Publications

Progress of the Quality Topics at the ICH Meeting in Seville

Stephan Rönninger, F. Hoffmann-La Roche supported by Jim Lyda, PDA and Steve Mendivil, Amgen

The International Conference on Harmonisation (ICH) Steering Committee and its working groups met in Seville, Spain from November 5-10, 2011.

ICH is a project representing three major drug development markets as well as regulators and delegates from industry pharmaceutical innovator trade associations. Delegates from the United States include the U.S. FDA and Pharmaceutical Research and Manufacturers of America (PhRMA); from Europe, the European Commission (EU), the European Medicines Agency (EMA) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) are represented; and, from Japan, members from the Ministry of Health, Labour and Welfare (MHLW), Pharmaceuticals Medical Devices Agency (PMDA), and/the Japan Pharmaceutical Manufacturers Association (JPMA) are in attendance. Observers also participate from Health Canada, the European Free Trade Association (usually represented by Swissmedic) and the World Health Organization (WHO).

On occasion, representatives from other interested authorities e.g., China, Chinese Taipei and India, have participated. Other interested parties from industry include the World Self-Medication Industry (WSMI) and the International Generic Pharmaceutical Alliance (IGPA). If biotech operations are focused on, delegates from the European Biopharmaceutical Enterprisees (EBE) or the Biotechnology Industry Organisation (US-BIO) are invited by the ICH Steering Committee to send representatives as an interested party.

Global Outreach Activities

The ICH Global Cooperation Group (GCG) is a subgroup of the ICH Steering Committee and is composed of representatives from each of the parties at the ICH Steering Committee, plus the observers (WHO, Health Canada and EFTA) and International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). The members of the Regional Harmonisation Initiative, (RHI) also participate, namely:

  • Asia-Pacific Economic Cooperation (APEC)
  • The Association of Southeast Asian Nations (ASEAN)
  • East African Community (EAC)
  • Golf Corporation Council (GCC)
  • Pan American Network for Drug Regulatory Harmonization (PANDRH)
  • The Southern African Development Community (SADC)

The Drug Regulatory Authorities and Departments of Health from Australia, Brazil, China, Chinese Taipei, India, Republic of Korea, Russia and Singapore are also members.
The ICH GCG welcomed, for the first time at this meeting, representatives of the East African Community, a regional harmonisation initiative composed of Burundi, Kenya, Rwanda, Tanzania and Uganda. The Global Cooperation Groups intention is to support the implementation of the ICH guidelines outside the ICH regions. They also sponsor trainings in their respective area of responsibility (www.ich.org/trainings/ich-trainings.html).

Heavy Metal Impurities (ICH Q3D)

During the ICH meeting in Seville, the Expert Working Group (EWG) completed a pre-step 2 ICH Q3D draft document that will be circulated to the ICH parties for informal feedback through February 2012. The major progress in developing the pre-step 2 draft included an agreement on the permissible daily exposure values for all metal impurities listed in the guideline for the oral, parenteral and inhalation routes of administration. A new risk-based control strategy section provides several alternatives to traditional testing including an example specific to biotechnology products illustrating overall reduced risk to contamination by metal impurities. No major issues are anticipated that will prevent the EWG from reaching consensus (Step 2) in June 2012. A public consultation will follow by publishing this draft document for comments by the U.S. FDA, EMA and PMDA. PDA may collect comments and provide feedback to the EWG at that time.

“Genotoxic impurities” ( ICH M7)

The ICH meeting in Seville was quite a successful one for the ICH M7 Expert Working Group. The first internal draft on M7, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, was finalized for initial review with the ICH constituencies (step 1 document). These comments will be consolidated at the next ICH meeting. A document for public comments might be available at the end of 2012.

