification can often be based on 
the experience gained during development or manufacture.   
 
A summary of formulations used in clinical safety and efficacy and in any relevant 
bioavailability or bioequivalence studies should be provided. Any changes between the proposed 
commercial formulation and those formulations used in pivotal clinical batches and primary 
stability batches should be clearly described and the rationale for the changes provided.  
 
Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies 
(e.g., bioequivalence) that links clinical formulations to the proposed commercial formulation 
described in 3.2.P.1 should be summarized and a cross-reference to the studies (with study 
numbers) should be provided. Where attempts have been made to establish an in vitro/in vivo 
correlation, the results of those studies and a cross-reference to the studies (with study numbers) 
should be provided in the Pharmaceutical Development section. A successful correlation can 
assist in the selection of appropriate dissolution acceptance criteria and can potentially reduce the 
need for further bioequivalence studies following changes to the product or its manufacturing 
process. 
 
Any special design features of the drug product (e.g., tablet score line, overfill, anti-
counterfeiting measure as it affects the drug product) should be identified and a rationale 
provided for their use. 
 
2.  Overages (2.2.2)  
 
In general, use of an overage of a drug substance to compensate for degradation during 
manufacture or a products shelf life, or to extend shelf life, is discouraged. 
 
  5
  Contains Nonbinding Recommendations  
 
Any overages in the manufacture of the drug product, whether they appear in the final 
formulated product or not, should be justified considering the safety and efficacy of the product.  
Information should be provided on the (1) amount of overage, (2) reason for the overage (e.g., to 
compensate for expected and documented manufacturing losses), and (3) justification for the 
amount of overage. The overage should be included in the amount of drug substance listed in the 
batch formula (3.2.P.3.2). 
 
3.  Physicochemical and Biological Properties (2.2.3)  
 
The physicochemical and biological properties relevant to the safety, performance, or 
manufacturability of the drug product should be identified and discussed. This includes the 
physiological implications of drug substance and formulation attributes. Studies could include, 
for example, the development of a test for respirable fraction of an inhaled product. Similarly, 
information supporting the selection of dissolution vs. disintegration testing (or other means to 
ensure drug release) and the development and suitability of the chosen test could be provided in 
this section. See also ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New  
Drug Substances and New Drug Products: Chemical Substances, Decision Tree #4 (Part 3) and 
Decision Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteria 
for Biotechnology/Biological Products. The discussion should cross-reference any relevant 
stability data in 3.2.P.8.3.  
 
C.  Manufacturing Process Development (2.3) 
 
The selection, the control, and any improvement of the manufacturing process described in 
3.2.P.3.3 (i.e., intended for commercial production batches) should be explained. It is important 
to consider the critical formulation attributes, together with the available manufacturing process 
options, in order to address the selection of the manufacturing process and confirm the 
appropriateness of the components. Appropriateness of the equipment used for the intended 
products should be discussed. Process development studies should provide the basis for process 
improvement, process validation, continuous process verification (where applicable), and any 
process control requirements. Where appropriate, such studies should address microbiological as 
well as physical and chemical attributes. The knowledge gained from process development 
studies can be used, as appropriate, to justify the drug product specification (3.2.P.5.6).  
 
The manufacturing process development program or process improvement program should 
identify any critical process parameters that should be monitored or controlled (e.g., granulation 
end point) to ensure that the product is of the desired quality.    
 
For those products intended to be sterile, an appropriate method of sterilization for the drug 
product and primary packaging material should be chosen and the choice justified.  
 
Significant differences between the manufacturing processes used to produce batches for pivotal 
clinical trials (safety, efficacy, bioavailability, bioequivalence) or primary stability studies and 
the process described in 3.2.P.3.3 should be discussed. The discussion should summarize the 
influence of the differences on the performance, manufacturability, and quality of the product. 
The information should be presented in a way that facilitates comparison of the processes and the 
  6
  Contains Nonbinding Recommendations  
 
corresponding batch analyses information (3.2.P.5.4). The information should include, for 
example, (1) the identity (e.g., batch number) and use of the batches produced (e.g., 
bioequivalence study batch number), (2) the manufacturing site, (3) the batch size, and (4) any 
significant equipment differences (e.g., different design, operating principle, size). 
 
In order to provide flexibility for future process improvement, when describing the development 
of the manufacturing process, it is useful to describe measurement systems that allow monitoring 
of critical attributes or process end-points. Collection of process monitoring data during the 
development of the manufacturing process can provide useful information to enhance process 
understanding. The process control strategies that provide process adjustment capabilities to 
ensure control of all critical attributes should be described.   
 
