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CDMOs have established strategies for handling new chemical entities with unknown biological activity.
The global market for highly potent APIs (HPAPIs) is growing at a healthy rate. According to market research firm Markets and Markets, demand for HPAPIs will expand at a compound annual growth rate of 8.5% from $16.02 billion in 2016 to $24.09 billion in 2021 (1). Rapid growth in the markets for oncology treatments (including generics) and antibody-drug conjugates is driving this expansion.
The manufacture of HPAPIs requires specialized facilities, equipment, and skills to ensure the safety of operators and the environment. As such, the bulk of HPAPIs are produced by contract development and manufacturing organizations (CDMOs) with these specialized capabilities. One of the challenges for CDMOs when accepting new projects, particularly those involving new chemical entities (NCEs), is identifying the level of potency, or biological activity, in order to establish appropriate safety and handling procedures.
There are two parts to an assessment of an NCE with respect to potency or biological activity. The first part, according to Simon Edwards, vice-president of sales and business development at Cambrex, is a risk assessment that produces an exposure “limit” or an exposure “range” (i.e., occupational exposure limit [OEL] or occupational exposure band [OEB], respectively). The limit or range is in units of mass per volume air (micrograms per cubic meter, mg/m3). The second part of the assessment is risk management, which involves establishing actions or preventive steps to keep exposures below the limit or range determined by the risk assessment. This work is undertaken through a collaborative effort between toxicology, safety, and engineering departments.
This general approach to risk assessment is reasonably well-standardized, but the way the results are displayed varies greatly because the application of uncertainty factors differs depending on the individual risk assessor. The standard approach, according to Cambrex, is incorporated into the International Council for Harmonization (ICH) guidance on impurity assessment (2), which is used by the American Conference of Governmental Industrial Hygienists (ACGIH) in a manner similar to the way FDA and the European Food Safety Authority (EFSA) conduct food ingredient risk assessments and EPA undertakes environmental risk assessments.
There is no standard system, however, because there are no regulatory compliance requirements for occupational exposure limits. “Having discussed this in depth with expert consultants, we feel that it is very unlikely that there will ever be a collaborative effort to establish a common system unless a regulatory mandate is introduced,” says Edwards.
This lack of a standard classification system is not a hindrance for CDMOs, however, according to Ramesh Subramanian, vice-president of strategic marketing with Piramal Pharma Solutions. “The actual nomenclature is not as relevant as the OELs themselves. So despite using various classifications, the industry is able to move forward with minimal issues, as the OELs provide the clarity that is needed to establish containment solutions,” he observes.
Because there are many possible pharmacophores and toxicity endpoints, Edwards stresses that risk assessment/risk management of NCEs takes a great deal of experience and chemical intuition. “Managing the potential exposure in manufacturing is not prescriptive either, as it is facility- and equipment-specific, and requires experienced engineers and safety people to implement correctly in order to protect employees, the facility, and the surrounding environment,” he states.
The key, according to Vivek Sharma, CEO of Piramal Pharma Solutions, is having an established potent compound category policy that defines the level of containment required depending on OELs or other toxicity data (e.g., LD50) and having predefined default criteria for containment in the absence of such data. “Quality CDMOs tend to default to a higher OEL when in doubt to ensure operator and staff safety,” he says. “Achieving a strong track record of safe HPAPI manufacturing also requires an understanding of the systems that are required to minimize the risks associated with potent compounds.” Sharma notes that proper facility design and engineering, including the heating, ventilation, and air-conditioning (HVAC) system, barrier isolation, and gowning/degowning 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,” he comments.
During early development stages, many drug sponsor companies do not have the toxicity data needed to ensure that their compounds are handled safely. The challenge for CDMOs then becomes ensuring that the right level of safety measures is implemented and followed when handling the molecule and the associated chemistry, according to Vince Ammoscato, site head-Riverview at Piramal Pharma Solutions. In the absence of any data, many companies default to a potent designation Category 3 (10µg/m3- 1µg/m3), he adds.
“The responsibility for containment rests with the CDMO since they are responsible for the safety of their employees. Having environmental, health, and safety (EHS) best practices with an excellent chemical hygiene program, which includes a potent compound handling policy that has been vetted through testing of the engineering controls and procedures, is paramount to ensuring NCEs are handled safely regardless of whether the potency levels have been established,” Ammoscato asserts.
There is the additional challenge, however, of the tendency by chemists and operators to make “dread”-based decisions on handling and how to respond to incidents, according to Edwards. “This type of response is really not necessary if the appropriate risk assessment is performed,” he notes.
The most common strategy when a CDMO is presented with a project involving an NCE, according to Edwards, is to initially ask the drug sponsor for available data, as this information should be available because the results-probably in vitro-have led them to move forward in the development of a NCE.
“In instances where the OEL of the molecule is unknown, there is no one common strategy for NCEs, but most CDMOs use some form of standard operation procedure,” Edwards says. “For either an NCE or synthetic intermediate, qualitative, or quantitative structure activity- and reactivity assessment-related data coupled with read-across and in-vitro data are used at Cambrex. These data are all important and come from many sources. The amount of data available depends on novelty of the pharmacophore,” he explains. Cambrex also calculates an OEL even when the sponsor has provided one.
Ramesh from Piramal adds that firms may use substructure- or chemotype-based OEL estimations that include consideration of the therapeutic class for guidance. “One approach involves comparison of the API’s properties to those of similar substances with known toxicities and assumption of a similar level of risk,” he notes. Some CDMOs have in-house categorization systems for determining the required safety measures.
“Regardless of the method, if there is any uncertainty, it is best to assume a compound is potent, despite the potential higher costs incurred,” Ammoscato states. “Frequent communication between the sponsor and the CDMO is then essential to ensure that necessary data can be generated and an appropriate decision on the potency of the compound be reached as early as possible,” he adds. The CDMO should also be prepared to respond as needed if additional toxicity data are developed indicating that reclassification is warranted. Furthermore, CDMOs should perform additional risk assessments as an HPAPI project moves through different stages of development and commercialization to ensure the implementation of optimal procedures and practices that both protect operators and the environment but are also practical and cost effective, according to Ammoscato.
1. Markets and Markets, “High Potency API /HPAPI Market by Type (Innovative, Generic), Synthesis (Synthetic, Biotech (Biologic, Biosimilar), Manufacturer (Captive, Merchant), Therapy (Oncology, Glaucoma, Hormonal Imbalance)-Global Forecast to 2021,” January 2017.
2. ICH, M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 5 version (2017).
Vol. 41, No. 10
When referring to this article, please cite it as C. Challener, “Managing Potentially Potent APIs," Pharmaceutical Technology 41 (10) 2017.