By Mark F. Witcher, Ph.D.
Janet Woodcock’s recent quote on the state of pharmaceutical development — “It’s not working…”1 — should not be a surprise to anyone. The industry has been struggling for years with long development times, high product failure rates, and frequent quality problems.2,3 But, Ms. Woodcock’s further statement — “and, it won’t work in the future” — is an especially troubling call for changes. Not only does the statement reflect a lack of confidence in the industry’s ability to develop new products, but it strongly suggests that the industry as a whole, and in my opinion, including regulatory agencies, needs to change the approaches and methods for developing, approving, commercializing, and manufacturing new products.
While stating problems and requesting change in the face of continued weakness and failure is relatively easy to do, the more important questions are: What does the pharmaceutical industry and regulatory agencies need to do differently? Very complex problems often require many solutions, but in my opinion, one fundamental change that reimagines the way things are done might make a significant difference. That change is moving the industry from being primarily compliance-centric to process- and product-centric.
Recently, it has become fashionable to be “patient-focused.” But the patient’s interest is best served by focusing on the products and processes as the primary design criteria for the efficient and reliable manufacturing of products demonstrated, at least to the extent possible, to be safe and effective. Design and development activities such as QRM (quality risk management) exercises tend to become unfocused, thus producing vague and confusing results when the patient’s needs are used as a poorly defined surrogate design criterion. Product quality and the manufacturing process’ performance are definable and provide immediate design and operational criteria that will serve the patient well when properly used.
If changes are to be made, both regulators and industry must modify their approaches within their scopes of control. The FDA’s job is to regulate. Industry’s challenge is to do everything else within the FDA’s regulatory framework. So, what is the solution?
The FDA’s Challenge
One possible solution is for the FDA to encourage the industry to become much more focused on developing practices for its products and processes instead of compliance as a primary endpoint. Such a shift could occur by changing its regulatory strategy from simple compliance with good manufacturing practices (GMPs) to requiring the industry to define and use its own manufacturing practices specific to and appropriate for the processes and products they manufacture. The approach would force the industry to identify product requirements and then develop and implement practice-based control systems necessary to satisfy those requirements.
The industry’s focus on compliance with GMPs that are vaguely defined in terms of sufficient and adequate criteria has resulted in an industry distracted from focusing on the products and processes. GMPs are intrinsically retrospective because they are developed almost exclusively as guidelines to remediate old problems. GMPs work when products and their development and manufacturing problems change little over time. The emphasis on compliance has led to the industry to chasing “what the FDA wants” rather than focusing and thinking about solving the complex problems and future challenges of products such as monoclonal antibodies and gene and cellular therapies.
An alternative to GMPs is to require appropriate manufacturing practices (AMPs) be developed based on the specific requirements of the product and its manufacturing processes.4,5 AMPs require defining the process’ requirements along with developing a well-thought-out rationale behind the practice used to meet the requirements. Because there are usually many routes to achieving high product quality, the activity of developing and justifying AMPs may be more important than the actual practices selected. Building AMPs also provides opportunities for optimizing the combination of process, facility, and infrastructure practices that expend efficient levels of effort necessary to achieve high product quality.4
GMPs are typically a subset of AMPs because appropriate practices, when developed using a good rationale for high product quality, can identify and create practices not yet current to GMPs. When developed by competent, knowledgeable, and diligent process engineers and product scientists using both good science and engineering, AMPs are always compliant with GMPs. But AMPs can also develop and establish new methods and approaches necessary to solve the important challenges created by advanced technologies through prospective optimization of various process, facility, and infrastructure configurations.
When AMPs were initially proposed,4 the motivation was to change the industry’s approach from using GMP guidelines exclusively as a design criterion to focusing more on the needs of product quality for developing and designing manufacturing processes and facility systems. At the time, GMPs appeared to be a chronic problem hindering design and development activities. However, with the ever-increasing complexity of the products and their processes, compliance as a primary design criterion has become an acute problem preventing the evolution of process and facility designs necessary to appropriately accomplish very complex manufacturing goals that include rapid delivery, affordable cost of goods, and the complex product control of unknown as well as known critical quality attributes.
