Beyond GMPs: The Latest Approaches to Good Manufacturing Practices

GMP is the acronym for Good Manufacturing Practice. The GMPs represent a set of regulations that were promulgated as a final rule by FDA in 1978 and intended to ensure the safety and efficacy of the nation's drug products. The GMPs, as we know them today, are the result of over a century of actions by industry and reactions by government and consumer groups to bring guidance and controls to the food and drug industry, resulting in a safe supply of food and medicines. GMP compliance is the foundation of the pharmaceutical industry and has become the benchmark for success of any enterprise involved in the development, manufacture or testing of human and animal drug products. Often, the prefix c is used to indicate cGMPs. The c stands for current and raises regulatory expectations beyond the stated regulations to include current, state-of-the-industry standards.

Without robust quality systems supporting the manufacture, testing, and distribution of pharmaceuticals, our society, as we know it could not survive. When patients use medicines, they do so with the implicit knowledge that entire organizations went to painstaking efforts and extremes to ensure that the drugs are of the utmost quality. The GMP regulations far surpass the Hippocratic oath's requirement to "First Do No Harm," by requiring process and laboratory controls, verification and approvals, quality controls, structure and organization, material management, validation, and accurate documentation of these and other requirements. These controls are intended to ensure safe, pure and efficacious medicines are produced and available to patients in need.

Besides patients, hundreds of thousands of government and private sector employees depend on the pharmaceutical manufacturing industry for their jobs and careers. Shareholders expect regulatory compliance to protect their investment. Countries depend upon the industry for the health of their citizens. Companies that cannot meet GMP requirements routinely suffer severe financial penalties in fines, lost revenue, and damage to their reputations.

Requirements

Industry personnel and government regulators involved in the research, production, and regulation of pharmaceutical products constitute society's most talented, dedicated workforce, devoted to their cause of helping mankind through the discovery and manufacture of medicines that cure and mitigate disease. The pharmaceutical industry is an intense, stringent, and competitive industry by nature. It is currently under extreme social and political pressure to deliver new medicines faster and cheaper. Existing regulations are being interpreted more conservatively and penalties for noncompliance — even for small errors — are at their highest in history.

People are not perfect, including the people who conduct the clinical studies, write the dossiers for submission and approval, obtain materials, and manufacture and package the medicines we consume. Good intentions can succumb to honest error, speed-to-market can lead to taking risky short cuts, and ambiguous data can be interpreted as acceptable. Regulations are necessary to provide a minimal guideline for ethics and acceptability. Without the GMPs, we would have chaos, and there would be no system to assess medicines.

Enforcement

Enforcement of the GMPs is essential. FDA currently assesses acceptability of a drug product through its application review and facility inspection process. Reviewers at various centers evaluate scientific merit and supporting evidence, and field investigators perform onsite investigations to assure the information submitted in the application is authentic. Field investigators also perform an evaluation of the manufacturing environment, equipment, controls, procedures, and personnel. All of this is accomplished, in large part, by reviewing required documentation.

The number of domestic establishments FDA is required to regulate exceeds 120,000. Annual imports to the US number nearly 8 million shipments of FDA-regulated products from about 500,000 foreign manufacturers. Many of these foreign facilities have never received an FDA inspection.¹ The agency is also being ordered by Congress to address even more complex issues, including bioterrorism, mad cow disease, foreign pharmacy imports, counterfeiting, and product diversion and tampering. Domestic and international regulatory agencies and customer expectations continue to demand increased compliance and consistent quality.

Most standards are well written and understood, but many are not and have been subject to multiple interpretations not only by industry but also by FDA itself.

New Initiatives

Until recently, more than 25 years had passed since the last major changes were made to FDA's regulatory systems. Cognizant of new challenges facing both industry and the agency, FDA has initiated several new programs.

"Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach" was announced on August 21, 2002. This new initiative is intended to commence "a systematic reappraisal of FDA's approaches to product quality regulations." FDA's current inspection program is overburdened with new obligations and an increasing number of firms requiring inspection, while the number of completed inspections has been decreasing over the past several years.²

FDA hopes to incorporate the most up-to-date concepts of risk management and use its resources effectively and efficiently to address the most significant public health risks, including:

• encouraging the early adoption of new technological advances by the pharmaceutical industry

• facilitating modern quality management techniques, including implementation of quality systems approaches to all aspects of pharmaceutical production and quality assurance

• encouraging risk-based approaches that focus both industry and agency attention on critical areas

• ensuring that regulatory review and inspection policies are based on state-of-the-art pharmaceutical science

• enhancing the consistency and coordination of FDA's drug quality regulatory programs, in part by integrating enhanced quality systems approaches into the agency's business processes and regulatory policies concerning review and inspection activities.

