While many contributing factors can play a role in affecting the quality of a medicine or its ingredients, microbial contamination control and issues related to sterilization must always be major considerations for any manufacturer. For both sterile and non-sterile pharmaceutical products, manufacturing processes must minimize potential risk to the patient and the product. On July 23–24, 2012, the U.S. Pharmacopeial Convention (USP) will be hosting a workshop entitled, “Microbiological Control of Compendial Articles,” which will take place at USP’s headquarters in Rockville, Md. Focusing on topics relevant to microbiological contamination and bioburden control, the workshop will highlight current and proposed USP public standards that help to ensure consistent quality in drug products and substances; dosage forms; and excipients
USP, a nonprofit scientific organization, develops standards for the identity, strength, quality and purity of drugs and their ingredients, which are published in the United States Pharmacopeia and National Formulary (USP–NF). Written or documentary standards for drugs or drug ingredients are expressed in USP–NF monographs, general chapters, and General Notices. A monograph is developed for a single article (e.g., drug substance, drug product, excipient), while a general chapter can apply across multiple articles. Above-1000 general chapters are informational, and contain no mandatory requirements unless specifically referenced in a monograph, General Notices, or a general chapter numbered below 1000. General chapters designated as below-1000 contain tests that may apply to items recognized in USP or NF, and may also be required by the Food and Drug Administration (FDA) to demonstrate conformance to a specification. While USP’s standards are applicable under U.S. law to drug substances and products marketed in the U.S., they also are used in more than 140 countries throughout the world.
The following provides a summary of new and ongoing USP standards setting activities focused on microbiological contamination and bioburden control to be addressed at the July workshop.
Quality Standards for Contamination and Bioburden Control—A Risk-based Approach
It is important that quality requirements for pharmaceutical products reflect the risks associated with their administration to target patient populations. Standards or regulations that do not result in any type of reduction of risk or improvement in product quality ultimately may deliver little to no added benefit to the end user.
For non-sterile pharmaceutical products, limited information is currently available in pharmacopeias or regulatory guidance documents with regard to bioburden control. When it comes to factors that can contribute to product bioburden, there are many critical items to consider, including the quality of raw materials, the environment surrounding the manufacturing process, and the training and experience of the people responsible for conducting quality control activities.
When developing effective standards for medicines, using a risk-based approach challenges us to consider multiple factors at once. Take, for example, the role that patient populations can play when assessing the risk of contamination. Calculating what constitutes minimal risk for a healthy person can produce very different results for a more vulnerable patient such as a pregnant woman or an immune-compromised cancer patient. The traditional approach of monitoring for contamination alone may not yield the level of specificity needed to properly protect the patient.
Even the type of dosage form of a drug administered can be a contributing factor when calculating risk. Water activity plays a role in microbial growth, and the potential for contamination can be different when using a tablet, syrup or a suppository, particularly when a patient’s immune response is compromised.
Product quality requirements vis-à-vis microbial risk will be the topic of our workshop’s plenary session with speakers from the FDA, industry, as well as members of USP’s Microbiology’s Expert Committee (EC), which has oversight for the development and approval of USP’s microbiology standards. USP’s proposal to develop a new chapter on risk-based approaches for bioburden control in non-sterile products is expected to be published in early 2013 in the Pharmacopeial Forum (PF)—USP’s free-access, online publication for posting and receiving public comments on standards in development. For more information about PF, go to http://www.usp.org/usp-nf/pharmacopeial-forum.
Microbiological Control and Monitoring of Aseptic Processing Environments
General Chapter <1116> Microbiological Control and Monitoring of Aseptic Processing Environments, following a major revision, became official on May 1, 2012 in USP 35–NF 30. Prior to this revision, General Chapter <1116> was focused on the evaluation and classification of clean rooms. The general chapter now incorporates recommended ways to support microbiological control of aseptic environments. Products manufactured in such environments include pharmaceutical sterile products, bulk sterile drug substances, sterile intermediates, excipients and, in certain cases, medical devices.
The information in General Chapter <1116> and the monitoring parameters provided for microbiological evaluation should be applied only to clean rooms, restricted-access barrier systems (RABS), and isolators used for aseptic processing. In healthcare product manufacturing, “aseptic” describes the process for handling sterilized materials in a controlled environment designed to maintain microbial contamination at levels known to present minimal risk. In any environment where human operators are present, microbial contamination at some level is inevitable. Even the most cautious clean-room environment design and operation will not eliminate the shedding of microorganisms if human operators are present.
A large proportion of products labeled as sterile are manufactured by aseptic processing rather than terminal sterilization. Because aseptic processing relies on the exclusion of microorganisms from entering open containers during processing, product bioburden as well as the bioburden of the manufacturing environment are important factors that govern the risk of unacceptable microbial contamination.
In General Chapter <1116>, types of aseptic processing are differentiated by the presence or absence of human operators. Recommendations described in <1116> include an emphasis on a routine microbiological evaluation program for controlled environments; good performance and training of personnel working in controlled environments; and the introduction of the use of contamination rates in place of straightforward microbial counts with regard to microbiological control and monitoring. Changes to <1116> include clarifi cation of limitations of counting methods used in microbiological evaluation, including sampling, recovery, data tracking and trend analysis. The chapter provides an improved description of microbiological incubation conditions relative to intended recovery (e.g., typical temperature and time, or modifi cation for slow growers). These and other revisions made to General Chapter <1116> will be discussed in greater detail at the workshop.
