Understanding ICH Q11—FDA's Guidance on the Development and Manufacture of Drug Substances

May 2, 2013
Pharmaceutical Technology, Pharmaceutical Technology-05-02-2013, Volume 37, Issue 5

The author provides a review of FDA's guidance document, Guidance for Industry: Q11 Development and Manufacture of Drug Substances, and its relation to the International Conference on Harmonization's Q11 document and its application to the industry.

In November of 2012, FDA issued Q11 Development and Manufacture of Drug Substances (1). The International Conference on Harmonization (ICH) Q11 Expert Working Group developed the FDA guidance (1). Additionally, the term "guidance" is a reflection of the agency's current thinking on this topic and should be considered as nonbinding recommendations only. Current FDA regulations for GMPs do not cover APIs specifically, so the adoption of ICH Q11 as a guidance document was deemed to be a reasonable approach by the agency. In accordance with this guidance, manufacturers can use alternate approaches needed in the development of drug substances. Q11, however, delineates two viable approaches for drug-substance development: traditional and enhanced (2). The traditional approach is premised on establishing set points and specific operating ranges for all process parameters (2). The control strategy for drug substances is predicated on process reproducibility and repeatability and the implementation of an effective program for drug-substance testing against predefined criteria. The enhanced approach entails the employment of risk-management strategies and the application of scientific knowledge to garner a better understanding of process parameters (2). The concept is to develop and implement control strategies and then employ these strategies over the drug-substance lifecycle to support a better understanding of critical quality attributes (CQA) needed to produce safe drug substances and the establishment of design space (as applicable).

To enhance the understanding of Guidance for Industry: Q11 Development and Manufacture of Drug Substances, it is important to have some basic knowledge of ICH and the interrelationship of guidelines published by ICH. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use was founded in 1990. Pharmaceutical industry regulators from the United States, Japan, and Europe were brought together for the succinct purpose of improving global harmonization of regulatory requirements needed to support the design and development for medicines that are safe and effective in their intended use (3). Guidelines developed by ICH Expert Working Groups are divided into four categories: quality guidelines, efficacy guidelines, multidisciplinary guidelines, and safety guidelines (3). Several countries have adopted ICH guidelines as law; however, FDA only considers the guidelines as guidance. Implementation of the guidance provided in Q11 requires knowledge of applicable ICH guidelines referenced specifically in of Guidance for Industry: Q11 Development and Manufacture of Drug Substances.

Manufacturing process development

One of the requirements needed for the manufacturer of quality drug substances are validated processes capable of providing repeatable results. In support of accomplishing the task of manufacturing a quality product, manufacturing process development requires adherence with six quality principles delineated within Q11:

  • Drug-substance quality linked to drug product

  • Process-development tools

  • Approaches to development

  • Drug-substance CQAs

  • Linking material attributes and process parameters to drug substance CQAs

  • Design space (1).

Manufacturers are expected to understand the impact of raw-material attributes on drug substances (e.g., CQAs). Additionally, the expectation is that quality risk management (QRM) tools be employed wherever possible (4). Furthermore, manufacturers should focus on the design and development of a fundamentally sound approach for drug development. As delineated in the introduction, a traditional or enhanced approach can be employed or a combination for the two for drug-substance development. It should be noted that the traditional approach has been the preferred method of drug development for years. Q11 and FDA's guidance allows for some flexibility so manufacturers can implement a system that works for them. There are, however, specific elements that need to be implemented: identifying all CQAs, defining the manufacturing process, and defining and implementing a control strategy.

Finally, the identification of CQAs and understanding the influence certain material attributes exude on the manufacturing process should be considered a crucial aspect of the process. This is the area where implementing a control strategy and employing QRM becomes essential; and the concept of design space is introduced into the manufacturing equation. According to Q11, design space is the multidimensional combination and interaction of two elements: input variables and process parameters (1). Design space (as defined by the manufacturer) is subject to regulatory oversight by FDA. ICH Q8 (2.4) provides additional detail on the topic of design space.

The submission process for the enhanced approach: document requirements. There are mandatory submission requirements in support of manufacturing process development that must be considered by drug-substance manufacturers. The submission must contain sufficient detail to support the claim for product safety and efficacy needed for eventual commercialization. For example, the expectation is that the following documentation be included as part of the drug-substance submission.

