Changes That May Be Affecting API

Introduction

Change is inevitable whether intentional or unplanned. Some people like to write the “C” in CGMP as a small “c” to reflect the fact that “current” really represents a changing set of rules. Such changes can occur in an industry because of shifting dynamics, environments, interpretations, or simply the passage of time.

What is truly significant is, according to FDA-CDER Director Janet Woodcock[1], that 2008 data indicates that foreign drug manufacturing sites now outnumber domestic drug sites and that the amount of foreign manufactured products continues to increase. Indeed, American pharmaceutical outsourcing continues to increase. Along with this ongoing trend, risks can grow with such escalation. Why one might ask? Risks always exist; however, risk will increase when direct control of variables is reduced, as is the case when contracting of supplies is expanded. Direct, full-time control of facilities and processes will normally be subject to fewer unknown variables than encountered as part of a supply chain or outsourced situation. This reduced control can enhance risk levels. It is also important to remember that changes that occur without recognition of risk or history are almost always doomed to repeat past mistakes.

If change occurs because history is forgotten or ignored by participants, such changes can lead to revisions that have a higher level of risk than if the history were considered and evaluated. These changes can at times become overbearing to the industry and even create unexpected constraints that make supply of good quality products difficult.

The Expert Work Group that developed and negotiated Q7A[2] (Q7 as ICH now identifies the Guidance), the API GMP, took change and history into serious consideration. Its intent and stated policies and proposals were written to allow for reasonable protection of all parties and materials: API, industry, suppliers, and the public.

Today, the API Industry is experiencing potential changes that can affect both manufacturers and regulators alike. This article seeks to very briefly discuss some of these developing trends that can, and will, have an impact on the current and future supply of API, its quality, and the risks that may become an issue in the future.

API Sourcing

API is supplied either by a firm’s own internal manufacturing or by contracting or purchasing the API from other sources. The location of the suppliers can be local to the USA, but more commonly the firms are from sources outside of the country of use. In other words, most API is now imported for use in the final drug products. Over the years, the shift to importing API continues to grow compared to practices that existed only 20-30 years ago. This change in sourcing has created new opportunities, but with it we have also experienced increased risks.

Types of Risks Being Encountered [3]

Reliability and Safety of Supply

Generically, the safety of many products, including drug and food supplies have come under fire in recent years. Contaminations of products with things that are known to be hazardous and from unknown compounds or elements that may not be originally detected or perceived initially to be a risk continue to be encountered within international commerce. How can anti-freeze (DEG) keep showing up in products that ultimately kill innocent people? How do unsafe compounds mysteriously and without warning find their way into API? Are these acts intentional or an accident caused by sloppy or poor GMP which is entirely preventable? Proper and appropriate GMP application is a critical requirement to protect consumers. However, intentional actions or practices that occur as an act of greed or for purely financial reasons which carry with it a high level of risk for the safety of consumers must be stopped and prevented whenever possible. Governments, Regulators, Industries, and Consumers all need to work together to eliminate risks caused by illegal or inappropriate activities that put consumers in serious jeopardy. Common risks include:

1. Are suppliers indeed the identified provider in regulatory filings or have the identified firm’s outsourced the API or its starting materials without notifying any other parties? Have all critical suppliers been inspected by regulatory authorities or the firms purchasing the materials for use in drugs?
2. Has a supplier made revisions to their process without notifying the purchaser of the material?
3. Are the manufacturers of the API, its intermediates or starting materials controlling change appropriately? Are these changes communicated and monitored appropriately? Is the impact of changes evaluated for its potential risk to the product use or user?

Regulatory Concerns

1. Are API producers and their suppliers conforming to dossiers or regulatory filings?
2. Do suppliers have real effective control and monitoring of their processes and products?
3. Are materials adequately protected from contamination?
4. Are analytical controls capable of detecting recognized risks?

Contamination

1. Can possible contamination be adequately monitored and controlled?
2. Are contaminants able to be detected?
3. Are systems in place to prevent intentional contamination?
4. Does analytical testing provide adequate detection of possible dangerous substances?
5. Can existing methods detect the presence of unknown, yet possibly dangerous materials? Is this a realistically achievable goal or objective of regulators?

Overall Risks

Are changes occurring in the API supply? The answer is a resounding yes! Are they new? Most likely not, but recent experiences have raised the level of concern by both the public and governments alike. These recent encounters with contamination have begun to erode the credibility and level of trust that historically existed with offshore suppliers. While cost benefits were always recognized by users of imported materials, the recent contamination risks were not fully recognized as a serious concern.

While contamination can occur anywhere, the recent upsurge in frequency is indeed troubling to most parties. How can one adjust its business and operations to add a safety net around outsourced suppliers?

While this article’s focus is API, recent headlines in the news have raised a high level of public awareness about both intentional and unintentional contamination of products for not only human food and drug use, but animal foods and drugs. The problems encountered have even extended to the paints used on toys and other products.

Why do these risks exist? It can be any one or combination of greed, ignorance, forgetting or ignoring history, and even innocent unknown events or contributors. No matter what the cause, the end product of the risk is completely unacceptable and requires action on the part of all parties: Industry, Governments, Regulators, and the Public. Having a safe and reliable supply of API, no matter where it is sourced, is an important concern that must be addressed by all parties.

