1. What, in your opinion, is the single largest trend with respect to high potency APIs?
ML: From my perspective, High Potency APIs have been exhibiting a continued growth in its market. My professional experience and focus has long been on Active Pharmaceutical Ingredients and the need for their Production, Distribution, and Quality to meet the intention of the internationally accepted API GMP. This growth, in the market and its producers, is the single largest and important trend that deserves attention by all players in this field.
More compounds of concern continue to be developed in both the synthetic chemical and biopharmaceutical arenas. High potency APIs offer the benefit of requiring lower amounts of compounds to be produced. However, these new HPAPI are not only highly potent, but are also potentially harmful when present, even at very low levels, in another product. This very risk is historically associated with the unexpected presence of penicillin type antibiotics or other sensitizing compounds being present in other products as a cross contaminant.
From my perspective, as one focused on regulatory compliance issues, all high potency APIs must be produced under conditions that protect any API substances from contamination and the inadvertent carryover of a different product being previously or simultaneously manufactured. While todays modern HPAPI facilities are meeting today’s requirements, I see a growing need to improve these technologies. To accomplish this task, I see a continued need to focus on the development of production and handling methods that will be either single-use systems and/or new technologies which can continue to improve upon today’s product protection of the API from cross contamination from other HPAPI produced at the facility or site. Such protection systems must focus on cleaning and removal systems utilized for such product protection purposes.
Multiproduct facilities pose the greatest risk to exposing one API to another high potency API. This growth in the HPAPI, the producers and the plants around the globe are creating many new players from even new countries. As the mix of manufacturing sites and countries keep changing, regulatory risks will continue to grow because it will become more expensive and difficult for regulators and drug product manufacturers to keep a close watch on API producers.
JB & KB: As a secondary processor of High Potency APIs (HPAPIs) i.e., dosage form scale up and manufacturing, the single largest trend we see at Alkermes Contract Pharma Services is the need for high containment technologies to safely handle and manipulate these materials. The number of HPAPI-products requiring lower Operator Exposure Levels (OELs) is increasing, resulting in containment challenges for equipment manufacturers who are trying to design and implement solutions requiring very high levels of containment.
EM: The only way is up for the multi-billion dollar high potency API (HPAPI) market. Continued growth is certain as translational science continues to evolve and identify more molecular targets specifically expressed or associated with certain pathophysiologies, diseases and conditions.
Currently, the majority of HPAPIs are anti-cancer products (cytotoxics and cytostatics). However, other HPAPIs include therapeutics such as hormones, narcotics and retinoids. Whilst we initially think of HPAPIs as chemically derived products, biological therapeutics – such as monoclonal antibodies – are also HPAPIs by their very nature.
Surveying worldwide and company-wide development pipelines, the area of oncology will clearly continue to dominate the types of HPAPI molecules coming through clinical trials to market launch. Not only is oncology the largest therapeutic area by far in terms of revenue generation for pharma, it is also one of the fastest growing, estimated at over 7% growth year on year for the next six years.
Our own experience as a Contract Manufacturing Organization (CMO) reflects this trend, and over the last few years we’ve seen a rising demand for the development, manufacture and handling of HPAPIs New Chemical Entities (NCE). This has primarily been within the area of anti-cancers but also in cancer-related treatments such as pain relief medication.
Interestingly, a significant proportion of these projects are being outsourced from big pharma. This represents a move away from previous API outsourcing habits, since historically big pharma would keep its cards close to its chest when it came to outsourcing NCE, on-patent products. However, the resource demands and level of specialization needed to manufacture relatively small volumes of HPAPI means that often it isn’t economically viable to keep this in-house. To that end, we’re seeing definite growth in demand for manufacturing of HPAPI destined for use in on-patent products. EvaluatePharma, Embracing the Patent Cliff World Preview 2018, June 2012
2. What are the market challenges to working with high potency APIs?
ML: Working with high potency APIs include a number challenges. These include not only the safety of employees and the protection of the environment, but the protection of the API themselves from contamination or cross contamination from other HPAPI made in the facility or the site. This risk can come from both previous and concurrent operations. Most firms do not have the luxury of a dedicated plant which increases the risk of contaminations. Expanding and developing the use of new technologies will continue to have a benefit in reducing these risks.
