While the outsourcing of pharmaceutical clinical supplies, both the dosage form and the packaging/labeling, has become commonplace these days, and thus, is well covered in literature, less is known about the outsourcing of clinical stage active pharmaceutical ingredients (APIs). Clearly, without sufficient quantities of the necessary API, clinical studies cannot occur.

The outsourcing of API supply for clinical studies is a very practical, capital-efficient and popular option for many small to mid-size drug developers that may not have the necessary infrastructure to produce small molecule APIs and reference standards. These companies can maximize speed and save on their own R&D costs by outsourcing the manufacture of clinical trial APIs to a trusted API-focused, small molecule contract development and manufacturing organization (CDMO). 

Why outsource API manufacturing?
By outsourcing, drug sponsors can take advantage of a CDMO’s operational expertise in terms of chemistry, manufacturing and control (CMC) technologies, Good Manufacturing Practice (GMP) facilities, quality, safety and environmental management systems, and standard operating procedures. Beyond that, a full service CDMO will also provide expertise for regulatory filing strategy and submission either through a standalone drug master file (DMF) or by supporting the sponsor in their filing. Some CDMOs have additional specialized expertise in certain chemistries or compound classes. For example, a CDMO may have an impressive track record for manufacturing high potent cancer drugs or drugs with a particular chemistry such as cannabinoids; some may only focus on parenteral preparations.

Outsourcing can make it possible for smaller biotech/pharma companies to obtain clinical supplies and expedite clinical trials. Many of these companies:

• May not have the scientific or technical expertise to independently develop the chemical entity they want to study under cGMP;
• Do not have the manufacturing technologies, scale or quality systems to supply material; and
• May not be able to access geographies due to a lack of shipping and logistics experience, permitting or licensing expertise.

Additionally, with COVID-19 and the general reshoring of API production, there’s now a greater focus to bring security of supply for clinical products back into the U.S. where the clinical studies are performed. Additionally, there are many smaller biotech companies whose research is dependent on a domestic U.S. funding source (NIH, NSF, BARDA, etc.) that require domestic manufacture of clinical trial APIs. In such cases, companies must find a manufacturing partner capable of domestic manufacture.

Even large pharmaceutical companies sometimes turn to CDMOs if they lack a domestic manufacturing footprint, need expedited delivery or have internal capacity constraints (lack of R&D resources) to produce material for clinical trials. Companies developing controlled substances, including a recent uptick in companies researching psychotropics, must have licenses required by the Drug Enforcement Administration (DEA) to legally research, manufacture, test, import, export and distribute APIs.

How to choose a suitable small molecule API-focused CDMO partner
There are several key attributes to look for in a CDMO:

1. Sponsor focused
Sponsor companies should choose a CDMO that is able to recommend solutions proactively and is customer-oriented. The organization must be responsive and have the infrastructure to move quickly when it needs to. Certain CDMOs that are large, global organizations sometimes tend to act slowly and conservatively. The contracting process alone with larger CDMOs can eat away months of precious development time and delay supplies.

Lead time may be a key factor for smaller biotech companies, who may underestimate the supply needs if trial timelines accelerate. Not having enough API to accommodate changes in clinical timelines may require the CDMO to pivot quickly and re-supply in an accelerated manner. It’s vital to consider what comes after the trial, and how well the CDMO can support further trials and any commercialization plans as sponsors move into Phase III. If the sponsor believes they have a strong product with a high chance of clinical success, they should be thinking several steps ahead and considering a line of sight to scale.

Sponsors must balance the importance of working with a CDMO that has the ability to scale up production, with the ease of working with a partner that is not enshrouded by bureaucracy, and can provide satisfactory focus and engagement toward the client. A customer-oriented CDMO will carefully consider their client’s needs, be responsive to input from the client, and truly understand what the client is trying to achieve, in order to act on these goals efficiently.

2. Robust technical capabilities
A successful CDMO should have proven technical capabilities. This applies to equipment, capacity, development experience/skill and knowledge across production and analytical development. Choosing a CDMO that has a track record in delivering cGMP clinical stage materials across multiple chemistries and sponsors is critical, especially since many CDMOs who claim to have clinical stage expertise have a limited complex cGMP API synthesis track record.

3. Low regulatory risk
Manufacturing small molecule clinical stage APIs must comply to global regulatory standards including those promulgated by the U.S. Food and Drug Administration (FDA). It’s best to always work with a CDMO that has global regulatory and quality experience and has supplied trial materials to many global clinical studies. A CDMO who strictly adheres to regulatory guidelines and has extensive knowledge on the regulatory processes enhances the sponsors chances of a timely completion of the trial, and ultimately an approval. A sponsor’s biggest priority should be to protect patient safety and minimize regulatory and quality risk from the API used in the trial. As such, partnering with a reliable CDMO that has well-maintained GMP facilities, a strong regulatory track record, and a robust quality system can significantly lower any regulatory risk.