Development and Manufacturing of APIs (ICH Q11)

After the public consultation phase, this EWG made good progress managing the 1,300 comments received from the three regions. The discussions focused on updating the chapters on:

  • Introduction and scope
  • Manufacturing process development
  • Description of manufacturing process and controls
  • Selection of starting materials
  • Control strategy including upstream controls
  • Process validation/evaluation and the option for continuous process verification

There were also discussions on submission of information on the section about the common technical document as well as change management activities during the commercial and product discontinuation phase. It is anticipated that further discussions among the constituencies, with focus on control strategy, should lead to the final version of this ICH guidance document (step 4 of the ICH procedure) before the end of the 2nd quarter in 2012. At that point it will be published for implementation by the three ICH regions.

Quality Implementation Working Group (Q-IWG)

The original remit of the Q-IWG was to provide considerations on implementing the final ICH guidance of Pharmaceutical Development (ICH Q8 R2), Quality Risk Management (ICH Q9) and Pharmaceutical Quality Systems (ICH Q10). In parallel, the ICH guidance on Development and Manufacturing of APIs (ICH Q11) was developed. The ICH Q-IWG ensured consistency in the messages provided.

The Q-IWG completed three more documents on points to consider. In Seville, the points to consider documents addressed the open questions from the 2010 training workshops performed in the three ICH regions (Tallinn, Washington D.C. and Tokyo) and more recently in Canada (Ottawa) and South Korea (Seoul). These documents address process validation/process verification, role of modeling in QbD, and design space. Combined with previously released question and answer documents and training materials, these documents provide a complete set of support guidances for implementation of the modern paradigm on development and manufacturing of pharmaceuticals in the twenty first century.

The new QbD points to consider document covers considerations and categorizations on the role of models in QbD which are used by industry in development. Suggestions for model validation and model verification are included in the document as well as answers to what has to be documented in regulatory submissions.

The document on design space describes in more detail the development and verification of design space during scale-up. Also, more details are provided on how to document the design space in a regulatory submission. The document ends with remarks on the lifecycle management of a design space.

The last points to consider document focuses on process validation and continuous process verification. General considerations were followed by a discussion of continuous process verification; this is the ICH term used for an enhanced approach of process validation during development and/or manufacturing. Please note that FDA uses “continued process verification” as a term describing the 3rd lifecycle stage in the process validation guidance. The suggested relationship to the requirements concluded the topic in the ICH document.

At this meeting, the ICH Q-IWG finalized their tasks according to the concept paper. A summary of the deliverables and achievements was provided to the GCG at ICH. These deliverables are published with the quality guidelines at the ICH homepage. They can be found at the ICH homepage at tinyurl.com/6uq67jm. To open the the folder on Q8/Q9/Q10 implementation and find answers to questions raised during the workshop and training breakouts on the training program and points to consider doucments, open either the Q8, Q9 or Q10 folders.

There are no further formal activities planned by the Q-IWG. However the GCG may ask former members to support an ICH sponsored training in emerging markets.

Manufacturing Practice of APIs (ICH Q7)

Activities related to this 10 year old ICH guideline were discussed briefly by the ICH Steering Committee. It has been suggested to set up a process to assess the currency of this guideline. This might result in an ICH Q7 Implementation Working Group (IWG) to potentially start after ICH Q11 is finished. The deliverable of such an ICH Q7-IWG might be a Q&A document.

Futher Activities

The Pharmaceutical Development (ICH Q8), Development and Manufacturing of Drug Substance (ICH Q11), Quality Risk Management (ICH Q9) and Pharmaceutical Quality Systems (ICH Q10), which support the ICH quality vision of 2003: “Develop a harmonised pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science,” will be further developed by the approval of the ICH Q11 guidance which is expected soon. Further activities will lead to the benefits of the implementation of the ICH paradigm for building-in quality and creating more efficient regulatory processes.

About the Author

Dr. –Ing Stephan Rönninger is the Head of External Relations Europe/Japan at F. Hoffmann-La Roche based in Basel, Switzerland. He is responsible for collaboration, information management and commenting regarding Quality Management, Good Manufacturing and Distribution Practice topics. He acts as the Chair and the European Regional Leader of the Regulatory Affairs and Quality Advisory Board for PDA and is one of the founders and co-chairs of the Paradigm Change in Manufacturing Operations.

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