Bikash Chatterjee, CEO Pharmatech Associates— a USP Company
Developing high-potency, high-performance drugs is hazardous, and the stakes are high for investors, the pipeline, and patients. This class of drugs—known as HPAPIs for short—represents a substantial and growing piece of the solid dose pie. But capitalizing on this market requires navigating a host of safety and regulatory issues, among other things.
Currently, up to 25 percent of all drugs are classified as highly potent1 and recent research on the HPAPI and cytotoxic drugs manufacturing market forecasts this number to continue to rise, with HPAPIs under development for targeted treatments in oncology, metabolic disorders, and autoimmune diseases.
In the U.S. alone, this market is expected to grow from $63.9B in 2020 to $163B in 2027.2 Market growth stems from demand for oncology and antibody drug conjugates, a rising focus on precision medicine and high potency active pharmaceutical ingredients (API), and technological advancements in manufacturing. Robust manufacturing facilities and operations to contain and handle highly potent compounds safely will have to increase to match demand.
HPAPIs are compounds that evoke a biological response at a very low dose. Some HPAPIs are also cytotoxic, meaning they inhibit cell growth, which is why they are such attractive candidates for oncology treatment. Adding fuel to the fire of expanding interest in the development of these materials, nearly 20 patents for biologic oncology treatment therapy will be expiring in 2023, potentially opening the door to biosimilars seeking a foothold as the standard of care for oncology treatment.3 Even without any impending patent cliff, the demand for cancer treatment therapies shows no signs of leveling off. There is a shortage of qualified contract development and manufacturing organizations (CDMO): many CDMOs simply do not have the facilities, equipment, or specialized personnel to handle high potency active pharmaceutical ingredients (HPAPI). Let’s examine the implications from those three key factors affecting innovators and generics manufacturers alike:
Facilities: Design for HPAPI Handling
The HPAPI market was adversely impacted during the pandemic, as much of the global HPAPI supply chain is sourced or produced in China and India. According to the economic development agency Germany Trade & Invest (GTAI), around 60 percent of APIs—including the lion’s share of high potency APIs of the world—originate in India or in China. As the virus spread globally, India temporarily placed an export curb on 26 drugs4 and various HPAPIs to avoid domestic shortages, accounting for around 10 percent of the country’s pharmaceutical exports.
For CDMOs, HPAPIs present a unique challenge. A typical HPAPI has a therapeutic daily dose of less than 10 mg and an occupational exposure limit (OEL) below 10 μg/m3 of air as an eight-hour time-weighted average (TWA). And a growing number of pharmaceutical compounds under development, known as ultra-HPAPIs, can require even more extreme levels of exposure control, down to an OEL range5 of 1-20 ng/m3. Handling compounds with exposure limits this low requires a combination of specialized facility design, specialized containment equipment, specialized Personnel Protective Equipment (PPE) as well as specialized training regarding equipment operation, material transfer, sampling, and testing.
Before embarking upon any manufacturing with an HPAPI, a qualified CDMO should develop a risk plan and a containment plan for the material before it enters the facility. The plan must study each processing and handling step and consider all routes of personnel exposure, from contact with material on an operator’s protective gown, to ingestion or inhalation. Factors such as the pharmacokinetics (PK) of the API and its physical characteristics, (e.g., liquid vs. powder) can greatly affect the routes of exposure to personnel. For example, materials that are easily absorbed through the skin will require very stringent gowning controls to prevent inadvertent personnel exposure.
If the API has an established Occupational Exposure Limit (OEL) or Operational Exposure Band (OEB), a CDMO can begin to prepare its risk mitigation plan for handling the material safely within the facility. One simple framework for evaluation is to build a chart correlating OEL limits with an OEB to better understand what level of facility and equipment containment control they will need for the API. An example of an OEL/OBE table is shown in Figure 1.
