By Mark F. Witcher, Ph.D.
In a recent article, Louis Garguilo of Outsourced Pharma presents some interesting information about the FDA’s worldwide manufacturing facility inspection program.1 His article also asks some important questions about how the overall quality of the products used in the U.S. can be improved. In particular, he asks the question: Do FDA inspections correlate directly with improved quality at global manufacturing facilities? I agree completely with his conclusion that a robust inspection effort does improve product quality. While testing manufacturing facilities for establishing product quality is consistent with the FDA’s performance-based regulatory strategy,2 testing facilities for product quality as a primary control strategy is an intrinsically unappealing approach in the 21st century for any pharmaceutical quality control program.3
The above question, however, raises another very important question: What other regulatory and industry practices and programs could better improve product quality? But before answering this follow-up question, perhaps understanding what types of control strategies are the most effective would be useful.
All control strategies, from process control of unit operations to procedure-based control practices used to operate a manufacturing facility, have the same requirements:
- Control – provide control of critical objectives.
- Proof of control – provide information to an unbiased observer that control was maintained.
- Facilitate a return to control – should control be lost, collect information necessary to conduct a root cause analysis for quickly returning the system to a state of control.
Based on good advanced process control (APC) concepts, control strategies can be divided into two categories:
- Retrospective, feedback control – These systems are based on monitoring quality attributes of the products produced and parameters of the manufacturing processes to provide corrective action to assure product quality.
- Prospective, feedforward control – Sometimes called anticipatory control, prospective control systems prevent upsets or poor performance by building intrinsically high-performing control strategies that take corrective action before upsets enter the process. For procedural control systems, the procedures can be prospectively designed, using quality by design methods, to achieve the three objectives listed above.
Facility inspections that measure manufacturing performance and product release programs are retrospective feedback control systems. Feedback systems are critical to achieving tight control because they provide corrective action in real time to eliminate any deviation between the actual and desired control states. In this case, the control strategy identifies facility, operational, and quality management system (QMS) deficiencies that are then used for taking corrective actions to strengthen manufacturing operations. However, feedback control systems are notoriously poor when sampling rates are low — in this case, infrequent inspections. Long delays in performance sampling could permit poor product to be manufactured for long time periods between identifying problems and taking corrective action. While increasing the inspection capability to decrease the time between inspections would be an improvement, the intrinsic weakness of a purely retrospective performance-based product quality approach must be understood and appreciated for its relatively poor ability to rapidly achieve high-quality products.
Feedforward control, on the other hand, is based on building quality into manufacturing systems from the beginning. While they are more difficult to build, prospective control strategies are significantly more effective than retrospective approaches. Effective feedforward control strategies can rapidly achieve high-quality manufacturing, especially when coupled with good qualification testing and ongoing monitoring of performance. Companies can create prospective manufacturing control systems, for both internal applications and suppliers, by using management-based guidelines to create QMS and infrastructure practices (GMPs, etc.) effectively designed to produce high-quality products. Any knowledgeable practitioner of APC knows that the most effective control is achieved by using prospective feedforward control to very quickly get close to the goals, combined with retrospective feedback systems to assure precise control is maintained.
Returning to the first question: How can the industry improve the quality of its products? The first tactic could be for the industry to increase the frequency of vendor inspections, using internal QC programs to inspect suppliers to assure compliance with the necessary supply agreements and adherence to appropriate manufacturing practices, including GMPs. Companies must aggressively supplement FDA inspections of their suppliers by taking a proactive role in assuring their suppliers provide the high-quality products necessary to achieve their own product quality requirements. Although mostly an aspiration, companies could even share inspection results of key QMS and product quality metrics with regulatory agencies to coordinate their efforts to set priorities in the best interests of patients.
The second tactic would be to place a primary emphasis and reliance on prospective methods for assuring supplier performance. Consistent with the good APC principles, the most effective industry and regulatory control program would be a coordinated effort to implement prospective strategies to assure suppliers have the necessary QMS programs in place prior to manufacturing material for use. Such programs might even include self-inspection and sharing of appropriate performance metrics associated with manufacturing performance and product quality metrics.
However, efficiently building and implementing prospective control strategies requires more sophisticated methods. By expanding life cycle process validation4 methods and integrating ICH Q8 concepts,5 an integrated life cycle process development and validation (LPDV) approach can provide such a route.6,7,8 Briefly, the LPDV approach uses the following four stages to simultaneously develop and validate the control strategy, primarily driven by quality by design concepts during the second (design) stage:
- Define – Identifies the goals and requirements of the control system, including the control system goals listed above,
- Design – Based on the goals, define the control strategy’s procedures, practices, and resource requirements using quality by design to anticipate the qualification and verification requirements necessary for success,
- Qualify – Using a prospective protocol, assure prior to full implementation that the control strategy provides control, and
- Verify/Operate – Measure ongoing product attributes, process performance, and QMS metrics to assure ongoing control.
Industrywide use of prospective control systems, perhaps developed using LPDV methods, might be accomplished using the FDA’s voluntary consensus standards (VCS) program to align prospective regulatory and industry standards or approaches for prospectively building supplier QMS programs in coordination with retrospective monitoring and inspection programs.9 By understanding the fundamental strengths and weaknesses of various control strategies and implementing appropriate methods, product quality can be significantly improved.
- Garguilo, L., New FDA Quality Report – A World Full of Inspections, Outsourced Pharma, June 3, 2019. https://www.outsourcedpharma.com/doc/new-fda-quality-report-a-world-full-of-inspections-0001
- L. X. Yu, M. Kopcha, Int. J Pharm, 528 (1–2): 354–9 (2017).
- FDA – Pharmaceutical CGMPs for the 21st Century – a Risk Based Approach (September 2004)
- FDA (CDER/CBER/CVM) – Guidance for industry: Process validation: general principles and practices. Jan 2011, Rev 1
- FDA (CDER/CBER) – Guidance for industry: Q8(R2) pharmaceutical development. Nov 2009. ICH, Rev 2.
- Witcher MF. Expanding the process validation paradigm and applying it to the biopharmaceutical product lifecycle from development through commercial manufacturing. Pharm Engr, 2013; 33(1): 1–8.
- Witcher MF, Integrating Development Tools into the Process Validation lifecycle to achieve six sigma pharmaceutical quality. BioProcess J, 17 (2018). https://doi.org/10.12665/J17OA.Witcher.0416
- M. Witcher, “Improving Prospective Product Development Methods Derived from Management-Based Regulatory Guidelines,” Pharm. Tech, June 2019.
- FDA (CDER) – CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality Guidance for Industry, DRAFT, February 2019.
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 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 a $50MM manufacturing facility. Prior to Covance, Witcher was VP of manufacturing at Amgen. You can reach him at firstname.lastname@example.org.