The world of Pharmaceutical CGMP compliance has certainly evolved since the 5th edition of this book was published about six years ago. We are now living in the post 9-11 era; national and global pharmaceutical business consolidations and expansions are continuing at a brisk pace; the FDA is changing its approach to regulating manufacturers; global harmonization of regulatory requirement and quality standards has been accelerated; availability and access to internet sources of information has exploded and counterfeiting and bioterrorism are part of the daily dialogue.
From a GMP impact perspective, the FDA changes are potentially significant. They have initiated a new framework for regulating manufacturing that now supports risk based regulation, quality-by-design, a quality systems approach, process analytical technology (PAT) application and similar initiates. It was recognized that historical regulatory approaches and initiatives were constraining manufacturing progress and the agency needed to change. FDA is showing signs of being committed to these new approaches. They have restructured the Office of Regulatory Affairs (ORA) to support risk based inspections. The offices of Compliance (OC) and Pharmaceutical Science (OPS) within CDER (Center for Drug Evaluation & Research) have been reorganized to handle quality-by-design initiatives. A quality-by-design pilot initiative for CMC (Chemistry, Manufacturing and Controls) submissions has resulted in a product approval. They have withdrawn guidance documents that conflict with its 21st Century Initiatives, adopted a number of the International Conference on Harmonization (ICH) standards and the FDA Quality Systems Guidance was just finalized and ahead of the ICH Q10 document.
These are all signs of progress and any efforts to make regulations and compliance more flexible by allowing for a variety of modern approaches and more science based evaluations is appreciated and should be embraced by a typically conservative pharmaceutical industry. These changes do not come without controversy. The reality is that FDA has less financial resources to deal with all these new technologies and harmonization efforts. This has resulted in fewer inspections (total numbers have decreased since 2003) and some of this decrease is by-design and coincides with their 21st century approach with risk based inspections. Recent criticisms of FDA have come from a number of areas. For example Representative Henry A.Waxman questioned FDA’s enforcement record stating concern over an agency that is in a state of “decline” over the past five years and that enforcement actions represented by Warning letters have declined by 50% from 2000 to 2005. Seizures also declined by 44%. Whether the reductions are a sign of enforcement weakness or the industry is getting better is yet to be seen. The truth is most likely somewhere in the middle.
An industry association recently filed a citizen’s petition to the FDA requesting that the agency increase inspections of drug manufacturing facilities located outside the U.S.A. They asserted that nearly half of all drugs marketed in the United States are produced or manufactured in foreign facilities but the vast majority of FDA inspections are of domestic facilities. And with the FDA facing budget cuts, most foreign facilities are not likely to be inspected. It would appear that asking for more FDA inspections would not be an industry position but when it comes to competition, fair play and a level playing field for U.S. drug requirements— everyone has a vested interest.
The current state of affairs can best be summed up by a discussion I had with a colleague that recently returned from a FDA/Industry Conference. When I asked about the overall theme coming from the speakers and participants he confirmed what many of us had suspected.
There is more dialogue and science based regulations/approaches appear to be the future. The chances of being inspected are less but if non-compliance is found during an inspection, the penalties are going to be more severe. This is especially true for firms having a history of repeat observations or recidivist behaviors.
This brings us back to this book. The 5th and previous editions have been successful in providing a wide audience of professionals and educators with the fundamental knowledge of CGMP regulations and current industry application. This text is invaluable for anyone directly involved in pharmaceutical manufacturing and control operations. It is also essential for GMP and quality auditors (private industry and government), quality assurance and control professionals, contractors and suppliers to the industry, industry consultants, pharmacy and pharmaceutical science educators.
The 6th edition continues in that tradition. Building on the excellent foundation a team of industry experts was assembled to update the text by applying their knowledge and experience in specific subject matter areas. The contributing authors collectively, have hundreds of year’s experience with most in industry and some in academic settings. We updated each chapter focusing on current practices, the priorities in the regulatory climate and included explanations or links to the relevant regulatory guidance documents that are readily available on the internet. In order to provide this value added new information, we re-focused on the basic GMPs and consolidated or eliminated some 5th edition chapters and appendices.
The basic information and structure of chapters one through twelve that cover the GMP regulations - Subparts A to K have been kept and expanded upon. While many of the new initiatives may change the approach, complying with the fundamental GMPs outlined in the first twelve chapters is the basis of GMP compliance. The remaining chapters provide valuable supplementary information in understanding and applying the regulations. In addition to being updated with the latest information Chapters 1 through 12 have some expanded sections. Chapter 3 includes more on quality professionals’ role/responsibility and also on GMP training and training programs. Chapter 5 on Equipment has an extensive maintenance & calibration section. Production & Process Controls in Chapter 7 has updates on SOP’s and validation practices and PAT initiatives. New labeling regulations and applications are covered in Chapter 8 and Chapter 11 on records/reports (documentation) has a current section on failure investigations.
There are a number of new and relevant chapters. Chapter 14 deals with the quality systems approach and risk management processes with a focus on understanding and application. Chapter 15 is quite extensive and specific about GMPs for Clinical Trial Materials. Contracting and Outsourcing continues to be a popular activity in this day of consolidation and contracting so Chapter 16 has been added. Chapter 18 covers the world of Bulk Pharmaceutical Excipient GMPs and compliance.
Chapter 17 on API’s has been updated according to the most recent ICH Q7A Guideline. Updated enforcement alternatives (Recalls, Warning Letters, Seizures and Injunctions) are included in Chapter 19 and updates on inspection procedures, the pre-approval inspection process and the Food & Drug Modernization Act are included in Chapters 21 and 22. We conclude the 6th edition with Chapters 22 and 23 that provide updates on worldwide GMP regulation and other quality approaches namely ISO 9000, Malcolm Baldrige and six sigma methodologies.
No book is complete without appendices and we have included the current and best list of guidance documents: CDER List of Guidance Documents, ICH Quality Guidance Document List and ORA Compliance Policy Guides. In the many years I have been involved with applying GMP regulations to operations, it has always surprised me that since 1978 the discussions, arguments and debates continue over mainly the intent and "how to" of GMP compliance. This all goes back to the original 1978 regulations and the intent of Congress. They intended that the agency (FDA) determine what constitutes current or the "C" in CGMP, based on their experience. The Congress also interpreted current as not necessarily widely prevalent. They did not require that a majority of manufacturers had to be following a practice before it was accepted as current. If a practice was shown to be feasible and valuable in assuring drug quality it could be considered current. This is what makes life in Pharmaceutical operations and CGMP compliance interesting.
For those professionals starting in pharmaceuticals, I would recommend a thorough read of the preamble to the GMPs, the GMP regulations, the related FDA guidance documents that provide further information/background and then look at industry practice and application. Finally, I would like to thank and extend my gratitude to all the contributing authors who spent their personal time to research, collect and complete the chapters. Their expertise and experience in applied GMP is much appreciated
.JPG)
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