In 2002, the U.S. Food and Drug Administration (FDA) began revamping the current good manufacturing practices (cGMPs) for pharmaceutical products through its “Pharmaceutical CGMPs for the 21st Century” initiative. In part, FDA undertook this initiative because the cGMP regulations had remained largely untouched since their inception in 1978, while tremendous advances had been achieved in manufacturing science, some of which were being adopted by pharmaceutical manufacturers. The initiative was designed to enhance and modernize the regulation of pharmaceutical manufacturing and product quality and to update the Agency’s regulation of pharmaceutical quality. In describing the program, FDA relayed its intent to encourage the pharmaceutical industry to adopt innovative manufacturing technologies by incorporating “quality systems” and “risk management” approaches into the regulatory schema. To further support the integration of the quality system and risk management approaches, FDA has recently finalized a guidance document, entitled “Guidance for Industry: Quality Systems Approach to Pharmaceutical Current Manufacturing Practice Regulations,” which is intended to help manufacturers implement these approaches.

FDA Guidance

In the September 2006 guidance document, FDA sets forth a comprehensive quality systems model that it believes will “support and sustain robust, modern quality systems that are consistent with cGMP regulations,” while still maintaining the intrinsic flexibility provided under the existing regulations. Moreover, the guidance articulates the fundamental philosophy embodied in the cGMP regulations, that “Quality should be built into the product, and testing alone cannot be relied on to ensure product quality.” The guidance document applies to manufacturers of finished pharmaceuticals, including products regulated by the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Veterinary Medicine (CVM). However, FDA states that the guidance may also be useful to manufacturers of components-including active pharmaceutical ingredients-used in the manufacture of these products.

FDA issued the guidance document for several reasons, including to help ensure that consumers receive high-quality drug products, to harmonize the cGMP regulations with other commonly utilized quality management systems, to aid in the successful management of many types of facility, equipment, and process changes without the need for prior approval, and to establish the necessary framework for implementing the “quality by design,” continual improvement, and risk management concepts. The guidance document discusses the key elements found in modern quality systems, including management responsibilities, resources, manufacturing operations, and evaluation activities, and where warranted, correlates the elements to cGMP regulatory requirements. Many of the quality systems elements correlate closely with the cGMP regulations.

Management Responsibilities

In the quality systems model described by FDA, management should play an integral role in the design, implementation, and management of the quality system, as their leadership is intrinsically tied to the success of the system. Management can support the quality system through actively participating in system design, implementation, and monitoring, including system review; advocating continual improvement of quality system operations; and allocating necessary resources to the system. Senior management should demonstrate a commitment to the quality system and its integrity, ensuring the system is aligned with the strategic plans devised for the company. According to the guidance document, management also has a responsibility to structure the company appropriately to support the product, quality, and management activities integral to producing quality products. FDA recommends that management ascertain and confirm that the quality system designed and implemented by the company includes clear organizational guidance and facilitates the systematic review of technical issues and problems. Moreover, under the guidance document, senior management should enunciate a strong commitment to quality in their company’s mission. Finally, because system review is a key component in evaluating the continuing suitability, adequacy, and effectiveness of a quality system, management should conduct periodic scheduled reviews of the quality system’s performance to assess the process, its product, and customer needs, and to incorporate changes to the system as needed.

Resources

According to the guidance document, appropriate allocation of resources is key to creating a quality system and complying with cGMP regulations. To that end, adequate resources must be allocated for quality system activities. The model sets forth that senior management (or its designee) should be responsible for providing adequate resources to supply and maintain facilities and equipment, to acquire and receive suitable materials, and for processing and laboratory analysis of finished drug product. In addition, under the model, senior management should encourage the organization to utilize problem-solving techniques and to be communicative, and should develop cross-functional groups to develop improvements to quality system procedures and processes.

As with other areas of manufacturing, personnel must be qualified to do the operations they are assigned in a quality system and should understand the effect of their responsibilities and activities on the product and the customer. On-going training is an essential element of the quality systems approach to enable employees to remain proficient in their operational capabilities as well as their understanding of the cGMP regulations. To support the quality system, a company is expected to institute training programs that evaluate training needs, provide training to satisfy those needs, evaluate the effectiveness of the training, and document training and any necessary re-training.

In instances where an operational process must be outsourced to a second party, the quality systems model requires the use of contracts, known as “quality agreements,” which specify the materials or service, quality specification responsibilities, and communication mechanisms. Under this approach, it is the manufacturer’s responsibility to determine that the contract firm is qualified before entering an agreement with the firm.

Manufacturing Operations

The guidance document states that significant overlap exists between the elements of a quality system and the existing cGMP regulation requirements for manufacturing operations, but reminds manufacturers that FDA enforcement programs and inspectional coverage remain based on the regulations. Elements of manufacturing that should be assessed under the quality systems approach include the design, development, and documentation of product and processes; the examination of system inputs (any material that goes into a final product, no matter whether the material is purchased by the manufacturer or produced by the manufacturer for the purpose of processing); the performance and monitoring of operations; and the management of non-conformities or deviations, including documentation of the investigation, conclusion, and follow-up actions.

Evaluation Activities

A robust quality system calls for a number of evaluation activities. Quality systems require continual monitoring of trends for use in improving systems, including monitoring data and information, identifying and resolving problems, and anticipating and preventing problems. The guidance document describes the need for procedures to collect data from monitoring, measurement, complaint handling, and other activities, as well as tracking this data over time, to evaluate the effectiveness of system controls. While the cGMP regulations call for product review on an annual basis at a minimum, a quality systems approach calls for more routine evaluation of the trends based on available data derived from the quality system.

In addition, the quality systems approach calls for routine, planned audits to evaluate the effectiveness of quality system implementation and maintenance and to assess whether processes and products meet the pre-defined specifications. A critical component of any audit is the development of an audit record and documentation of corrective actions, including the personnel involved, the responsibilities of each, and supervisory oversight and follow-up through completion. Under a quality systems approach, evaluation activities should include tools such as quality risk management, a tool used in the development of product specifications and critical process parameters, and corrective action, a tool that is reactive in nature for system improvement to help ensure that significant problems do not recur.

The guidance document put forth by FDA supports the development and implementation of a comprehensive quality system model for pharmaceutical products intended to facilitate compliance with cGMP regulations because the primary goal of a quality system is to provide consistent and sustainable production of safe and effective products. Specifically, according to the guidance document, successful quality systems share the following characteristics, including: employing science-based approaches; making decisions based on an understanding of the intended use of a product; properly identifying and controlling areas of potential process weakness; responding to deviation and investigation systems in a manner that leads to timely remediation; implementing sound methods for assessing and reducing risk; utilizing well-defined processes and products that extend throughout the product life cycle; adopting systems for careful analysis of product quality; and employing philosophically — and financially — supportive management.

FDA believes that when fully developed and effectively managed, a quality system will lead to consistent, predictable processes thereby ensuring that pharmaceuticals are safe, effective, and available for the consumer.

Gary C. Messplay is a partner in the Washington, D.C. office of Hunton & Williams LLP (www.hunton.com), where he is head of the law firm’s Food and Drug Practice. He can be reached at
gmessplay@hunton.com. Colleen Heisey is an attorney in the firm’s Food and Drug Practice.