Enabling Technology Can be Critical To Timely CMO Delivery

APIs that are advancing from discovery into the clinic are increasingly complex, and the chemistry and/or biology necessary to manufacture these compounds requires increasing sophistication. The selection of a CMO (Contract Manufacturing Organization) is the crucial decision in the life of any outsourced project. Therefore, it is imperative to select a CMO that can produce the desired compound, to the desired specifications, in the desired timeframe. One key consideration in the selection process is the technology available in the toolbox of the CMO. As the majority of new APIs under development are still small molecules, this article focuses on the required “classical” chemical capabilities for constructing such molecules. Some selected technologies include: chemocatalytic and biocatalytic transformations, transition metal couplings, high pressure chemistry, cryogenic technologies, hazardous reactions and chromatographic technologies like Simulated Moving Bed. Consideration should be given to the ability of the CMO to practice the required technologies at all scales - from laboratory to pilot plant to commercial production equipment.

Frequently, an API entering the development pipeline at a pharmaceutical company will require one or two key technologies to synthesize the molecule. First, identify the key technologies required for the synthesis. For example, if the compound contains a biaryl moiety, a likely technology is a transition metal coupling, for instance, a Suzuki coupling. At this stage in the outsourcing program, it is important to brainstorm if any functionally equivalent technologies could be utilized. Continuing with the biaryl example, can a Negishi coupling be employed? Then, generate a list of CMOs that practice the key technologies. Helpful resources for this aspect of the exercise include the InformEx, ChemSpec, and CPhI show guides, web searches, and CMO literature and websites.

Once a list of potential CMOs is generated, further examination is required to pare it down to a short list of potential suppliers. Be aware that some CMOs claim they are “experts” at literally dozens of technologies. Therefore, it is imperative to perform due diligence with respect to technology. At this stage, some of the initial questions to ask the various CMOs, perhaps in the form of a questionnaire or a telephone interview, include: Is this technology performed in house, or is it outsourced? Is the technology scalable at your facility, kilo laboratory, pilot plant and full scale production, to support the complete development / commercialization continuum? Is the technology in question performed routinely, or is it a rarity? How many kilograms has the CMO produced utilizing the specific technology?  Although the answers to these questions will help narrow the list of potential CMOs, further investigation is still required.

Doveryai no Proveryai

This Russian proverb, roughly translated as “trust, yet verify,” was popularized during the nuclear arms reduction talks between the then Soviet Union and the United States during the 1980s. This same proverb can be equally applied to the current discussion on technology at a CMO. It is important for the client to verify the claims of a CMO. Consider utilizing the following five R’s:

• Required equipment – view the necessary hardware (laboratory, kilo laboratory, pilot plant and full-scale production) as part of the site visit. This technique can be particularly useful for technologies like SMB chromatography, where specialized equipment is required.
• Redacted batch records – review copies of a synthetic transformation that required this technology.
• Redundancy – verify how many times the CMO has performed the required technology. Is it a rare or routine part of their tool box.
• Relevant publications – read any publications or patents written by the CMO on this technology.
• References – secure contact information from customer(s) whose project utilized this core technology. Then, follow up with the reference to determine their satisfaction with the CMO.

A CMO with expertise in a key technology in-house will greatly assist in the timely execution of a scale-up campaign. Therefore, technology should be included as one item in the decision matrix for CMO selection. It is imperative to perform due diligence during the CMO vetting process regarding technology. Utilization of the 5 R’s technique can facilitate the verification of the required technology within the CMO. Inclusion of technology as a criteria for CMO selection will insure there are few surprises during the scale up campaign and will improve the probability for an on-time delivery of the API.