Setting USP–NF Compendial Specifications in a Complex Supply Chain

With today’s global pharmaceutical supply chain, setting United States Pharmacopeia–National Formulary (USP– NF) compendial specifications for excipients is becoming increasingly complicated. This is due in part to the vast number of ingredients used in drug product formulations and the variety of ingredient sources and manufacturing methods, as well as the need to consider an excipient’s functionality. 

The modernization and updating of excipient monographs and the move away from nonspecific titrations to modern chromatographic analytical methods have made it increasingly clear that excipients typically are not small molecules, but rather very complex substances that require different types of specifications than small-molecule APIs. As a result, setting specifications for excipients is not straightforward¹.

In February 2017 the FDA and USP held a workshop titled, “Critical Importance of Excipients in Product Development: Why Excipients are Important Now and In the Future”². The workshop highlighted the importance of advancing the science of excipient selection and regulatory evaluation and discussed how excipient quality and variability impact generic drug development. The USP Excipient Impurities Joint Subcommittee recently published a Stimuli article in the May/June issue of Pharmacopeial Forum titled “The Complexity of Setting Compendial Specifications for Excipient Composition and Impurities”³. The article discusses the need to provide clear guidelines for setting excipient specifications. It also discusses the existing International Council for Harmonisation Q3A (R2) guidelines⁴ and USP General Notices and Requirements^{5, 6}, and the difficulties in applying these guidelines to excipients, and the types of components and impurities found in excipients. 

The subcommittee is considering development of a general information chapter to provide guidance on setting specifications for excipient composition and impurities and is seeking input from excipient manufacturers and users. Input from all stakeholders is critical to the development of composition and impurity specifications. The subcommittee encourages all interested parties to comment on the views and approaches presented in the Stimuli article. 

The Stimuli article is intended to:

• Provide the subcommittee’s views on the complexity of excipient composition; 
• Introduce definitions for “excipient composition,” “simple excipient,” “complex excipient,” and “excipient impurity;” and 
• Describe the challenges facing the USP Excipient Monographs 1 and 2 Expert Committees in setting specifications for different excipient components and impurities and provide guidance and a proposed direction for establishing standards and specifications for excipient components and impurities. 

To facilitate these goals, a survey was launched concurrently with the article’s publication to obtain feedback and comments from stakeholders regarding the idea of developing a general chapter on excipient composition and impurities. The survey objectives are to: 

• Identify overall needs and challenges regarding the current written standards (monographs and General Notices) on impurities in excipients; 
• Assess the level of satisfaction with the current written standards on impurities for excipients; 
• Identify opportunities for improvement; 
• Analyze input on modernizing documentary standards on impurities in excipients; and 
• Determine potential challenges to implementing the new approach. 

Links to the Stimuli article and the survey are available in the excipients section of the USP website at usp.org/ excipients. 

References 

1. Tong (Jenny) Liu, Catherine Sheehan, and Steven Wolfgang, “Challenges and Opportunities in Developing Up-to-Date USP–NF Excipient Monographs,” American Pharmaceutical Revue, May/June 2016, pages 32-38. 

2. FDA and USP Workshop on Standards for Pharmaceutical Products, “Critical Importance of Excipients in Product Development: Why Excipients are Important Now and In the Future,” February 27-28, 2017, https://tinyurl.com/work shop2-17. 

3. http://www.uspnf.com/pharma copeial-forum. 

4. International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Impurities in New Drug Substances Q3A (R2), October 25, 2006, https:// tinyurl.com/ICHQ3AR2, accessed March 5, 2018. 

5. USP 41–NF 36, General Notices and Requirements, Section 3.10 Applicability of Standards. 6. USP 41–NF 36. General Notices and Requirements, Section 2.20 Official Articles.