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Companies faced with real or threatened FDA sanctions are usually least prepared to react effectively.
The current Good Manufacturing Practices (GMPs) regulations for finished pharmaceuticals and medical devices have been around, in one form or another, for over 25 years. During this time, FDA has provided interpretation and guidance to aid companies in their efforts to comply. Yet, when found to be out of compliance by FDA, some companies experience difficulty making effective corrections in a timely manner. When compliance is finally achieved, it is only after several failures and misdirected expenditures of time and money, often leading to chronic deficiencies even more difficult to remedy. To achieve effective, sustainable corrections to GMP deficiencies, companies need to take a systems-based, organizational approach to compliance.
Recent trends in US Food and Drug Administration (FDA) warning letters attest to the agency's continued priority on GMPs and reflect the challenges companies have in achieving and maintaining GMP compliance. While the number of warning letters the FDA has issued over the past three years has declined, 47 percent of all violations cited in 2005 were GMP deviations. To help prevent occurrence, or reoccurrence, of GMP deviations, regulatory experts including FDA recommend that manufacturers identify and correct the underlying systemic causes of noncompliance, rather than focus on the specific symptoms. This allows manufacturers to redesign quality subsystems to improve both operational efficiency and regulatory compliance.
A company facing a long list of observations at the end of an FDA inspection may react with great energy and purpose to fix each one. However, when the company focuses on the specific symptoms rather than the underlying causes (i.e., the systems), audit after audit will identify additional examples of system weaknesses. Rapidly this becomes a repetitive, frustrating cycle of failure resulting in chronic GMP noncompliance and ongoing, costly adversity with the FDA. One pharmaceutical company that received a Warning Letter for GMP deficiencies, for example, found itself subjected to restrictions on product approvals and export certificates for five years despite repeated efforts to address the cited problems. Prohibitions of the original Warning Letter were kept in force because subsequent inspections conducted over the ensuing five years found continuing GMP problems.
The road to an FDA injunction is usually a long and frustrating one for both FDA and the company. From the company's perspective, it has made good faith attempts to correct the problems cited by FDA. Typically, it has devoted large sums of money and staff resources, hired consultants, developed and executed action plans, etc., yet at each assessment by FDA, new or similar GMP failings are identified. Ironically, company management redoubles its efforts, restarting the same cycle of plans, committees, consultants, milestones, commitments, new beginnings and, predictably, repeated failures.
FDA, too, becomes frustrated that its best efforts have not elicited effective, voluntary corrective action. It has accepted the proposed corrective action plans and the promises of management and patiently awaited results. When, in spite of these efforts, sustainable compliance is not achieved, FDA may begin to believe management of the company is unwilling or unable to fix its problems.
Unfortunately, an FDA injunction or the threat of one does not suddenly enable a company to do what it has not been able to do before. Long before FDA considers injunction, a strong admonition from FDA to correct violations either in writing or in a face-to-face meeting frequently doesn't provide insights about how to make corrections. In fact, it can exacerbate the situation by requiring or suggesting many specific activities that do not contribute to resolution of the underlying problems or offer insight to the mechanics of correcting problems.
A systems-based approach is the key to breaking the cycle of GMP failure. FDA has identified six subsystems (See Figure 1) reflected in the pharmaceutical GMP. Together these subsystems make up a quality system. A systems approach leads to effective and sustainable corrections to FDA inspectional findings or a Warning Letter. The most significant benefit, however, is that it proactively prevents GMP problems.
Figure 1. The diagram below shows the relationship among the six subsystems in pharmaceutical manufacturing-the quality system and the five manufacturing systems. The quality system provides the foundation for manufacturing systems that are linked to and function with it to achieve compliance and consistently produce a quality product.
FDA first recognized the value of a quality system approach to GMPs in its 1996 publication of the Quality System Regulation for Medical Devices. FDA realized that a quality system provides the means for assuring consistently high quality of healthcare products.
