To meet growing demand for highly potent drugs, pharma companies must either face a large investment or partner with an experienced CMO. Ash Stevens says CMOs with demonstrated expertise should be at the top of the list – but what else should they offer?
Growing global demand for targeted therapeutics in oncology is one of the key factors driving increased demand for contact manufacturing service providers experienced in the development and manufacture of highly potent active pharmaceutical ingredients (HPAPIs) such as small molecule cytotoxic compounds and antibody drug conjugates (ADCs).
The manufacture of HPAPIs presents many challenges; however, given the high toxicity of these compounds, safety is the first and foremost consideration. Manufacturers must have robust engineering controls, risk assessment and risk management processes in place to ensure a safe work environment and prevent cross-contamination.
The manufacture of HPAPIs presents many challenges; however, given the high toxicity of these compounds, safety is the first and foremost consideration
While some major pharmaceutical firms have made the significant investment needed to ensure safe and effective HPAPI production, many life science companies elect to outsource these projects to contract manufacturing organisations (CMOs) with expertise in working with highly potent substances. The global market for cancer drugs in 2013 totalled US$91bn, according to IMS Institute for Healthcare Informatics, and grew at a compound annual growth rate (CAGR) of 5.4% from 2008–2013.1 Research and consulting company Ace Business and Market Research Group (ABMRG) predicts that the oncology market will reach $109bn by 2020.2 IMS notes that 22 new oncology therapies were launched in the past two years alone, many of which were small-molecule drugs, and 30% of all preclinical and phase I clinical development products are cancer therapies.1 It should also be noted that although 60% of highly potent drugs are for the treatment of cancer, highly potent therapies have also been shown to be effective and are in development for the treatment of other diseases ranging from glaucoma to hormonal imbalances and respiratory disorders.3
All of this activity is driving demand for HPAPIs that, according to market research firm RNCOS, comprise the fastest growing segment of the worldwide API market and will be valued at $15.3bn by 2017.4 Notably, more than 25% of all drugs worldwide are classified as highly potent, according to business research and consulting company Roots Analysis.3 The group also reports that 76 CMOs with more than 100 production facilities worldwide provide services related to HPAPIs, and since 2006 more than 60 projects have been completed to either expand or add new capacity to facilities.
Pharmaceutical companies that outsource HPAPI development and manufacturing are looking for a CMO that has a proven track record for both safely and effectively managing projects involving highly potent compounds. Such a record includes not only successful commercial production of HPAPIs, but also an excellent audit history, comprehensive documentation and regulatory records.
Achieving such a history requires an understanding of the potential risks associated with the production and handling of HPAPIs and the systems that are required to minimise those risks. Proper facility design and engineering controls are the first requirement, which includes the heating, ventilation and air conditioning system (HVAC), approaches to barrier isolation, the incorporation of gowning/degowning areas, and much more. Appropriate containment safeguards, and comprehensive quality management systems are also a must. Of course, expertise in synthetic organic chemistry and process development, scale-up, purification capabilities, and highly sensitive analytical instrumentation and techniques are also required.
Continual education and training of chemists, engineers and operators is crucial to ensure that they are aware of the risks
Continual education and training of chemists, engineers and operators is crucial to ensure that they are aware of the risks and are familiar with the use of personal protective equipment (PPE) and standard operating procedures (SOPs). Without highly skilled personnel and trained personnel, the safe and effective production of HPAPIs will be a challenge, even in the most advanced facilities.
Because highly potent therapies are administered at very low doses, and increasingly they are developed for highly targeted populations, often they are low-volume products. As a result, in addition to CMOs with demonstrated expertise with HPAPI production, pharmaceutical companies are looking for partners that have the capability to support both the development and commercial manufacture of highly potent compounds to avoid any need for process transfers. CMOs that can support a safe, reliable, and regulatory compliant supply chain of HPAPIs are most likely to succeed as preferred single-source supplier.
At the initial stages of an HPAPI project, the risk associated with the active substance is frequently unknown since comprehensive toxicity data is not yet available. Proper handling of such compounds is absolutely critical to ensure the safety of personnel. One approach for determining initial procedures is to compare the HPAPI to similar substances/structures with known toxicities and assume a similar level of risk. Some CMOs have in-house compound categorisation systems that they use to determine the required safety measures.
Frequent communication between the pharmaceutical company and the CMO is crucial
Whatever method is used initially, frequent communication between the pharmaceutical company and the CMO is crucial at this point. Agreement must be reached as early as possible on the risks associated with a given compound. Of course, if additional toxicity data is developed that indicates reclassification is warranted, the CMO should be prepared to respond as needed.