As a result of the initiative, multidisciplinary working groups are developing guidance documents in various phases of completion. These documents are available on the agency's website (www.fda.gov) including:

• Part 11, Electronic Records, Electronic Signatures — Scope and Application

• Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical cGMP

• Sterile Drug Products Produced by Aseptic Processing: Current Good Manufacturing Practices

• Comparability Protocols — Protein Drug Products and Biological Products, Chemistry, Manufacturing, and Controls Information

• PAT — A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance

FDA is also making important changes to its inspection program, including:

• The Office of Regulatory Affairs (ORA) and the Center for Drug Evaluation and Research (CDER) signed a memorandum of understanding establishing a Pharmaceutical Inspectorate (PI) within ORA. This PI will be staffed with highly trained individuals within ORA who will devote most of their time to conducting human drug quality inspections and other complex or high-risk pharmaceutical operations.

• To serve as a member of the PI, an investigator will have to obtain and maintain a Level III Drug Certification. This certification signifies that an individual has received extensive training on advanced technology in the pharmaceutical manufacturing process and how those technologies are evaluated during an inspection.

• A board has been established to review certification packages; select candidates for membership into the PI; and develop, update, and maintain the curriculum for the Level III Drug Certification program.

• The pre-approval inspection compliance program has been revised, giving field offices more opportunity to utilize a risk-based approach in determining the necessity of pre-approval inspections.

• The agency is emphasizing a risk-based approach in selecting inspection sites to ensure its limited resources are appropriately utilized.

FDA is looking internally at quality systems and controls to enhance the consistency and predictability of their internal inspection program. The key message FDA wants to deliver is that "FDA is regulating product quality to serve the patient, and drug companies should view the patient as a customer, too." In the past, a lack of knowledge of what affected product quality led to FDA micromanagement of the inspection processes. FDA is adopting a more scientific and systems-based approach. If processes are well understood and controlled, FDA will be able to redefine their inspection approach.

The agency also is conferring with private corporations, universities, and independent consultant groups to improve the way it manages its responsibilities. It is clear FDA believes there is no alternative but to continue in this direction.³

Challenges

Certain challenges face both FDA and the biopharmaceutical industry. Policy, regulation, and procedures must be known and practiced consistently so that industry can align practices with FDA expectations. The demands on manufacturers and regulators are increasing to the point where the system must change if it is to continue to function.

Future challenges facing pharmaceutical manufacturing organizations include:

• manufacturing agility

• drugs aimed at smaller populations

• custom drugs for genetic populations.

Industry needs to stand its ground on scientific issues. The new initiative asserts that the regulatory process should be about science and an open exchange of views in order to assess product quality. FDA's new dispute resolution process also is directed at promoting and supporting such an approach.

In September 2004, FDA issued the final report on its "Pharmaceutical GMPs for the 21st Century" initiative. The report addresses the outcomes of the original program and some additional efforts, in varying degrees of completion, that will become ongoing programs. Of significant interest, FDA formed the Council on Pharmaceutical Quality, which has been charged with policy development, coordination, and continuing change management, including the ongoing implementation of specific quality management systems within FDA's operations.

Additionally, FDA issued a draft guidance titled Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations.⁴ Although this document is neither intended to create expectations for pharmaceutical manufacturers beyond current regulations or requirements, nor is it intended to be a guide for inspections, it will have a significant effect on future regulatory inspectional expectations and outcomes. The entire report is available at www.fda.gov.

Quality Systems

FDA has expressed interest in

quality systems

, both internal to the agency and as they apply to industry. What are quality systems and how are they used? Depending on whom you ask, you will receive a different response. The World Health Organization (WHO), International Conference on Harmonization (ICH), and American Society for Quality (ASQ) all differ on the topic to some degree. Even within individual companies, the definition often varies and the interpretation and use are unclear. However, one thing is clear: industry is empowered — and required — to define appropriate quality systems.