A systems-based approach to establishing a competent quality system can be effectively developed and executed using an interdisciplinary team structure formed around the subsystems of the GMP regulations (for drugs or devices, Figure 2). Each core team, representing a subsystem, is chartered to initially define the existing assigned subsystem and to assess its performance using various quality data. Based on their findings and employing risk-assessment principles, each team designs a new subsystem assuring the controls incorporated are commensurate with the risks posed. This may involve building on what exists, completely redesigning it, or more commonly, doing both. This process frequently identifies opportunities to improve process efficiency in a context that assures a proper balance between efficiency and compliance.
Next, the team creates documentation to support the level of controls that have been created. The team identifies metrics to be used in assessing future performance, training needs and necessary linkages between the subsystems. The team also eventually oversees the implementation of the new subsystem.
Critical to the success of this process is the interdisciplinary make-up of the teams—all stakeholders should be represented, i.e., quality, manufacturing, research and development, engineering, marketing, etc. This enriches the talent pool that will contribute to the creation of the subsystem and prevents the development of subsystems that are not workable throughout the organization. Each team should have an external third-party expert member to provide an objective perspective, provide technical and regulatory advice and aid the team in avoiding cultural "blind spots." A process facilitator can assure team efficiency, achievement of milestones, and resolution of issues.
Figure 2. Core Team Structure Recommended organizational structure for a core team approach to creating an effective quality system for a pharmaceutical company:
Overseeing the entire project is the steering committee that may be variously called the leadership or management team. It consists of senior-most managers representing the various functional areas of the company along with a third-party senior management expert for objective regulatory assistance. This team establishes the vision, provides the necessary resources and commitment, assures linkages between the various teams, serves as the change agent for cultural and system issues, and resolves issues that invariably surface during the course of the project. It also reflects senior management's commitment to quality. A project manager is often required to assure the project is completed on budget and on time.
Documenting a quality system on paper is not enough to assure a company's regulatory or business health. If organizational values are not in sync with quality principles, procedures may get changed but behaviors may not. In this situation, any system corrections that are made will not last. The values reflected in the company's organization and support systems impact behaviors that ultimately influence the manner in which the quality system is executed. The manner in which employees are motivated, rewarded, compensated, and promoted influences their behaviors. Sometimes little attention is given to the behavioral impact these support systems have on a company's quality system implementation. The actions of management, particularly when in conflict with its words, communicate clear messages to the organization. Implementing a systems-based team approach to enhancing the quality system itself can have a positive effect on culture, but a concerted effort must be made by management to assure alignment of values with the quality system. This can be very difficult.
Using organizational development and management tools, the company must determine which assumptions and beliefs support or hinder successful implementation of a new quality system. Communication must be planned and managed to assure clarity, effective conveyance of key ideas, and consistent support of ongoing development. Support systems—particularly those involving human resources policies, compensation schemes, career planning, recognition and reward systems, hiring and promotion practices, among others—must be evaluated to assure alignment. Providing the necessary attention to organizational culture can speed the process of quality system implementation, as well as assure its ultimate success.
Establishing a quality system that meets a company's regulatory and business needs is challenging. Companies faced with real or threatened FDA sanctions are usually least prepared to react effectively. Frequently, their efforts of the past have been unsuccessful, leaving little insight into new approaches. However, even a company in this situation can develop a successful approach if it recognizes the value of a systems approach to creating a quality system, understands the value of a robust quality system in achieving regulatory and business objectives, and appreciates the impact and role of organizational culture. With this foundation, a process employing interdisciplinary, systems-focused teams can result in a sustainable, compliant quality system that can withstand regulatory challenge and achieve efficiencies that meet the business needs of the company.
Ron Johnson is the executive vice president of The Lewin Group, a Quintiles company. Maxine Fritz is the vice president of pharmaceutical quality systems and validation services for Quintiles Consulting.