Have you ever joined Richard Denk in a PDA Chapter? LyophiliationWorld is glad to propose an interview with the most reputable expert in Containment in the industry.
Richard is an expert in consulting and planning of high containment HPAPI, ADC, highly active pharmaceutical products for Aseptic Biotech, OSD and API facilities. He is Chair of ISPE in Containment for ISPE (DACH countries). Responsible for the ISPE Containment Manual, he wrote a GMP Paperback on Containment & Hygieninc Design and he is frequently speaker in international conferences.
Where do you think Containment is going?
The Biopharmaceutical sector is a fast-growing industry with a lot of new innovative medicines to treat and cure diseases we never thought could be cured. Around 40% of the new coming medicines in Biopharmaceutical are for the treatment of cancer. Almost all of them are considered as high-potent or toxic drug.
I have been working for more than 20 years with high potent substances. First in the chemical sector, then at API level (Active Pharmaceutical Ingredients) and OSD (Oral Solid Dosage). At the beginning it was a challenge to reach an OEL (Occupational Exposure Level) down to 1 µg/m³ which is according to the Containment Pyramid I developed an OEB 4/5 (Occupational Exposure Band). Now with the new Biopharmaceutical medicine we have OELs down to 1 ng/m³ or even below. The Containment Pyramid will need soon a 7th Band if these extreme potent products are the new generation of medicines.
For many people this low OEL level is not easy to understand and it is also not easy to explain. I will try to make it simple: everything below 400 µg/dm² it’s considered visibly clean on a nice polished stainless-steel surface; The same with concentrations in the air. Below, around 100-200 µg/m³, we can`t see any dust exposure. With the new requirements for high potent/toxic substances we are up to 100.000 times below what we can see. This entails a new approach in Cleaning to Prevent Cross Contamination for cGMP (current Good Manufacturing Practice) or to protect the operator working in that area.
An additional challenging aspect in Aseptic Processing is that Isolators are used in positive pressure according cGMP requirements to protect the product from surrounding contamination. To drive this change, I am writing international standards on Containment and integrate my experience on Containment, Cleaning and Aseptic Processing with the new cGMP and Occupational Safety regulations.
In Containment I have been chairing for more than 10 years the ISPE CoP (Community of Practice) for DACH countries. In 2015 we published the ISPE Containment Manual which is already one of the most successful documents published from the ISPE.
In Cleaning I have set up an Expert Group with toxicologist, cleaning experts and a GMP Inspector. In 2017 we published our first PDA (Parenteral Drug Association) Document about Preventing Cross Contamination and set limits for cleaning of non-product contact surfaces as we have in Isolators or on the fill&finish part.
The PDA Letter with the title “Isolator Surface and Contamination Risk to Personnel and Patient” November 6/2017 is one of the most downloaded documents since it covers the table for cleaning requirements for non-product contact surfaces that we also have within a Lyophilizer.
For freeze dryer users, what should be the highest priority and consideration to set?
All inner surfaces of a Lyophilizer are considered as non- or indirect product contact surfaces. The Cleaning of those surfaces was done up until recently based on Riboflavin Studies and Visual Clean. As mentioned, Cleaning and Preventing Cross Contamination in shared Equipment was also not regulated for the Lyophilizer, but the bottom of the shelves are used to push the stopper into the Vials (stoppering). Any contamination from previous cycles and/or unappropriated cleaning could jeopardize the next. To provide here more scientific data for the Cleaning of Lyophilizer and to protect the Operator the same expert group I mentioned before worked the last 2 years on another PDA Paper to Prevent Cross Contamination during Lyophilization. This document will be published within the next few months and LyophilizationWorld will be asked for spreading the word.
Is the integration between Lyo and barrier system (RABS or isolators) hard to design? what are the main steps to follow?
The Integration of an Isolator is not hard to design, or it shouldn’t be for isolator manufacturers. In your question you mentioned RABS or Isolators and here we should be clear that Isolators are the only technology to provide safety for and from high potent products. Even Isolators must be specific designed to work safely with those products. For instance, appropriate highly efficient self-contained filters like FiPa should be installed before the air return ducts to avoid spreading the high potent volatile substances in other areas. Another important part is the loading and unloading system of the Lyophilizer. As vials can break during Lyo loading the hygienic design of this technology is very important for cleaning and to prevent spreading of the high potent substance in other areas due to the use of poor designed mechanical transfer systems. With high potent/toxic substances is a lot to consider and I am very keen to support the Biopharmaceutical Industry as a worldwide recognized Expert.
What do you recommend when a production line is not following the right standards?
The recommendation is very easy. Follow the standards and try to implement them. To implement cGMP and Occupational Safety Requirements most of the time new production lines are needed, as the existing ones are not designed to work with this kind of high potent products. For instance, at SKAN we support our customers from the design of the production line to the Surface Decontamination Cycle Development and the Microbiological Qualification. Now we also provide the Cleaning Validation documents including Quality Risk Management and the Method for Cleaning for the whole aseptic filling line including the Lyophilizer. Cleaning and the Prevention of Cross Contamination are hot topics from the EMA and FDA.