Efficient development of optimal routes and manufacturing processes for the production of increasingly complex small molecule APIs requires extensive expertise, advanced equipment and technology, and a right-first-time mentality. Demonstration of these capabilities has resulted in growing demand and a need for continual investment at Alcami’s Germantown, Wisconsin facility.

Strong Demand

Despite much discussion of the growing importance of biologics in the pharmaceutical industry pipeline, small molecule drugs still account for the greatest percentage of drug sales and make up the greatest percentage of drugs in development today.1,2 As a result, the global small molecule active pharmaceutical ingredient (API) market is expanding at a rate of approximately 7.0% per year from 2016 to 2027 to reach a value of $279.7 billion, according to Cooked Research Reports.3

In 2016, Mordor Intelligence estimated the value of the global pharmaceutical contract manufacturing market to be $65.1 billion, growing at a CAGR of 6.35% to reach $94.38 billion by 2022.4 The growth in demand for highly potent APIs (HPAPIs) is contributing to this strong growth of the small molecule API market. Markets and Markets predicts that the global HPAPI market will reach $24.09 billion by 2021, rising at a compound annual growth rate (CAGR) of 8.5% from 2016 to 2021.5 HPAPIs are particularly challenging to manufacture, as they require highly specialized facilities, equipment and personnel. The extensive capital investment needed to establish safe and efficient production processes is an important factor driving outsourcing to contract manufacturing and development organizations (CDMOs). 

Outsourcing is particularly driven by small and mid-sized pharmaceutical companies, which account for a large portion of new drug discovery efforts. These companies have limited resources to pursue development and commercialization of their promising candidates. CDMOs that offer integrated services and can tailor their advanced technologies and supply chain solutions to their specific customers are needed to facilitate development and reduce time to market.

Right-First-Time Mentality

Driving a predictive approach from the start of each project, rather than remediating process issues after the fact, accelerates development of optimum processes that afford cost-effective and highly efficient production operations. At Alcami, rather than focus on just the empirical results, we focus on the intent and purpose of each process to understand all of the relevant factors. Predicting which parameters may impact process performance is a critical, yet often underemphasized, step in development. We then apply a design of experiments (DoE) approach, in conjunction with techniques such as principle component analysis, to establish the process design space. Having a predictive DoE model allows us to identify optimal and robust processes very early on. Often such an approach is viewed as cost and time prohibitive — and thus limited to use at later process development and commercialization stages. However, a risk-based approach to determine where such studies are most value-added, coupled with our use of automated parallel reactor platforms, mean we can execute these studies quickly and with minimized cost implications, even in the early clinical phases. 

Customers are integrated into the governance process as much as possible, from the very earliest development stages through commercialization.

As an example, a recent customer project involved a cryogenic reaction where purity profile and, ultimately, yield were known to be influenced by a number of different factors. Often with such reactions, the assumption was colder was better for purity control. However, through the use of DoE, a predictive design space model was able to be created, and the chemistry team was able to show what the predicted optimum of the multivariate conditions was, and then verify it in the lab. This led to use of a higher-than-expected optimal temperature range on scale. Modeling of the reactor system heat transfer from small scale calorimetry experiments was then used to establish the most effective engineering controls, such as an automated flow meter, to control the addition rate to maintain the ideal temperature range. This effort translated into a 20% increase in the yield of the key intermediate.

Focus on Solid-State Chemistry

Knowledge of the solid-state characteristics of solid small molecule APIs is crucial to the development of their safe and effective formulated final product. Successful and consistent oral solid dosage formulations are inherently dependent upon the physical properties and solid-state characteristics of crystalline compounds.

The right-first-time approach to solid-state chemistry has led us to broaden our focus from primarily polymorphs to crystal habits. While the polymorph of a compound has an impact on the performance of the formulated product — mostly due to variable solubility and, therefore, bioavailability — formulation performance is more directly impacted by crystal habit. Crystal habit may or may not be tied to polymorph, but it will impact things such as particle size distribution, bulk density and compressibility. These are classic factors in solid oral dosage formulation, and inconsistency in these API attributes can lead to variable formulation results in things such as tablet friability or content uniformity.

