When are GMPs Sufficient & Adequate, & When are They Not Good Enough?

As many recent pharmaceutical product quality problems have shown, current Good Manufacturing Practices (GMPs) as defined by regulatory guidelines and current best practices may not be “good enough” in the 21st Century. 1 ^, 2 ^, 3  Although, much of the quality problems can be traced to not following basic GMPs, some of the failures still beg the question: How can better manufacturing practices be developed to support more efficient and reliable high-quality manufacturing in the future?

If you manufacture anything, from TVs and baby food to antibodies and CAR-T cells, you must use good manufacturing practices as opposed to using bad manufacturing practices. GMPs is a lot more than aseptic technique and clean rooms. What GMPs really means is manufacturing practices necessary for achieving the product requirements of the manufacturer along with a high-quality product for the consumer. The manufacturing requirements, and thus the appropriate and necessary practices, obviously vary widely from one product to another. Both bad TVs and bad CAR-T cells may have significant adverse consequences for both the manufacturer and consumer. So how do we define the “Good” in GMPs within the context of the multitude of products that need to be manufactured?

In the larger scheme of things, “Good” has two functional definitions. The first definition is both an internal and external performance based regulatory test that measures the manufacturing practice’s ability to reliable and consistent produce a product that meets the consumer’s needs (yes – TVs too). This definition is largely a retrospective test measured against a criterion of sufficient and adequate to assure the reliable production of safe and effective products. The test for sufficient and adequate practices is primarily based on the product and manufacturing data (performance-based metrics) that proves retrospectively to a reasonable level of certainty that the manufacturing systems did and will continue to manufacture the required pre-defined product quality. This regulatory definition of “good” for pharmaceuticals is consistent with and satisfies the current FDA’s focus on performance-based regulatory policies, including GMPs.3

The second, more complex and difficult definition of “Good” is associated with using GMPs as a design criterion for prospectively developing practices for manufacturing new products. As future products and their processes become increasing complex, the various manufacturing practices may also become more complex for a wide variety of reasons. Mixing complexity with predicting the future performance of new manufacturing processes raises a couple of important issues.

First, new technology, particularly new biopharmaceutical and cell-based technologies, have a lot of inherent, difficult to pre-identify, uncertainty and variability. Defining where the boundaries between sufficient and insufficient, and adequate and inadequate are very difficult to define prospectively. The second issue is the lack of data. The manufacturing practices, processes, and facilities have to be defined, designed, qualified, and operated in many cases before any significant amount of commercial scale data are available. In addition, these practices may have to support the product’s approval and initial distribution before any statistically meaningful real-time performance data can be generated. This approach could be problematic even for a large-scale TV manufacturer. Thus, the use of GMPs based on existing regulatory guidelines and previously established industrial best practices likely provides a weak foundation as a design criterion for defining and designing the new practices required to manufacturing future products.

In the old days before biotechnology, the two definitions (regulatory and development) for pharmaceuticals were relatively consistent and compatible. Solid guidelines and past best practices proved to be effective for manufacturing similar new products. However, as they say: the times, they are a changing. FDA, in my opinion, likely anticipated problems when they realized that for biotechnology-based products, “the process (along with its practices) defines the product.” With biologics presenting very real manufacturing challenges and cellular and gene therapies over the near horizon, they ventured into management-based regulations (e.g., the forward-looking ICH Q8 and especially the 2011 Process Validation guidelines).4 ^, 5 However, they probably very quickly realize a conundrum that could greatly inhibit an industry focused almost entirely on “giving the FDA what they want” rather than concentrating on what methods and practices the various technologies required for best manufacturing high quality products. With such an approach, industry would interpret management-based guidelines as standards to be rigidly followed, thus shutting down any opportunity for the vital continuous improvement necessary to deal with the looming sophisticated medical and biopharmaceutical technologies of the 21st century. 3

While FDA has backed away from management-based guidelines, 3 they likely understand that they must continue to be prospectively involved for any hope of getting the manufacturing practices and systems that will ultimately pass the retrospective GMP challenges required for approval. This understanding is reflected in FDA’s request for discussion during the early product definition, process development, and various validation activities necessary for successfully bringing everyone up a steep learning curve. 6 ^, 7   Another recent, very encouraging development is the Consensus Voluntary Standards (CVS) initiative. 8 CVS could provide an important mechanism by which the industry and regulatory agencies can work together using continuous improvement to establish and evolve prospective management-based approaches for dealing with the unknown-unknowns of mid 21st century products.

