Quality Systems for Drugs and Biologics - Pharmaceutical Technology

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Quality Systems for Drugs and Biologics
FDA is modernizing and streamlining current good manufacturing practices. The author examines FDA's evolving approach to quality systems and how a manufacturer can implement a quality system framework.


Pharmaceutical Technology


FDA is applying a "six-system inspection model" in which the overarching quality system embodies five overlapping subsystems: production, facilities and equipment; laboratory controls, materials, and packaging-and-labeling (8). FDA will continue to monitor manufacturing plants through its inspection program and will continue to advance the training of its investigators in the latest technologies. FDA will focus the detailed inspection of a system so that the findings reflect the state of control in that system for every product (profile) class. A system is considered out of control based on GMP deficiencies that suggest lack of quality assurance. If one of the six systems is out of control, then the firm is considered out of control.

Design controls


Figure 2: Today's model.
FDA is being much more explicit about the industries' scientific and regulatory responsibilities by making product design and process development part of the quality system and focusing on measurement and control (9). The agency has clearly placed the burden of evaluating and demonstrating adequacy and acceptability on the manufacturer. This shift is going to take a substantial effort and will affect research and development more than in the past. An ongoing dedication of more resources will be needed on the "front end" of process design and development. A huge increase is needed in the early and very detailed understanding of the process and product formulation. This will probably mean more time, effort, people, and money than the 1980s process validation movement and may take years to realize the benefits on the "back end." GMP requirements will have much more impact on pharmaceutical development.


Figure 3: Tomorrow's promise.
With the quality system approach, FDA hopes manufacturers will apply an effective, knowledge-based scientific management of the entire product life cycle, from research to nonclinical (in vitro and GLP) studies to pharmaceutical development, clinical manufacture, clinical development (human trials), approval, commercial manufacture, and the postmarketing life of the product. This GMP paradigm shift will change the basic premise of the manufacturing process, completely shifting the point of regulatory and scientific emphasis by moving the regulatory anchor from the fixed process to fixed (constant) outputs (see Figures 2 and 3).

For the industry to evolve to the new model, companies must be open to change. The change will be more complex than just reengineering manufacturing processes where FDA will play a substantial role in the change. The current product life cycle is very inflexible by the regulatory approach where the process is fixed within the operating ranges established in regulatory filings and approvals, and change is difficult and often requires preapproval. Because of this, companies are reluctant to submit supplemental applications and "reopen" product approvals. This reluctance is a result of substantial delay in implementing changes because of regulatory review. There is usually a limited ability to fully understand the potential clinical impact of changes. Currently, the process is not fully understood when a product is newly developed and standards and expectations change with time (e.g., analytical methods, impurity profiles, limits of detection). Companies have chosen to live with poorly understood, inefficient, low-yield processes instead of going through another round of regulatory review and approval and run the risk that additional clinical trials and/or preapproval inspections might be required.

FDA's vision is for industry to focus on reducing variability through process understanding (e.g., application of knowledge throughout the product life cycle). It is a "cradle-to-grave" systematic approach where product quality and performance are ensured through the following:

  • Design of effective and efficient manufacturing processes
  • Product and process specifications based on a mechanistic understanding of how formulation and process factors affect product performance
  • Application of continuous real-time quality assurance.


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