Introduction
The Food and Drug Administration (FDA), Center for Drug Evaluation and Research Director, Dr. Janet Woodcock, defined high quality drug products as those that, 1) consistently and reliably deliver the clinical performance and other characteristics stated on the label, 2) are free from contamination, and 3) are available [1]. Although most drug products are at least minimally susceptible to the deleterious effects of microorganisms, sterile drug products and non-sterile drug products with stringent microbial limit specifications due to their nature (e.g., high water content) or the source materials (e.g., animal or plant extracts) are of higher risk due to the impact microbial contamination can have on their clinical performance and patient safety. Pharmaceutical microbiology focuses on the manufacturing techniques, process controls, and finished product attributes that limit the harmful effects of microorganisms on the drug product.
Recently, the international pharmaceutical manufacturing community has focused efforts on describing quality by design (QbD) for pharmaceutical manufacturing, including pharmaceutical microbiology quality attributes, via the publication of guidance from the International Conference on Harmonization (ICH). ICH Q8 defines QbD as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management” [2]. This article will focus on how QbD principles can be used to improve the microbiological quality of pharmaceuticals, discuss the use of QbD to improve regulatory flexibility, and explain how manufacturers have employed QbD in the form of parametric release to improve manufacturing efficiency and maintain product quality while reducing regulatory burdens.
QbD as it Applies to Pharmaceutical Microbiology
The microbiological quality of pharmaceuticals can be assured through the identification of the product attributes necessary to ensure clinical effectiveness and patient safety. A risk based analysis of the manufacturing process must then be conducted to identify factors that may interfere with the delivery of these attributes. Only then can a control strategy be implemented to minimize the risk of product contamination during the manufacturing process and maximize product quality.
A product’s critical quality attributes are the physical, chemical, biological, or microbiological properties or characteristics necessary to ensure product quality [2]. Although there are dozens of physical and chemical quality attributes that can affect overall product quality [3], there are only three critical quality attributes affecting the microbiological quality of the drug product: sterility for injectables, ophthalmics and other sterile dosage forms; pyrogenicity for injectable drug products; and microbial limits for non-sterile drug products. The control of sterility, pyrogenicity, and microbial levels are not new concepts for the pharmaceutical industry and manufacturers have implemented and continuously improved methods to control these critical quality attributes for decades. However, recent initiatives such as the GMPs for the 21st century and ICH Q8, Q9, and Q10 have served to re-emphasize process control in order to improve manufacturing efficiency and product quality through risk-based assessments of the overall manufacturing process [2,4,5].
A product’s critical quality attributes can be assured through the identification and management of critical control points and the control of critical process parameters. A critical control point is defined as “a step at which control can be applied and is essential to prevent or eliminate a pharmaceutical quality hazard or reduce it to an acceptable level” [6]. Critical control points affecting the microbiological quality of the drug product are those that, if not properly managed, could lead to an increased risk of microbial and/ or pyrogen contamination in the finished drug product. Examples of critical control points affecting microbiological product quality include the bulk holding times for all sterile drug products, the sterilization step for terminally sterilized products, exposure of aseptically processed drug products to the environment (including gowned personnel) during filling, and aqueous phase holding times for some non-sterile drug products. However, the exact number and type of critical control points for a given manufacturing process will depend upon the nature of the product (dosage form, filling process, container closure system, etc.), the sterilization or microbial control processes, the manufacturing environment, and the manufacturing equipment.
The identification of critical process parameters is another key step in the development of a quality risk management program [7]. ICH Q8 defines a critical process parameter as “a process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality” [2]. Like critical control points, critical process parameters associated with microbiological product quality will depend upon the nature of the product and the manufacturing process. Products sterilized by moist heat or radiation will rely on a dose of sterilant capable of killing microorganisms without significantly degrading the product or the container closure system. The critical process parameters for aseptically processed drug products will include the filtration variables (choice of filter, filtration conditions, filter sterilization, integrity testing), exposure of the product to the manufacturing environment (including personnel when applicable), and the sterilization of manufacturing equipment and container closure components. The pyroburden of the active pharmaceutical ingredients, water, excipients, and container closure components will also affect the overall product quality. Non-sterile drug products with microbial limit considerations [8] will be affected by factors such as raw material bioburden, water content of the drug product during manufacturing, the duration of manufacturing, the manufacturing environment, and steps in the manufacturing process shown to be microbicidal (e.g., heat, extreme pH, desiccation).