An assessment of the ability of the process to reliably produce a product of the intended quality 
(e.g., the performance of the manufacturing process under different operating conditions, at 
different scales, or with different equipment) can be provided. An understanding of process 
robustness can be useful in risk assessment and risk reduction (see ICH Q9 Quality Risk 
Management glossary for definition) and to support future manufacturing and process 
improvement, especially in conjunction with the use of risk management tools (see ICH Q9  
Quality Risk Management). 
 
D.  Container Closure System (2.4) 
 
The choice and rationale for selection of the container closure system for the commercial product 
(described in 3.2.P.7) should be discussed. Consideration should be given to the intended use of 
the drug product and the suitability of the container closure system for storage and transportation 
(shipping), including the storage and shipping container for bulk drug product, where 
appropriate. 
  
The  choice  of  materials  for  primary  packaging  should  be  justified.  The  discussion  should 
describe studies performed to demonstrate the integrity of the container and closure. A possible 
interaction between product and container or label  should be considered. 
 
The choice of primary packaging materials should consider, e.g., choice of materials, protection 
from moisture and light, compatibility of the materials of construction with the dosage form  
(including sorption to container and leaching), and safety of materials of construction.  
Justification for secondary packaging materials should be included, when relevant. 
  
If a dosing device is used (e.g., dropper pipette, pen injection device, dry powder inhaler), it is 
important to demonstrate that a reproducible and accurate dose of the product is delivered under 
testing conditions that, as far as possible, simulate the use of the product.  
 
E.  Microbiological Attributes (2.5) 
 
Where appropriate, the microbiological attributes of the drug product should be discussed in this 
section (3.2.P.2.5). The discussion should include, for example: 
 
  7
  Contains Nonbinding Recommendations  
 
	   The rationale for performing or not performing microbial limits testing for non sterile drug 
products (e.g., Decision Tree #8 in ICH Q6A Specifications: Test Procedures and 
Acceptance Criteria for New Drug Substances and New Drug Products: Chemical 
Substances and ICH Q6B Specifications: Test Procedures and Acceptance Criteria for 
Biotechnology/Biological Products)  
 
 	  The selection and effectiveness of preservative systems in products containing antimicrobial 
preservative or the antimicrobial effectiveness of products that are inherently antimicrobial 
 
 	  For sterile products, the integrity of the container closure system as it relates to preventing 
microbial contamination  
 
Although chemical testing for preservative content is the attribute normally included in the drug 
product specification, antimicrobial preservative effectiveness should be demonstrated during 
development. The lowest specified concentration of antimicrobial preservative should be 
demonstrated to be effective in controlling microorganisms by using an antimicrobial 
preservative effectiveness test. The concentration used should be justified in terms of efficacy 
and safety, such that the minimum concentration of preservative that gives the required level of 
efficacy throughout the intended shelf life of the product is used. Where relevant, microbial 
challenge testing under testing conditions that, as far as possible, simulate patient use should be 
performed during development and documented in this section.  
 
F.  Compatibility (2.6) 
 
The compatibility of the drug product with reconstitution diluents (e.g., precipitation, stability) 
should be addressed to provide appropriate and supportive information for the labeling. This 
information should cover the recommended in-use shelf life, at the recommended storage 
temperature and at the likely extremes of concentration. Similarly, admixture or dilution of 
products prior to administration (e.g., product added to large volume infusion containers) should 
be addressed. 
  8
  Contains Nonbinding Recommendations  
 
III.  GLOSSARY (3) 
 
Continuous Process Verification:  An alternative approach to process validation in which 
manufacturing process performance is continuously monitored and evaluated.  
 
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. 
 
Formal Experimental Design:  A structured, organized method for determining the relationship 
between factors affecting a process and the output of that process. Also known as Design of 
Experiments. 
 
Lifecycle:  All phases in the life of a product from the initial development through marketing 
until the products discontinuation.  
 
Process Analytical Technology (PAT):  A system for designing, analyzing, and controlling 
manufacturing through timely measurements (i.e., during processing) of critical quality and 
performance attributes of raw and in-process materials and processes with the goal of ensuring 
final product quality.  
 
Process Robustness:  Ability of a process to tolerate variability of materials and changes of the 
process and equipment without negative impact on quality. 
 
