Meeting Unmet Patient Needs with Small-Volume APIs

At the invitation of Pharma’s Almanac, Dr. Stephen Munk, CEO of Ash Stevens, discusses the need for CDMOs with specialized, small-volume manufacturing capabilities that will support the industry as it moves towards a more personalized and precise approach to treating disease. 

Personalized medicine, precision medicine, evidence-based medicine and patient-centered outcomes research dominate the landscape today and are driving the need for significant change in manufacturing strategies. Pressure is mounting to accelerate the development and commercialization of novel drugs with greater efficacy than current treatments, while also increasing their quality and safety. Competition from generics/biosimilars is also growing, and the age of the blockbuster is passing.

Fortunately, advances in personalized and precision medicine are creating numerous opportunities to improve the quality of life for patients with unmet medical needs. Greater understanding of diseases mechanisms and genetics, combined with innovative manufacturing technologies, is leading to the development of novel treatments and diagnostic tools. Increasingly potent, targeted therapies are, in particular, attracting attention due to their greater efficacy at lower doses and with reduced side effects. 

 FDA provides strong support for the rapid development of these novel drugs through the use of Fast Track and Breakthrough Therapy Designations and Accelerated Approval and Priority Review processes. These designations are attributed to drug candidates with good preclinical and/or clinical data demonstrating novel mechanisms of action, or that the therapies are more efficacious than the currently available standard of care. The Orphan Drug designation, meanwhile, provides advantages to drugs intended for the treatment of a disease affecting less than 200,000 US citizens and encourages the development of small-volume products. These special designations therefore provide tremendous benefit for both patients and the advancement of the scientific community’s understanding of underlying disease mechanisms and therapeutic interventions.

The shift to personalized medicine and growing interest in orphan drug development has created a need for contract development and manufacturing organizations (CDMOs) that have capability for small-volume manufacturing of very specialized drug substances, including highly potent active pharmaceutical ingredients (HPAPIs). Technical competence in the validation of production processes and analytical methods, often under accelerated timelines, to ensure preparation of a complete regulatory package for filing, is essential. 

Awareness of Process Safety Issues

With increasing pressure to deliver faster turnaround times and lower manufacturing costs, there is impetus to deemphasize the need for comprehensive process safety evaluations and accept greater safety risks. Inattention to process safety can, however, lead to devastating consequences. To conduct safe manufacturing processes, an effective process safety strategy and process safety management system are needed within a culture that emphasizes safety. 1

Prior to acceptance, proposed projects must be evaluated to determine whether the capabilities of the CDMO are compatible with the capabilities and staffing of the CDMO, and only those projects for which suitable facilities, equipment and skilled personnel are available should be accepted. From a process safety perspective, once a project is initiated, both theoretical and experimental analyses must be conducted to determine the thermodynamic and kinetic properties of all materials involved in the process and the process itself, both under normal and worst-case scenario conditions.

Implementing Advanced Quality Initiatives

Many Life Science companies developing drugs are looking to apply the principles of Quality by Design (QbD) to their manufacturing processes to better comply with current regulatory guidelines for QbD with the anticipation that QbD will become a requirement at some point in the future.2 

FDA guidelines provide a structured framework anchored in statistical methods to provide accurate understanding and control of pharmaceutical manufacturing processes. Implementing QbD services can be expensive for CDMOs, requiring new equipment, statistical support and the training and/or hiring of personnel. Although QbD remains a guideline and not a regulatory requirement, the momentum is in the direction of more QbD work for CDMOs as drug developers try to get out ahead of the regulatory curve. 

For Ash Stevens, the early adoption of a QbD approach has contributed to the company’s extensive track record for commercialization of APIs and continues to facilitate accelerated approvals. The use of a practical qualification strategy also enables Ash Stevens to efficiently validate the processes it develops following QbD principles.3 Appropriate preparation and planning ensures that all central issues are identified and surprises during validation are minimized. Experience with the latest guidelines also means that Ash Stevens can address the issues of importance to the various regulatory agencies.