QbD and Regulatory Flexibility
In addition to improving manufacturing efficiency and product quality, QbD may also be used to achieve improved regulatory flexibility. Demonstrated process understanding can result in fewer supplements, reduced supplemental filing categories, and in certain instances, a reduced requirement for finished product testing for batch release. The amount of manufacturing flexibility will be commensurate to the size of the design space and the degree of process understanding.
Design space is defined as “the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality” [2]. The variables and parameters affecting the microbiological quality of the drug product are those related to the critical quality attributes of sterility, pyrogenicity, and microbial limits. These might include temporal manufacturing parameters (e.g., holding times, sterilant exposure times), product attributes (e.g., heat labilty, antimicrobial properties, water activity, container closure system), or processing variables (e.g., type of equipment used, human interventions). The effect of process variability on product quality is investigated through the process known as “Design of Experiments” which will be used to define the upper and lower control limits of the design space. [2]. The scope of these experiments will determine the size of the design space and the amount of manufacturing flexibility.
A control strategy is a set of controls derived from current product and process understanding that is used to ensure the consistent production of quality products [2]. Like the design space, the control strategies for pharmaceutical microbiology should focus on variables affecting the sterility, pyrogenicity, and microbial content of the product. However, the control strategy will use product and process understanding and risk analysis to insure that manufacturing is conducted within the design space. For instance, the control strategy for terminal sterilization processes might focus on methods of pyroburden monitoring of the raw materials and the consistent application of the correct dose of sterilant during terminal sterilization processes. The control strategy for aseptic processing operations might focus on the monitoring of the pyroburden and bioburden of the raw materials, environmental monitoring and trending in the production areas, and limiting sterile product exposure to the environment during filling. The control strategy for non-sterile drug products might consider factors such as raw material bioburden, manufacturing steps that reduce bioburden, and the water activity of the drug product throughout the manufacturing process.
Operation within the approved design space is not considered a process change and would not require additional regulatory assessment through the post approval change process. [2,9,10,11,12]. For example, the design space for a drug product sterilized using moist heat will include the minimum heat input necessary to achieve a satisfactory sterility assurance level for the drug product (lower control limit) and the maximum heat input that can be tolerated by the product and container closure system (upper control limit). This design space will be supported by studies demonstrating the suitability of the upper and lower control limits. Once approved in a product application, operation within these limits does not require additional regulatory notification. Operation outside of the approved limits will require additional regulatory review and approval. The same can be said for the design space for aseptic filling operations. Parameters such as product and equipment holding times, operator interventions, and filtration conditions will be investigated, validated, and reported in the product application. Once approved, operation within the parameters specified in the application does not require additional regulatory notification.
Another example of how QbD principles have been used to achieve regulatory flexibility from the FDA via the chemistry, manufacturing, and controls regulatory review process is through the use of comparability protocols. Comparability protocols use process understanding obtained through manufacturing experience to describe validation test design and acceptance criteria [13]. They are essentially a description of the design space, process understanding, and validation study acceptance criteria obtained from previous manufacturing experience that clearly describe how QbD has been integrated into manufacturing process. Approval of the comparability protocol results in reduced reporting categories for subsequent notification to the application file and expedited implementation of manufacturing changes.
The Paradigm of Parametric Release
Parametric release, first approved by the FDA in 1985, is an excellent example of the utilization of QbD principles in the production of sterile pharmaceutical drug products [10]. Parametric release allows for sterile drug products, regulated by FDA’s Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), and Center for Biologics (CBER), to be released for marketing without a finished product sterility test as long as certain defined critical terminal sterilization parameters are met for individual production batches to fulfill the intent of 21 CFR 211.165 (a) and 211.167(a)[14, 15]. Terminal sterilization parameters identified through experience with the compounding and sterilization process, sterilization equipment, drug product, and container closure system must be successfully validated to attain a desired sterility assurance level. A manufacturing firm’s control strategy supported by process understanding and a record of reproducible results makes regulatory flexibility possible. Providing documentation of this to the regulatory authority could allow the FDA to issue a waiver which would result in shorter product storage times between the completion of manufacturing and market release. This is consistent with the FDA’s desired state in which extensive product testing and limited manufacturing process understanding is replaced with QbD and extensive process understanding and control, resulting in obviated end point product testing [9,10,16,17,18]. Table 1 lists examples of critical control points, critical process parameters, and control strategies involved with sterility assurance and pyrogen control for parametrically released drug products.
