Regulatory authorities Pharmaceutical Inspection

The Pharmaceutical Inspection Cooperation Scheme (PICS) was established in 1995. It brings together regulatory authorities from different countries, for the purpose of developing harmonised GMP requirements and inspection techniques, with the goal... 

Only three countries, Tunisia, Uganda and Zimbabwe, do not issue a GMP certificate. The drug regulatory authorities in these three countries do conduct GMP inspections, but do not issue a specific document which indicates that a manufacturing plant has attained GMP standards. The MCAZ does, however, provide a GMP certificate at the manufacturer s request to facilitate international registration and export of products. In Malaysia, various types of certificates are issued GMP certificates Certificate of Pharmaceutical Product for export and Certificate of Free Sale for medical devices and cosmetic products. Cyprus has no clear criteria for issuing a GMP certificate instead. 

This chapter will focus on some, but not all, of the areas in which the U.S. Food and Drug Administration (FDA) and the European Union (EU) regulatory authorities have attempted to coordinate their efforts to provide uniform rules and standards for the pharmaceutical industry. Specifically, we will review the efforts to harmonize approaches relating to inspections (including public disclosure of confidential information) and product approval or authorization (including clinical trials). While space limitations do not provide sufficient opportunity to describe each regulatory authority s system or the harmonization attempts in detail, it is our hope to provide some background of where the efforts are now, where the efforts are intended to go, and what we believe will be the results of these efforts. In addition, the author is much more familiar with the U.S. system than the EU system because of his experience and daily exposure with FDA, this chapter will focus more on the U.S. structure. 

In the approach to Year 2000, regulatory authorities tended to survey and monitor the preparations being made by pharmaceutical and healthcare companies to cope with the feared millennium bug rather than conduct detailed computer validation inspections. This factor seems to have delayed comprehensive inspections of computer vahdation. A few sporadic citations for the noncomphance of isolated computer systems arose in 1999, but there were no prominent censures in this area. 

Since the start of the new millennium, regulatory authorities have returned to conducting more comprehensive examinations of computer systems. The most significant inspections are typically focused in MRP II or TIMS network applications and include supporting computer network infrastructure. Recent inspections at Eli Lilly, Argus Pharmaceuticals, and Solvay have all taken this approach. The expectations on networks are basic but have often been unsatisfied ... 

GxP regulatory authorities also have a duty of care to the pharmaceutical and healthcare companies inspected, but what constitutes their duties is not precisely defined. Few cases have been successfully brought against GxP regulators. 

An important aspect of this new approach is the expectation that pharmaceutical and healthcare companies will implement any corrective actions identified as the result of a site inspection across the whole of their operations. Effective coordination of corrective actions is vital for large multinational organizations. An example form that might be used to collate computer validation inspection history is presented in Table 16.1. The FDA and MHRA already have access to inspection databases and have the ability to readily trend data and track repeated offences on particular topics across multiple sites in a firm s organization. Indeed, regulatory authorities may in the future share inspection findings with the MRA parmer regulatory authorities. 

The concept behind the MRA is that one regulatory authority will accept the findings of another authority with confidence in the rigor of the inspection process and hence negate the reason to conduct its own inspection of the same pharmaceutical or healthcare company. This is all good theory but requires harmonized inspection standards, practices, reporting, and training. 

Inspection Report will snmmarize the inspection and include an index of all documentation provided to the inspector. In addition the Inspection Report will capture the corrective actions that the pharmaceutical or healthcare companies will share with the regulatory authority to close any adverse observations made by the inspector. There may also be other lessons that will be acted upon that will not be openly shared with the regulatory authority. 

A citation of noncompliance, known as a 483, may be drafted by the FDA at the close of the on-site inspection with a pharmaceutical or healthcare company. An opportunity to clarify issues is given before the close of the inspection and the formal issue of the citation. Similar reports are written by the EU agencies and the Australian TGA, but unlike the FDA citations that are available to the public in accordance with the U.S. Freedom of Information Act, these reports are confidential to the inspected company and the regulatory authority. 

Without documentation, there is no physical evidence that validation took place, regardless of whether it was sufficient. Hence the saying If it ain t written, it ain t done. GxP regulatory authorities may well believe on a personal level that a pharmaceutical or healthcare company did conduct suitable validation to accept GxP compliance without documentary evidence. It is imperative that pharmaceutical and healthcare companies collate documentation supporting their validation as evidence to be presented to GxP regulators on inspection. 

Pharmaceutical and healthcare companies typically like to think of themselves at Level 3. A compliant validation capability would rank between Level 3 and Level 4. A validation capability below Level 3 will almost certainly be regarded by GMP regulatory authorities as insufficient for GMP. Noncompliance may not be identified on an initial or limited inspection. Pharmaceutical and healthcare companies must not become complacent and should prepare for further and detailed inspections. The regulators position with individual cases of GMP noncompliance will vary with the severity of the deficiencies they find. Generally, they will give the pharmaceutical or healthcare company a period of time to take corrective actions before they take the matter further. 

The Committee was informed by the European Medicines Agency (EMEA) of a proposed approach to facilitate inspections and to avoid duplication of inspections. A GMP database was being established in the European Union by Member States that would provide information on and outcome of inspections. The database was expected to be released in 2006. Access rights were being discussed with WHO, the Pharmaceutical Inspection Cooperation Scheme (PIC/S), the European Directorate for the Quality of Medicines (EDQM) and other organizations. Different levels of access will exist including one for public access and others for national medicine regulatory authorities, WHO and PIC/S. 

As a minimum, the personnel responsible for inspecting manufacturing sites should have relevant qualifications and experience in pharmaceutical manufacturing, quality assurance, GMP, performing inspections and audits, chemistry and quality control. Ideally they should have an inspection background from working with a regulatory authority. 

All actions described here are taken from the details provided in the WHO publication Qualify Assurance of Pharmaceuticals,Volume 2, Chapter 4 Inspection of pharmaceutical manufacturers and inspection of drug distribution channels. These guidelines or other similar systems operated by national drug regulatory authorities should be followed in detail. 

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