Quality:   The suitability of either a drug substance or drug product for its intended use. This 
term includes such attributes as the identity, strength, and purity (from ICH Q6A  Specifications: 
Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: 
Chemical Substances). 
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  Contains Nonbinding Recommendations  
 
PHARMACEUTICAL DEVELOPMENT  ANNEX 
 
1.  INTRODUCTION (1) 
 
This annex provides further clarification of key concepts outlined in Q8 Pharmaceutical 
Development (the Q8 parent guidance). In addition, this annex describes  the principles of quality 
by design (QbD).5 The annex is not intended to establish new standards or to introduce new 
regulatory requirements; however, it shows how concepts and tools (e.g., design space) outlined 
in the Q8 parent guidance could be put into practice by the applicant for all dosage forms. Where 
a company chooses to apply quality by design and quality risk management (ICH Q9 Quality 
Risk Management), linked to an appropriate pharmaceutical quality system, opportunities arise to 
enhance science- and risk-based regulatory approaches (see ICH Q10 Pharmaceutical Quality 
System).6   
 
Approaches to Pharmaceutical Development 
 
In all cases, the product should be designed to meet patients needs and the intended product 
performance. 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. An applicant might choose either an empirical approach or a more 
systematic approach to product development, or a combination of both. An illustration of the 
potential contrasts of these approaches is shown in Appendix 1.  A more systematic approach to 
development (also defined as quality by design) can include, for example, incorporation of prior 
knowledge, results of studies using design of experiments, use of quality risk management, and 
use of knowledge management (see ICH Q10) throughout the lifecycle of the product. Such a 
systematic approach can enhance achieving the desired quality of the product and help the 
regulators to better understand a companys strategy. Product and process understanding can be 
updated with the knowledge gained over the product lifecycle. 
 
A greater understanding of the product and its manufacturing process can create a basis for more 
flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of  
relevant scientific knowledge provided in the registration application. It is the knowledge gained 
and submitted to the authorities, and not the volume of data collected, that forms the basis for 
science- and risk-based submissions and regulatory evaluations. Nevertheless, appropriate data 
demonstrating that this knowledge is based on sound scientific principles should be presented 
with each application. 
 
Pharmaceutical development should include, at a minimum, the following elements: 
 
 	  Defining the quality target product profile  (QTPP) as it relates to quality, safety and 
efficacy, considering e.g., the route of administration, dosage form, bioavailability, 
strength, and stability 
                                                 
5 Terms that appear in bold italic type in this  annex are defined in the annex glossary, section IV (4). 
 
6 Available on the Internet at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
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  Contains Nonbinding Recommendations  
 
 
	   Identifying potential critical quality attributes (CQAs) of the drug product, so that those 
product characteristics having an impact on product quality can be studied and controlled 
 
	   Determining the critical quality attributes of the drug substance, excipients, etc., and 
selecting the type and amount of excipients to deliver drug product of the desired quality  
 
	   Selecting an appropriate manufacturing process  
 
	   Defining a control strategy  
 
An enhanced, quality by design approach to product development would additionally include the 
following elements:  
 
	   A systematic evaluation, understanding and refining of the formulation and 

manufacturing process, including 

 
o	   Identifying (through, e.g., prior knowledge, experimentation, and risk assessment) 
the material attributes and process parameters that can have an effect on product 
CQAs 
o	   Determining the functional relationships that link material attributes and process 
parameters to product CQAs 
 
	   Using the enhanced product and process understanding in combination with quality risk 
management to establish an appropriate control strategy, which can, for example, include 
a proposal for a design space(s) and/or real-time release testing  
 
As a result, this more systematic approach could facilitate continual improvement and innovation 
throughout the product lifecycle (see ICH Q10). 
 
II.  ELEMENTS OF PHARMACEUTICAL DEVELOPMENT (2) 
 
The section that follows elaborates on possible approaches to gaining a more systematic, 
enhanced understanding of the product and process under development. The examples given are 
purely illustrative and are not intended to create new regulatory requirements. 
 
A.  Quality Target Product Profile (2.1)  
 
The quality target product profile forms the basis of design for the development of the product. 
Considerations for the quality target product profile could include: 
 
	   Intended use in clinical setting, route of administration, dosage form, delivery systems 
	   Dosage strength(s) 
	   Container closure system 
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	   Therapeutic moiety release or delivery and attributes affecting pharmacokinetic 
characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug 
product dosage form being developed 
 	  Drug product quality criteria (e.g., sterility, purity, stability, and drug release) appropriate 
for the intended marketed product 
 
B. 	 Critical Quality Attributes (2.2) 
 
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.  
CQAs are generally associated with the drug substance, excipients, intermediates (in-process 
materials), and drug product.  
 
CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, 
drug release, and stability. CQAs for other delivery systems can additionally include more 
product specific aspects, such as aerodynamic properties for inhaled products, sterility for 
parenterals, and adhesion properties for transdermal patches.  For drug substances, raw materials,  
and intermediates, the CQAs can additionally include those properties (e.g., particle size 
distribution, bulk density) that affect drug product CQAs. 
 
Potential drug product CQAs derived from the quality target product profile and/or prior 
knowledge are used to guide the product and process development. The list of potential CQAs 
can be modified when the formulation and manufacturing process are selected and as product 
knowledge and process understanding increase.  Quality risk management can be used to 
prioritize the list of potential CQAs for subsequent evaluation.   Relevant CQAs can be identified 
by an iterative process of quality risk management and experimentation that assesses the extent  
to which their variation can have an impact on the quality of the drug product. 
 
C. 	 Risk Assessment: Linking Material  Attributes and Process Parameters to 
Drug Product CQAs (2.3) 
 
Risk assessment is a valuable science-based process used in quality risk management (see ICH 
Q9) that can aid in identifying which material attributes and process parameters potentially have 
an effect on product CQAs. Risk assessment is typically performed early in the pharmaceutical 
development process and is repeated as more information becomes available and greater 
knowledge is obtained. 
 
Risk assessment tools can be used to identify and rank parameters (e.g., process, equipment, 
input materials) with potential to have an impact on product quality, based on prior knowledge 
and initial experimental data. For an illustrative example, see Appendix 2. The initial list of  
potential parameters can be quite extensive, but can be modified and prioritized by further 
studies (e.g., through a combination of design of experiments, mechanistic models). The list can 
be refined further through experimentation to determine the significance of individual variables 
and potential interactions. Once the significant parameters are identified, they can be further 
studied (e.g., through a combination of design of experiments, mathematical models, or studies 
that lead to mechanistic understanding) to achieve a higher level of process understanding.  
  12
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D.  Design Space (2.4) 
 
The relationship between the process inputs (material attributes and process parameters) and the 
critical quality attributes can be described in the design space (see examples in Appendix 2). 
 
1.  Selection of Variables (2.4.1)  
 
The risk assessment and process development experiments described in Section 2.3 can lead to 
an understanding of the linkage and effect of process parameters and material attributes on 
product CQAs and also help identify the variables and their ranges within which consistent 
quality can be achieved. These process parameters and material attributes can thus be selected 
for inclusion in the design space.  
 
A description should be provided in the application of the process parameters and material 
attributes considered for the design space, those that were included, and their effect on product 
quality. The rationale for inclusion in the design space should be presented.  In some cases, it is 
helpful to provide also the rationale as to why some parameters were excluded. Knowledge 
gained from studies should be described in the submission. Process parameters and material 
attributes that were not varied through development should be highlighted. 
 
2.  Describing a Design Space in a Submission (2.4.2)  
 
A design space can be described in terms of ranges of material attributes and process parameters, 
or through more complex mathematical relationships. It is possible to describe a design space as 
a time dependent function (e.g., temperature and pressure cycle of a lyophilization cycle), or as a 
combination of variables such as components of a multivariate model.  Scaling factors can also 
be included if the design space is intended to span multiple operational scales. Analysis of 
historical data can contribute to the establishment of a design space. Regardless of how a design 
space is developed, it is expected that operation within the design space will result in a product 
meeting the defined quality.  
 
Examples of different potential approaches to presentation of a design space are presented in 
Appendix 2. 
 
3.  Unit Operation Design Space(s) (2.4.3)  
 
The applicant can choose to establish independent design spaces for one or more unit operations, 
or to establish a single design space that spans multiple operations. While a separate design space 
for each unit operation is often simpler to develop, a design space that spans the entire process 
can provide more operational flexibility. For example, in the case of a drug product that 
undergoes degradation in solution before lyophilization, the design space to control the extent of 
degradation (e.g., concentration, time, temperature) could be expressed for each unit operation or 
as a sum over all unit operations. 
 
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4.  Relationship of Design Space to Scale and Equipment (2.4.4) 
 
When describing a design space, the applicant should consider the type of operational flexibility 
desired. A design space can be developed at any scale. The applicant should justify the relevance 
of a design space developed at small or pilot scale to the proposed production scale 
manufacturing process and discuss the potential risks in the scale-up operation.  
 
If the applicant proposes the design space to be applicable to multiple operational scales, the 
design space should be described in terms of relevant scale-independent parameters. For 
example, if a product was determined to be shear sensitive in a mixing operation, the design 
space could include shear rate, rather than agitation rate. Dimensionless numbers and/or models 
for scaling can be included as part of the design space description. 
 
