“Issues at the development, production, regulatory interface”

Guest editor’s note: Fourth symposium on active pharmaceutical ingredients (APIs): “Issues at the development, production, regulatory interface”

Fabian, Arthur C

THE DRUG INFORMATION Association sponsored the above symposium at the Baltimore Marriott Inner Harbor Hotel, Baltimore, MD, from November 8-11, 1998. Over 225 participants from 21 countries gathered to discuss issues where significant regulatory policy change is presently occurring and also where change appears to be just over the horizon. The attendees were from both the generic and trade sides of the industry and were primarily a mixture of regulatory, quality assurance/quality control chemical development, production, and analytical personnel, along with key Food and Drug Administration (FDA) spokespersons.

The core sessions were preceded by Sunday afternoon discussion groups chaired by Juliana King of the Amgen Corporation. This afforded the opportunity to explore specific topics in a setting of about 20 people each. The topics covered were “Concurrent Validation,” “Cleaning Validation,” “Validation of Sterile Bulk Processes,” and “API Stability.” The objective of each was participation by the group, rather than a presentation by an individual.

A unique addition to the symposium was the “Extended Q&A” sessions held on the evening of the second day. Juliana King also organized this session. It provided interested attendees with an opportunity to further question several of the symposium presenters and offer alternative perspectives in a smaller setting. Four simultaneous, two-hour sessions were held with excellent attendance and led to in-depth discussion on ideas for present and future regulatory policy on the core presentations.

The core presentations consisted of five sessions: “GMP During Development,” “Bulk Active Post Approval Changes (BACPAC),” “API Globalization Initiatives,” “An API Potpourri,” and a “Panel Discussion” focused on the International Conference on Harmonization (ICH) effort to develop globally-applicable, Good Manufacturing Practices (GMPs) for API. By way of introduction, Dr. Arthur Fabian of the SST Corporation (the program chairperson) explained that the “heart and soul, respectively” of the symposium was FDA’s BACPAC initiative and the ICHI/GMP effort.

The following are six papers presented at four different core sessions. In the first, Dr. David DeTora of Merck explains how his company manages GMP compliance during the ever-changing developmental phase of a project. In his presentation entitled “GMP Compliance During Development,” he focuses on four key aspects for a “GMP Baseline,” namely, material control, calibration and maintenance, cleaning, and documentation. He discusses an approach to solve the paradox of assuring consistency during the significant developmental changes associated with process optimization and an increasing knowledge base. This approach is based not only on his company’s ideas, but the results of his own informal survey to determine how other companies managed this apparent dilemma. He emphasizes the need to allow science to be the driver for most decisions during the developmental phase of a project.

Louis Angelucci of Foster-Wheeler finishes the first session by focusing on design trends in developmental facilities. He relates that the API industry has become much more conscious of cGMP requirements in facility design in recent years. He presents several specific trends such as: containment, equipment dedication, segregation of process areas, microbial monitoring, and the emphasis on process validation.

Two papers are presented from the BACPAC session. One, “Product Quality Research Initiative (PQRI),” by Drs. Daniel Gold and Stephen Byrn and the second, “BACPAC: A European Perspective.” Although PQRI is an initiative distinct from BACPAC, it nevertheless forms the foundation for a key issue in the BACPAC world, that of being able to unambiguously demonstrate equivalence of the pre- and postchange API. In the latter presentation, Dr. Chris Oldenhof exhorts the agency and industry to recognize the opportunity that BACPAC affords, especially for API manufacturers. He demonstrates, by using beta lactams as a commercial example, the importance of making process changes and then shows how the present system is unable to handle this reasonably, especially in the multi-customer long-chain supplier world of a generic, API, beta lactam manufacturer. He proposes two potential solutions to this problem and hopes to see one of them in the forthcoming FDA draft on BACPAC I.

Symposium attendees, in general, expressed the hope that the forthcoming BACPAC I draft document would afford much needed regulatory relief to allow both applicants and API manufacturers (Type II DMF holders) to make changes in site, scale, equipment, specifications, and process more efficiently. A persistent theme of the industry spokespersons was the need to effectively manage the above changes, not avoid them. Many expressed the idea that innovation needs to be encouraged, not impeded, by any regulatory system.

In the third core session, Professor Helga Moller applies the thinking of the German Industrial Pharmacy Section, FIP, to the ICH/ GMP effort, specifically in the difficult area of defining the starting material for an API synthesis. Presently, several groups are discussing this issue which needs to reach a consensus, since everyone agrees that multiple definitions for this term (and others) should be avoided to allow unambiguous communication internationally. Her paper, with co-author, Dr. Oldenhof, proposes a novel, science-based, approach to defining the starting material for any synthetic scheme.

The fourth core session discussed issues that were future-oriented and contained papers that did not have a common theme. Dr. Fabian’s paper will follow wherein he presents his thoughts on “Principles for Effective Regulatory API Policy.” Explaining that these principles are not yet recognized as existing, he proceeds to postulate what they might be and discusses each in detail. He then retrospectively examines API policy in the areas of process change, investigational new drug/new drug application (IND/NDA) documentation, GMPs, and process validation to show how ineffective policy in these areas violates these principles, whereas effective policy does not. He emphasizes the future use of the principles as a tool with which one can assess policy emanating from FDA or from the regulatory department of one’s own company. He also uses the principles to construct an approach to GMP across the lifecycle of a project.

In summary, the symposium was quite successful in providing an international forum for all parts of the API industry to exchange valuable ideas and information on the critical issues of the day. The six papers follow.

Drug Information Journal, Vol. 33, pp. 737-738, 1999 Printed in the USA. All rights reserved.


Executive Director, Technical Affairs, SST Corporation, Clifton, New Jersey

Reprint address: Arthur C. Fabian, PhD, Executive Director, Technical Affairs, SST Corporation, 635 Brighton Road, Clifton, NJ 07012.

Copyright Drug Information Association Jul-Sep 1999

Provided by ProQuest Information and Learning Company. All rights Reserved