The new draft aseptic guideline, as it is often referred to in this industry, was initially released for industry feedback in 2002 by the Food and Drug Administration (FDA) as a concept paper. It was later discussed at a meeting of the Advisory Committee for Pharmaceutical Sciences, and was subsequently influenced by a Product Quality Research Institute working group comprised of 41 aseptic processing experts from varied industrial, academic, and regulatory backgrounds. The FDAís objectives in revising the 1987 guidance document are to provide greater clarity and to better reflect current manufacturing practices and capabilities.

Posted in September of 2003 for public commentary, this draft guidance document has several key differences from the 1987 version. The differences are focused in the following areas: cleanroom design; personnel; process design; quality control; environmental monitoring; and production records. This article will focus on two of these areasócleanroom design, and personnel training, qualification, and monitoring.

Cleanroom Design

Although the 2003 draft guidance document contains many differences from the 1987 guide, including additional recommendations for clean air classifications for particulate and microbes, air velocity, and pressure differential, arguably the most significant difference is that the current draft includes a section on cleanroom design.

The 2003 draft guidance document seeks to capture elements of cleanroom management that we in the industry have long acknowledged. Specifically, the more traffic there is in, or immediately proximal to, the core manufacturing area, the higher the operational risk. The 2003 draft guidance document addresses the need to optimize personnel and material flow, to minimize the number of personnel and the number of interventions or transfers, and to add automation (for example, online weight checks, sterilize-in-place functions, and robotics) to further reduce the risk to the product. It also addresses cleanroom design and construction from a cleaning and sanitization perspective. For example, it recommends selecting seamless flooring and eliminating unnecessary equipment and fixtures, including floor drains.

There are detractors who may argue that the 2003 draft guidance document goes too far because it does not allow for the possibility that an aseptic operation without these elements can be successfully managed. If one views the 2003 draft guidance document as prescriptive, it may place a significant burden on some manufacturers who are already capable of producing sterile product. Although it is true that a ìone size fits allî approach inevitably leaves some on the outside looking in, it is my view that these newer cleanroom design recommendations are sound and will improve the likelihood of manufacturing a sterile product.

Personnel Training, Qualification, and Monitoring

One of the most striking omissions of the 1987 guide is the lack of focus on the impact of personnel on the aseptic process. It is widely acknowledged that ìpeopleî are the chief contributors of contamination in the processing environment. Minimizing the risk from both thoughtless and deliberate personnel behaviors requires training and supervision.

The 2003 draft guidance document emphasizes training in aseptic technique, cleanroom behavior, microbiology, hygiene, gowning, patient safety hazard posed by nonsterile products, and specific, written standard operating procedures governing the operation. Additionally, the document recommends ongoing training and evaluation by qualified supervisors to determine that operators are conforming to all requirements, and stipulates that quality control professionals should provide oversight. Training is recommended for both operations personnel and laboratory personnel who are responsible for sampling in the area.

Gowning qualification is determined through post-gowning microbiological sampling. In the 2003 draft guidance document, re-qualification is recommended semi-annually, or yearly for automated operations with minimal personnel intervention. Routine glove monitoring is required since the stated goal for manufacturing is to have contamination-free gloves throughout the process. The 2003 draft guidance document stipulates that an investigation should be initiated whenever an operator exceeds established levels or shows an adverse trend.

Overall, the 2003 draft guidance document provides more input into the aseptic process than the 1987 version, including a clear bias toward more automation and less personnel involvement. Some may find this approach too limiting. Others will appreciate the codification of the practices they already employ. However, as with all FDA guidance documents, alternative approaches may be justified if there is a sound scientific basis.

References

1 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing ñ Current Good Manufacturing Practice, DRAFT GUIDANCE, (August ,2003), U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Office of Regulatory Affairs (ORA).

2 Guideline on Sterile Drug Products Produced By Aseptic Processing, (June, 1987), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Office of Regulatory Affairs (ORA), Food and Drug Administration.

3 J. Agallaco. ìSome Further Comments on Aseptic Processing Guidance, Or the Fool on the Hill,î PDA Journal of Pharmaceutical Science and Technology Vol. 57, No. 5, pp. 324-330.