5.  Design Space Versus Proven Acceptable Ranges (2.4.5)  
 
A combination of proven acceptable ranges does not constitute a design space. However, proven 
acceptable ranges based on univariate experimentation can provide useful knowledge about the 
process. 
 
6.  Design Space and Edge of Failure (2.4.6)  
 
It can be helpful to determine the edge of failure for process parameters or material attributes, 
beyond which the relevant quality attributes cannot be met. However, determining the edge of 
failure or demonstrating failure modes are not essential parts of establishing a design space. 
 
E.  Control Strategy (2.5) 
 
A control strategy is designed to ensure that  a product of required quality will be produced 
consistently. The elements of the control strategy discussed in Section P.2 of the dossier should 
describe and justify how in-process controls and the controls of input materials (drug substance 
and excipients), intermediates (in-process materials), container closure system, and drug 
products contribute to the final product quality. These controls should be based on product, 
formulation, and process understanding and should include, at a minimum, control of the critical  
process parameters and material attributes. 
 
A comprehensive pharmaceutical development approach will generate process and product 
understanding and identify sources of variability. Sources of variability that can have an impact 
on product quality should be identified, appropriately understood, and subsequently controlled. 
Understanding sources of variability and their impact on downstream processes or processing, 
in-process materials, and drug product quality can provide an opportunity to shift controls 
upstream and minimize the need for end-product testing. Product and process understanding, in 
combination with quality risk management (see ICH Q9), will support the control of the process 
such that the variability (e.g., of raw materials) can be compensated for in an adaptable manner 
to deliver consistent product quality. 
 
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  Contains Nonbinding Recommendations  
 
This process understanding can enable an alternative manufacturing paradigm where the 
variability of input materials could be less tightly constrained. Instead, it can be possible to 
design an adaptive process step (a step that is responsive to the input materials) with appropriate 
process control to ensure consistent product quality. 
 
Enhanced understanding of product performance can justify the use of alternative approaches to 
determine that the material is meeting its quality attributes. The use of such alternatives could 
support real time release testing. For example, disintegration could serve as a surrogate for 
dissolution for fast-disintegrating solid forms with highly soluble drug substances.  Unit dose 
uniformity performed in-process (e.g., using weight variation coupled with near infrared (NIR) 
assay) can enable real time release testing and provide an increased level of quality assurance 
compared to the traditional end-product testing using compendial content uniformity standards. 
Real-time release testing can replace end-product testing, but does not replace the review and 
quality control steps called for under GMP to release the batch. 
 
 
A control strategy can include, but is not limited to, the following: 
 
 	  Control of input material attributes (e.g., drug substance, excipients, primary packaging 
materials) based on an understanding of their impact on processability or product quality 
 	  Product specification(s) 
 	  Controls for unit operations that have an impact on downstream processing or product 
quality (e.g., the impact of drying on degradation, particle size distribution of the 
granulate on dissolution) 
 	  In-process or real-time release testing in lieu of end-product testing (e.g., measurement 
and control of CQAs during processing) 
 	  A monitoring program (e.g., full product testing at regular intervals) for verifying 

multivariate prediction models 

 
A control strategy can include different elements. For example, one element of the control 
strategy could rely on end-product testing, whereas another could depend on real-time release 
testing. The rationale for using these alternative approaches should be described in the 
submission. 
 
Adoption of the principles in this guidance can support the justification of alternative approaches 
to the setting of specification attributes and acceptance criteria as described in ICH Q6A and 
Q6B. 
 
F.  Product Lifecycle Management and Continual Improvement (2.6) 
 
Throughout the product lifecycle, companies have opportunities to evaluate innovative 
approaches to improve product quality (see ICH Q10). 
 
Process performance can be monitored to ensure that it is working as anticipated to deliver 
product quality attributes as predicted by the design space. This monitoring could include trend 
analysis of the manufacturing process as additional experience is gained during routine 
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  Contains Nonbinding Recommendations  
 
manufacture. For certain design spaces using mathematical models, periodic maintenance could 
be useful to ensure the models performance. The model maintenance is an example of activity 
that can be managed within a companys own internal quality system provided the design space 
is unchanged. 
 
Expansion, reduction, or redefinition of the design space could be desired upon gaining 
additional process knowledge. Change of design space is subject to regional requirements. 
 