If AMPs were used, what would it mean for the pharmaceutical industry? Initially, probably a lot more work, but the eventual dividends from the investment in developing AMPs would be significant in terms of more efficient operation and better product quality through better manufacturing. In the long run, it could also result in a significant reduction in regulatory oversight as performance improves, moving the industry closer to realizing the FDA’s 21st century goal of “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.” 6,7
Searching for “what the FDA wants” has been frustrating and to some extent counterproductive, particularly for sophisticated new products where the FDA likely doesn’t know what it wants until it sees and understands them. The pharmaceutical industry is in a much better position to figure out what its products need to be successful. Using AMPs would force the industry to create more sophisticated methods and approaches, further supporting one of the FDA’s most important goals, fostering continuous improvement.6
Because AMPs require prospective analysis and the development of better practices, the industry will have to improve many of its methods and approaches. The new products have significant unknown critical quality attributes that can only be controlled using more sophisticated development methods that identify and control a process’ performance. Such improvements will come from more sophisticated life cycle approaches that use unambiguously defined versions of tools such as quality by design (QbD) and ICH Q8 Design Space.8 Emphasis on life cycle integration of information and knowledge from early medical research through commercial manufacturing for the development of AMPs can lead to better products and, possibly, higher rates of successful commercializaton.9
The industry must also identify, develop, and use more effective QRM methods.10 Currently, the approaches in ICH Q9 – QRM such as FMEA (failure mode and effect analysis) and HACCP (hazard analysis at critical control points) – describe methods for structuring risks. But they do not have mechanisms for properly assessing a risk’s uncertainty, leading to the unintended use of the costly and inefficient precautionary principle (better safe than sorry), resulting in suboptimal risk management.10
Developing AMPs might also open up opportunities for using alternative facility designs that are more scale- and capacity-efficient, thus providing rapid access to flexible manufacturing assets, allowing much faster, more efficient product development through the approval sequence.11 More advanced facility designs can also facilitate less regulatory approval overhead by encouraging standardized facility layouts and the infrastructures required to run them, possibly leading to fewer pre-licensure inspections.12 In addition, AMPs combined with more flexible layouts could lead to more rapid introduction of advanced manufacturing technologies such as continuous manufacturing.13
Aligning The FDA And Industry
One possible alignment mechanism is the FDA’s Voluntary Consensus Standards (VCS) initiative.14 For any changes in the way new products are developed and manufactured, both the FDA and the industry have to be on the same page. Changing from GMPs to AMPs will require better approaches for interacting and communicating between the agency and industry. The change would require the FDA to make it clear to industry that “it doesn’t know what it wants, but it will know it when it sees it based on understanding a well-defined rationale.” In order for this approach to work, the FDA must aggressively work with industry to learn and understand the practices defined by the industry to achieve appropriate practice-based controls required to assure high product quality. Both can work together using VCS to identify and use better approaches for efficiently managing product life cycles to quickly and cost-effectively bring new therapies to patients who urgently need them.
To a large extent, AMPs would place a much greater, but necessary, burden on the industry to prospectively develop solutions to complex future problems. By reimagining the current regulatory approaches and making industry fully responsible for all the practices, perhaps the industry will rise to the challenge and eliminate all the obvious, stupid, and incompetent compliance mistakes seen in FDA inspections.15
About The Author:
Mark F. Witcher, Ph.D., has over 35 years of experience in biopharmaceuticals. He is currently a senior consultant with Brevitas Consulting. Previously, he worked for several engineering companies on feasibility and conceptual design studies for advanced biopharmaceutical manufacturing facilities. Witcher was an independent consultant in the biopharmaceutical industry for 15 years on operational issues related to: product and process development, strategic business development, clinical and commercial manufacturing, tech transfer, and facility design. He also taught courses on process validation for ISPE. He was previously the SVP of manufacturing operations for Covance Biotechnology Services, where he was responsible for the design, construction, start-up, and operation of their $50-million contract manufacturing facility. Prior to joining Covance, Witcher was VP of manufacturing at Amgen. You can reach him at email@example.com.