Speciality Chemicals, September 2016
Targeted therapies can be administered in much lower doses because they are distributed within the body to a specific site of action, rather than systemically. Side effects are also significantly reduced. Highly potent drugs – those with occupational exposure limits (OELs) of < 1 μg/m3 – also require much lower doses.
Antibody-drug conjugates (ADCs) are both highly targeted and highly potent and consequently have received significant attention from bio/pharmaceutical manufacturers. Contract development and manufacturing organizations (CDMOs) with established track records in the successful development, scale-up and commercialization of highly potent small-molecule APIs, biologic drug substances and formulated products are benefitting from the growing number of ADCs in development.
Highly Potent Market Expanding
The overall market for highly potent active pharmaceutical ingredients (HPAPIs) is expanding at a healthy pace, in large part due to ADCs. Some estimates suggest that approximately 25% of drugs on the market today are formulated with HPAPIs. The overall HPAPI market is predicted to be growing at around 10%/year.
Grand View Research estimates the HPAPI market will be valued at $25.86 billion by 2022. While small-molecule drugs currently account for the largest percentage of sales, the biologic segment, including ADCs, is the most lucrative and will grow at a high compound annual growth rate (CAGR) of 14.7% from 2015 to 2022. Increasing numbers of generic HPAPIs will drive growth in this segment as well. Regionally, North America currently accounts for the greatest percentage of sales ($4.5 billion in 2014), but the highest growth rate (14.0%) will be seen in Asia Pacific.
Most HPAPIs are intended as anti-cancer therapies (including ADCs), but there are many highly potent compounds developed for other therapeutic applications, such as diabetes, cardiovascular disease and central nervous system and musculoskeletal disorders. According to Transparency Market Research, there are currently nearly 290 small-molecule targeted therapies in development for the treatment of cancer. There are also large numbers of highly potent biologic drugs – including antibodies and ADCs, among others, that are in the pharmaceutical industry pipeline. Examples of HPAPIs that are not classified as oncology drugs include hormones, narcotics, and retinoids.
CDMOs are the Winners
The manufacture of highly potent compounds requires specialized facilities, equipment, operating procedures and operator skills and training. In addition, because of the limited doses required for HPAPIs, generally only relatively small volumes of these drug substances and formulated products are needed. As a result, investment by branded drug manufacturers, and particularly small virtual/start-up companies, in the high level of specialized equipment and expertise often is not economically practical. While some large pharmaceutical companies have invested in in-house capabilities, most have elected to outsource the development and manufacture of HPAPIs and formulated potent drugs to contract service providers.
Results of the 2016 Nice Insight CDMO Outsourcing Survey reflect this trend. Half of the nearly 600 bio/pharma professionals already utilize or plan to acquire specialized, HPAPI research, development and/or manufacturing capabilities from CDMOs. In addition, nearly 40% use or plan to use CDMOs for potent packaging activities. Drug manufacturers also rely heavily on CDMOs that offer specialized technologies for enhancement of the delivery of potent compounds (BCS Class II – IV compounds including peptides). The most popular services in this area are the development of controlled release formulations and excipients that enhance bioavailability. Specific production capabilities of interest include solvent-capable rotor and rotor-fluidized bed processing, plus Wurster column bead drying, layering and coating.
Roots Analysis identified 96 CMOs/CDMOs worldwide that are focused on HPAPI manufacturing; approximately 40% of their 130-plus production facilities are dedicated to manufacturing of both HPAPIs and cytotoxic drugs. Many have recently expanded their capabilities, including Capsugel, Idifarma, Labochim, Medichem, OPKO Health, ScinoPharm, WuXi PharmaTech and Fermion, among others. In fact, since, 2006, more than 100 investments involving the additon of new facilities and / or expansion of existing capacities have been made. In addition, the market research firm notes that over 15% of CMOs/CDMOs have established comprehensive services in order to support both HPAPI and formulated cytotoxic drug manufacturing. Examples include AbbVie, AMRI, Baxter BioPharma Solutions, CordenPharma and Fareva.
Challenges are Numerous Though
Not only the potency and cytoxicity of HPAPIs pose challenges to their manufacture. Their low dosages often require specialized formulating technologies; such as liquid fill hard capsules (LFHC) and soft gelatin capsules, to ensure that drug delivery occurs as appropriate.
Facilities must have controlled airflow (single-pass) and pressure systems with filtration capabilities, airlocks and vestibules around both laboratory and manufacturing suites. The use of isolators and automated handling equipment is increasingly common as a means for effectively minimizing the potential for exposure of operators and the environment to potent compounds. Industrial hygiene and extensive operators training programs are also essential.
Appropriate facilities, engineering controls and safety protocols are increasingly imperative as newer HPAPIs under development have ever declining OELs. These very low exposure levels create further challenges with respect to analysis and the need for ever higher levels of containment.