III. 	 SUBMISSION OF PHARMACEUTICAL DEVELOPMENT AND RELATED 
INFORMATION IN COMMON TECHNICAL DOCUMENT (CTD) FORMAT (3) 
 
Pharmaceutical development information is submitted in Section P.2 of the CTD.  Other 
information resulting from pharmaceutical development studies could be accommodated by the 
CTD format in a number of different ways, and some specific suggestions are provided below. 
However, the applicant should clearly indicate where the different information is located. In 
addition to what is submitted in the application,  certain aspects described in this guidance (e.g., 
product lifecycle management, continual improvement) are handled under the applicants 
pharmaceutical quality system (see ICH Q10).  
 
A.  Quality Risk Management and Product and Process Development (3.1) 
 
Quality risk management can be used at different stages during product and process development 
and manufacturing implementation. The assessments used to guide and justify development 
decisions can be included in the relevant sections of P.2. For example, risk analyses and 
functional relationships linking material attributes and process parameters to product CQAs can 
be included in P.2.1, P.2.2, and P.2.3. Risk analyses linking the design of the manufacturing 
process to product quality can be included in P.2.3. 
 
B. 	 Design Space (3.2) 
 
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 (P.3.3). If appropriate, additional information can be provided in the section of 
the application that addresses the controls of critical steps and intermediates (P.3.4). The product 
and manufacturing process development sections of the application (P.2.1, P.2.2, and P.2.3) are 
appropriate places to summarize and describe  product and 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 product specification (P.5.6). 
 
C. 	 Control Strategy (3.3) 
 
The section of the application that includes the justification of the drug product specification 
(P.5.6) is a good place to summarize the overall drug product control strategy. However, detailed 
information about input material controls and process controls should still be provided in the 
appropriate CTD format sections (e.g., drug substance section (S), control of excipients (P.4), 
  16
  Contains Nonbinding Recommendations  
 
description of manufacturing process and process controls (P.3.3), controls of critical steps and 
intermediates (P.3.4)). 
 
D.  Drug Substance Related Information (3.4) 
 
If drug substance CQAs have the potential to affect the CQAs or manufacturing process of the 
drug product, some discussion of drug substance CQAs can be appropriate in the pharmaceutical 
development section of the application (e.g., P.2.1). 
  17
  Contains Nonbinding Recommendations  
 
IV.  ANNEX GLOSSARY (4) 
 
Control Strategy:  A planned set of controls, derived from current product and process 
understanding that ensures 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 Process Parameter (CPP):  A process parameter whose variability has an impact on a 
critical quality attribute and therefore should be monitored or controlled to ensure the process 
produces the desired quality. 
 
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. 
  
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). 
 
Lifecycle:  All phases in the life of a product from the initial development through marketing 
until the products discontinuation (ICH Q8). 
 
Proven Acceptable Range:  A characterized range of a process parameter for which operation 
within this range, while keeping other parameters constant, will result in producing a material 
meeting relevant quality criteria. 
 
Quality:  The suitability of either a drug substance or a drug product for its intended use. This 
term includes such attributes as the identity, strength, and purity (ICH Q6A). 
 
Quality by Design (QbD):  A systematic approach to development that begins with predefined 
objectives and emphasizes product and process understanding and process control, based on 
sound science and quality risk management. 
 
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. 
 
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.  
 
  18
  Contains Nonbinding Recommendations  
 
Appendix 1.    Differing Approaches to Pharmaceutical Development 
 
The following table has been developed to illustrate some potential contrasts between what 
might be considered a minimal approach and an enhanced, quality by design approach regarding 
different aspects of pharmaceutical development and lifecycle management. The comparisons 
are shown merely to aid in the understanding of a range of potential approaches to 
pharmaceutical development and should not be considered to be all-encompassing. The table is 
not intended to specifically define the only approach a company could choose to follow. In the 
enhanced approach, establishing a design space or using real time release testing is not 
necessarily expected. Current practices in the pharmaceutical industry vary and typically lie 
between the two approaches presented in the table. 
 