As with most APIs under development today, the chemistry of HPAPIs is increasing in complexity. Therefore, CMOs that specialise in HPAPI development and manufacturing must have state-of-the art equipment for performing a wide range of chemical transformations and purifications, and be able to carry out those processes in a safe, contained manner.
Cross-contamination concerns must also be addressed. One approach involves the use of dedicated systems. Some CMOs are also investigating the use of disposable technology as a solution to preventing inadvertent carryover of a product from a previous production run.
Most importantly, companies should regard demonstrated safety performance as the top criterion when selecting a CMO. Safety and attention to detail must be integrated into the CMO’s DNA from the top down and bottom up. In addition to having the necessary engineering and process controls in place to handle HPAPIs, continuous training and monitoring, including third party verification, monitoring and training is essential for safe operations.
For example, Ash Stevens, an experienced CMO that has been developing and manufacturing HPAPIs for more than five decades, has an active chemical hygiene programme in place that monitors the facilities’ air quality and waste streams to ensure personnel, the facility, the community and client’s investments remain safe. In addition, the company’s environmental health, safety and security (EHS&S) programme is certified by ChemStewards, a third party EHS&S verification programme sponsored by the Society of Chemical Manufacturers and Affiliates (SOCMA). ChemStewards not only ensures that Ash Stevens is compliant with all EHS&S regulations and best practices, but also mandates that the company improves upon its EHS&S programme on a continuous basis. Ash Stevens’ EHS&S programme has been recognised by SOCMA at the association’s annual meeting with seven ‘silver awards’ over the past five consecutive years for continuous improvement in various focus areas of the ChemStewards programme.
Most importantly, companies should regard demonstrated safety performance as the top criterion when selecting a CMO
Ash Stevens employs an industry recognised five-band system for the categorisation of potent compounds at its state-of-the-art manufacturing facility located in Riverview, Michigan. The company has the appropriate engineering and process controls in place for potent compound handling and manufacturing at scale with occupational exposure limits (OELs) down to 1.0µg/m3 (Category IV). Category IV manufacturing capabilities extend up to the 4,000 litre reaction scale with batch sizes up to 250kg depending upon the bulk density of the material. Reactor suites are equipped with single pass air and split butterfly valves for contained charging, handling and manufacturing of potent compounds.
Isolations are conducted in Rosenmund filter dryers equipped with glovebox technology for contained handling and packaging. For handling highly potent compounds with OELs <0.1µg/m3 (Category V), Ash Stevens maintains a state-of-the-art high potency suite with incoming and outgoing HEPA filtered air and corresponding airlocks. The suite is equipped with a specially designed hood for the synthesis of potent compounds and barrier isolation equipment for the contained handling, drying and packaging of highly potent APIs. The floors of the suite are coved and have seamless walls for easy cleaning. Third party independent verification found the suites’ operational capabilities to be safe at OELs of 10ng/m3.
Ash Stevens has a long history and impeccable safety record of working with highly potent compounds going back more than 50 years. Demand for HPAPI manufacturing services is likely to increase in the future. The manufacture of APIs is moving towards greater regulatory scrutiny, containment control and more potent therapeutics. High potency manufacturing is an integrated process requiring continuous improvement and technical innovation. CMOs with an established track record in dealing with the current high potent manufacturing environment will be in the best position to advance their expertise and meet the challenges of the next five to 10 years.
1. IMS Institute for Healthcare Informatics, www.imshealth.com/portal/site/imshealth/menuitem.c76283e8bf81e98f53c753c71ad8c22a/?vgnextoid=19b381d71adc5410VgnVCM10000076192ca2RCRD&vgnextchannel=5ec1e590cb4dc310VgnVCM100000a48d2ca2RCRD. Accessed 1/8/2015.
2. Ace Business and Market Research Group, www.prnewswire.com/news-releases/global-oncology-market-to-hit-109-billion---spotlight-on-drug-life-cycle-management-ma-and-pipeline-strategies-283206481.html. Accessed 1/8/2015.
3. Roots Analysis, http://www.rootsanalysis.com/reports/view_document/hpapis-and-cytotoxic-drugs-manufacturing-market/64.html. Accessed 1/8/2015.
4. RNCOS, www.rncos.com/Press_Releases/Global-HPAPI-Market-to-Reach-USD-15-3-Billion-by-2017.htm. Accessed 1/8/15.