There are multiple facets to consider in this type of regulated industry. Not all clinical stage drug manufacturers perform commercial manufacturing routinely and vice versa. Thus, they are subject to different regulations and inspection intervals, etc. For example, Purisys is a CDMO that manufactures APIs spanning preclinical to late-stage clinical studies, but also routinely manufactures products for niche (including orphan drug) commercial purposes.

Purisys also custom manufactures new chemical entities and reference standards for pharmaceutical customers. As such, Purisys is a commercial manufacturer as well as a clinical stage CDMO that undergoes a ‘Six Systems GMP Inspection’ with the FDA. This is a systems-based approach to GMP and is aimed at ensuring a robust quality system model for pharmaceutical products. Purisys is routinely inspected for compliance on a regular cadence by the FDA to meet the high standards necessary for clinical and commercial manufacturing.

What to keep in mind during the outsourcing partnership
When entering into a partnership with a small molecule API CDMO, drug sponsors should plan out a strategy and a reasonable timeline, and negotiate expectations as much as possible upfront, before the work begins. This sets a good precedent to follow for all parties, with each side working off the same set of expectations. Setting the right expectations can be easier with a Request for Proposal (RFP). It typically accelerates the outsourcing process by helping align the customer and the manufacturer, with little room for miscommunications or misunderstandings. 

An experienced CDMO will provide advice during the RFP process that will prove useful to the sponsor as they set their objectives for the work and connect to the downstream drug product and clinical study stakeholders. If done right, work on the front-end of API development can accelerate the downstream drug product supply as some of the solid-state impurities and physical characteristics can be optimized during API development. Some of this information may prove useful to further protect intellectual property (IP) of the sponsor and a good CDMO can advise on ways to generate useful IP related information.

However, it’s important to note that when the drug development is more complicated than typical, or the molecule is being synthesized for the first time, issues will come up.  Choosing a CDMO that can work through and complete all tasks despite encountering obstacles throughout the development process is key. It’s important for the sponsor and CDMO to constantly communicate and align on a common understanding on what can be expected, especially related to timing. Some projects may take as little as 3-6 months to go from concept and business negotiation to GMP supply, depending on the capacity of the CDMO and the complexity of the project.

Others may take several years, due to the complexity of development. Sponsors should be prepared for timelines to shift over the course of a development project, however, a good CDMO will communicate openly and in a timely manner, while also thinking about ways to bridge the project plan back to its original timeline. In these cases, the sponsors and CDMO must communicate well and work together to constructively solve the problem, whilst managing expectations from internal stakeholders.

Safety and environmental compliance are critical elements in any small molecule API development program. Having controls in place and experience with employee safety are especially important when developing and manufacturing a molecule for the first time. These must be discussed in detail at the beginning during the RFP stage to make sure the CDMO has the capabilities and suitable policies and practices to proceed, including any capital investment needed (if any) to allow the CDMO to handle the molecule safely. For example, permits may be needed on site for handling certain solvents or substances. Also, some CDMOs may refuse to perform certain types of chemistries or hazardous reactions in their facilities. To start the project off on the right footing with trust on both sides, a clear understanding of all the various aspects of the manufacture must be established early on.

Sponsors may also want to confirm lab certifications that they deem important to the manufacture, such as ISO accreditation which demonstrates quality compliance with international standards. Not all CDMOs are required to have ISO certifications, but by employing a CDMO that has ISO accreditation and is also FDA-inspected, a sponsor can have a greater degree of confidence in the work-product generated by the CDMO partner.

Purisys recently received two global ISO certifications: ISO 17025 (Testing and Calibration Laboratories) and ISO 17034 (Reference APIs Producers). These certifications support Purisys’ analytical laboratories and reference standard program, further ensuring the quality of its services, and the purity and potency of the products it generates.

Conclusion
Although outsourcing the manufacture of clinical trial APIs is gaining popularity and becoming more common nowadays, choosing the right CDMO partner can be a daunting task. Sponsors are well-served to carefully consider factors such as the level of client focus and engagement, capacity and quality of technical capabilities (including expertise in the specific therapeutic area of interest), and experience with regulatory support. Once a partner is chosen and the business is negotiated, both parties must work together to set expectations upfront and navigate the process with flexibility.