One Man’s Opinion
Introduction
I recently read with great interest that ICH has embarked on some very significant changes in structure and organization1. While change based upon historical experience can improve effectiveness; some changes sometimes undermine effective improvements. As a member of the Expert Work Group that negotiated and wrote the only GMP guidance (ICH Q7) adopted by the International Conference on Harmonization, I am especially interested in sharing my opinion about the changes being proposed and implemented by the organization.
The article referenced above enticed me into searching what ICH has done since my personal work with ICH ended in 2000. I examined what revisions to structure and processes are or have been considered and/or implemented by ICH. My objective here is to share some history with the industry and ICH so that others can benefit wherever possible. What I intend to discuss is how we operated historically during the few years ICH Q7A (now titled ICH Q7) was written and implemented by ICH and other non-ICH members. What in my opinion worked well and where opportunities exist for improvement.
I am especially interested in sharing my opinions of whether ICH is going forward in a manner that addresses historical experience, needs and issues from the world’s regulatory community while assuring that the industries being regulated are able to be represented, recognized and considered during the harmonized regulatory process. Special focus on issues that surround API GMP compliance is of special importance in this article.
History
Prior to 1998, before ICH initiated an assignment to develop GMP guidance for ingredients that were used to produce drug products, regulatory demands upon regulators and drug firms had grown significantly. GMP for drug ingredients (BPC) needed recognition as being different from what was written for drug products. 21 CFR Parts 210 and 211 being used as a guide for BPC, was not really reasonable or appropriate.
As FDA and other equivalent agencies started to inspect outside their own countries, it became apparent that drug product GMP was being applied incorrectly to active ingredients. This very fact resulted in ICH being approached to develop a harmonized GMP that could work internationally for drug ingredients. This was the real start of an API GMP! A guidance, that recognized the technical and complex differences between drug products and drug substances or API, was needed.
My personal involvement with ICH began when I was requested by senior management of PhRMA to be PhRMA’s Topic Leader of the Q7A Expert Work Group (EWG) being established by ICH. This specific EWG was being formed to develop a new harmonized guidance for the Good Manufacturing Practices to be applied to what became identified as Active Pharmaceutical Ingredients (API). This EWG was authorized by the ICH Steering Committee in February 1998 and held its first official meeting in April 1998. The final draft of the API GMP Guidance was approved by the ICH Steering Committee and signed on 10 November 2000 by the regulatory members of the EC, Japan, and the United States. Following the Guidance’s issuance for adoption by the ICH regions, some members of the EWG developed an Official API GMP Training Program and spent additional time conducting Q7A training programs to regulators and members of industry within the USA and around the world. I was pleased to be a member of the group that continued to communicate sharing the EWG’s intent with the world.
How the ICH Q7 EWG Operated from 1998-2000
ICH worked with the support of IFPMA and operated under the direction of a strong ICH Steering Committee which was comprised of official members of the regulatory agencies and industrial members from the EU, Japan, and the USA. Once an Expert Work Group was nominated and approved, a chair was usually appointed from the region that was the primary sponsor of topic being developed. In this case, that sponsor was from Europe.
The Q7A EWG worked very quickly in consolidating already written GMPs into a single draft. The EWG then discussed and proposed revisions that the experts believed were appropriate and in the best interests of all parties. The official members of the EWG knew that the manufacturing of both active and inactive ingredients that made up Bulk Pharmaceutical Chemicals (BPC) and their country of origin were in a worldwide arena going beyond the three region area of ICH. Understanding the global impact of the subject being addressed, the EWG asked that participation in the work group be opened up to include experts from other countries including China and India. This request was forwarded to the ICH Steering Committee for action.
While the EWG official voting members were the six official members of ICH, all participants were welcome and everyone’s opinions were considered on an equal basis. The output of the EWG required Steering Committee approval and the signatures of the Regulatory Body members of the ICH Q7A EWG.