FDA has provided its definition of quality system within the draft guidance referenced above. It reads: "Quality System — formalized business practices that define management responsibilities for organization structure, processes, procedures and resources needed to fulfill product/service requirements, customer satisfaction, and continual improvement. In the cGMP regulatory context, the quality system establishes the foundation to promote the effective functioning of the five other major systems."⁴ FDA also states that the overarching philosophy in both the cGMP regulations and in robust modern quality systems is that quality should be built into the product, and testing alone cannot be relied on to ensure product quality. The guidance document goes into detail on acceptable models for quality systems and states that the cGMP regulations are inherently flexible to enable manufacturers to implement a quality system in a form that is appropriate for their specific operations.

Defining quality systems requires careful thought and consideration. Quality systems need nurturing and support as they evolve. Every enterprise should have a quality manual that outlines its philosophy and expectations. Subordinate to that, standards and procedures that outline the execution and expectation of the quality philosophy and requirements are needed. Those procedures yield data and metrics that management must review for acceptability and corrective action. This structure, including all the operational specific systems required to ensure product quality, should constitute an enterprise's quality system.

One useful way of defining quality systems is to say that they cover all the business-process systems that can, in any way, affect product quality or compliance. For example: raw material ordering and qualification, pest control, manufacturing, packaging and labeling, and others. Within this broad definition of quality systems it is important to identify the subset of processes formally owned by and the responsibility of the Quality Assurance Unit, for example: complaint reviews, product review, disposition, audits, and change control. Within the overall quality systems, these constitute the Quality System itself.

System-Based Inspections

System-based inspections (SBIs) are risk-based, shifting the regulatory focus from specific products and processes to assessing the strength of the systems that are meant to prevent and resolve manufacturing difficulties. This risk-based systems approach affords a broader scope to inspections, with the potential for significant business impact not only to individual products at a site but to all products that fall under the relevant quality systems.

Within FDA, definitions differ somewhat when applied to system-based inspection technique. The Center for Radiological Health (CDRH) was the first center to formalize a system-based inspection program through its quality system inspection technique (QSIT) compliance program, implemented in August 1999. CDER began a similar pilot program of the same name in January 2001, which has since been formalized as the Compliance Program Guidance Manual 7356.002. This manual is currently in use for inspections of all human drug facilities. The Center for Biologics Evaluation and Research (CBER) also is implementing system-based inspections for blood products under a new compliance program.

The CDRH QSIT approach is based on seven major quality sub-systems: management controls; design controls; corrective and preventive actions; facility and equipment controls; material controls; records, documents, and change controls; and production and process controls. The CDER program is based upon six major sub-systems: facilities and equipment, materials, production, packaging and labeling, laboratory control, and the Quality System itself. The CBER blood product system-based inspection will be based on five sub-systems: quality assurance, product testing, donor eligibility, production and processing, and quarantine and inventory management.

The CDER QSIT approach consists of dividing entire plant systems into the six distinct sub-systems mentioned above, following 21 CFR Parts 210 and 211. Although QSIT and the new draft guidance document are specific to drug and biological drug product manufacturers, they can easily and effectively be applied to active pharmaceutical ingredient (API) manufacturers. Each of the six quality sub-system categories identified by CDER may contain several subordinate systems. These six major quality sub-systems are the foundation for both full and abbreviated inspections. A full inspection requires evaluation of at least four of the QSIT-defined sub-systems, whereas abbreviated inspections require review of only two sub-systems. Companies that are new to FDA, have previously demonstrated noncompliance, or have a pending PAI usually undergo the full inspection. Firms with compliant histories and those that have recently been inspected (such as contract manufacturers who were recently inspected for different clients) may receive abbreviated inspections. The Quality System itself is part of every inspection.

CDER's QSIT inspection may focus on the following key areas within the Quality System:

• management review

• complaint reviews

• discrepancy and failure investigations

• change control

• product improvement projects

• reprocess and rework

• returns and salvages

• rejects

• stability failures

• audits

• corrective and preventive action

• documentation

• quarantine products

• validation

• training and qualification.

The other five CDER identified quality sub-system headings are systems that typically are the responsibility of functions other than the quality assurance (QA) department. However, to be effective and under control, these sub-systems require QA oversight, review, and approval.

