Introduction
PDA Technical Report Number 33 (TR33), Evaluation, Validation and Implementation of New Microbiological Testing Methods, was originally published in 2000 and was the first guidance document for how to select, validate and implement alternative and rapid microbiological methods (RMM). The document quickly became the gold standard for RMM validation strategies and has been used to successfully qualify new microbiology technologies within the U.S. and Europe. From time to time, PDA Technical Reports require revision in order to take advantage of changes to existing analytical methods and the introduction of new methods, regulatory guidance and pharmacopeial revisions. For these and many other reasons that will be highlighted in this article, a PDA Task Force was assembled to review the current version of the technical report, determine where gaps existed and to recommend areas for improvement and clarification. In addition, new topics for discussion were to be developed based on changes to the regulatory and pharmacopeial environments. The task force team started their activities in Q4 2007 and is composed of subject matter experts in RMM and alternative microbiology technologies representing the pharmaceutical industry, vendors and suppliers of microbiology systems and instrumentation, regulatory agency officials, consultants, statisticians and PDA staff (the team membership is provided).
As an introduction, examples of additional topics that will be provided in the final TR33 include new technology platforms that have been introduced over the last nine years, alignment with the informational chapters provided in the U.S. and European Pharmacopoeias (USP <1223>, Validation of alternative microbiological methods and Eur. Pharm. 5.1.6, Alternative methods for control of microbiological quality, respectively), recent regulatory acceptance of alternative microbiology methods, and enhanced discussions of risk-based approaches to microbiology testing, Quality by design (QbD) and Process Analytical Technology (PAT). Most importantly, the revision will provide the reader with a much greater appreciation and practical guidance for “how to” validate new microbiology methods and associated systems and instrumentation based on our collective experience since 2000. Although it is not possible to provide an in-depth review of the work in progress, the following sections will provide a glimpse into what the final document may look like.
The Validation Process
TR33 will recommend the use of an analytical equipment qualification model and not a process validation model that will allow for the validation of the complete system. Topics will include proof of concept studies, design qualification, user requirements, functional design specifications, the use of risk assessment and decision matrices, validation plan design, and what qualification components are covered and where they are covered during the Instrument Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). Specific guidance including acceptance criteria will be provided when evaluating a new method for accuracy, precision, specificity, limit of detection and quantification, linearity, range, ruggedness, robustness and equivalence. Additional considerations may be provided with regard to software validation, system noise, false positives, false negatives and the use of environmental isolates.
Statistics
Choosing the best statistical strategy is one of the most challenging aspects of qualifying a new microbiology method, especially when the new method will take the place of an existing method. The goal of this section is to demystify the use of statistics and satisfy the guidance expressed in both the USP and the Eur. Ph. informational chapters on the same subject. For example, TR33 will provide direction and practical examples on how to choose the appropriate statistical model based on sample size, expected recovered counts and confidence levels.
Technology Update
The current TR33 includes a section on microbiology technologies that were state of the art at the time of publication in 2000. The revised technical report will include an overview of these same technologies but will add new technology platforms that have been recently introduced or as with microbial identification, were considered out of scope. These will include detection, quantification and microbial identification methods and instrumentation whose core technologies are based on microbial growth, the detection of cellular viability, nucleic acid amplification, the presence of cellular components, and analytical and optical spectroscopy.
Alignment with USP <1223> and Eur. Ph. 5.1.6
Minor differences exist between the current TR33, USP <1223> and Ph. Eur. 5.1.6. These include acceptance criteria for some of the validation criteria, such as precision, in addition to definitions and the use of statistics. The revised TR33 will attempt to recommend validation strategies that will be aligned with both pharmacopoeias.
Regulatory Perspectives
Over the last nine years, numerous companies have received regulatory approval for the implementation of alternative microbiology methods, both in the U.S. and in Europe. However, differences exist in the manner in which regulatory agencies expect validation to be conducted, the process by which results are reported, and whether regulatory prior approval is required. The latter may depend on the method or technology, the method application and/or whether the method to be changed appears in a previously approved regulatory submission or marketing authorisation. This section will explore the regulatory strategies that should be considered when developing, validating and implementing a new method, including the use of a Comparability Protocol, Type Variation, Drug Master File, and PAT/QbD approaches.
Microbial Identification
The current TR33, USP <1223> and Eur. Ph. 5.1.6 lack guidance on how to qualify new microbial identification methods and their associated instrumentation. This section will provide specific guidance on validation strategies and testing criteria, and will also highlight some of the guidance provided in a proposed USP informational chapter the same topic.
Site Commissioning and Technology Transfer
Many companies will perform the initial qualification of a new microbiology method or RMM at a central location, such as a corporate microbiology laboratory or a microbiology technology center of excellence. This section will provide guidance on how to transfer these methods to a secondary laboratory or manufacturing site, including the use of IQ, OQ and PQ strategies at the receiving location.