Given that the development definition of good is more challenging than the regulatory definition, what is the path to prospectively developing effective manufacturing practices? One possible path is based on developing practices that are appropriate for reaching predefined goals. Would striving for Appropriate Manufacturing Practices (AMPs) within a lifecycle process development and validation paradigm provide a more transparent and effective path to developing the practices necessary to accomplish the product goals required for success? 9 ^, 10 The 21st Century with its rapidly changing uncertainty and complexity is a thinking person’s arena that requires everything be done for well thought out reasons.

One of the primary requirements of AMPs is an explanation provided by a rationale to document the thinking behind the practice’s approach. Writing rationales requires a clear understanding of the entire lifecycle of the necessary product, process, facility and practices. While current approach for creating GMPs uses best practices and standards as a safe approach to meeting regulatory expectations, AMP requires thoughtful examination of the practice’s entire lifecycle. 11 The AMP’s rationale might also provide a method of incorporating the Quality Risk Management results and control strategy approach to provide an institutional memory regarding why things are being done as defined in the practice. By using a lifecycle development and validation paradigm, AMPs can be developed using Quality by Design (QbD) to meet both retrospective regulatory expectations and the prospective challenges of developing products, processes, practices, and systems to meet the patient’s medical needs of the 21st century and beyond.

• 1Wechsler, J. “Quality Manufacturing Key to Reducing Drug Shortages,” PharmTech.com, Nov. 29, 2018. http://www.pharmtech.com/print/368114?page=full
• 2Peters, R. “Bio/Pharma Needs Ideas and Incentives to Advance Manufacturing, "Pharmaceutical Technology 43 (12) 2019. http://www.pharmtech.com/biopharma-needs-ideas-and-incentives-advance-manufacturing
• 3 a b c d Yu LX, Kopcha M. The future of pharmaceutical quality and the path to get there. Int J Pharm, 2017; 528(1–2): 354–9. https://doi.org/10.1016/j.ijpharm.2017.06.039 PMid: 28619448
• 4FDA (CDER/CBER) – Guidance for industry: Q8(R2) pharmaceutical development. Rev 2. (Nov. 2009).
• 5FDA (CDER/CBER/CVM) – Guidance for industry: Process validation: general principles and practices., Rev 1, (Jan. 2011).
• 6FDA Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products Guidance for Industry DRAFT GUIDANCE https://www.fda.gov/media/109951/download
• 7Eastern Research Group, Inc. “Assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs in PDUFA V Interim Report: Fiscal Years 2013-2014 (10/1/2012 – 9/30/2014)” https://www.fda.gov/media/90778/download
• 8FDA (CDER) – CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality – Draft Guidance for Industry, February 2019.
• 9Witcher, M. F.; “Achieving Excellence in Biopharmaceutical Development and Manufacturing by using Appropriate Manufacturing Practices (AMPs),” BioProcess J, Vol. 14, No. 4, Winter 2015. http://dx.doi.org/10.12665/J144.Witcher
• 10Witcher, M. F., “Using a Patient Centered Risk-benefit Structure and Appropriate Manufacturing Practices (AMPs) for Successfully Developing and Manufacturing Effective Cell Therapy Products.” BioProcess J, Vol. 15, No. 2, Summer 2016.
• 11Witcher M. F. Integrating development tools into the process validation lifecycle to achieve six sigma pharmaceutical quality. BioProcess J, 2018; 17. https://doi.org/10.12665/J17OA.Witcher.0416