Aspect  Minimal Approaches   Enhanced, Quality by Design Approaches 
Overall    Mainly empirical     Systematic, relating mechanistic understanding of 
Pharmaceutical  material attributes and process parameters to drug 
  Developmental research often 
Development  product CQAs 
conducted one variable at a time 
  Multivariate experiments to understand product 
 
and process 
  Establishment of design space 
  PAT tools utilized 
Manufacturing    Fixed    Adjustable within design space
Process 
  Validation primarily based on    Lifecycle approach to validation and, ideally, 
initial full-scale batches  continuous process verification 
  Focus on optimization and    Focus on control strategy and robustness 
reproducibility  
  Use of statistical process control methods 
Process    In-process tests primarily for    PAT tools utilized with appropriate feed forward 
Controls  go/no go decisions   and feedback controls 
  Off-line analysis     Process operations tracked and trended to support 
continual improvement efforts postapproval 
Product    Primary means of control    Part of the overall quality control strategy  
Specifications 
  Based on batch data available at    Based on desired product performance with 
time of registration  relevant supportive data 
Control    Drug product quality controlled    Drug product quality ensured by risk-based 
Strategy  primarily by intermediates (in- control strategy for well-understood product and 
process materials) and end  process 
product testing 
  Quality controls shifted upstream, with the 
possibility of real-time release testing or reduced 
end-product testing 
Lifecycle    Reactive (i.e., problem solving    Preventive action  
Management  and corrective action) 
  Continual improvement facilitated 
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  Contains Nonbinding Recommendations  
 
Appendix 2.   Illustrative Examples 
 
A.  Use of a Risk Assessment Tool 
 
For example, a cross-functional team of experts could work together to develop an Ishikawa 
(fishbone) diagram that identifies potential variables that can have an impact on the desired 
quality attribute. The team could then rank the variables based on probability, severity, and 
detectability using failure mode effects analysis (FMEA) or similar tools based on prior 
knowledge and initial experimental data. Design of experiments or other experimental 
approaches could then be used to evaluate the impact of the higher ranked variables, to gain 
greater understanding of the process, and to develop a proper control strategy. 
 
Ishikawa Diagram  
 
  DDrryyiinngg    AAnnaallyyttiiccaall 
 
 
  TTeemmpp 
  
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AAiirr  FFllooww  SSaammpplliinngg 
 
  
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  TWabaletet  r 
      PPrreeccoommpprreessss  iinngg    WWaatteerr  SSuubbssttDDaannrruuccggee   Content
TTeemmpp//RRHH  MMaaiinn  CCoommpprreessssiinngg  BBiinnddeerr  AAggee 
        PP..SS.. 
OOppeerraattoorr  FFeeeeddeerr  SSppeeeedd  TTeemmpp  PPrroocceessss  CCoonnddiittiioonnss 
     LLOODD 
TTrraaiinniinngg  PPrreessss  SSppeeeedd  SSpprraayy  RRaattee 
  PPuunncchh  PPeenneeDDttrraaeettppiiootthhnn     SSpprraayy  PPaatttteerrnn  DDiilluueennttss 
    
PPllaanntt    TToooolliinngg  PP..SS.. 
  FFaaccttoorrss    FFrrFFaaeemmeeeedd     SSccrraappee  DDoowwnn  PPLL..OOSS..DD  
    
CCoommpprreessssiinngg   CChhooppppeerr  SSppeeeedd  OOtthheerr 
  MMiixxeerr  SSppeeeedd    LLuubbrriiccaanntt 
  EEnnddppooiinntt  DDiissiinntteeggrraanntt  RRaaww 
BBiinnddeerr  MMaatteerriiaallss 
 
   GGrraannuullaattiioonn 
  PPoowweerr 
TTiimmee 
 
 
 
 
 
 
 
 
 
 
 
 
 
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  Contains Nonbinding Recommendations  
 
 
B.  Depiction of Interactions 
 
The figure below depicts the presence or absence of interactions among three process parameters 
on the level of degradation product Y. The figure shows a series of two-dimensional plots 
showing the effect of interactions among three process parameters (initial moisture content, 
temperature, mean particle size) of the drying operation of a granulate (drug product 
intermediate) on degradation product Y. The relative slopes of the lines or curves within a plot 
indicate if interaction is present. In this example, initial moisture content and temperature are 
interacting; but initial moisture content and mean particle size are not, nor are temperature and 
mean particle size. 
 
 
  3300%% 
3300%% 
  11..55 
IInniittiiaall  

 11..00  1155%% 
YY mmooiissttuurree   
%%
00..55  ccoonntteenntt  ((IIMMCC))  1155%% 
00 
((dd ==  440000   mm))  ((TTeemmpp  ==  8800CC)) 
5500 
110000CC  110000CC 
11..55 
6600CC 
11..00 
YY  6600CC 
TTeemmppeerraattuurree 
%%
00..55 
00 
((dd ==  440000   mm))  ((IIMMCC  ==   2222..55%%))
5500 
770000  mm  770000  mm 
11..55 
11..00  110000  mm  110000  mm  MMeeaann   
YY
%% ppaarrttiiccllee  ssiizzee
00..55 
((dd )) 
5500
00 
((TTeemmpp  ==  8800CC))  ((IIMMCC  ==  2222..55%%)) 
1155  2200  2255  3300  6600  8800  110000  11  22 33  44 55  66 77  
IInniittiiaall  MMooiissttuurree  TTeemmpp ((CC))  MMeeaann   PPaarrttiiccllee   
CCoonntteenntt  ((%%))  SSiizzee ((xx110000  mm)) 
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  Contains Nonbinding Recommendations  
 