  • An overall summary of the development process including: CQAs; description of design stages; description of material attributes; description of process parameters; and description and development of design spaces should be provided.

  • CQAs of the drug substance shall be listed.

  • A detailed discussion of the manufacturing process history needs to be provided.

  • Manufacturing development studies, including risk assessments employed in support of commercial development, including the control strategy, must be provided.

Description of process and process controls employed in manufacturing. It is imperative that the manufacturers of drug substances provide a detailed description of the manufacturing process and the processing controls employed. The most efficient way to adequate delineate processes is through the creation of flow charts. Flow charts are an inherent requirement, regardless of submission type. In fact, Q11 requires that a flow chart be provided as part of the submission process.

Material-selection process

In support of the development and manufacture of drug substances, it is imperative that the quality and physical properties of starting and source materials (note: there is no difference in source versus the starting materials the vernacular used varies by region) be understood (1). Similar to manufacturing process-development requirements, the selection of starting and source materials is also premised on adherence with applicable principles. Principles associated with the material selection process, as delineated within Section 5.1 of Q11 are:

  • Selection of starting materials for synthetic drug substances

  • Selection of starting materials for semisynthetic drug substances

  • The selection of source and starting materials for biotechnical/biological drug substances (1).

Drug substance manufacturers must implement a QRM strategy. Effective implementation of QRM will result in a better understanding of risk and the link between risk and the number of process steps. Also needing to be considered are drug-substance material properties and the management of drug impurities (1). According to Q11, regulatory authorities will assess the controls employed by manufacturers, "including those needed how impurities are formed in the process; how changes in the process could affect the formation, fate, and purge of impurities" (1).

As a point of reference, ICH Q7 is an excellent starting point when it comes to understanding the need for the employment of GMPs needed for managing starting materials (5). Application of ICH 7 has become mandatory in some ICH regions (e.g., the European Union). It should be noted that unlike reagents, starting material should be considered a significant structural fragment of the drug substance. Similar to synthetic drug substances, semisynthetic drug substance starting materials must be understood and adequately described (e.g., "chemical synthesis and elements of biological origin" [1]). When considering the selection of raw materials for biotechnological/biological drug substances, manufacturers should apply the ICH 5 series (6-10) of guidance documents (6).

Submission of relevant information. In support of the submission process, manufacturers are required to provide a list of the raw materials being used and their specifications, supported by written justification as to why these materials are acceptable. This justification is required for synthetic, semisynthetic, and biotechnological/biological drug substances.

Control strategy

A control strategy is the development and implementation of adequate controls to ensure the continued repeatability of process performance and the ongoing assurance of finished product quality. The control strategy and subsequent control steps implemented are premised on a thorough understanding of manufacturing processes, the expected behavioral characteristics of raw materials, and sources of variability associated with a CQA (1). Elements of an effective control strategy typically include:

  • Controls employed for raw materials

  • Controls associated with the design manufacturing process

  • In-process controls (i.e., testing and process control points)

  • Controls placed on the drug substance (e.g., release testing) (1).

Submission of relevant information. In support of the submission process, the control strategy employed must be provided in sufficient detail that includes a detailed description for each of the control-strategy elements. The information can be depicted in a table or through the use of a visual aid (e.g., flow chart delineating control points). As a minimum, the following control-strategy plan elements should be included in the submission:

  • Description of manufacturing-process controls

  • Controls employed for materials

  • Controls for identified critical process steps

  • Controls for the drug substance

  • Container closure systems (5).

Process validation

It is a fundamental expectation that manufacturers of drug substances validate their processes as appropriate. From an ICH perspective, 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" (1). The targeted result of process validation is the collection of scientific evidence to support claims that a process is stable and capable of providing a predictable and repeatable output. Validation activities are expected to be pursued from initial drug-substance design through to the processes employed for manufacturing, including packaging.

Employing the CTD format for information submission

Drug substance quality, safety, and efficacy data must be compiled and placed into the Common Technical Document (CTD) format. Additional guidance pertaining to FDA's requirement for electronic submissions can be found in Guidance for Industry: Providing Regulatory Submissions In Electronic Format—Certain Human Pharmaceutical Product Applications And Related Submissions Using the eCTD Specifications (11). According to ICH M4, the CTD is broken down into four modules (note: the first bulleted point is not part of the CTD):

  • Module 1—Region-Specific Information

  • Module 2—Quality and overall summary and clinical overview and summary

  • Module 3—Quality

  • Module 4—Nonclinical study reports

  • Module 5—Clinical-study reports (12-16).