In recent years, there has been an increase in the number of firms approved for pharmaceutical manufacture implementing parametric release as firms leverage process understanding and manufacturing experience in exchange for regulatory flexibility and expedited product release times [10]. The paradigm of parametric release may be expanded to other areas of product quality microbiology where a demonstrated mechanistic understanding of the risk factors and risk mitigation strategy for the sterilization process may ease the regulatory burden [2].
Summary
This article has provided a general overview of how QbD can be applied to pharmaceutical microbiology. Process understanding and risk management can be used to identify the critical process parameters and critical control points that, when properly managed, ensure delivery of product possessing the critical quality attributes of a high quality drug product. The design space, developed through experimentation, supported with validation studies, and maintained using a control strategy, will define the amount of manufacturing flexibility for a given process. Additional regulatory flexibility may be gained through avenues such as comparability protocols and parametric release where documented process understanding is exchanged for reduced filing categories for process changes and obviated end-product testing.
It can be argued that the manufacturers of sterile pharmaceuticals are ahead of the curve as far as the implementation of QbD is concerned since a key critical quality attribute of the product, sterility, needs to be designed into the manufacturing process and not simply demonstrated by end product testing. Because of this, manufacturers of sterile pharmaceuticals have been applying QbD principles to their manufacturing processes for decades through validation studies for the depyrogenation and sterilization of components, equipment, and finished drug product. This has resulted in greater sterility assurance, improved product quality, less dependence on end product testing, and reduced reporting categories for firms demonstrating superior process understanding and control. In the future, QbD can be used to improve the microbiological quality and availability of pharmaceuticals through facilitation of post-approval changes, including the implementation of rapid microbiological methods, and the development of improved manufacturing processes for aseptically filled, terminally sterilized, and non-sterile products.
Acknowledgement
The authors would like to thank James McVey, Lawrence Yu, Robert Lionberger, Pam Winbourne, Jon Clark, and Russ Madsen for review of this manuscript and valuable discussion of the QbD paradigms.
References
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2. ICH Harmonized Tripartite Guideline: Pharmaceutical Development Q8 (R1). 13-November-2008.
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12. Food and Drug Administration. Guidance for Industry: for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products. November 1994.
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Dr. Stephen E. Langille joined the FDA in January 2000 and now serves as a senior product quality microbiology reviewer in the Office of Pharmaceutical Science. He received his B.S. in Biology from the University of Massachusetts and his Ph.D. in Microbiology from the University of Maryland. He is one of the drug microbiology staff’s representatives to the FDA Pharmaceutical Inspectorate Program, a member of the FDA Standards Working Group, and the FDA liaison to the USP Parenteral Products – Industrial Expert Committee.
Dr. Lynne A. Ensor is the Microbiology Team Leader in the FDA’s Office of Generic Drugs. She received her B.S. in Biology and Ph.D. in Microbiology from the University of Maryland at College Park and completed her postdoctoral fellowship research at the University of Maryland’s School of Medicine, Baltimore. Dr. Ensor has written research articles for peer reviewed journals and textbook chapters, as well as given technical presentations at internationally attended scientific conferences. Dr. Ensor’s previous experience includes employment at Roche Biomedical Laboratories and serving as a script consultant for the Discovery Channel.
Dr. David Hussong is the Associate Director for New Drug Microbiology in the Office of Pharmaceutical Science in FDA’s Center for Drug Evaluation and Research. He directs the New Drug Microbiology Staff that reviews microbiological quality aspects described in the Chemistry, Manufacturing and Controls technical section of new drug applications. He is also an FDA liaison to the USP Microbiology and Sterility Assurance Committee of Experts. He holds a Ph.D. in microbiology is from the University of Maryland. He has done research at the US Dept of Agriculture and the Office of Naval Research, where he studied environmental Salmonella and Legionella, and developed methods for their detection. He has 25 years of FDA experience and is a Commissioned Officer in the US Public Health Service at the rank of Captain.
To contact the author please, email him directly at: [email protected]