Major pharmaceutical and emerging biopharmaceutical companieshave a plethora of choices in utilizing contract-manufacturingorganizations (CMOs) available in the global market place for their custom synthesis needs. However, establishing a collaborative relationship with a few manageable and reliable vendors/partners can be challenging. This article will focus exclusively on proven CMO selection criteria for outsourcing custom-synthesis of small molecule building blocks and starting materials to support API (active pharmaceutical ingredient) development. Typically, these building blocks would require anywhere between 2-8 synthetic steps for their preparation. They are customarily designated as “starting materials,” the starting point from which a GMP synthesis to the API (active pharmaceutical ingredient) would begin.
Criteria for CMO Selection for Small Molecule Starting Materials
Syntheses of most small molecule new chemical entities (NCEs) (whether they are still in candidate seeking stage, preclinical, or already in clinical development) are modular in nature. Depending on the structural complexity of these molecules, anywhere from 2-5 sub-units may be needed for their assembly. In many instances, these building blocks themselves may pose formidable synthetic challenges that need to be overcome, before their preparations could be achieved on scale.
In all likelihood, new chemical entities that are in toxicological or clinical development within the U.S. and Europe will have non-GMP starting materials being procured from CMOs located in emerging markets, such as China, India and Eastern Europe. The starting material requirements, depending on the program and its stage in development, may range from a few hundred grams to multiple tons.
The question then arises as to how would one go about selecting CMOs to address key starting materials needs for projects in various developmental phases? One of the options is to work with CMOs that are appropriate only for certain phases in a project e.g., when a few hundred grams of a chemical intermediate are required for a pilot tox study, it is better to work with expert kilo lab suppliers who have a fast turnaround and are adept in scaling up sub-optimal chemistry. It is always advantageous to have well-established evaluation parameters regarding a vendor’s (CMO) ability to deliver, prior to working with them. In our opinion, the following traits are must haves for any CMO:
- delivers quality material (right compound with the right quality, right amounts, within the right timeline and shipped to the right place)
- adept in practicing a Science-driven approach to chemical operations
- possesses the required infrastructure (production and analytical) and talented staff; credible, transparent, honest & reliable in all business dealings
- efficient (customer focus) and EHS (environmental health and safety) compliance.
The aforementioned list is a framework to build upon. Nevertheless, it is generally broad in its scope, offers a good starting point and general guidelines that have been useful in our outsourcing endeavors. Let us elaborate a little further on the specifics of the criteria:
Even an ironclad confidentiality and/or service agreement with a CMO does not completely ensure a client protection of niche technology associated in the synthesis of a starting material. Employees at a given CMO may switch employers and carry proprietary information with them. For instance, if a cost-effective biotransformation procedure is employed in the preparation of a complex, chiral molecule, it is better not to outsource its procurement to an emerging market supplier, unless the supplier is thoroughly vetted and is renowned in the industry and has established systems in place that guarantees confidentiality. One would expect restricted access to employees working on a critical technology, e.g., having in place proprietary codes for critical reagents. Limiting outsourcing to easily accessible compounds, from commercially available raw materials that utilizes standard synthetic procedures to emerging market suppliers can obviate this problem. To further mitigate this risk, each of the starting materials needed for an API must be procured from different suppliers. As a critical part of the service agreement, the contracting party should negotiate for the right to transfer technology created by the CMO.
Material Quality and Delivery
Timely drug development of an NCE depends to a large extent on the timely delivery of starting materials in the desired specs and in the right quantities. In many early development programs, this can be challenging since procedures are typically un-optimized. Forecasting time to prepare some of these compounds, in larger quantities, can be challenging. Having the right CMO, who thinks creatively and is technology-savvy, may often ameliorate this issue. One of the options is to screen many CMOs beforehand, build a stable from the chosen few, after establishing a history with them through experiences drawn from low-risk outsourced projects. As part of the due diligence, the sourcing manager should get input from the peers in the industry for further clarification on the CMOs capability to deliver. Building a preferred list categorizing different CMOs along the lines of production capacity, technology fit, prior history and feedback from peers in the industry is definitely helpful.