Vendor and Supplier Expectations
The revised TR33 will provide an enhanced section on working with new microbiology method vendors and suppliers. Topics may include the selection of a vendor/supplier, financial stability, field service, repair and technical support capabilities, the availability of supplies and consumables, vendor audits and how and when to use vendor data and Drug Master Files in support of end-user validation activities and regulatory submissions.
Risk Analysis
This section will provide alignment with risk management approaches that a company would find within ICH Q9, FDA cGMPs for the 21st Century and other relevant guidance documents. Specifically, the technical report will discuss risk analysis models and their applicability to the qualification and implementation of new microbiology methods.
Equivalence
In most cases, demonstrating equivalence of a new microbiology method to the existing method may be required. This section will provide enhanced guidance on how to practically and statistically demonstrate equivalence between two microbiology methods.
Automated Systems
Many new microbiology methods and RMMs are fully or semiautomated with regard to sampling testing and/or data acquisition. This section will discuss the differences between a new method that represents the automation of a current compendial or conventional method, or whether the new method is a scientific or technological alternative to a current compendial or conventional method.
Return on Investment
This section will provide guidance on the use of return on investment (ROI) and other financial models that can be used to economically justify the implementation of an alternative microbiology method to management.
Stressed, Injured and Viable But Non-Culturable (VBNC) Organisms
Because many new microbiology methods employ technologies that do not rely on the growth of microorganisms to be detected, enumerated or identified, the results may be significantly different than what may have been historically observed when using conventional methods. Therefore, it is necessary that a discussion of these types of microorganisms be provided, including the potential impact on detection, enumeration and identification methods.
Acceptance Criteria
Some of the newer microbiology technologies may provide significantly different results than conventional methods, especially when the new methods rely on the detection of viability markers, rather than the growth of microorganisms. This section will provide additional guidance on how to handle these differences during the validation process as well as direction on setting new acceptance criteria, baseline levels and/or specifications when using these types of methods.
Summary
The timing for completion of the revised TR33 is anticipated to occur in the middle of 2010. The process will include the development of a final draft by the task force team, review and approval by PDA management and the PDA Science Advisory Board, and a formal review and comment period by the PDA general membership.
The revision of PDA TR33 is a long-anticipated document that we hope will provide enhanced guidance and practical strategies for the development, validation and implementation of alternative microbiology and RMM technologies. It is anticipated that technology vendors and suppliers, their end-users, regulatory agencies and all others who desire to use alternative microbiological methods will utilize this technical report. We applaud the hard work by the task force team thus far and their names are provided below.
Michael J. Miller, Co-chair Jeanne Moldenhauer, Co-chair
John Albright Claude Anger
Dilip Ashtekar Peter Ball
Joseph Chen Anthony Cundell
Steven Douglas William Fleming
Ren-Yo Forng Gary Gressett
Paul Hargreaves Jienping Jiang
Robert Johnson David Jones
Richard Levy Des Lincoln
Patrick McCarthy Patrick McCormick
Paul Newby Miriam Rozo
Bryan Riley Heather Wilson
Liz Young Pascal Yvon
Dr. Michael J. Miller is an internationally recognized microbiologist and subject matter expert in pharmaceutical microbiology, Process Analytical Technology (PAT), isolator design and qualification, and the due diligence, validation, registration and implementation of rapid microbiological methods. Currently, Dr. Miller is the President of Microbiology Consultants, LLC (http:// microbiologyconsultants.com). In this position, he is responsible for providing microbiology, regulatory and quality solutions for the pharmaceutical and biopharmaceutical industries. Over the past 20 years, Dr. Miller has held numerous R&D, manufacturing, quality, consulting and business development leadership roles at Johnson & Johnson, Eli Lilly and Company, Bausch & Lomb, and Pharmaceutical Systems, Inc.
Dr. Miller has authored over 90 technical publications and presentations in the areas of rapid microbiological methods, PAT, ophthalmics, disinfection and sterilization, and is the editor of PDA’s Encyclopedia of Rapid Microbiological Methods. He currently serves on a number of PDA’s program and publication committees and advisory boards, and is cochairing the revision of PDA Technical Report #33: Evaluation, Validation and Implementation of New Microbiological Testing Methods.
Dr. Miller holds a Ph.D. in Microbiology and Biochemistry from Georgia State University (GSU), a B.A. in Anthropology and Sociology from Hobart College, and has served as an adjunct professor at GSU and the University of Waterloo, School of Optometry. Recently, he was appointed the John Henry Hobart Fellow in Residence for Ethics and Social Justice, awarded PDA’s Distinguished Service Award and was named Microbiologist of the Year by the Institute of Validation Technology (IVT).
Jeanne Moldenhauer is Vice President at Excellent Pharma Consulting. She chairs the PDA’s microbiology and environmental monitoring interest group. Additionally she serves on the PDA’s Scientific Advisory Board, the Technical Books Advisory Board and teaches at the Training and Research Institute. She was the founder of the Rapid Microbiology User’s Group.