Recent API Focus

1. New or previously unidentified Impurities
2. Increasing numbers of old API are being required to become a part of the FDA NDA or Approval Filing Process. GRAS or historically acceptable API may be challenged by FDA and be requested to undergo FDA Review and Approval actions
3. Unidentified supplier changes
4. Inadequate analytical testing of materials which are unable to identify potential high consumer or patient risk
5. Increasing focus on unknown or theoretical possibilities
6. Demands from regulators for specifications (Chemical and/or Microbiological) that historically have not been requested or considered as a concern

Outsourcing Risks

While most, if not all, risks can exist no matter what is the sourcing of an API or its materials, hazards can and will increase or become more difficult to control when a firm’s direct local control of an operation is reduced or is non-existent. Such outsourcing risks need to be evaluated by an API purchaser or consumer, and steps should be taken to increase monitoring and evaluation of such suppliers.

Regulatory bodies need to evaluate such suppliers during review inspections to assure that facilities for producing and controlling API and their starting materials are adequate and capable of providing the controls and quality necessary to meet minimum product needs. Records need to be carefully examined to assure that no changes in suppliers or facilities have occurred which could adversely affect the materials being supplied or its quality and purity. Appropriate specifications should be demanded by authorities and unreasonable or inappropriate quality attributes should be eliminated so as to not dilute quality control efforts used to protect the API and its user population.

Firms that purchase or use API and their intermediates/starting materials should perform adequate reviews of the facilities and records to be sure that all of the mentioned risks are examined and appropriately monitored. While it is impossible to gain absolute assurance that every intentional or unintentional act can always be detected, every reasonable effort should be made to help reduce high-risk actions or practices from causing a significant risk to people or consumers of the API.

While there are numerous Risk Management activities used across industry, none of these can be 100% effective. The existing API GMP does an acceptable job in establishing sound guidance for the manufacture of quality API. Q7A, when properly interpreted and implemented, can protect the API supply and the public. Continued vigilance by all parties will always be necessary to provide a safety net . . . especially for the unknown!

References

1. Wechsler, Jill, “FDA Waves a Big Stick”, PharmTech.com, Pharmaceutical Technology, June 2009, page 34.
2. Guidance for Industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, August 2001, ICH.
3. Lazar, Max, “API GMP Warning Letter Update-Evolving Expectations and Basic Deficiencies”, Commentary, Journal of GXP Compliance, Spring 2009 Volume 13 Number 2, pages 87-96.

Max Lazar retired from Hoffmann-La Roche Inc. in 2001 after 35 years, where he was Vice President, FDA & DEA Compliance. In that position he was responsible for compliance oversight of all of the Roche USA businesses including Active Pharmaceutical Ingredients, Pharmaceuticals (Solid, Liquid, and Sterile), R&D, Diagnostics, Fine Chemicals and Vitamins. Following his retirement, he established a consulting business specializing in API GMP issues and the training of personnel covering the ICH Q7A Guidance. As a voting member of the ICH Expert Work Group (EWG) that developed and negotiated this new international standard, Max is uniquely qualified to share and explain the EWG’s intent of this new guidance. His involvement in this new API GMP pre-dates the ICH activity itself.

His more than 40-year career in the Pharmaceutical Industry includes numerous memberships and chairs of committees. He founded and chaired the Pharmaceutical Manufacturers Association’s Bulk Pharmaceutical Committee of the Quality Control Section. This chair lasted thru the reorganization of PMA into PhRMA and until Max’s retirement in 2001. He has presented at numerous meetings and training programs including SOCMA, PDA, DIA, PhRMA, Barnett, and IIR both domestically and overseas.

Max was named Topic Leader for the Pharmaceutical Research and Manufacturers Association’s (PhRMA) ICH Q7A team that developed the API GMP document for ICH. He represented USA industry at the PIC/S Canberra Conference which preceded the ICH API activities and worked with FDA during the 1980 – 2000 era addressing all of the API industry related regulatory issues including the 1987 NDA Re-Write Guidelines and GMP activities. He was one of five invited industry representatives at the WHO/CDC/FDA Diethylene Glycol Contamination Prevention Workshop that followed the Haitian tragedy where almost 100 children died. This workshop developed recommendations for consideration by the Pan American Health Organization and WHO. Max was named as PhRMA’s representative on the FDA PQRI initiative that developed the initial Bulk Substance projects.

He was Vice Chair of the USP Pharmaceutical Waters Expert Committee (2000-2005) and has been re-elected to another 5-year term (2005-2010) as a member on this USP Expert committee. He conducts training and consultations on API GMP (ICH Q7A) and other FDA Compliance issues. While specializing in API, Max’s experience provides him with expertise in many areas of FDA compliance including laboratory, documentation, sterile and oral dosage forms as well as devices, diagnostics and radiopharmaceuticals.

For his contribution to Q7A, he was awarded the USA FDA Commissioner’s Special Citation “For outstanding cooperation and achievement in developing an internationally harmonized good manufacturing practice guidance for active pharmaceutical ingredients used in human drug products.”

He is a member of numerous professional organizations. He is on the Editorial Board of the Journal of GXP Compliance, the Editorial Advisory Board of American Pharmaceutical Outsourcing and the Advisory Board of the GMP Manual, Maas & Peither AG – GMP Publishing. Max is listed in numerous editions of Who’s Who including Who’s Who in America and is a graduate of Brooklyn College of the City University of New York. He has contributed to several books dealing with APIs, and has written and published several guidances covering Bulk Pharmaceutical Chemicals (API) as chair of the PhRMA and PMA Bulk QC Committee and Workgroups. He resides in Surprise, AZ.

The author can be contacted at [email protected]

This article was printed in the November/December 2009 issue of Pharmaceutical Outsourcing, Volume 10, Issue 7. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com  and subscribe for free.