Setting the Bar in Highly Potent API Manufacturing

Growing numbers of new drug substances, particularly oncology therapies, have very high potency and thus can be toxic upon exposure even at low levels. Specialized manufacturing equipment, procedures, and systems are required to ensure worker safety and protection. Recently, custom manufacturers with expertise in the production and handling of highly potent APIs (HPAPIs) joined in a roundtable discussion with the Pharmaceutical Sciences, Manufacturing & Marketplace Report to examine the latest issues and technology developments in the field. Participants included: John Michnick, associate director of sales and business development for Cambrex; Jean-François Marcoux, technical business manager with Novasep; Waldo Mossi, senior director of business development at Helsinn Advanced Synthesis; Stefan Stoffel, head of chemical manufacturing for Lonza; and Trevor Calkins, director of process development and manufacturing for SAFC.

Critical mass for HPAPI manufacturingPharmaceutical Sciences, Manufacturing, & Marketplace Report: What are the key attributes for HPAPI production services?

Calkins (SAFC): Perhaps the most important attribute a customer is going to be looking for is the assurance of the ability to manufacture HPAPIs safely and the documentation to prove it. SafeBridge certification is really the ultimate proof that a facility’s handling capabilities are up to par. The certification covers four broad areas: program management, hazard identification and evaluation, hazard control, and communication, education and training. Achieving SafeBridge certification is demanding, and only a few sites around the world have been shown to meet these standards.

Mossi (Helsinn): Many clients have expressed a preference to work with experienced US or European CMOs with stellar audit and regulatory records. Proper facility engineering, effective containment safeguards, and proven quality systems help to reduce potential risk related to facility audits and supply-chain continuity.

Michnick (Cambrex): Specifically, clients are seeking HPAPI handling knowledge and expertise. Instruments, equipment, and facilities must have appropriate heating, ventilation, and air conditioning (HVAC), barrier isolation, and separate gowning and degowning areas based on the toxicological and chemical/physical properties of the molecules.

Marcoux (Novasep): Having SafeBridge certification showing our ability to handle very toxic compounds with occupational exposure limits (OEL) of 0.03 µg/m³/h and lower (SafeBridge 4) is also a key point. It requires specific expertise and equipment that few manufacturers master. Currently, the demand for low OEL compounds is increasing due to the development of immuno-conjugate drugs, among other factors. Purification capabilities are also critical.

Stoffel (Lonza): Customers are looking for seamless execution of their complex HPAPI projects. Due to their limited volume requirements, often only single sourcing strategies are applied, even at maturity. Therefore, the establishment of a reliable source that can provide security of supply is key. If the CMO does not need to be changed between first clinical supplies, product launch, and regular market supplies, customers save effort, time, and cost for technology transfer, and they can leverage potential optimization based on process knowledge.

Challenges in HPAI manufacturingPharmaceutical Sciences, Manufacturing, & Marketplace Report: What are the main challenges that you face as an HPAPI manufacturer, and what advances have been made to help overcome these challenges?

Michnick (Cambrex): Some of the main challenges we have seen revolve around the complexity of the HPAPI chemistry and the assessed risks associated with exposure limits and occupational safety. To help resolve the challenges, we focus on constant communication with our clients. Our HPAPI chemists, production teams, and project managers work alongside and educate clients on HPAPI procedures, SOPs [standard operating procedures], and training associated with the exposure limits of their compounds.

Stoffel (Lonza): Getting to mutual recognition that a compound is classified as an HPAPI and has to be handled adequately can represent a challenge. It is key to synchronize the toxicity and safety aspects at the beginning of a project stage and ensure we’re not compromising on safety. Lonza has established a six-band safety categorization system that can easily be referenced to a client’s in-house categorization system or the widely utilized SafeBridge four- band system. This transparent determination of the appropriate containment and safety measures helps to maintain quality products. If during drug development, additional toxicologica data is generated that allows reclassification of an intermediate or API, we are happy to re-assess the production concepts.

Calkins (SAFC): One of the biggest challenges involves materials handling, particularly when manufacturing HPAPIs on a larger scale. Bottles with alpha–beta connectors are too large and heavy to manipulate. We have addressed this issue by creating a system that allows hazardous reagents to be dispensed directly from drums. The drum and reactor are attached to a portable isolator, and a powder-transfer system is used to move the reagents from one to the other. The system is also used if the reagent is not hazardous, but the contents of the reactor are. The reactor is on load cells, enabling all components of the reaction to be added while minimizing manual handling requirements. We also use this system to transfer the completed reaction mix to a Nutsch filter.