Even though invited, China and India did not participate in our face to face meetings. I must add that any and all written communications sent to ICH via a member group were seriously considered and incorporated into our work documents.
The ICH Q7A Guidance was written and approved in an incredibly short period of time. The EWG was successful in resolving all issues, agreeing upon acceptable alternative approaches, and recognizing the importance of getting a harmonized API GMP Guidance issued. Of particular importance was the decision to separate BPC into active and inactive ingredients and focus the guidance’s application on API even though it could easily apply to inactive materials when appropriately interpreted. This decision helped limit the scope of regulatory oversight to a more reasonable level. Including inactive ingredients in the scope of Q7A would have significantly increased the inspectional workload responsibility of DRAs to levels not supportable by the authorized staff of the regulatory authorities.
Positive and Negative Impacts of ICH Q7A
Are ICH Actions to Change its Historic Structure and Organization Warranted?
Yes, but before we start this discussion, I must point out that these comments are focused upon the impact of the ICH Q7 Guidance upon the world and why the need to expand ICH participation grew. The significant growth of the world economy and the shifting of manufacturing among countries have played a major role in what has contributed to a need for ICH to revise its structure and practices.
Since ICH was originally formed in 1990, manufacturing, sourcing and development of pharmaceuticals have continued to shift. The last 50 years of the 20th century saw a major change in the location of pharmaceutical production and development from the United States, Europe and Japan to a much larger sphere encompassing many more regions and countries of the world. Today, we are experiencing a world with greater markets, manufacturing and distribution issues and more regulatory bodies that seek jurisdiction over their own environments.
The original focus of ICH was effective and valuable in addressing real needs of the pharmaceutical arena. The world had growing complex issues that needed attention to help get valuable medicines approved and distributed around the world. The three region organization of ICH worked, but needed to expand its participation in the modern world. By March 1999, the ICH Steering Committee established the ICH Global Cooperation Group (GCG) as a subcommittee of the ICH Steering Committee2. The GCG was formed to help meet intensifying interest and application of ICH Guidelines beyond the ICH Regional participants.
Historically, for ICH Q7A, the official members of the EWG were from Europe, Japan and the United States with official signatures coming from the regulators of those three areas. For clarification, it should be noted that in November 2005, ICH Q7A was renamed ICH Q7.
The API GMP guidance was drafted, negotiated and approved in record time for an ICH Guidance. The need for this guidance was driven by the absence of a harmonized API GMP that was available to both industry and regulators of both drug products and pharmaceutical ingredients used or produced around the world. Before its adoption by ICH and its members, there were numerous disagreements with both firms and regulators over what was appropriate GMP for Active Pharmaceutical Ingredients. Since its issuance by ICH, many other countries have also adopted the guidance and the EU has incorporated the terms of the guidance into its law. The availability and use of the harmonized ICH Q7A Guidance has greatly contributed to resolving issues that existed in its absence.
As we have discussed, since the November 2000 approval of ICH Q7A, expanding regulatory participation, harmonization and organizational issues have further evolved on a world-wide basis. ICH has modified its organization and international membership participation. The evolution has been driven by growth in the industry with expanding and changing markets which have impacted so many in the drug industry.
What ICH works on is having a significant effect upon many countries. As the impact grows, so does the interest by countries and areas of the world that needed to comply with these standards. More regulatory bodies from more countries wanted direct input into proposed pharmaceutical standard practices. Because of increased demands upon the DRAs, there continues to be a growing interest in expanding the sharing of inspectional findings. This helps all parties to deal with the growth being encountered.
I have mixed emotions about the actions being taken by ICH. One can understand why ICH has made the decision to take steps to be internationally recognized on a broader scale than existed under its original structure. Expanded international participation was inevitable. The decision to:
Evolutionarily expand its sphere of influence through:
- Increased participation from beyond the original Tripartite3 membership of Europe, Japan, and the United States
- Improving its recognition as an independent harmonizing authority associated with drugs and pharmaceuticals, and
- Creating internationalized application of its Guidance by increasing the regulatory authorities and countries that will adopt and support the content of what is published.