According to FDA's guidance, organization of the electronic submission should be in folders that align with Modules 2 through 5 (11).

Lifecycle management

ICH Q11 requires the manufacturers of drug substances to implement continuous-improvement practices throughout the entire lifecycle of each drug substance. The employment of science and risk-based approaches for each lifecycle stage is a fundamental expectation of the ICH Q11 Guidance Document (1). A true lifecycle will encompass all stages from initial design and development, validation of processes, manufacturing, commercialization, and end-of-life. Manufacturers are expected to evaluate manufacturing processes, the control strategy, and ongoing product safety and efficacy. All knowledge garnered during these evaluations, including knowledge gained from post-market surveillance activities, should be used to drive ongoing product improvement. Additionally, information collected should include:

  • Process-development activities

  • Technology-transfer activities

  • Process-validation studies

  • Change-management activities (1).


In summary, FDA's guidance for industry, premised on ICH Q11, provides a blueprint for drug-substance manufacturers to follow when preparing a submission as part of the drug- substance application process, regardless whether a traditional or enhanced approach to design and development is pursued. It is imperative that subsidiary ICH and FDA guidance documents be reviewed and understood as these documents provide relevant information required as part of the drug-substance submission process. Fundamental requirements needing to be described, in sufficient detail, in support of the submission process are design and development, manufacturing processes, control strategy, use of starting materials, CQAs, approach to QRM, design space, and approach to continuous improvement. In closing, the CTD format has become the prescribed submission format for regulatory authorities. Ensuring that all of the technical data (i.e., quality, safety, and efficacy) required by the CTD format is organized by specific module will hopefully facilitate an orderly and efficient review of the drug substance application by the appropriate regulatory body.


1. FDA, Guidance for Industry: Q11 Development And Manufacture Of Drug Substances (FDA, November 2012).

2. ICH, Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/biological Entities) (May 2012).

3. ICH, ICH Website homepage, www.ich.org, accessed January 12, 2013.

4. ICH, Q8 (R2) Pharmaceutical Development (ICH, August 2009).

5. FDA, Guidance for Industry: Q7A Good Manufacturing Guidance For Active Pharmaceutical Ingredients (FDA, August 2001).

6. ICH, Q5A (R1) Chemical Synthesis and Elements of Biological Origin (ICH, September 1999).

7. ICH, Q5B Quality Of Biotechnological Products: Analysis Of The Expression Construct In Cells Used For Production of R-DNA Derived Protein Products (ICH, November 1995).

8. ICH, Q5C Quality of Biotechnological Products: Stability Testing Of Biotechnological/Biological Products (ICH, November 1995).

9. ICH, Q5D Derivation and Characterization of Cell Substrates Used for Production Of Biotechnological/Biological Products (ICH, July 1997).

10. ICH, Q5E Compatibility Of Biotechnological/Biological Products Subject To Changes In Their Manufacturing Process (ICH, November 2004).

11. FDA, Draft—Guidance For Industry: Providing Regulatory Submissions In Electronic Format—Certain Human Pharmaceutical Product Applications And Related Submissions Using the eCTD Specifications (FDA, January 2013).

12. FDA, Guidance for industry: M4Q: CTD–Quality (FDA, August 2001).

13. ICH, M4 (R3) Organization Of The Common Technical Document For The Registration Of Pharmaceuticals For Human Use (ICH, January 2004).

14. ICH, M4E (R1) The Common Technical Document For The Registration Of Pharmaceuticals For Human Use: Efficacy (ICH, September 2002).

15. ICH, M4Q (R1) The Common Technical Document For The Registration Of Pharmaceuticals For Human Use: Quality (ICH, September 2002).

16. ICH, M4S (R2) The Common Technical Document For The Registration Of Pharmaceuticals For Human Use: Safety (ICH, December 2002). PT

Bob Mehta is a principal consultant and recruiter at GMP ISO Expert Services and provides consulting service in pharma, biotech, medical device, API, and food/dietary supplement industries, contact@gmpisoexpert.com

Submitted: Dec. 28, 2012. Accepted: January 24, 2013.