ICH Q11: BIO Comments on International Conference on Harmonisation; Draft Guidance on Q11 Development and Manufacture of Drug Substances

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on the “International Conference on Harmonisation (ICH); Draft Guidance on Q11 Development and Manufacture of Drug Substances.”  We appreciate the efforts of FDA and other ICH parties to harmonize the scientific and technical principles relating to the description and justification of the development and manufacturing process in the Common Technical Document (CTD) to enable a consistent approach for providing and evaluating this information across the three international regions. Overall, BIO agrees with and supports the Draft Guidance, which is consistent with Quality-by-Design (QbD) principles and provides enough flexibility to establish a risked-based approach with a variety of project circumstances.  We have provided the following general comments and specific line-by-line changes to enhance the value of the document to biopharmaceutical manufacturers.

BIO represents more than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment. 

I. Positive Changes and Useful Examples in the Guidance to be Retained

The Draft Guidance makes several positive recommendations that make significant progress towards a more science and risk-based approach, which should be retained in the final document.  These recommendations, such as approaches to starting material selection and justification and appropriate use of data from smaller-scale studies to support process validation, are discussed in greater detail in our specific comments.

The Draft Guidance provides useful examples that compare the traditional approaches to the enhanced approaches.  BIO also appreciates the inclusion of examples and sections that address the specific concerns for biotechnological/biological entities.  For example:

  • Section 3, Manufacturing Process Development, serves as a good roadmap for developing a strategy for manufacturing process development and defining the critical aspects that need to be investigated.  The subsection outlining the information that should be included in a submission is also informative.


  • Illustrative Example 2, Use of Quality “Risk Management to Support Lifecycle Management of Process Parameters, provides a very useful approach on how process parameters can be categorized using Quality Risk management, and most importantly provides a potential regulatory mechanism on how future changes to such parameters can be handled post-approval at an ICH level, which can help in driving for global harmonization for post-approval changes.


  • Illustrative example 4, Selecting an Appropriate Starting Material, is a good example of how to consider all general principles in conjunction, rather that applying each general principle in isolation.

Case studies and mock-ups developed for ICH Q8, such as Sakura tablets by the Japanese National Institute of Health Sciences (NIHS) and “Examplain” hydrochloride by theEuropean Federation of Pharmaceutical Industries and Associations(EFPIA), were very helpful.  Please consider developing similar mock-ups or case studies for this guideline.

II. Flexible Regulatory Approaches to QbD

The Draft Guidance states that “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 authorisation. (Lines 82-84)  BIO agrees that the application of flexible regulatory approaches, especially as it applies to post approval change management, is an important concept that should be retained in the final document. 

III. Critical Process Parameters and Consolidation of ICH Guidelines:

There is no mention in the Draft Guidance of Critical Process Parameters associated with drug substance.  The definition of parameter criticality is a challenge for many companies, and general approaches to defining criticality should be described.  Equally the link between critical process parameters and design space have not been addressed in this guidance as well as in Q8, thus leaving a significant gap in driving for global harmonization of “What constitutes a design space”.  We hope that the ICH Q11 Expert Working Group (EWG) will take this under consideration and provide additional guidance in this area.

Overall it may make sense after finalizing Q11 to consider consolidating Q8 and Q11 into one ICH guideline on Pharmaceutical development with the following parts.  By doing this it may be possible to eliminate some of the redundant text in Q11.

1.      General development approaches (ICH Q8 (R2)-Part II)

2.      DP specifics (ICH Q8 (R2)-Part I)

3.      API specifics (ICH Q11 core)

4.      Examples (ICH Q11 examples)


BIO appreciates this opportunity to comment on the “International Conference on Harmonisation; Draft Guidance on Q11 Development and Manufacture of Drug Substances.”  Specific, detailed comments are included in the following chart.  We would be pleased to provide further input or clarification of our comments, as needed. 

Read full comment letter here