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Establishing OEL data and ensuring appropriate engineering controls are crucial aspects of safe handling.
Editor’s Note: This article appeared in the October 2019 issue of Pharmaceutical Technology Europe.
Handling high-potency APIs (HPAPIs) is increasingly important for drugs such as antibody-drug conjugates, which can have occupational exposure levels (OELs) below 0.1 µg/m3 (100 ng/m3). Contract development and manufacturing organization (CDMO) Piramal Pharma Solutions opened a new wing at its Riverview, MI, USA site in 2019 that is dedicated to the production of HPAPIs with low occupational exposure levels (OELs). Prior to this addition, the site had the containment capability and engineering controls to safely handle HPAPIs with OELs down to 1 µg/m3. The new wing is designed to handle HPAPIs with OELs less than 1 µg/m3 and as low as approximately 20 ng/m3. Pharmaceutical Technology Europe spoke with Vince Ammoscato, vice-president and Riverview site head, about some best practices for handling HPAPIs.
PTE: What are some of the biggest challenges for handling HPAPIs?
Ammoscato (Piramal): The biggest challenge, especially as a CDMO, is establishing the correct, data-driven, most up-to-date, OELs for chemical entities. Obviously, early on in development, OEL data does not exist, especially if you are looking to make drug substance/API that will be used to establish a toxicology profile (for a toxicology study). As a result, one would involve the product sponsor/client, and our expectation is that the client would give us their thoughts on what the potential OEL could be, based on structural alerts, the proposed indication, and therapeutic effect(s) of the chemical entity. Additional third-party support, such as industrial hygienists/toxicologists, can be employed to propose an OEL based on all those factors.
Industrial hygienists/toxicologists will do an assessment for you, or on behalf of the sponsor, that will establish what the OEL could be for the chemical entity. Otherwise, you would use data like the LD50 [median lethal dose] if available. Our approach is to always default to a more conservative occupational exposure band (OEB) in terms of containment best practice. Safety for our employees is paramount and as a result, we would rather be sure about our containment approach; if the data later suggests a chemical entity is less potent, then you can adjust your containment approach based on the actual OEL.
Our typical client is sophisticated, and I would say only about 20% of projects do not have an OEL at the start. The majority have some level of data and recommend an OEL during the request for proposal process. The OEL is based on data or based on the potential client’s internal risk levels. Big Pharma companies, as an example, automatically default an oncology asset to their Category IV or V OEB. This approach offers protection to the sponsor/client by recommending the chemical entity as potent and once data is established, the OEB can be adjusted accordingly.
The other challenge that we are managing is, even though we have been an HPAPI site for more than 30 years, going to the next level (OEB V) of containment-where you start handling chemical entities with OELs in the ng/m3 range-causes safety concerns with employees. We have the appropriate engineering controls and we have put systems and processes in place to be able to handle the highly potent compounds. However, as chemists and EH&S [environmental health and safety] professionals, we know that establishing all the pertinent data is very important and with the appropriate training, our employees continue to feel safe as they work with these highly potent chemical entities.
We have created a culture of safety using industry best practices and have engineered a state-of-the-art facility that makes employees comfortable from a containment perspective.
PTE: When handling HPAPIs, what are some of the best practices for engineering controls and measuring the quality of the environment in your classified manufacturing spaces?
Ammoscato (Piramal): The first line of defense is your engineering controls. Proper facility design and engineering, including the heating, ventilation, and air-conditioning systems; approaches to barrier isolation; and the incorporation of gowning/de-gowning areas are key considerations. Appropriate facilities, engineering controls, and safety protocols are, in fact, increasingly imperative as newer HPAPIs under development have ever declining OELs. Facilities must have controlled air flow (single-pass) and pressure systems with filtration capabilities and airlocks and vestibules around both laboratory and manufacturing suites. The use of closed restricted air barrier systems (RABS), isolators, automated handling equipment, and disposable technologies are increasingly common as means for effectively minimizing the potential for exposure of operators and the environment to potent compounds. The use of appropriate personnel protective equipment (PPE), comprehensive quality management systems, industrial hygiene programs, highly detailed operating procedures, and extensive training programs are also essential. It is really about verified containment more than anything, which requires establishing actual data to prove that the engineering controls you designed and put in place actually work as designed. This verification can be established through surrogate testing of the containment systems.
We used surrogate testing with a third-party contractor. They tested all our containment technologies with a surrogate (naproxen) and performed all the required operations when handling a potent chemical entity. Sampling points were strategically placed during the testing to detect any breaches within the engineering containment controls. Having that data to support the engineering containment controls instills confidence in our employees and ensures that we are working safely.
Big Pharma, or the more sophisticated clients, expect you to have dynamic surrogate data [replicating process activities using a surrogate compound] confirming the containment capability for them to bring their projects to your site.
Some of them do EH&S audits as part of their due diligence, not only quality audits. So, during the EH&S audit they might ask for that information. They will ask, ‘How do you know that your containment solutions can actually handle down to 20 ng/m3 in terms of OEL?’ Having the dynamic surrogate testing results answers their question.
PharmTech: What technologies have you used to improve manufacturing efficiency?
Ammoscato (Piramal): Closed systems (glovebox technology) play an important role in containment. We've employed one-time use, disposable gloveboxes, which ensures containment but also helps with capacity planning and minimizes the amount of downtime for cleaning and cleaning verification.
PTE: What are some of the challenges and best practices in packaging/shipping HPAPIs?
Ammoscato (Piramal): As a site we have always dealt with HPAPIs, so nothing has really changed. You just need to ensure there is no open handling of materials. Packaging is all done within glovebox technology. With regard to shipping, you follow your shipping procedures, with secondary containment systems in terms of the shipping container. We ensure through standard operating procedures that we have all the appropriate documentation and labeling to establish and communicate to the receiving party that the material they are receiving is a HPAPI. You also want to do your due diligence to ensure that the facility you are shipping to can actually handle the HPAPI in terms of receiving it and managing it at their facility.
Pharmaceutical Technology Europe
Vol. 31, No. 10
When referring to this article, please cite it as J. Markarian, "Best Practices in Handling HPAPIs," Pharmaceutical Technology Europe 31 (10) 2019.