Mossi (Helsinn): There are two main challenges. First is defining the categorization class and OEL with limited information available from the client. Helsinn's solution is the use of internal assessment coupled with outsourcing hazards analysis and definition of appropriate OELs by an external expert group experienced in the field. Second is containment and protection in high-risk areas, such as product charging, isolation, milling, and transfer. Helsinn's solution has been to engineer its facilities to further mitigate that risk. A new, state-of-the-art, fully closed and comprehensive containment system was installed [at our facilities] that is capable of managing the entire process from raw material to finished HPAPI, including cytotoxic molecules.

Advances in HPAPI technologyPharmaceutical Sciences, Manufacturing, & Marketplace Report: On an industry level, what are some recent technology developments that have advanced HPAPI capabilities?

Marcoux (Novasep): The challenge in HPAPI manufacture is to bring together very high containment capabilities with advanced purification technologies within the same facility. Industrial preparative chromatography is now generally well-established as a state-of-the-art purification technique for the production of APIs and is also becoming key for HPAPI production.

Mossi (Helsinn): Biotech and pharma development has evolved in recent years to leverage the value of cytotoxic compounds while minimizing drawbacks. Much of this evolution can be attributed to antibody-drug conjugates (ADCs) and cytotoxic analogs. Several CMOs are contemplating collaborative opportunities to support diverse manufacturing technologies for ADCs (i.e., cyto, linker, antibody).

Looking aheadPharmaceutical Sciences, Manufacturing, & Marketplace Report: What do you anticipate in terms of market and technology developments in the HPAPI space in the near term? Longer term?

Stoffel (Lonza): At present, there are a very large number of compounds in clinical trials for oncology indications. As established pharmaceutical and emerging biotech companies increasingly devote development resources into oncology products, a continued expansion in the demand for HPAPIs and cytotoxics can be expected. At the same time, the target compounds become more potent while the related synthesis processes become increasingly complex. A broad technical set-up and the ability to cover a great variety of unit operations, scales, and reaction conditions in a contained fashion is required, along with the ability to safely and efficiently handle the product and waste-related process streams, at any scale.

Marcoux (Novasep): From a technology point of view, the advent of single-use production technologies could probably strongly benefit HPAPI production. Most of the current single-use devices, however, are not compatible with the use of organic solvents yet. When ready, it could definitely become a major tool for overcoming containment, cleaning, and cross-contamination issues.

Calkins (SAFC): ADC products are starting to be approved for use in cancer, and many more are under development. The ability to take an HPAPI and conjugate it to an antibody via linker technologies is going to become more important in the future as the number of these products rises.

Mossi (Helsinn): There is a chance for additional regulatory guidance related to product classification (i.e., cyto vs. HPAPI). It is not clear, however, if this guidance will allow global agencies to align perspectives. CMOs that properly assess OEL categorization and compound classification will have the best chance to serve future market needs. HPAPI benchmarking, fully closed systems, and standardization for cleaning procedures and cleaning validation are areas that could further advance the technology in this space.

Recent investmentPharmaceutical Sciences, Manufacturing, & Marketplace Report: What recent investments have you made or are planning in your HPAPI production capabilities?

Mossi (Helsinn): Helsinn expanded existing HPAPI containment facilities in 2012 with a new state-of-the-art, fully closed and comprehensive containment system that will be fully validated and operational in March 2013. GMP manufacturing will begin before the second quarter of 2013.

Marcoux (Novasep): Novasep recently announced a $4-million investment to expand its HPAPI manufacturing capabilities at its Le Mans, France site for the synthesis, purification, and isolation of very highly potent compounds with an OEL lower than 0.03 µg/m³/8 h at kg scale. Cryogenic chemistry at -60 °C in Hastelloy reactors and large-scale high-performance liquid chromatography and drying in confined areas will be available for the manufacture of ADC toxins at commercial scale.

Michnick (Cambrex): In the US, Cambrex Charles City recently added preparative chromatography and milling and micronization equipment and is currently undergoing an expansion to increase large-scale capacity for HPAPIs. In Europe, the Cambrex Karlskoga site is being upgraded to increase capacity and capabilities for developing and manufacturing HPAPIs.

Stoffel (Lonza): In 2012, Lonza upgraded its Visp, Switzerland HPAPI center of excellence with a small-scale train for clinical and niche commercial HPAPI quantities (10–100 kg/campaign) and integrated its proprietary microreactor technology into the mid-scale cGMP setup there. HPAPI processes benefiting from continuous flow technologies can now be well-contained within one single cGMP-facility with outputs per campaign ranging from 10s to 1000s of kg. Lonza also established a dedicated manufacturing train for cytotoxic compounds under cGMP that combines fermentation and chemical capabilities with the handling of highly potent compounds that can be used for the production of either microbially derived secondary metabolites (toxins) or chemical compounds. In addition, our ADC capacity in Visp is being doubled and will be on stream in 2014.