An extensive full-factorial DoE was conducted in order to gain an understanding of what crystallization conditions controlled crystal habit for a specific API. It was found that there were not only primary interactions of cooling rate and concentration, but secondary interactions of solvent denaturant concentration and water content that dictated the crystal growth patterns. Without the use of a high-resolution experimental design, it would not have been possible to understand the interplay of so many factors. Experience is key in first establishing where to look, and the experimental design is key in how to look.

Growing Center of Excellence

The Germantown, Wisconsin API production facility was established in 2004, first expanding in 2009 and again in 2013, when a new commercial production bay containing seven reactors was added as well as the addition of the new administrative center. In September 2017, we formed a Center of Excellence for API development, scale-up and commercialization at the facility.

This right-first-time approach has allowed Alcami to provide its customers with consistent and continuously improving results. The resulting increased demand has been driving the need for continued investments to increase throughput and capacity, including new drying and isolation equipment. We have also invested in the facilities and equipment needed to produce controlled substances, and in June 2017, received a Drug Enforcement Agency (DEA) Bulk Manufacturer registration to complement our Analytical and Researcher registrations. We now have the capability to develop and manufacture up to Schedule I and II products, respectively.

Combined, these investments are part of our commitment to provide customers with seamless, efficient end-to-end small molecule services, enabling them to execute all parts of API development and manufacturing in one US-based location. In addition, we will be using the API Center of Excellence as a platform to further advance our approach to control strategy at each phase of the development process, through a series of investments targeted at infrastructure, workforce, tools and technology. The goal is to accelerate drug substance and product development, risk quantification and management, and the design, scale-up and commercialization of quality manufacturing processes for our customers, all from our location in Germantown.

Perhaps most exciting is the completion of investments to expand our capability for HPAPI manufacturing. The facility was designed to be highly flexible, as the Germantown site is a multiproduct production campus. Flexibility under high containment conditions is a real challenge. Our approach was to include multiple levels of containment within each suite to allow the use of a mix of portable and fixed pieces of process equipment — affording the ability to run hydrogenations, cryogenic chemistry, distillations and isolations. A mix of glass-lined and Hastelloy reactors are included to ensure the ability to handle a broad range of chemistries. As a result, we are able to rapidly set up a suite for many different types of operations.

Two state-of-the-art cGMP production suites equipped with engineering controls designed to meet or beat the established Occupational Exposure Limit (OEL) of minimally 0.03 μg/m3 (SafeBridge® Category 3) will be operational in Q4 2017. Alcami now has the capability to support projects involving highly potent compounds from development through commercial production, eliminating the need for customers to transfer their projects from one facility to another.

We are already preparing for process validation to support the potential commercial launch of an HPAPI at the site in the new suites. Overall, the process, operational and technology enhancements Alcami has made across development, clinical and commercial manufacturing have increased our production capacity by over 50%. Investments are also ongoing to increase automation capabilities for more efficient high-throughput reaction screening, which will enable more rapid and cost-effective use of DoE. We have also been investing in process analytical technology, such as our new focused beam reflectance measurement (FBRM) probe, to allow real-time monitoring of crystallization or milling processes and thus enhanced tracking of crystallization kinetics and growth and particle sizing during full-scale manufacturing.

Well-Received Approach

Having a robust development approach and process control strategy, coupled with state-of-the-art equipment for containment, process monitoring and automation, positions Alcami to provide customers with optimum synthetic routes and production processes for their small molecule drug substances. Customers appreciate knowing that Alcami has a control strategy in place across all API-related activities. This approach is also applied across the broader Alcami organization, thus leading to a much stronger supply chain, ensuring critical clinical milestones are met and commercial supply is maintained.

References

  1. Agnes Shanley. “Stronger Pipelines And Approvals Drive Small-Molecule APIs And CMO Opportunities.” Pharm. Tech. 31 Mar. 2015. Web.
  2. Jim Miller. “Small-Molecule API CMOs Are Thriving.” BioPharm International 28.10 (2015): 10-12.
  3. Global Small Molecule API Market Research Report — Forecast to 2027. Rep. Market Research Future. Aug. 2016. Web.
  4. Global Pharmaceutical Contract Manufacturing Market — Growth, Analysis, Forecast To 2022. Rep. Mordor Intelligence. Jun. 2017. Web.
  5. 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. Rep. Markets and Markets. Jan. 2017. Web.