If the HPAPI is a new chemical entity (NCE) for which no exposure limits have been established, a CDMO will have to gather the information necessary to develop a containment and operational risk mitigation plan. Sources of information could include the toxicity and safety data provided by the drug sponsor as part of their pre-clinical studies, literature searches, and evaluating the toxicity profiles of similar chemical structures. The most relevant pharmacological and toxicological data sets should be linked to the most serious health effect and will be used to establish the acceptable daily exposure (ADE) and OEL calculation. Although the OEB framework can help steer the operation toward the most suitable level of containment, the containment strategy must be tailored to each specific operation and process stage.
The next step is an intensive task-by-task exposure risk assessment of the HPAPI handling process to evaluate specific exposure risks based on the established OEL, and the pharmacological and toxicological actions of the compound, to protect the operators and prevent potential cross-contamination. Last, but not least, the manufacturer will have to complement their operational risk mitigation plan with a monitoring program specifying sampling and analytical testing for specific compounds, to measure, monitor and trend containment operations.
Equipment: Operational Considerations for Safe Handling
Sophisticated HPAPI facility design elements incorporate several tools to ensure safe handling of potent materials. Units are available for primary and secondary containment of the entire process including solid charging containment, sampling, and unloading of material. For product sampling, liner ports can help lock in and lock out glass sampling bottles. To aid in the product unloading process, manufacturers can use a variety of liner systems and customized isolators for processing. Hard-walled or flex-walled isolators that are negatively pressurized to the room within the manufacturing space can greatly reduce the risk of an inadvertent exposure or cross contamination. Single-pass, dedicated HVAC systems ensure there is no commingling of any material between areas. Employing a negative pressurization cascade around the primary processing areas is one way of providing additional protection that material is being controlled and contained in its designated area. Single use isolators are very effective in reducing the risk to operators and simplifying the cleaning operation between batches.
Creating dedicated one-way personnel and material passthroughs can minimize the potential for cross contamination. Using a dedicated equipment train for all primary product contact equipment reduces the likelihood of product cross contamination. However, most CDMOs--unless the area is a dedicated operation with dedicated equipment and a detailed cleaning procedure--will require test methods and a monitoring program. For all non-processing support equipment, disposable material is the first choice. Still, when that is not possible, a detailed material removal process will need to be developed and qualified under protocol and coupled with analytical methods that have the resolution to measure the OEL levels of the API and its degradation components.
Modern Regulatory Landscape
Regulatory standards have continued to evolve with technological advancements. Historically, many HPAPI facilities were dedicated operations as cited above. Even so, the advent of isolator and disposable system technologies, together with continued advancement in PPE and industrial hygiene practices, have made multi-use facilities a reality. Regulations covering the sterile processing of highly potent products impose stricter handling and employee safety requirements than those covering standard drug product processing.
Along with health safety standards such as Occupational Health and Safety Management System (OHSMS) 18001 and ISO 14001, the U.S. and European current Good Manufacturing Practice (cGMP) guidelines cover HPAPIs, detailing how manufacturers should try to avoid cross-contamination, address material and equipment cleanability, and measurement. HPAPI handling requirements are also set out in the FDA guidance on aseptic processing, and in ICH Q10, which addresses a risk-based quality management system. Several additional International Organization for Standardization (ISO) standards pertain to HPAPIs, including ISO 13408 on aseptic processing; ISO 14664- 1 on cleanrooms and controlled environments; and ISO 11134, 11137, and 14937 on sterilization.
Define Potency, Manage Risk
Drug sponsors and CDMOs must grapple with several complications when attempting collaboration. First, there is no universally accepted standard for describing and evaluating exposure limits. Yet, both parties must truly understand how to measure and describe potency before embarking upon risk strategy development. Whether using OEL or OEB or some other tailored control banding framework, it is still very difficult for both parties to move forward without a clear understanding of the basis for describing potency. Once the industrial hygiene specialist has a firm grasp of the exposure data’s basis and an effective methodology for evaluating the workplace, it can develop a mode of action that will contain the right level of control.
