In his preview of the upcoming USP workshop, R. Tirumalai described the importance of microbial contamination control and issues related to sterilization being major considerations for any manufacturer: “manufacturing processes must minimize potential risk to the patient and the product” [1]. This is the underlying concept for the U.S. Pharmacopeial Convention (USP) workshop entitled, “Microbiological Control of Compendial Articles,” which will take place at USP’s headquarters in Rockville, MD on March 18–19, 2013. The workshop will highlight current and proposed USP public standards focusing on topics relevant to microbiological contamination and bioburden control.
This update provides considerations and information of additional USP standards-setting activities related to microbiological contamination and bioburden control to be addressed at the March workshop.
A Risk-based Approach to Microbiological Quality Standards
One of the workshop’s plenary sessions will engage speakers from the U.S. Food and Drug Administration (FDA), industry, including members of USP’s Microbiology’s Expert Committee (EC).The development of a new USP chapter on risk-based approaches for bioburden control in non-sterile drug substances and drug products offers the opportunity of transparency and discussion of some crucial ‘hot topics’. There is an ongoing industry discussion about appropriate quality criteria of excipients and drug products as they relate to patient risk. Risk assessments are now routinely performed across the industry as new products are being developed. A discussion about objectionable microorganisms usually finds an appropriate place in this risk-based approach. Global harmonization of quality criteria for excipients is an ongoing activity, yet microbiological criteria harmonization is slow (see Global Compendia section).
Global Compendial Activities
The pharmaceutical industry has become risk-based in order to allow for quality to be the inherent theme for developing and manufacturing of medicines in a global market. The supply chain has become broadly global and commonly complex with excipient supply crossing many borders and legal agreements such as MRAs (i.e. APR mutual recognition agreements) allowing countries to manufacture and sell medicines in other regions with limited additional quality testing requirements. To capture the cultural diversity of a global supply chain when developing a quality initiative, it is important to bring together all stakeholders and quality initiators to ensure needs of each are met, and quality for the patient remains the top priority. Harmonization provided a means for the three major pharmacopeia, USP, EP (European Pharmacopeia), and JP (Japanese Pharmacopeia) to collaborate and come to consensus on quality attributes and methods for excipients, drug substances and drug products in their respective monographs. Consensus requires good information, historical data, sharing of perspectives and collaborative activities agreed by all parties. Developing harmonized microbiological quality criteria for excipients has been on a long road, but some excipients are now harmonized. Still, many remain not harmonized, causing additional testing and dependence on knowledge of the differences that exist in the three pharmacopeia. Microbiological methods have a better record, with the most common microbiological methods (Sterility Test, Bacterial Endotoxin Test, and Microbiological Examination of Non-sterile Products) now harmonized. Improved communications and collaboration relevant to current development of microbiological standards has occurred in the last 10 years. Members of the standards development expert committees of USP, experts from the EP, and experts from the JP now share perspectives to assist in the ongoing promise to industry for more global standards. Experts from the EP and JP will be joining the participants of the workshop in a session that offers their latest views of compendial microbiology.
USP <1116>- Current Thinking
General Chapter <1116> Microbiological Control and Monitoring of Aseptic Processing Environments, recommends current thinking of ways to support microbiological control of aseptic environments, in particular clean rooms, restricted-access barrier systems (RABS), and isolators used for aseptic processing. This chapter is based on the concept that in any environment where human operators are present, microbial contamination at some level is inevitable. So, the revised chapter describes monitoring in a practical approach, using frequency of contaminant recovery rather than comparison of counts to ‘target counts’.
What is on the minds of most quality control microbiologists covering sterile manufacturing operations is how to implement this approach of ‘contamination rates’. The workshop session about USP <1116>will offer more clarity and opportunity to develop more confidence in using the new approach.
Sterility Assurance and Sterilization
The Microbiology EC continues to progress and publish new proposed chapters for sterilization methods in order to meet the expressed needs of stakeholders “for USP to modernize and provide greater clarity to content related to these broad-reaching and technically demanding topics”[1].
The 1229.x-series of general chapters are intended to provide valuable information and guidance about processes for sterilization. Of these chapters, three will be offi cial in 1S to USP 36 (August 2013):
- <1229>Sterilization of Compendial Articles,
- <1229.1>Steam Sterilization by Direct Contact
- <1229.2>Moist heat Sterilization of Aqueous Liquids
While <1229.3> Bioburden Monitoring is currently proposed in PF (Pharmacopeial Forum), several more are being proposed in PF for public comments:
- <1229.4> Sterilizing Filtration of Liquids
- <1229.7>Gaseous Sterilization
- <1229.8>Dry Heat Sterilization
- <1229.10>Radiation Sterilization
<1229.4>Sterilizing Filtration of Liquids will be discussed at the workshop to provide an early look at the intent, content and use of the proposed draft chapter.
