21^st Century cGMP Inspections

By J. Robert Yeoman

In August 2002, the Food and Drug Administration (FDA) announced a major new initiative titled Pharmaceutical cGMPs for the 21^st Century: A Risk-Based Approach. This two-year program for human drugs, biologics and veterinary drugs has a number of ambitious objectives. One objective is the adoption of risk-based approaches to focus both industry and FDA attention on critical areas. A second objective is to enhance the consistency and coordination of regulatory programs. To achieve these ambitious goals, FDA is devoting considerable manpower resources to what is obviously a very important initiative.

Risk-Based Approach
Starting in 2003, FDA introduced a risk-based management approach to identify categories of pharmaceutical manufacturing sites that are potentially of higher risk. Effective January of this year, the Center for Drug Evaluation and Research (CDER) reorganized its Office of Compliance, creating a new division of Compliance Risk Management and Surveillance. This new division has as one of its key focuses the development of risk management approaches to facility inspections. According to the FDA summary progress report released February 21, 2003, the sites identified in 2003 as high risk are sterile drug manufacturers, non-medical gas prescription drug manufacturers, and sites of new registrants not previously inspected by FDA. Starting in 2004, FDA expects to introduce a more detailed risk model to predict where FDA inspections are most likely to achieve the greatest positive public health impact.

Transitioning to risk-based inspections appears to offer the prospect of less frequent inspections for many companies in the medical gases business. Today the average interval between inspections in our industry is already well over the mandated two-year frequency, so in practical terms for most firms, there may not be much apparent change in the frequency of inspections from current practice.

Maintaining Diligence
This risk-based approach should not be regarded as an invitation to relax ongoing compliance activities. When future inspections do occur, it is probable that they will be more detailed and thorough than past experiences. It is also likely that FDA will expect lower risk manufacturers to be able to more easily achieve and maintain full compliance. FDA could use its enforcement authority to severely punish firms that relax their diligence with financial penalties and other sanctions as an example to other companies to maintain their compliance programs.

GAWDA members should anticipate that the agency may factor in the compliance history of an individual company. A poor track record could land you into a higher risk category and subject your company to increased FDA scrutiny.

Improving Consistency of Inspections
With more than 650 brand new FDA inspectors entering the field, the consistency of future inspections at medical gas facilities remains a valid concern. FDA has acknowledged that this issue cuts across the entire pharmaceutical manufacturing spectrum, and recently announced new measures to improve inspection consistency.

A program called Turbo 483 was introduced in 2002 to computerize the writing of 483s and the archiving of the completed documents into a database. Field inspectors can now assemble a 483 from a menu of standardized wording, which should help improve the clarity and consistency of inspectional observations.

An additional FDA benefit to standardized 483 observation wording is an enhanced ability to develop and analyze data on the frequency that different inspectional observations are cited. Over time, this data could become a key FDA input to decisions regarding future changes in drug GMP requirements and new program and initiative development.

Large firms and those with poor compliance track records of compliance should take heed. This new process facilitates FDA compiling easily assessable compliance profiles on companies. Multiple manufacturing sites and/or a history of recurring violations could increase the risk of being cited for a repeat violation in the future. The output from the Turbo 483 process potentially appears destined to become a key input to FDA's future risk assessment models.

Central Review of Warning Letters
Effective March 2003, FDA rescinded the authority of the district offices to issue warning letters for violations of the GMP requirements. This major policy change is designed to identify and resolve possible program inconsistencies before warning letters are issued to manufacturing firms. All warning letters will now be issued by FDA headquarters.

In practical terms, this change increases the gravity of any warning letters issued to a company. Warning letters must now receive the full and immediate attention of the company's management to appropriately and effectively remediate any and all items.

Product Specialists and Inspection Teams
FDA has begun including product and process specialists on pharmaceutical inspection teams in an initiative to strengthen consistency in making regulatory decisions and to improve communications within the agency. The appearance of FDA inspection teams at medical gas facilities is becoming increasingly commonplace. Medical gases firms should ensure that their inspection management procedures and employee training include how to handle a team of inspectors.

Introducing product specialists on medical gas inspections may not be as significant a change from current practice as you might think. The FDA staff expert on medical gases, Duane Sylvia, is now quite frequently consulted by field inspectors for advice and guidance on medical gas products and processes. It is not known at this time, however, if FDA intends to make wider use of medical gas “experts” on inspection teams than is the current practice.

Preparing for 21^st Century Inspections
Over the next 18 months, FDA will be fully implementing these major changes to its inspection processes to achieve the biggest bang for its inspectional buck. The potential for less frequent inspections of medical gas firms should not be inferred that FDA is no longer concerned about medical gas manufacturing. Quite the contrary. FDA remains well aware of the potential serious consequences connected to medical gas mix-ups, and can be expected to factor that into the risk model developed to establish the inspection frequency for medical gas cylinder manufacturing facilities.

Ultimately, the best preparation for a medical gases 21^st century cGMP inspection is to be in compliance at all times with quality systems and compliance programs that evolve with changing requirements and industry practice.