Science and Technology
Technical assessment of a CMO and their fit for a project is a key role of the sourcing manager. It is imperative that the procurer is able to evaluate the technology objectively and identify what type of supplier may best fit the needs. Knowledge of modern organic synthesis, process development, pilot plant or manufacturing operations, FDA and ICH guidelines for APIs are skill sets that a procuring manager must have. This facilitates the sourcing manager maintaining credibility within the project team - in terms of project costs justification, timelines, etc. – and also with the CMO during the course of a campaign and associated contractual negotiations. In many instances, when a client-provided technology is unfeasible for scale-up operations, having a procuring manager judge effectively on alternate chemistry provided by the supplier on viable solutions to the chemistry team leaders is critical. Gaining credibility from the chemistry team leader is important for both the CMO and the procuring manager. A competent manager will constantly update his/her knowledge base by keeping up with current trends in the scientific literature and the CMO industry. Obviously, a science-driven procurement manager with excellent business skills will be required to handle this effectively, within the pharma client organization.
Assessment of the scientific competence of a CMO may not be easy to accomplish solely from experiences derived from a single project, a trend is desired. However, during the course of a preparatory campaign, one can glean from weekly updates and teleconference discussions, problem-solving capability and the underlying scientific competence of a CMO. While limited “hand holding” may be needed in isolated instances, our preference would be to have a CMO operate independently and ask for occasional guidance from the customer. A balanced synergistic approach to solving problems may be warranted in cases where process improvements are absolutely needed. In such instances, a mutual agreement on the scope of process changes is needed, prior to execution of any operations. It is always helpful when a client provides a template for weekly report updates and general guidelines on how basic analytical data (such as HPLC analysis, Mass Spectral and proton NMR spectra) should be presented for the CMO.
Equipment and Personnel
It is the procuring manager’s responsibility to acquire intimate knowledge of the CMO’s equipment capability and the type of chemistry that can be executed in the facility. Furthermore, it is the skill set of the technical staff that works on the client’s chemistry and their experience base that becomes more important. Prior to initiating any work, as part of the due diligence, the client must interview key employees at the CMO facility to gain familiarity on the type of chemistry that has the best chance of flawless execution. In cases where a site visit may not be possible, telephone interviews would suffice. Of course, this should be followed up with additional fact-findings about the CMO from other customers in the pharma industry. A technical site assessment visit to a CMO facility is recommended. The procuring manager for the chemistry team leaders within the client’s company should then summarize their findings about the CMO. A checklist is helpful, but it should be complemented by a written summary highlighting some of the intangibles; e.g., a statement of proven expertise in macro-cyclization chemistry, more accuratly describes the skill set possessed by a CMO.
Quality and Compliance
Once the starting material suppliers are identified for projects entering phase II, Quality compliance should become an integral part of the CMO selection criteria. At the time of sourcing starting materials for tox and phase I lots, rarely are synthetic methods analytical testing methods fully optimized. So, assessment of material quality is made primarily on standard available analytical data (proton NMR quantitation, Carbon NMR spectra, HPLC and mass spec.). Once a project moves deeper into development, procedures to prepare starting materials and analytical testing methods to assess their purity become more defined and robust. Ensuring that the CMO operates within the framework of an FDA-approvable quality system (SOPs that offer guidelines for chemical production and release) - while conducting a preparatory campaign for a starting material - is the responsibility of the Quality assurance group within a client’s organization. As part of the audit, the Quality assurance auditors can verify and demand that a CMO provide documented proof that a given chemical is produced and released at a given site. For starting materials needed to support pivotal phase II-phase III API supplies, Quality compliance assessment (a paper questionnaire assessment initially) followed by an on-site audit at the CMO facility are needed. It should be noted that , regulatory requirements around change control go up significantly when a starting material is just a few steps upstream to the API.