Vapor phase sterilization is a complex process with chemical and physical attributes that make validation a ‘not so simple’ activity. Along with the development of a new USP chapter about vapor phase sterilization,<1229.11>, the topic of biological indicators for validating this method is a timely discussion that will be included at the workshop.
Ongoing Challenges of Sterile Compounding
Compounding of sterile medicines has been a common activity for over a century. Potential of microbial contamination is inherent in the complexity of delivering pharmaceutical compounds to patients with chronic or acute illness, and can lead to injury or death if not properly controlled. Despite the building of quality into products using sterilization processes and robust packaging approaches, there are many good reasons in the medical fi eld to deliver medicines in alternative ways that circumvent the intent of the initial sterile packaging. When the latter practice occurs in a clinic, hospital, or compounding pharmacy, special measures must be taken to ensure sterility is maintained. USP General Chapter <797> Pharmaceutical Compounding – Sterile Preparations is a compilation of risk-based practices intended to provide direction for sterile compounding, and expresses the perspective of microbiologists, pharmacists and regulators. This area is challenging due to the extent of compounding practices globally. Sterile medicines are compounded in different environments ranging from minimal to extensive control of air quality, personnel, and good practices. The workshop will have a roundtable discussion about causes of contamination related to recent outbreaks, and ways to prevent them.
"The classical sterility test, as found in the pharmacopeia, relies on the demonstration of microbial growth."
A Rapid Sterility Test for Short Shelf-life Products
The classical sterility test, as found in the pharmacopeia (harmonized by USP, EP and JP), relies on the demonstration of microbial growth. Limitations of this test include low sensitivity and lengthy time to generate results. The Microbiology EC is seeking to identify a new referee test based on modern methods. “Certain cytotherapy or regenerative medicine products and radiopharmaceuticals are administered to patients prior to results from sterility testing. So, a more rapid result test would be very beneficial in these situations.”[2]
- The following were objectives placed on the search and development activity for the new method: Method has to have broad application
- Method instrumentation or supplies cannot be single-sourced or patented
- Method should be able to be applied in any lab
Current status of this activity will be discussed during the workshop.
Depyrogenation – Use, Validation and Endotoxins
Changes planned for the sterilization processes series of chapters (<1229.x) include sterilization by dry heat, <1229.8>. However the use of a dry heat sterilization cycle may not always provide capability of depyrogenation. The intent of depyrogenation is very different than sterilization. Thus understanding and developing methods intended to depyrogenate have been separated into the <1228.x> series. A session at the workshop will include a discussion about current thinking for removal or reduction of bacterial endotoxins. Part of this discussion will convey some useful guidance relating two collaborative parts of an approach for generating reduction in risk of pyrogenic contaminants in excipients, drug substances, components and drug products. A holistic approach can have as much of an impact as a direct depyrogenation process on the reduction of levels of endotoxin in drug product.
The same session will include a valuable discussion about calculating endotoxin limits for large volume parenterals (LVPs), and a unique opportunity to hear the most recent interpretation by the FDA about their Q&A document for endotoxins and pyrogen testing.
The Challenge and Opportunity
USP workshops offer an education in current thinking and methods of practice that are considered when developing strong and relevant public standards. Participating in a workshop offers an open forum for cross-fertilization of information on current technologies and capabilities along with the challenges that face everyone concerned about ensuring the manufacture of good quality pharmaceutical products. In-Process Revision allows public comment on new or revised standards and is one way to provide timely input to current standards. Participation in a USP workshop provides another avenue for discussion and comment for the revision process. For a complete workshop agenda and related registration information, go to: http:// uspgo.to/microbiology-workshop.
References
- Tirumalai, R. 2012. “USP Improves, expands standards related to microbial contamination and bioburden control”, Amer. Pharm. Rev. May-June 2012, pp. 24-33.
- Agalloco, J.P. and D. Singer. 2012. “Stay ahead of the curve –An update on sterility assurance topics in the USP”, J. Valid. Technol. 18 (3) pp.24-28.
Click here to view an interview with Dr. James E. Akers, Chair, USP Microbiology Expert Committee regarding this workshop.