Sterility Assurance and Sterilization
General Chapter <1211> Sterilization and Sterility Assurance of Compendial Articles is an important product safety-related chapter in USP–NF. The adverse clinical consequences associated with the intravenous administration of contaminated materials can be severe, and the risk associated with poorly prepared and controlled sterile products has long been recognized within several pharmacopeias.
Over the course of several decades, various monographs, general chapters and general information chapters have been developed and revised by USP to address sterility and sterility assurance as well as control processes used to manufacture compendial articles purported to be sterile. The collection of sterility-related information in USP−NF became increasingly complex with subsequent additions and revisions over time, resulting in stakeholders expressing a need for USP to modernize and provide greater clarity to content related to these broad-reaching and technically demanding topics.
The Microbiology EC evaluated USP−NF’s current sterility-related content and developed an action list of potential changes. Among these was a decision to keep General Chapter <1211> focused on sterility assurance in future revisions. However, the new General Chapter <1229> Sterilization of Compendial Articles has been developed as a chapter devoted to overarching principles of sterilization. In addition, USP has initiated the development of the 1229.x-series of general chapters. Of the 11 related chapters to be developed, eight will focus on distinct processes for sterilization, how those processes are to be developed and which materials are most suitable for their use.
• <1229.1> Steam Sterilization by Direct Contact
• <1229.2> Steam Sterilization of Aqueous Liquids
• <1229.4> Sterilizing Filtration of Liquids
• <1229.6> Chemical Sterilization
• <1229.7> Gaseous Sterilization
• <1229.8> Dry Heat Sterilization
• <1229.10> Radiation Sterilization
• <1229.11> Vapor Sterilization
The other three general chapters in the 1229.x series will address areas related to these processes:
• <1229.3> Monitoring of Bioburden
• <1229.5> Biological Indicators for Sterilization
• <1229.9> Physicochemical Integrators and Indicators for Sterilization
In the strictest definition of sterility, a specimen is deemed sterile only when there is complete absence of viable microorganisms. However, absolute sterility cannot be demonstrated in compendial articles and other related items because of the inherent statistical limitations and the destructive nature of the current test, as described in General Chapter <71> Sterility Tests. Sterility, therefore, is defined in probabilistic terms that establish an acceptable level of risk, and can be accomplished only by the use of a validated sterilization process under appropriate current good manufacturing practices.
In General Chapter <1229>, the basic principles for control of sterilization processes—including method development, validation and ongoing assurance—are discussed. The chapter also describes the establishment and justification of sterilization processes that rely on microbial inactivation; the use of sterilization indicators and integrators that confirm that processing is complete; the selection of an appropriate sterilization process; and routine process control.
General Chapter <1229.1> Steam Sterilization by Direct Contact focuses on what is perhaps the most common of all sterilization processes. General Chapter <1229.2> Steam Sterilization of Aqueous Liquids addresses the steam sterilization of solutions, suspensions and emulsions. This is the method of choice for aqueous parenteral products, in-process aqueous liquids, laboratory media and biological waste materials.
In the March–April 2012 issue of PF, General Chapters <1229> and <1229.1> were published and public comments on the chapters were collected until May 31, 2012. Similarly, General Chapter <1229.2> was published in the May–June 2012 issue of PF with the comment period ending on July 31, 2012. General Chapter <1229.3> Monitoring of Bioburden will be published in the July–August 2012 issue of PF, and comments will be accepted until September 30, 2012.
At the workshop, the current status of the <1229.x> series of chapters will be discussed, including a specific overview of the draft General Chapter <1229.4> Sterilizing Filtration of Liquids, which deals with the physical removal of microorganisms from the material to be sterilized. The physical removal and retention of microorganisms depend on the upstream bioburden, the properties of the solution, the filtration conditions, and the filter itself. The draft chapter includes a discussion of retention mechanisms, factors affecting retention, filter efficacy, validation of sterilizing filtration, integrity testing principles and methods, pre-filtration bioburden control and troubleshooting.
Replacing Microbial Assays with Rapid Methods
Conventional microbiology tests found in the pharmacopeias, such as sterility tests, rely on the demonstration of microbial growth. Limitations of these tests include their low sensitivity as well their timeand labor-intensive nature. USP is seeking to identify new referee tests or procedures (used by FDA or a third party to assess regulatory compliance) based on modern methods that can detect and enumerate microorganisms in a more rapid and sensitive manner.
USP is also in the process of updating General Chapter <1223> Validation of Alternative Microbiological Methods as a guide to users interested in validating microbiological methods, including those based on modern technologies.
Updates will be provided during the workshop on the status of both of the aforementioned activities.
Providing Input to the Standards-setting Process
USP relies on expertise and input from manufacturers, regulators and other stakeholders for the development of strong and relevant public standards. Meetings like the upcoming July workshop serve as open forums for exchange on current technologies and capabilities as well as the challenges that face everyone concerned about ensuring the manufacture of good quality pharmaceutical products in support of global public health. For a complete workshop agenda and related registration information, go to: http://uspgo.to/microbiology-workshop.
Author Biography
Radhakrishna Tirumalai, Ph.D., is a Principal Scientific Liaison in USP’s Science and Standards Division and works on the development and revision of general chapters related to microbiology and toxicology, together with USP’s relevant expert committees. He represents USP on various external task forces and committees related to Sterilization, Sterility Assurance and Biocompatibility. He earned a Ph.D. in Biochemistry. Dr.Tirumalai’s industrial experience encompasses process and product research and development as well as product manufacturing. He has authored many publications and peer-reviewed articles and is a frequent speaker at conferences and instructor on pharmacopeial microbiology globally. He can be contacted by email: [email protected].