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Revised USP Micro Chapters Address Changing Technologies

by David Hussong, PhD, Eagle Analytical Services, Radhakrishna Tirumalai, PhD, USP, Edward Tidswell, PhD, Merck, and Donald Singer, GSK

As technological advancements around microbiological testing continue to grow within the pharmaceutical industry, USP’s Microbiology Expert Committee seeks to update some of its microbiology chapters. For each five-year cycle, the Expert Committee has an established workplan intended to help meet USP’s standards-setting goals. Some of the workplan’s major initiatives in the current USP cycle (2015–2020) include sterilization processes and sterility assurance, parametric release, depyrogenation, endotoxin testing, rapid sterility testing of short-life products and a test for the presence of Burkholderia cepacia complex.

Sterility Assurance and Sterilization

While all products purported to be sterile must meet the requirements of USP <71> Sterility Tests, sterility assurance is achieved only through validated, robust sterile manufacturing processes. Currently, USP <1211> Sterilization and Sterility Assurance of Compendial Articles addresses principles of sterility assurance but provides information on only a few sterilization processes. In response to stakeholder feedback requesting greater information on specific sterilization methods, USP initiated a two-stage revision approach over ten years ago. Phase 1 focused on correcting outdated content with up-to-date information. This became official in the 2010 USP 33-NF 28. Phase 2 involved significantly rewriting the general chapter.

The initial focus of Phase 2 was sterilization, followed by content relevant to sterility assurance. In determining how to update the sterilization material in USP <1211> (which had its origins in the late 1980s), the Expert Committee decided to split the content. Information relating to sterilization would be removed from the existing USP <1211> and that chapter renamed “Sterility Assurance”—its main focus. The Expert Committee recognized that a separate sterilization chapter should:

  1. Provide a roadmap for the design and control of the process for sterile product manufacture,
  2. Introduce a means of extending terminal sterilization to more sensitive products,
  3. Offer enhanced detail on all the core elements of sterility assurance, and
  4. Include key details to expand application of parametric release.

The result has been development of a new series of general chapters, the <1229.x> series. In support of USP <1229> Sterilization of Compendial Articles, which covers overarching concepts of sterilization, each new general chapter is dedicated to an individual sterilization process or related topic.

To date, 15 general chapters have been developed to provide valuable information and guidance on distinct methods of sterilization. This effort emphasizes that bioburden is the “true” target of sterilization processes, thus, knowledge of its resistance is essential. Another key element involves encouragement of terminal sterilization processes to enhance patient safety.

The Expert Committee also recognized that the notion of completely destroying a large population of highly-resistant biological indicators (BI), worst-case assumptions, and use of overkill sterilization parameters as the arbiter of cycle appropriateness hampers broader adoption of terminal sterilization processing. Therefore, alternative methods of moist heat sterilization cycle design and qualification (including development of bioburden/BI and bioburden methods) are described to aid wider application of terminal sterilization processes to improve process control.

Parametric Release

The sterility test is technically and statistically inadequate to detect anything other than gross contamination. While defining the scope of the USP <1222> Terminally Sterilized Pharmaceutical Products—Parametric Release revision, the Expert Committee recognized that:

  1. Increased adoption of parametric release is important because it leads to increased patient safety, and
  2. Sterility assurance is not best served by end product tests.

In support of these concepts, a parametric release program must be designed, validated and controlled based on the user’s understanding of process control, critical process parameters and risk points. This completely revised content is applicable to all methods of terminal sterilization. In fact, some enhanced or advanced aseptic manufacturing could be candidates for parametric release. One pivotal change in both USP <1222> and USP <1211> is that parametric release is the default mode of product release, not sterility testing. In other words, a parametric program of release should be in place where feasible. Terminally sterilized products should then be released parametrically.

Depyrogenation

During the revision process for the <1229.x> series of chapters, the Expert Committee decided to develop a general chapter <1228.x> series on depyrogenation separate from the chapter on dry heat sterilization in order to better align with current industry practices. The intent of depyrogenation is very different from that of sterilization. Thus, the <1228.x> series of general chapters includes descriptions of various methods used for depyrogenation of materials and product streams. While defining the scope of <1228.x>, the Expert Committee recognized:

  1. Changes in current thinking on product lifecycle and advances in parenteral formulation and manufacturing,
  2. Renewed industry focus on raw material quality, and
  3. Shift in active ingredients from small molecule APIs to biologics.

These changes challenged the narrow, prescriptive requirements for depyrogenation initially proposed for dry heat in the original USP <1211>. To date, five new general chapters have been developed to provide valuable information and guidance on distinct methods of depyrogenation. Referencing the concepts of quality-by-design and risk management, the USP <1228.x> series proposes alternatives to traditional thinking around designing, executing and assessing depyrogenation processes. These concepts include:

  1. Using appropriate calibration materials; while current calibration standards (USP reference standard endotoxin or control standard endotoxins) are convenient, some depyrogenation methods, particularly those that are part of product streams, may be better challenged by naturally occurring (or native) endotoxin
  2. Demonstrating a reduction of endotoxin to safe levels based on the calculated endotoxin limit rather than establishing a process minimum of 3-log reduction in endotoxin (or lipopolysaccharides, i.e., LPS) activity, irrespective of the initial endotoxin burden or process capability

Endotoxin Testing

The bacterial endotoxins test is a critical requirement for injectable products and medical devices required to be pyrogen-free. In 2012, the U.S. FDA withdrew its 1987 guidance, Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices. As a result, stakeholders lost useful guidance on a variety of issues related to “best practices” for the bacterial endotoxins test. To fill this void, a new chapter, USP <1085> Guidelines on the Endotoxins Test, was proposed in the July-August 2018 issue of Pharmacopeial Forum (1). More specifically, this chapter provides guidelines on the bacterial endotoxins test relative, but not limited to, control standard endotoxins, control of standard curves, analyst training and qualification, calculation of endotoxin limits for ingredients, drug products with single and multiple active ingredients and resolution of out-of-specification results.