FDA compliance investigators have latitude, with concurrence from the district office, to reduce a full inspection to an abbreviated inspection. This may sound like good news, but it usually indicates that the firm has failed early in the inspection process or that one or more of the QSIT systems is significantly out of control, and FDA does not intend to expend the time and resources to complete an inspection of the remaining systems. Whenever the quality systems portion of the inspection fails, the inspection is terminated, and the agency contemplates regulatory action.

Quality systems are designed to be proactive and preventative. Companies should conduct internal audits periodically to ensure that proper processes and practices are being followed. When properly designed, monitored, and followed, quality systems can reduce waste and rejected material, improve personnel efficiencies, empower employees, and place appropriate accountability on those responsible for the production, quality, and review of those systems. Moreover, they can prevent major manufacturing problems, resulting in fewer and shorter inspections, and ultimately a more efficient industry and government.

Systems Thinking

The systems approach is much more than a force-multiplier for FDA. It is a tool companies can use to their advantage. The systems paradigm is a way of thinking about the strategic environment — how to develop processes that achieve strategic goals. Forward-thinking organizations can use it to strategically analyze and respond tactically to changes in the business and regulatory environments by sustaining an adaptive and productive organizational culture.

A hunger for knowledge about quality systems and how to consistently apply and implement them exists within both FDA and industry. Existing regulations are antiquated. The bar has been raised, as evidenced by inspectional findings, regulatory actions, and penalties. Although the 1978 GMP rule does not require quality systems, CDER's compliance program mentions quality systems and investigators expect industry to have them.

Many companies do not have quality systems in place because they are not required by regulations. However, the pharmaceutical industry needs these programs to ensure consistency and high-quality products. Regulatory agencies should be able to evaluate a firm's quality systems and determine compliance through a process of synthesis rather than analysis. FDA should not have to weed through weeks of data on a specific topic — review of the system governing that data should allow quick determination of control, adequacy, and compliance.

Quality Management

Management is the critical component in a quality system. Management mandates the need and design of quality systems and is ultimately held accountable for reviewing outcomes and supporting corrective action.

A quality management team (QMT) is necessary and should consist of the highest level of management possible at a manufacturing site with accountability and the resources needed to affect change. The QMT should be the governance vehicle that supports the execution of a quality plan. The quality plan must encompass all the systems, as well as metrics, organizational needs, corrective action procedures, and resource support.

FDA often cites a process, piece of equipment, or documented practice as unacceptable. Usually, it is not until a warning letter or consent decree appears that management is cited, at which point it is too late.

Without key management taking action through the QMT, the quality plan and subsequent efforts are diminished, and results may falter. The QMT provides a forum for discussion and support of the quality plan and ensures it is regularly reviewed, updated, and executed, and it is a living document driving closure to notated issues and process and system improvements.

Conclusion

The new FDA initiatives outlined in this article will provide the basis for compliance programs into the future. In the face of new threats and constraints, FDA continues to update and reinvent its regulatory strategy to ensure a safe and efficacious supply of pharmaceutical products. Successful enterprises will acknowledge these changes quickly, to survive and thrive in the current environment. GMP compliance — and implementation of the quality systems that support compliance — is the foundation of the pharmaceutical industry and the benchmark of success for enterprises involved in the development, manufacture, or testing of human and animal drug products.

Note: Additional information on guidance documents, "Pharmaceutical cGMPs for the 21st Century," and other FDA initiatives can be found at www.fda.gov.

References

1. Arling E. Integrating QSIT into quality plans...

Biopharm International

2004; 17(6):44-46,48,50-52.

2. Horowitz D. A risk based framework for GMP regulatory oversight. Presented at GMP by the Sea; 2004 Aug 24; Cambridge, Maryland.

3. Woodcock J. Keynote address. Presented at Interphex; 2004 March 16; New York, New York.

4. FDA. Draft guidance for industry: quality systems approach to pharmaceutical current good manufacturing practice regulations. Available at www.fda.gov/cder/guidance/6452dft.htm.

Edward Arling is associate director of quality assurance at Amgen Inc., 4000 Nelson Road AC22A, Longmont, CO 80503, 303.401.7860, fax 303.401.7603, earling@amgen.com.