Facilitating Process Development

While initial laboratory syntheses are focused on making enough of an API as fast as possible for preclinical testing, process development focuses on multiple aspects for process improvement. Effective process development and optimization is most efficient when integrated with scale-up and cGMP manufacturing operations. CDMOs with integrated capabilities from early-stage drug substance development through commercial manufacturing can potentially effect a smoother transition from the laboratory to commercial manufacturing, streamlining the process, reducing complexity and building process knowledge. These benefits are particularly realized when key stakeholders, such as process chemists and engineers working on the project, transition with the process through the various stages of scale-up to ensure the tech transfer proceeds seamlessly.

Accelerated Capabilities

Drugs with Fast Track or Breakthrough status place even more pressure on a CDMO to rapidly scale processes to expedite the delivery of potential new therapies to patients. Here especially, a well-integrated team of engineers and process chemists are essential to bringing the process online and meeting accelerated timelines.

In general, scale-up must be achieved without changing the manufacturing
process used for the production of pre-clinical/toxicity testing quantities, in order to avoid any delay in the initiation of clinical trials. It is therefore important to improve the efficiency of the laboratory process with respect to process cycle times, waste minimization and yield.4 Increasing the productivity of kilo-scale processes for clinical trial material can also be an important factor for accelerating the development of a Fast Track drug.

It is also important to recognize that because the timelines are reduced, clinical trials involve fewer patients and the quantity (number of batches) of manufactured material that is subjected to testing is fewer. As a result, there is generally less time to gather full information about how the process can potentially impact product API quality, which can present challenges when it comes to qualification of process performance as regulatory agencies do not permit a less well-developed CMC section of the NDA. At the same time, the margin of error is much slimmer than what is acceptable for a standard drug candidate. CDMOs must work closely with the drug sponsor and FDA to identify and mitigate any potential issues before they arise. 

Experience with the development of comparability data that can be used to relate initial analytical data, with data obtained using validated methods developed for process performance qualification and specification determination, is very important. The use of a QbD approach and early determination of critical quality attributes can help ensure that analytical methods developed under accelerated conditions still allow for the demonstration of process and product control.

HPAPI Expertise

HPAPI manufacturing requires much higher investment in specialized facilities and equipment than CDMOs, which provide traditional API manufacturing services. These CDMOs must also 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.4


Finding a CDMO that can meet all of the above criteria can be a real challenge. To date, Ash Stevens has received fourteen FDA manufacturing approvals for innovator APIs, including four Fast Track projects. With a business model predicated on providing the safest and highest quality work product possible, while meeting delivery obligations on budget and on time, combined with the ability to provide expert regulatory and analytical support for all phases of drug development and commercialization, Ash Stevens has developed a reputation as a reliable full-service CDMO with the capabilities needed to manufacture specialized small-volume APIs, including highly potent and other complex drug substances under traditional and highly accelerated timelines.4


  1. Ammoscato, Vince, Sean Lapekas. “Process Safety Evaluations Crucial to Successful CDMO Operations.” Pharma’s Almanac. Mar. 2015. Web.
  2. Munk, Stephen A. “Growing Demand for Small-Molecule CDMO Services.” Pharma’s Almanac. 4 Jan. 2016. Web.
  3. Ammoscato, Vince, Charles Stankovic. “Process Performance Qualification Prep: A Strategic Approach Leads to Success.” Pharma’s Almanac. 19 Aug. 2016. Web.
  4. Munk, Stephen A.“Qualities for Fast Track Success.” Manufacturing Chemist. Jan. 2015. Web.


Stephen A. Munk, Ph.D

Dr. Stephen Munk has been with Ash Stevens Inc. since 1997, serving as President since 1998 and CEO since 2001. He is experienced in drug discovery, development and manufacturing, both as a scientist and as a manager. Prior to joining Ash Stevens, Dr. Munk worked at Allergan, Inc. as a drug discovery scientist and subsequently as the co-team leader of the adrenergic drug discovery team. Under Dr. Munk’s stewardship, Dr. Munk is also an Adjunct Professor of Chemistry at Wayne State University and has served on the Board of Directors of MichBio.