Rapid Methods

Conventional microbiology tests, such as sterility tests, found in the major pharmacopeias, rely on demonstrating microbial growth. Limitations of these tests include their low sensitivity and their time- and labor-intensive nature. Many cytotherapy or regenerative medicine products, radiopharmaceuticals and compounded pharmacy products are administered to patients prior to receiving results from sterility tests. A more rapid sterility test would be better in such instances from a patient safety perspective. These issues prompted USP to assemble a panel of technology experts and representative stakeholders from the sterile compounding, positron emission tomography, cell therapy and pharmaceutical and contract testing industries. This panel helped USP establish user requirement specifications, review risk-based approaches and recommend suitable technologies for the rapid sterility testing of short-shelf-life products (2). All of this has led to a new general information chapter on a risk-based approach for rapid sterility tests, USP <1071> Rapid Sterility Testing of Short-Life Products: A Risk-Based Approach, proposed in the September-October 2018 issue of Pharmacopeial Forum. The next step involves conducting proof-of-concept studies to demonstrate the reliability of the proposed methods. Based on these studies, a general chapter will be developed and published in a future Pharmacopeial Forum for public comment.

About the USP Microbiology Expert Committee

Through its General Chapters-Microbiology Expert Committee, USP develops and revises general chapters for the advancement of pharmaceutical microbiology consistent with the organization’s mission of quality medicines, food ingredients and dietary supplements. The current Expert Committee consists of industry experts and consultants along with U.S. FDA liaisons.

The Microbiology Expert Committee is responsible for general chapters that address microbial test procedures and microbial control of processes and environments. Its responsibilities do not extend to drug or product monographs, which are handled by other USP Expert Committees, although the Microbiology Expert Committee does support the development of microbiological requirements for all monographs via consultation with the relevant monograph Expert Committees. A separate Expert Committee handles monographs and informational general chapters on pharmaceutical waters.

USP General Chapters Microbiology Expert Committee 2015–2020
  • David Hussong (Chair)
  • James Akers
  • James Agalloco
  • Dilip Ashtekar
  • Anthony Cundell
  • Richard Friedman (U.S. FDA)
  • Dennis Guilfoyle
  • Rajesh Gupta
  • Laura Huffman (FDA)
  • David Lau (FDA)
  • Karen McCullough
  • Russell Madsen
  • Robert Mello
  • Randa Melham (FDA)
  • Andrea Ottesen (FDA)
  • Marla Stevens-Riley (FDA)
  • Donald Singer
  • Paul Stinavage
  • Colleen Thomas (FDA)
  • Edward Tidswell
  • Radhakrishna Tirumalai (USP)

B. cepacia Complex

B. cepacia complex (BCC) species are gram-negative, rod-shaped bacteria that include opportunistic pathogens. Many grow in preserved aqueous oral liquids and topical products and can potentially overcome antimicrobial preservative systems and antiseptics, possibly causing serious infections in individuals with cystic fibrosis and chronic granulomatous disease, mechanically ventilated patients, the immunosuppressed and those with serious underlying disorders. No standard method exists, however, for the detection of BCC even though they are considered an objectionable species in many dosage forms. To meet this critical need, the Expert Committee has developed a general chapter, also proposed in the September-October 2018 issue of Pharmacopeial Forum, USP <60> Microbiological Examination of Nonsterile Products—Tests for Burkholderia Cepacia Complex, that includes a method to test for the presence of BCC.

Conclusion

USP is committed to continuous revision and improvement of its standards and values the input of users in the field. Indeed, this input is critical to the success, not only of USP, but also of the industry as a whole. Stakeholder feedback helps to ensure that USP’s standards are sufficiently comprehensive in application and scope, reflecting current practices in industry. Thanks to this feedback, the Microbiology Expert Committee hopes that planned revisions of the microbiology chapters address the concerns of those involved in pharmaceutical microbiology.

References

  1. USP 41-NF 36. 2018. The United States Pharmacopeial Convention, Rockville, MD.
  2. USP Modern Microbiological Methods Expert Panel, 2017 Stimuli to the Revision Process: The Development of Compendial Rapid Sterility Tests. Pharmacopeial Forum 43 (5) Sept.-Oct. 2017

About the Author

David Hussong is the Chief Technical Officer at Eagle Analytical Services. In 2014, he retired from the U.S. Public Health Service as a Commissioned Corps Officer after 30 years with FDA. In addition, he is currently the chair of the USP Microbiology Expert Committee for the 2015–2020 cycle.

Radhakrishna Tirumalai, PhD, is a Principal Scientific Liaison in the Science Division of USP. He is the Liaison to the USP Expert Committee on Microbiology.

Edward C. Tidswell, PhD, is Executive Director, Microbiology QA for Merck & Co. with global ownership over microbiological issues, sterilization and sterility assurance.

Donald Singer is a GSK Senior Fellow and Manager of Microbiology for Biopharmaceutical GMP Operations at GSK Research and Development, where he has oversight of microbiology for all sterile clinical products in development.