Edition 4 / May 2019
Dr. Iris Ziegler
Director of Pharmaceutical Sciences & QbD
The 2nd APV Conference on Highly Potent Drug Products in the Pharmaceutical Industry, which took place March 19-20, 2019 in Wiesloch (close to Heidelberg), Germany, provided participants with an inside view of practical solutions for challenges the pharma industry faces when having to develop, manufacture and test drug products with highly potent drug compounds. In contrast to many other conferences and seminars on highly potent compounds, the APV conference series traditionally focuses on drug products rather than chemicals, offering answers to problems operators, scientists & managers have to overcome in their daily routine when working with these highly potent compounds. The conference was co-hosted by myself, CordenPharma’s Director of Pharmaceutical Sciences & Quality by Design, and three other experts from Big Pharma with many years of experience in a highly potent environment. They each actively brought their specific expertise into the discussions & round table forum – from a Quality Assurance perspective (Dr. Horst-Dieter Friedel, Bayer), from a manufacturing background of highly potent biologic clinical supplies (Dr. Karoline Bechthold-Peters, Novartis) and from the drug product development area with both low & highly hazardous compounds (Dr. Susanne Page, Roche).
And as a special bonus of the conference all participants had the opportunity to visit nearby CordenPharma Plankstadt to tour our state-of-the-art manufacturing facilities for highly potent solid dosage forms. Organized under the Highly Potent & Oncology Platform, CordenPharma Plankstadt is our center of excellence for the development & manufacturing of highly potent drug products from early stage development to full commercial scale for compounds down to an OEL level of 0.1 µg/m3/8h. The conference participants were able to view both our new early-stage development lab providing full primary containment for batch sizes from as little as 10 g up to ~1 kg, as well as the commercial-scale manufacturing plant where phase 3 clinical supplies & commercial batches are manufactured at a 100 – 150 kg scale in primary containment. These fully-contained facilities relieve operators of the necessity to wear personal protective equipment, as the compounds are safely contained by Glatt technical solutions and other organizational measures during manufacturing and cleaning.
Not only did the CordenPharma Plankstadt site visit give insight into real life highly potent handling with intensive discussions about the pros & cons of different equipment, containment solutions and challenges in a primary containment plant, but the overall conference program also provided a unique learning experience for both newcomers and experts in the field of highly potent drug products which was very appreciated by all involved.
Throughout the two days about 50 participants heard from various international speakers in the pharmaceutical industry, from equipment manufacturers to legal experts, discussing the requirements and technical solutions for working with highly hazardous compounds. Most importantly they learned how to apply effective risk mitigations in their daily routine for different hazards throughout all stages of development & manufacturing. Topics such as hazard vs. risk, quality vs. safety and efficiency vs. effectiveness were common themes in all the presentations, viewed from different perspectives, which fostered lively discussions throughout the conference.
The APV Highly Potent conference sets itself apart from other “high potent” workshops because it focuses on an extremely important, but often forgotten aspect – the human factor. As part of a moderated plenum discussion allowing participants to vote and contribute online, the impact of 10 human factor categories on many of the challenges & risks were identified by the speakers. All the participants clearly recognized them as not often being adequately addressed in their operational routines, or as moderator Christian Wilkens concluded at the end, “overlooked until another aircraft has crashed again,” thereby comparing them to the aerospace industry. In this context the majority of participants admitted that 30 – 50% of the time operators had gotten “so used to handling highly potent compounds” that they had underestimated the associated risks.
The next two speakers addressed a different angle by focusing on the exposure risks for nurses and health care personnel during the handling and administration of drug products, instead of the usual focus only on operators. Prof. Irene Krämer from University Hospital in Mainz, DE shared her daily challenges in handling products in an oncology unit, and expressed her hopes for a more hospital-friendly focus in the development of new drug products. Dr. Silke Weber from Roche complemented this session by sharing Roche’s experience in defining the actual risks for health care personnel resulting from primary packaged products.
Basic definitions, measures and risk mitigations for handling of highly hazardous compounds were of course part of the conference’s program. Speakers from Roche (Dr. Silke Weber) and Novartis (Dr. Marc Abromovitz) then provided a slightly different perspective on small molecules, concluding with a similar statement that it is the “risk rather than the hazard of the compound” which we have to consider & mitigate when handling highly potent compounds. Good risk controls derived from scientific risk assessments are essential to avoid excessively expensive measures for lower risk situations on the one hand, and actual health risks for operators, environment & health care personnel on the other hand. In other words, hazard does not always equal risk!
Another common theme was science-driven risk control in routine handling, as addressed by Dr. Rainer Nicolai (Roche), whom presented risk mitigations for the transfer of drug substances from an API unit to a drug product facility, Alexandru Gheorghe (Evonik), whom outlined the scale-up of highly potent formulations in sterile manufacturing, and myself, providing a science-driven approach for selecting the best dosage form for highly potent solid drug products in different phases of development. Successfully balancing the risks arising from the Biopharmaceutical Classification System (BCS), the Manufacturing Classification System (MCS), and the stability of the product with the safety, health & environmental hazards of the drug substance at each stage of development requires a science-driven and continuously updated risk management approach as part of a Quality by Design driven development.
A practical topic of note was cleaning and cleaning-related issues in a high potent environment from the perspective of SHE monitoring (Dr. Lars Restetzki, Roche), from the viewpoint of a contract manufacturer handling many different products (Norbert Straub, Excella), and from the angle of solutions provided by the equipment manufacturer (Michael Maintok, Glatt).
In the final session, the European authority requirements for manufacturing highly potent products in shared facilities were summarized by Dr. Franz Schönfeld, Regierung von Oberfranken and Dr. Claudia Sehner (all of Boehringer Ingelheim) with an explanation of what is needed in a good PDE report to address the risks and be compliant with the EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. Adreas Flückinger, who had been the Head of Health, Safety & Environment at Roche for more than a decade, concluded the program in answering an often asked but so far unresolved question: Will ANVISA finally follow the EMA approach for shared facilities? ”Yes, but…” he said, explaining the obstacles that still need to be overcome in this context.
In summary, the 2nd APV Conference on Highly Potent Drug Products looked at many innovations, still unresolved issues and challenges for the pharmaceutical industry’s increasing demand in handling highly potent compounds & drug products. All participants concluded this was a highly informative & effective conference addressing the world of hazardous compounds in a different layout…hopefully to be repeated very soon!
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