ADCs pose additional manufacturing challenges. Not only are both biopharmaceutical and chemical manufacturing capabilities needed, the ability to conjugate highly potent small-molecule APIs to biologic components is required.
As importantly, the conditions used to ensure safety and sterility conflict when producing these potent compounds. Sterility of biopharmaceuticals is typically achieved by using positive pressure to prevent any contaminants from entering the production area. When working with HPAPIs, however, negative pressure is utilized to reduce exposure to operators. One approach to this problem is to dissolve the HPAPI in a separate isolator in a different room that is under negative pressure. Once in solution the risk of exposure via airborne contamination is reduced, and thus the remaining production steps – conjugation of the payload to the antibody, purification and final formulation/filling can be performed in other areas under positive pressure.
It is also essential to ensure that no free small-molecule HPAPI remains in the final ADC product following conjugation of the payload to the antibody. Any residual HPAPI left in the product following the final purification step could pose a significant safety risk for patients.
For any type of HPAPI product manufactured in multiproduct facilities (i.e., CDMO production sites), the cleaning process is crucial for ensuring that no residual potent compound remains in the equipment; given their very high potency, even minute quantities as impurities in a different product can affect both its safety and efficacy. Comprehensive cleaning protocols and advanced analytical capabilities are therefore a necessity.
CDMOs providing support for HPAPI discovery and development work also must deal with significant uncertainties with respect to the potency of the new compounds they work with . Often there is insufficient data for early development compounds to assign a potency level. In these cases, CDMOs must assume that compounds are potent until additional toxicology data is available.
The lack of a consistent, industry-wide approach to assigning potency levels can also be confusing for CDMOs, some of which have developed their own proprietary systems that can conflict with those used by their customers. The continual performance of risk assessments as an HPAPI project moves through different stages of development and commercialization is essential to ensuring the implementation of optimal procedures and practices that will ensure the safety of workers and the environment.
CDMO Relationships Matter
Given the challenges of manufacturing highly potent, targeted APIs, and antibody-drug conjugates in particular, it is not surprising that drug manufacturers are selective in the outsourcing partners they choose for HPAPI projects. Not only are they seeking CDMOs that have the capacity and specialized capabilities, but those that have a demonstrated history of safely producing HPAPIs and formulated potent drug products in a timely manner.
Such companies have strategies in place for addressing discrepancies between their compound classification systems and those of their customers, particularly if there is overlap . Choices include opting for the customer’s risk assessment, whether higher or lower than the CDMO’s, or taking the most conservative value to ensure the highest level of safety, despite the fact that project timelines and costs will likely be higher.
CDMOs also need to have a demonstrated ability to estimate OELs for new chemical entities (NCEs) and intermediates with little toxicity information. Service providers with extensive experience in handling HPAPIs have a greater knowledge base to draw upon when considering issues such as inter-individual variability and the potential for is mutagenicity, genotoxicity, carcinogenicity and teratogenicity.
Increasingly, CDMOs that can provide the full range of support from early-stage development of HPAPIs through HPAPI and final drug product manufacture are seen as being advantageous for projects involving highly potent compounds. Integrated providers are also viewed as presenting lower risk due to elimination of the need for both physical product and technology transfer from one provider to another. Cost and time savings can also result, leading to faster times to market.
Relationships between pharmaceutical companies and CDMOs with HPAPI manufacturing capabilities and their equipment suppliers are also changing. Equipment manufacturers are challenged to provide easy-to-operate systems with simple but effective automation and controls that are robust and reliable and ensure the safety of workers and the environment and the purity of the product. Those goals can’t be achieved working in isolation. In fact, equipment manufacturers today do more than supply machinery. They are deeply involved in the development of solutions for their customers and assist with the implementation of projects that require the integration of many different pieces of equipment.
The highly potent API market is an increasingly important segment of the overall API market. The high capital investment and extensive expertise required for HPAPI and potent drug manufacture is driving the use of contract service providers. However, there are numerous challenges in manufacturing the highly potent APIs and formulated drug products in development today — particularly ADCs. The most successful CDMOs have a demonstrated track record of performance and collaborating closely with customers that has resulted in the building of trust — a key component of relationships surrounding highly potent projects.
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2. Grand View Research, Inc. “High Potency Active Pharmaceutical Ingredients (HPAPI) Market Worth $25.86 Billion By 2022.” October 2015. https://www.grandviewresearch.com/press-release/global-high-potency-active-pharmaceutical-ingredients-hpapi-market.
3. Transparency Market Research, “Rising Cost of Drug Development Leads HPAPI Manufacturers to Outsource Production,” March 30, 2016. http://www.prfree.org/news-rising-cost-of-drug-development-leads-hpapi-manufacturers-to-outsource-production-240256.html
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