At the heart of handling HPAPI is making sure that both the drug sponsor and CDMO agree upon the level of risk. For innovator companies this is easier to do, as they have had to develop and compile much of the necessary data as part of the drug development process. Generic HPAPI manufacturers may not have all this data, since it is not required for the regulatory submission. In some cases, the available data may be old, outdated or generated using a framework or methodology that is not in line with modern characterization methods. In all cases, both the drug sponsor and manufacturer must work together to assemble an accurate potency picture.
Business Risks from a Fragmented CDMO Market
Drug sponsors must also study the risks as well as benefits of pursuing an outsourcing strategy, since the CDMO market remains highly fragmented, with more than 500 CDMOs offering services worldwide.6 As CDMOs look to increase their market share through investment in service offerings like HPAPI manufacturing, there is always a risk of acquisition. To hedge against this before deciding to bring HPAPI manufacturing in-house, some drug sponsors may pursue an outsourcing strategy with a qualified CDMO to better understand the capital investment in facilities and equipment to safely manufacture the product, and the specific expertise that must be resident to continue to support these programs come what may.
Digitization
Along with CDMO capability, the adoption of digital tools impacts HPAPI capability. Modeling and simulation of toxicological, chemical, and physical properties of compounds can facilitate development—particularly for early phase projects with very limited experimental data. Making this information available before extensive testing and measuring begins means that technicians have a greater understanding going into the detailed process development. This could ultimately guide more efficient process design, reducing the complexity for handling highly potent material.
Even though HPAPIs may be produced in modern and automated facilities, some production steps—especially in clinical phase manufacturing—are still performed manually, requiring highly skilled and trained operators. The high turnover rate of its personnel—especially on the shop floor and in the lab—can challenge many CDMOs. Using virtual or augmented reality as part of intensive training before embarking upon HPAPI development studies can help users more rapidly learn realistic handling, cleaning, and movement techniques.
Finally, the chief difficulty of process digitalization is capturing and curating disparate new data sources, including data from production equipment, analytical instruments, production planning, and QA systems. Applying machine learning to analyze, visualize, and predict process behaviors will have a cascade effect that leads to better, more efficient processes and more effective digital tools that reduce the risk of handling and processing HPAPIs in development.
About the Author Bikash Chatterjee has worked in the bio-pharmaceutical, pharmaceutical, medical device and diagnostics industry for over 30 years, guiding the approval of a dozen new products within the U.S. and Europe. He developed and transferred products and processes to satellite operations and CMOs throughout his career, designing and implementing systems to satisfy the requirements for ICH Q8, Q9, and Q10, e-pedigree, risk-based validation, and developing a six sigma-based methodology to support the PAT initiative. He is an ISO 9000 certified lead assessor and six sigma / lean manufacturing master black belt. Chatterjee is a member of the USP national advisory board, past chairman of the Golden Gate Chapter of the American Society of Quality (ASQ), and the author of “Applying Lean Six Sigma in the Pharmaceutical Industry” (ISBN: 978-0-566-09204-6). He holds a B.A. in biochemistry and a B.S. in chemical engineering from the University of California at San Diego.
References
1.https://www.rootsanalysis.com/reports/view_document/hpapi-andcytotoxic-drugs-manufacturing/299.html
2.https://www.researchandmarkets.com/reports/5309486/immunooncology-global-market-trajectory-and?gclid=Cj0KCQiA6NOPBhC PARIsAHAy2zBACrtHT-
3.https://www.centerforbiosimilars.com/view/as-patents-expireoncology-biosimilars-poised-to-expand-authors-say
4. https://www.mordorintelligence.com/industry-reports/ highpotencyapis
5.https://www.chemanager-online.com/en/news/understandingrequirements-safe-hpapi-manufacturing
6. https://www.marwoodgroup.com/wp-content/ uploads/2022/02/2022.02.14-Pharma-CDMO-Whitepaper.pdf