An additional challenge occurs when using a CMO or a custom supplier which has multiple customers with various different compounds being produced. It is critical to be able to assure that cleaning and isolation of these other materials is properly implemented within accepted GMP conditions to prevent any potential GMP or regulatory issues from developing.
JB & KB: There is significant expense involved in setting up a pharmaceutical manufacturing plant to manage high containment processes, particularly since the equipment tends to be quite expensive due to its bespoke/customized nature. However, as the sector becomes more established and equipment manufacturers develop more flexible systems for use in secondary processing of highly potent compounds, it is likely that platform prices will be driven downwards.
EM: Whilst the HPAPI market represents an attractive proposition within the pharmaceutical industry, it remains a relatively ill-defined area for contract manufacturers in terms of the level of future demand. What adds to the challenge is the lack of a universally accepted definition of high potency substances.
The fact that each pharma company has its own preferred method of classification, be it SafebridgeTM, an adaptation of SafebridgeTM or a company’s own proprietary system, all adds to the ambiguity around the market. Nevertheless, a general rule of thumb is an Occupational Exposure Limit of 10μg/m3 or less, should such data be available for a development candidate. However, CMOs are being asked to develop APIs that do not have all the data necessary to classify (or not) as an HPAPI. In these instances, careful judgment and risk assessments are made based on the pharmacology, any known selectivity data and any early toxicology data like positive chromosomal aberration and mutagenicity tests. With no single way of categorizing levels of API manufacture in the HP arena, and a lack of reliable statistics on the precise level of demand for high potency API in bulk drug substance level, manufacturers face a major challenges trying to assess future interest in the marketplace.
SN: A decade ago, the ability to handle high potency APIs was a differentiating capability in the market place. In recent years, however, there has been significant expansion by vendors to support the rapidly growing oncology drug market resulting in increased competition. This has driven vendors to differentiate themselves. For example, a percentage have contracted with a third party such as SafeBridge TM to certify their high potency operations and advertise themselves accordingly. Another direction, and one that Aptuit has implemented, is to possess both high potent API and drug product capabilities within their organization. This brings some operational synergies but more importantly convenience to customers. As competitive pressures continue to increase with more vendors, the high potency API market will reflect more and more the “normal” API market, where a demonstrated track record and experience will be critical to partner selection.
3. Is there a market or region of the world that is currently growing or increasing their expertise and market share in high potency APIs?
JB & KB: There are a number of regions that now have collective experience and expertise in HPAPI handling. Germany and Switzerland for example, have increased their output over the past number of years at the primary API processing level. In the area of secondary processing, several companies in Ireland are now actively engaged in development and/or commercial scale production of pharmaceutical products using HPAPIs. At Alkermes Contract Pharma Services European facility in Ireland, we have increasingly seen greater demand for our HPAPI capabilities in secondary processing, from those companies seeking to outsource their dosage form development and manufacturing requirements. Naturally they are seeking a Contract Manufacturing Organization (CMO) with a track-record in secondary processing of high potency product, with systems and procedures in place to handle low OELs.
EM: In terms of consumption of pharmaceuticals in general, Asia and the Pacific (ASPAC) are the fastest growing markets, primarily due to the rising healthcare standards within the region, especially in China and India. In particular, the Asia Pacific market for oncology drugs – which could be roughly translated to HPAPIs – is growing extremely rapidly.
In parallel, the number of manufacturers of API and Drug Products is also rising. However, this doesn’t necessarily mean that confidence in HP outsourcing to ASPAC is growing at the same pace.
Perceived adherence to quality and safety guidelines still influences the decision as to where HPAPI are produced, and companies looking to outsource are understandably sensitive to potential risk, either real or perceived, to their IP or personnel safety. This is something that API players in the East will be addressing in the next five to ten years in order to fulfill their HP potential in the long term.
Although Asia Pacific is increasing its global market share, the market leaders within the field of high potency API remain North America and Europe. The North American industries dominate with a majority market share, while Europe has historically occupied around a third of the market. Until a universal or at least a more consistent global safety and quality standard is introduced across all territories, we believe the West will continue to dominate in the HP space.
4. Where do you see the market for high potency APIs in 5-10 years?
ML: I see the HPAPI market continuing to expand over the next five to ten years. I believe this growth will be driven by technology developments that create ever increasing numbers of drugs that have higher pharmacological activities than exist today.