All of the above activities contribute to a growth in the international influence and respect associated with ICH.
What ICH is doing should have beneficial effects in the future. However, these revisions must always recognize the need to remember its history and the necessity to always work closely with members of the pharmaceutical and drug manufacturers from around the world. This industry plays a vital role in protecting the public health and all practices and programs must be open and transparent while avoiding bureaucratic, closed and unproductive obstacles. I hope that the eventual policies and programs produced by the new ICH will allow participation by experts from industry and regulators on an equal professional basis. While regulatory membership will always need to have ultimate approval over pharmaceutical standards and requirements, industry experts must have the ability to assure that what is issued by the new ICH will continue to recognize and respect input from industrial experts. Both sectors (Industry and Regulatory Agencies (DRA)) need to recognize their responsibilities to protect the public health. ICH must assure that even comments from unaffiliated experts have an ability to offer their help and participate in the earlier steps of guidance development and approval. The “old” system did NOT offer that flexibility. I would strongly suggest that practice be revised.
Expanding International Cooperation
Since 1990 and especially following the turn of the century, “Global Cooperation” has grown and has affected ICH meetings and participation4; there are now six Regional Harmonization Initiatives (RHIs) and eight Regulatory Authorities (DRA/DoH) that “are now invited” to participate in the ICH bi-annual meetings where regulatory members participate in the Global Cooperation session of the ICH Steering Committee. These include:
The growth in global cooperation and participation has certainly helped, extend the international impact of ICH issued drug related practices, and level the “playing field” as so many countries now participate in drug development, DRA , and drug production industries.
What Were the Major Benefits Created by ICH Agreements and What Should the World Learn From the History of What ICH Accomplished?
The ICH has been very effective in opening up opportunities for many parties to enter into a cooperative effort in harmonizing the application of many types of guidance including Quality which is where the Q7 Guidance resides. As noted above, the ICH Q7 Implementation Working Group (IWG) issued “ICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Questions and Answers”5.
This document has provided added value through the expanded cooperation of ICH and other parties such as PIC/S (Pharmaceutical Inspection Co-operation Scheme)6and the consolidation of questions and answers raised during training programs conducted since the issuance of the original ICH Q7A now designated as ICH Q7. The current document adds another level of value which further interprets and clarifies the original guidance.
ICH has grown into a truly international organization that exists for worldwide harmonization. It is moving from three regions of the world to all regions of the world. Its organization is based in Switzerland and recognized under Swiss law. It has been implementing a growing world-wide impact and influence. As early as 1999, the ICH had already started to take steps to globalize is organization and structure and by late 2003 was expanding its sphere of influence to a more global basis. In May of 2005, the ICH Global Cooperation Group (GCG) actually added to its Mission Statement: . . . to ICH Guidelines regionally and globally . . . this reference to its global impact7.
Today, the approved IWG’s Q & A covering Q7 moves to Step 5 for formal implementation by today’s regulatory bodies made up of:
- European Union
- Japan
- USA
- Canada
- Switzerland
The important factor is that ICH assures that the organization remains committed to allowing open and free exchanges of opinion and allow all parties interested and knowledgeable in any subject being developed should be allowed to be considered on an equal footing with regulators.
A Look From Above
Let’s take a high level look at what ICH did right and what opportunities still exist.
ICH has shown that DRA and industry can indeed work together. Harmonization does make regulatory effectiveness more efficient and provide avenues for international cooperation that did not exist. Expanding its sphere of influence over the years has proven to be a real benefit to all parties. Focusing on cooperation also helps reduce duplication for all parties in the pharmaceutical industry.
Since 1990, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use issued more than 70 Guidelines and additional Questions and Answers Guideline documents.