C.  Presentations of Design Space 
 
Example 1: Response graphs for dissolution are depicted as a surface plot (Figure 1a) and a 
contour plot (Figure 1b). Parameters 1 and 2 are factors of a granulation operation that affect the 
dissolution rate of a tablet (e.g., excipient attribute, water amount, granule size.) 
 
      
    
Figure 1a: Response surface plot of   Figure 1b: Contour plot of dissolution 
dissolution as a function of two parameters  from example 1a. 
of a granulation operation. Dissolution 
above 80% is desired. 
 
                                                 
 
Figure 1c: Design space for granulation  Figure 1d: Design space for granulation 
parameters, defined by a nonlinear  parameters, defined by a linear combination 
combination of their ranges, that delivers  of their ranges, that delivers satisfactory 
satisfactory dissolution (i.e., >80%).   dissolution (i.e., >80%). 
 
Two examples are given of potential design spaces. In Figure 1c, the design space is defined by a 
nonlinear combination of parameter ranges that delivers the dissolution critical quality attribute. 
In this example, the design space is expressed by the response surface equation resolved at the 
limit for satisfactory response (i.e., 80% dissolution). The acceptable range of one parameter is 
dependent on the value of the other. For example: 
  If Parameter 1 has a value of 46, then Parameter 2 has a range of 0 and 1.5 
  If Parameter 2 has a value of 0.8, then Parameter 1 has a range of 43 and 54 
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  Contains Nonbinding Recommendations  
 
 
The approach in Figure 1c allows the maximum range of operation to achieve the desired 
dissolution rate. In Figure 1d, the design space is defined as a smaller range, based on a linear 
combination of parameters. 
 
  Parameter 1 has a range of 44 and 53 
  Parameter 2 has a range of 0 and 1.1  
 
While the approach in Figure 1d is more limiting, the applicant may prefer it for operational 
simplicity. 
 
This example discusses only two parameters and thus can readily be presented graphically. When 
multiple parameters are involved, the design space can be presented for two parameters, in a 
manner similar to the examples shown above, at different values (e.g., high, middle, low) within 
the range of the third parameter, the fourth parameter, and so on. Alternatively, the design space 
can be explained mathematically through equations describing relationships between parameters 
for successful operation. 
 
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  Contains Nonbinding Recommendations  
 
Example 2:  Design space determined from the common region of successful operating ranges 
for multiple CQAs. The relations of two CQAs (i.e., tablet friability and dissolution) to two 
process parameters of a granulation operation are shown in Figures 2a and 2b. Parameters 1 and 
2 are factors of a granulation operation that affect the dissolution rate of a tablet (e.g., excipient 
attribute, water amount, granule size). Figure 2c shows the overlap of these regions and the 
maximum ranges of the proposed design space. The applicant can elect to use the entire region as 
the design space, or some subset thereof. 
44--55%% 
>>  8800%%  33--44%% 
7755--8800%%  22--33%% 
7700--7755%%  <<  22%% 
6655--7700%% 
6600--6655%% 
 
      
Figure 2a: Contour plot of dissolution as a  Figure 2b: Contour plot of friability as a 
function of Parameters 1 and 2.  function of Parameters 1 and 2. 
 
 
 
Figure 2c: Proposed design space, 
comprised of the overlap region of 
ranges for friability and/or dissolution. 
 
  24
  Contains Nonbinding Recommendations  
 
Example 3:  The design space for a drying operation that is dependent upon the path of 
temperature and/or pressure over time.  The end point for moisture content is 1-2%.  
Operating above the upper limit of the design space can cause excessive impurity formation, 
while operating below the lower limit of the design space can result in excessive particle 
attrition. 
 
 
35% 
30%  Excessive 
Design space   impurity  
upper limit  formation 
25% 
nt
e
nt
o 20% 
C
e 
r
u 15% 
st
oi
M Design space  
10% 
lower limit 
Excessive 
5%  particle 
attrition
Endpoint  { 
criterion0  % 
0  2 4   6 8  1 0 12   
time (hr) 
 
 
  
 
  25