Oncology continues to grow as a disease area of focus at almost all innovator firms, with investments in both drug discovery and development, predominantly driven by the unmet needs of patients. The principal need for most cancers is the availability of safe and effective targeted drugs that treat the advanced stages of the disease, when patients often stop responding to chemotherapy. Interest in high potent drugs that can treat cancers have followed suit, as they can play an important role in achieving those objectives. The percentage of drugs classified as “highly potent” with occupational exposure limits (OELs) = 10µg/ m3, has been progressively increasing, and is currently estimated to be 25% of the global pharmaceutical development pipeline.
Market size and drivers for growth
New Chemical Entities (NCE’s), particularly those intended for use in oncology, are now designed to be highly selective in their interaction with biological targets, with pharmacological activity often being achieved with very small amounts of the active ingredient. These high potent NCE’s also are active for a longer duration in the body, thereby reducing the dosing frequency required, while potentially increasing patient compliance and minimizing discomfort. Finally, since these compounds are much more selective towards the target of interest, they can reduce side effects, and minimize damage to the tissues surrounding the diseased area. Due to these reasons, targeted, potent therapies offer significant benefits over their lower potency counterparts. In addition, within the oncology market, a niche market segment is Antibody Drug Conjugates (ADC), which are cytotoxic small molecules linked to monoclonal antibodies. ADCs, certain oncology drugs, and other high-potency compounds (such as hormones) require high-containment manufacturing. The anti-cancer market with its unprecedented growth is the engine that fuels the High Potency Active Pharmaceutical Ingredients (HPAPI’s) market, since 60% of highly potent APIs are targeted towards oncology. The global HPAPI market, which was $12.6 billion in 2014, is projected to reach $25.1billion by 2023, at an estimated CAGR of 7.8%.
This growing demand and explosive growth has in turn led to an increased demand for HPAPI production. Firms with existing HPAPI capabilities have been busy expanding their facilities, while many without, have sought to acquire existing businesses or add HPAPI capacity. In this article, we provide the various classifications under which high potency compounds are categorized, review regulatory requirements that govern manufacture, discuss the HPAPI manufacturing landscape, and finally, review the recent market activity in this area.
Categorizing compounds based on potency:
A compound is generally defined as highly potent if it has:
• an occupational exposure limit (OEL) of =10 µg/m3,
• a daily therapeutic dose of =10 mg/day or
• a 1 mg/kg/day dose produces serious toxicity in laboratory animals.
OEL is the maximum permissible concentration of a hazardous substance in the workplace air so as to ensure health and safety of the people engaged in work. OEL levels define the threshold that a physically fit individual can be exposed to in an 8 hour work time. However, there is a high level of uncertainty associated with each compound.
Most new developmental products do not have the toxicity information available. Often companies work on products where it may be difficult to determine the potential risk of exposure. At present, there is no official guidance for the safe handling of highly potent compounds.
Most companies have a banding system that categorizes compounds based on their toxicity and this dictates the handling containment required to work with the compound. Often companies can determine an exposure limit of a known compound based on the lowest therapeutic dose, but many other factors have to be considered, including the form of the API (liquid or powder), the formulation process and the frequency of contact.
To add some structure, in recent years, several systems have been proposed for categorizing drug substances according to their potency, based on the use of occupational exposure limits (OELs) or occupational exposure bands (OEBs). There are currently two commonly used programs—a five-tiered system such as the one used by Merck & Co., and a more frequently used four-tiered system devised by the industrial hygiene consultancy - SafeBridge. A description of both these systems is given in the tables below.
SafeBridge system is now widely accepted among CMOs. SafeBridge’s system involves ranking a compound for potential potency and toxicity on a scale of I to IV. Category I covers low-irritant drugs, while Category II, currently the largest, includes drugs that can cause organ toxicity. Category III is the first tier of potent drugs that cause genetic effects plus organ toxicity, and finally, a tier Category IV, of the most potent compounds.
It is essential that there exist a well-defined framework for HPAPI classification as any confusion or mistakes while classifying compounds could have a significantly detrimental effect on safety.
Regulatory and manufacturing guidelines
Handling, containment, manufacturing, facility design, machinery and regulatory requirements of these compounds are more stringent and different from conventional APIs.
In general, good manufacturing practices (GMP) apply to the production of highly potent and cytotoxic compounds. The only regulatory body to have flagged up the importance of bringing in updated guidance for safely dealing with HPAPIs is the European Medicines Agency (EMA). In 2005, EMA (European Medicines Agency) published a concept paper on HPAPIs, though it was mainly focused on high potent product segregation rather than classification. The concept paper primarily addressed the need to update GMPs and have better clarity on classification systems in order to determine requirements for working with specific compounds. In 2011, EMA introduced another concept paper mentioning the requirement for a toxicological tool and a risk-based scientific approach to establish exposure limits. Thenin January 2013, EMA published a draft guideline on setting health based exposure limits. The primary purpose of this guideline was to advocate the assessment of pharmacological and toxicological data of individual active substances, which would allow establishment of safe threshold levels as mentioned in the GMP guideline. Around the same time, the EU came up with proposed amended text for managing the concern of cross- contamination in chapters 3 and 5 of GMPs.
There are cGMP guidelines from other regulatory bodies such as FDA and others for Japan, Switzerland, India and China but they do not address the issue of occupational health hazards.
FDA also recommends risk based assessments in this field. However, the guidelines issued by the organization only deals with cross contamination issues associated with the production and not on worker protection.