Competition among firms and economic changes between world regions will further create the implementation of new facilities and technologies. Facilities can be expected to be built in locations that offer better economies for labor, energy, and application of new technologies. Sites and firms that can stay at the forefront of HPAPI will benefit the most. Today, single-use technologies may appear unfeasible for small molecule synthetic API; however, new materials of construction, new engineering designs, and or new scientific developments may greatly enhance the feasibility of single-use vessels for running chemical reactions. Such a development could provide the industry with the ability to fully contain and eliminate the risk of cross contamination due to cleaning system and procedure failures.
JB & KB: Approximately 25% of drugs in development worldwide are classified as high potency and this percentage is expected to grow according to industry sources. With this increase in high potency products, greater production capacity will be required. However the days of having fully dedicated facilities for one product are coming to an end and therefore the need exists for highly contained yet flexible modular processing suites that can be designed to safely handle HPAPIs at a commercial scale. To support the challenges of dealing with products with low OEL, companies are becoming more demanding of containment equipment manufacturers. Flexible containment solutions are now being sought by companies to help address their needs and this is a trend we expect to continue to grow over the next few years.
EM: As we’ve discussed, the HPAPI market is growing year on year, with the main segment of growth being the development of oncology treatments. If forecasts are to be believed, the oncology segment of the pharma industry will significantly outpace other therapeutic areas and go from a value of $64bn in 2011 to $104bn in 2018.
This will have a huge impact on the API market in general. Historically, big pharma outsourced API production for more established products, especially those suffering from generic erosion, and managed newer, on-patent API in-house. However, if the current significant development focus on HPAPI continues to demonstrate greater efficacy and reduced side effects over currently marketed products, HPAPIs will likely become one of the dominant areas in the marketplace. Consequently, this will mean more HPAPI manufacture will have to be outsourced in order for large pharma brands to remain competitive.
Looking forward, it will be key that CMOs continue to focus on safety for our manufacturing personnel, minimize any potential for contamination and provide cost-effective and efficient solutions when manufacturing relatively small campaigns of HPAPIs.
SN: While continued expansion is anticipated by all, it may be greater than anticipated as there are more market drivers than just oncology, for example, increased health and safety concerns and more specific drugs. With respect to health and safety, more organizations have as a default position that containment be used when there is limited toxicological information or a new target is being pursued. It can be expected that this trend will continue. Similarly, an increasing portion of APIs under development display increased specificity, requiring containment to be safely handled.
5. Any additional or closing thoughts on the topic?
ML: Those of us that have been involved with the drug industry for many years have witnessed and experienced almost every conceivable scenario. My own experience does confirm that history can and will likely repeat itself. Major migrations to developing countries or regions, low cost labor, energy, or raw materials will always attract manufacturing. The firms and locations with the newest and most cost effective operations, with technical talent to be a leader, will get the first opportunities to attract business. In the drug field, exhibiting the proven ability to produce high quality and pure conforming products will gain market share. Ultimately firms and countries that exhibit a lack of ethics or safety for consumers eventually lose business to the more reliable producers.
Challenges and regulatory risks associated with classical API are actually increased by the additional high potency API manufacturing requirements. The HPAPI business, it manufacturers, and its customers will face increasing regulatory challenges which will need to be answered, in my opinion by the development and application of new technologies. Without this happening, this will be a costly field in which to participate.
JB & KB: Use of HPAPIs in the manufacture of pharmaceutical drug products will become much more evident in the next five years. Training and experience levels of people involved in the handling of HPAPIs will be critical to successfully managing the demands of those seeking secondary processing of highly potent compounds. At Alkermes Contract Pharma Services European facility in Ireland, we are introducing a graduate program onsite whereby our operators will be specifically trained on the handling of HPAPIs. We have also found a significant advantage in establishing a well-designed risk management system to consistently assess the activities involved in bringing a contained product on site. Another trend we expect to see is an increase in high-potency, high-dose compounds requiring manufacture to final dosage form. Manufacturing providers will need to be able to efficiently and cost-effectively produce this next wave of compounds coming through development. Having an established track record in dealing with the current high potent, low dose products will help prepare CMO providers to advance their expertise onto the more challenging high-potent, high-dose compounds that will likely require contract manufacturing in the coming five to ten years.