Integrity, Reliability and Credibility (Customer Focus)
Any CMO who betrays trust by divulging to third parties highly sensitive client confidential information is a cause of great concern. It may have far reaching implications, beyond just jeopardizing any deliverable timeline. The client should act quickly to learn the specifics of the breach and immediately defer the matter to the legal team within the organization to take matters further. Obviously, the CMO who betrays a client trust should be removed from its portfolio of suppliers.
On the other hand, a CMO who works with a sense of urgency, communicates well in a timely manner sharing good, bad and unexpected data, flexible in adjusting the work schedule to ensure timely deliverables in the right quality, sticks to a deliverable commitment and at the right price is an asset. We can rightfully call them partners. It takes time to build rapport between the CMO for the client and vice versa. While trust may take years to build, it is a trait that is easily lost within a short amount of time. Once credibility is lost it is hard to regain in this highly competitive industry.
Efficiency and Cost of Goods
Efficiency in unit operations has a profound impact on the cost of goods of any chemical, e.g., CMOs who routinely employ statistically designed experiments to identify critical reaction parameters to optimize reaction yields have a distinct competitive edge over their competitors. While not the major factor in many projects that are in the early development stages, sometimes cost of goods can tip the scale to make a starting material unviable for ultimate commercialization. In this niche space, CMOs with an edge on process development and optimization may play an important role in ensuring commercial viability. While upfront costs may be high, the client is well rewarded later, when significant economic benefits can be achieved with commercial volumes.
Whether to procure a few hundred grams of starting materials to support a pre-clinical candidate in pilot tox study or multi-tons to support commercial launch of a new drug, careful selection of a CMO to suit a pharmaceutical company’s new drug development needs is a major responsibility. It rests primarily on the pharma client to do the homework well before making any decisions on procurement. There are literally hundreds of CMOs around the world to support all small molecule contract-manufacturing needs. The key is screening, identifying, testing and finally selecting these rare few for a pharma company’s CMO stable. In order to build and maintain the aforesaid CMO stable, a talented and business-savvy sourcing staff is needed Another point to consider are the staff turnovers at a CMO and potential impact on client relationship. Qualification, therefore, is not just a one-time event, but rather a continuous process in maintaining a strong collaborative relationship.
Irrespective of the scale of work in a chemical facility, strict adherence to worker safety, and compliance with Environmental and Health regulations are the foundations that a production facility should be built upon. In cases where a full-fledged EHS audit may not be feasible for those CMOs who cater to 1-10 kilogram supplies of a chemical, at least an EHS questionnaire should be made available and the degree of compliance assessed. It is the duty of the assessor to verify the contents of the completed questionnaire from the CMO, during a site visit. Safety SOPs should be freely shared between a client and a CMO as part of the overall collaboration between the two parties. It has been mentioned already that the CMO is an extension of the pharma client, whose reputation may be in jeopardy whenever EHS compliance practices are either ignored or transgressed during operations. Better to have some agreed upon commitments to safe work practices first, prior to execution of a project.
Over the past 15 years, this writer has conducted over 50 CMO technical site visits and the foregoing criteria have helped us screen and identify the best entities to collaborate with. While we have had certain disappointments along the way, the overwhelming majority of our CMO picks have either met or exceeded our overall deliverable expectations
Srinivasan Babu obtained a Ph.D. in organometallic chemistry from Iowa State University in 1987 under the guidance of Prof. Richard Larock. For the past 22 years, he has held various positions within the process development department at Monsanto, G.D. Searle, Agouron, Pfizer and Genentech. He leveraged that experience for the past 13 years by getting involved in sourcing key intermediates for API synthesis in various phases of development at Agouron, which later merged with Pfizer. Presently, he heads the sourcing group for the small molecule pharmaceutical sciences (SMPS) dept. at Genentech Research and Early Development (GRED). His responsibilities now include establishing outsourcing collaborations to support all aspects of Pharmaceutical Sciences, ranging from custom synthesis, process chemistry, preformulation and formulation and