Manufacturing HPAPI’s: Captive and contract
Manufacturing HPAPI is a complex process, and involves manufacturing and processing in clean room operations with containment facilities. In most instances, special safety considerations for employee protection and facility design are required when dealing with highly potent API’s. These processes are generally carried out at negative pressure to prevent materials from entering the environment, with workers wearing full protective gear. This differs from the containment requirements at manufacturing units of traditional APIs.
HPAPI manufacturing requires significant investments (in millions of dollars) over and above that of conventional API manufacturing. These include appropriately designed facilities, with the necessary engineering and containment controls in place to handle potent compounds, as well as requiring highly trained and experienced staff to ensure safe and contained operations.
Innovator firms have developed strategies that suit their needs best. Larger pharmaceutical firms, that have several clinical programs ongoing in high potents, may choose to invest in captive capacity to address their needs. Mid-size and smaller firms on the other hand have focused on utilizing Contract Development and Manufacturing Organizations (CDMO’s) and Contract Manufacturing Organizations (CMO’s) to drive their programs forward. Lack of an in-house manufacturing facility and absence of internal expertise are the primary drivers that encourage these firms to outsource to (CDMOs). Irrespective, we expect all innovators to eventually utilize CDMO’s/CMO’s to fulfill some aspect of their HPAPI needs due to the flexibility, and cost efficiency that these providers offer.
Furthermore, CDMOs/ CMOs providing contract HPAPI manufacturing services must be prepared to adopt, improve, and/or implement new protocols, equipment, training, and technologies to meet the ever-rising bar for risk reduction and regulatory compliance in HPAPI manufacturing. Continuous improvement is essential to sustaining safe operations, mitigating risk, and attracting client opportunities
CDMOs come in different shapes and sizes with respect to the services they offer, from integrated providers that offer a suite of services, to those with expertise focused exclusively in a single area. For example, some CDMO’s can offer both HPAPI and also the ability to formulate the drug product at scale. Other CDMO’s prefer to build a deeper vertical around a single offering- for example, the ability to go to significantly low OEL levels. The industry has also witnessed multiple strategic collaborations between client firms and CMOs wherein a few chosen/preferred suppliers service most of the development and manufacturing requirements of the client.
With HPAPI manufacture, there are certain key factors that innovators need to consider as they evaluate the build vs outsource decision.
• Large capital investment.
• Absence of an official guidance on safe handling of highly potent substances by pharmaceutical regulatory bodies
• Stringent need for specialized equipment and facility design with containment controls
• High investment required prior to NDA approval– coupled with the difficulty to predict commercial success
• OEL/Toxicity not confirmed until very late in development, it is a late phase decision
• Assumption of highest level of containment in early clinical development due to absence of data
There are the preferred features for CMOs having HPAPI capabilities:
• Exemplary track record of safety and regulatory compliance
• Robust Environment, Health & Safety (EH&S) practices
• Ability to provide both development & manufacturing services to avoid tech transfers
• Proper engineering controls and cleaning procedures to prevent cross- contamination
Many life science firms developing potent small-molecule drugs prefer to use a HPAPI manufacturer in the U.S. Or Europe that has a sustained and exemplary track record for safety, regulatory compliance, and a successful audit history when working with HPAPIs. The ability to support both the development and commercial manufacture of highly potent compounds in order to avoid any need for process transfers is also often preferred. The demanding nature of HPAPI manufacturing requires careful scrutiny of the potential CMO/ CDMO partner’s chemical hygiene and environmental, health, and safety (EH&S) programs as well as an understanding of their commitment to HPAPI manufacturing, and continuous improvement. When it comes to HPAPI manufacturing, there is no middle ground – it is “all in” or nothing.
HPAPI deals and investments
An expanding list of contract businesses are strengthening their offering by investing
in or acquiring high potent drug substance/drug product capabilities.
Strategy is a combination of either
• Entering/expanding HPAPI footprint (higher potency, getting into Hormones etc., expanding capacity etc.)
• Adding capabilities to become more integrated (drug product addition for an API firm and vice versa) Some recent activities are summarized below.
These activities indicate that HPAPI facilities are predominantly located in the West, mainly in the US followed by countries like UK, Germany, Switzerland, Italy etc. This is due to the fact that most clients prefer to outsource HPAPIs to suppliers in the West due to perceived superior quality and safety track records. Proximity to the CMO is an additional factor while deciding to outsource HPAPI since they will seek better control over development and manufacturing activities.
Conclusion
HPAPI manufacturing is a capital intensive process that requires technical expertise and state of the art manufacturing facilities. Although there are guidelines for segregation of high potent products, it is vital that there exist an industry wide approved framework for HPAPI classification. This eliminates ambiguity related to compound potency, especially when a pharmaceutical company is planning to outsource the manufacture of HPAPIs to a CMO. Additionally, regulatory bodies need to address the issue of occupational health hazards and worker protection for the manufacture of high potent APIs
High potency needs are expected to grow due to growthin oncology and the need for selective targeted therapies Despite innovator’s captive capacity, outsourcing in this segment is expected to grow at close to double digits driven by mid-size, small-size, and virtual firms. CDMO partners with a track record of HPAPI development and manufacture, a clean safety and compliance record, proximity to innovators and a long term commitment to service business can expect to benefit from the growing market.
At Piramal, we are focused on building an integrated platform with leadership capabilities in each element. With our state- of-the-art ADC facilities, our fill finish/aseptic capabilities, we are now focused on adding HPAPI manufacturing capabilities, to offer clients an integrated solution that includes both drug substance and drug product. We expect to continue to invest in those areas that address our clients’ future needs.
(The author is CEO at Piramal Pharma Solutions)
(Courtesy: CPhI Pharma Insights)