ABSTRACT

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.