In my opinion, the greatest benefit of ICH has been how it influenced regulatory bodies around the world including FDA that industry does have some very valuable experience that can lead to very valuable benefits for regulators! Number one in this topic was industry’s very strong desire to create one very major change in the filing of drug applications around the world. Today, I believe that most, if not all regulatory bodies associated with human and animal drugs, agree with the enormous benefits realized by the development of harmonized drug filing procedures and forms that were ultimately adopted by ICH as the CTD or Common Technical Document8. In my opinion, this success by both FDA and industry evolved into a recognition that DRA and industry can both benefit from a successful harmonization effort. I also believe, while on a much smaller scale, that the writing and adoption of ICH Q7A (later renamed ICH Q7) could possibly be the second most important guide issued by ICH. Why you ask, given the many important harmonized guides issued by ICH since its inception in 1990?
ICH Q7 was NOT a guidance that specially applied to drug filing issues. It was the first harmonized Guidance to cross into Good Manufacturing Practices (GMPs) and more specifically applied to Active Pharmaceutical Ingredients (API). By the last decade of the 20th Century, the application of GMP around the world lacked clear direction and expectations for the key component of drug products. API and the regulatory bodies interpreting and inspecting such producers were driving industry and the public into a growing level of risk and frustration. The accomplishment in 2000 to have a Harmonized GMP Guide for API provided an incredible release of tensions around the world. The API GMP was issued about 15 years ago. Its validity and staying power is reinforced by the fact that ICH has only needed to issue a “Questions and Answers” document to clarify current regulatory (DRA) positions9. The existing API GMP Guidance is capable of proper application for many more years.
While it was always easy to communicate if you were a member of a group that had an active representative in ICH, historically it was much more difficult to provide information to ICH directly when such membership did not exist! It is for this reason that I hope the future ICH process and organization assures that the ICH Secretariat and Leadership remain open to receiving direct communication from non-members when a subject is under consideration or negotiation. ICH must provide a mechanism to allow for private sector input and consideration. This open sharing of expertise, even during early steps of guidance development, should be allowed so that information, concerns, and expertise can always be considered.
References
- S.Milmo, “ICH Prepares for Major Reform,” Pharmaceutical Technology 39 (5) 2015
- http://www.ich.org/about/vision.html
- http://www.ich.org/about/history.html
- http://www.ich.org/about/organization-of-ich/coopgroup.html
- Questions and Answers: Q7 Implementation Working Group; ICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients; ©ICH 2015.
- Preface to reference 5.
- http://www.ich.org/about/vision.html; Advancing Harmonization for Better Global Health; June 14, 2015.
- “The Value and Benefits of ICH to Drug Regulatory Authorities – Advancing Harmonization for Better Health”; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2010; ICH Secretariat; Geneva, Switzerland.
- ICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Questions and Answers; June 10, 2015; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; ICH Secretariat; Geneva, Switzerland.
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, 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 well as the Excipient GMP (IPEC) Guidance. His almost 50-year career in the pharmaceutical industry includes numerous memberships and chairs of professional committees. He founded and chaired the Pharmaceutical Manufacturers Association's (PMA) Bulk Pharmaceutical Committee of the Quality Control Section. This chair lasted through the reorganization of PMA into PhRMA and until Max's retirement in 2001. Max was named by PhRMA, Topic Leader and voting member of the ICH Expert Work Group Q7A team that negotiated and developed the ICH API GMP document. 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." Max represented USA industry at various significant API meetings including: the BPC PlC/S Conference in Canberra, Australia that preceded the ICH meeting that officially started work on an international API GMP; the WHO/CDC/FDA Diethylene Glycol Contamination Prevention Workshop that followed the Haitian tragedy where almost 100 children died; he was named as PhRMA's representative on the FDA PQRI initiative for the initial Bulk Substance projects. He was Vice Chair of the USP Pharmaceutical Waters Expert Committee (2000- 2005), re-elected to another 5-year term (2005-2010) as a member on this USP Expert committee, and is currently an official member of the USP Water Panels (2010-2015). Max can be contacted at: [email protected]