Andrew G. Edwards is a senior consultant at EduQuest.

Andrew G. Edwards

In 2002, the US Food and Drug Administration publicly recognized a need for change with its 

 current good manufacturing practices (CGMP) for the 21st century initiative

 (1). This new approach to GMP compliance and enforcement recognized that FDA and the drug and biologics industries were not where they needed to be in terms of quality, manufacturing science, and risk management. This changing world of GMP applied to human and veterinary drugs and biological drug products. Key to FDA's approach has been to request a holistic cradle-to-grave management of quality issues. 

The quality system should be an integrated framework within which the design, manufacture, packaging, labeling, and distribution take place. Commitment from management is crucial; without it there is no quality system. The underlying principles are:  

 Ensure quality is designed and built into the product

Reliance on appropriate and documented processes and procedures

Provide documented, objective evidence of what was done during design and manufacture

Management responsibility and control of the quality system

Process—the quality of a product is governed by the quality of the processes used in its manufacturing

Feedback loop for corrective and preventive actions. (A feedback loop helps find any flaws that may be in a validated process or product. Validation is not 100%, it is a probability. Corrective and preventive action systems are the feedback loop to continuously improve your products and processes.)

In the changing, evolving world of GMP regulations, quality concepts are changing. The original GMP regulations started with a product-focus and quality control. Next was a shift to a process-focus and quality assurance. Now drug and biologics manufacturers face an enormous paradigm shift with the new model of quality systems (see Figure 1). 

However, this new evolutionary step is not new to FDA because the medical device industry has already adopted the quality-system approach in 1996 (2). Other industries also have adopted this approach (e.g., the automotive industry). Guidance is available from American National Standards Institute and International Organization for Standardization (ISO) on what is required in a quality system that parallels the medical device regulation (3, 4). FDA's approach has been to focus on quality by design and the control and reduction of variability by encouraging the use of sophisticated process analytical technologies (PAT) (5). Following the revised GMP guidance and the adoption of new technological advances, FDA hopes manufacturers will consistently maintain high-quality products and improve their manufacturing efficiency. FDA believes this should help lower costs and prevent shortages of critical medicines owing to failures that can result in product recalls. The estimated potential worldwide cost savings from efficiency improvements in the pharmaceutical industry is as high as $90 billion (6). 

In October 2006, FDA issued a final guidance on quality systems intended for use in the manufacturing of human and veterinary drugs, including biological drug products (7). This guidance provides manufacturers with the ability to make technological improvements more readily, with appropriate regulatory oversight, and it offers guidance for defining management responsibilities, allocation of quality resources, dividing manufacturing duties between the quality unit and the production staff, and reviewing records and evaluating data. 

The quality systems approach describes the responsibilities of the "quality unit," which combines the duties of quality control and quality assurance, "ensuring that the various operations associated with all systems are appropriately planned, approved, conducted, and monitored." The quality unit also is responsible for ensuring that controls are implemented and used; seeing that procedures and specifications are adhered to (at the manufacturer and at any contractors); approving or rejecting incoming materials, in-process materials, and drug products; and reviewing production records and investigating unexplained discrepancies. 

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. 

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. 

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 (

 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. 

FDA encourages a risk-based regulatory approach where relevant regulatory policies and procedures are modified to accommodate the most current level of scientific knowledge. The change would focus on increasing the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance. More focus in the development stage is needed to design the capability of process-control strategies to prevent or mitigate the risk of producing a poor quality product. 

This step is much more about a new philosophy and operational culture than it is about new standard operating procedures and a new quality manual. There may be a need to vastly improve and retool cross-functional and cross-departmental communication and coordination. A silo-based approach simply will not work. Every part of the organization that touches on the product life cycle will need to operate in a much more integrated way. Most of the advances that have occurred, and are anticipated to occur, are bringing the development, manufacturing, quality assurance, and information and knowledge-management functions so closely together that these four areas should be coordinated in an integrated manner. There may be a need to also include some of the not-so-obvious players such as regulatory, marketing, product surveillance, senior management, and so forth. Management responsibility and involvement is absolutely critical to the quality system. The current business model based on speed-to-market must strike a different balance and approach with more emphasis on doing it right. 

Process design, process controls, and resource allocations will need to be based on risk assessment and risk management (10). Long-standing concepts of hazard control that use failure mode and effects analysis (FMEA) as well as hazard analysis and critical control point (HACCP) principles may not be familiar to the drug and biologics industries. FDA believes there will be significant regulatory benefits by improved ability to understand and implement changes with less FDA oversight and preapproval, faster and more predictable FDA review, analysis, and approval of new products and CMC changes, and fewer preapproval and shorter GMP inspections. The real business benefits (in cost, time, and efforts) are:  

 Better science, efficiency, predictability, and control

Less waste, rejection of materials, and rework

Greater ability to identify and correct root causes.

There is a practical relationship between quality and today's business realities (profit and cost-of-goods) where business objectives can be used to drive quality-system improvements. An understanding is also needed of the basic operational and scientific principles behind quality systems, quality by design, and PAT. There are core principles common to them all:  

These principles boil down to one common theme:  Know what you're doing, why, when, and how. The same core principles drove the development of FDA's GMP regulations as well as the standards by the ISO and International Conference on Harmonization and serve as the fundamental basis for the various operational excellence methods (Six Sigma, lean manufacturing, etc.). 

The overarching context for the core principles are the application of hazard control—an umbrella term that broadly describes the various risk-based concepts that FDA has been discussing (see Figure 4). Hazard control includes:  

The concepts of hazard control should be applied to the product and the process. These concepts are described in Table I. 

Articles

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.