Custom synthesis means the exclusive synthesis of compounds on behalf of the customer, i.e., you can order a specific molecule that is only synthesized on your request on the scale, with the purity and with the specification or methods you require.
There is a big difference between the conditions used for small-scale custom synthesis of entirely new molecules and those used for standard multi ton per annum manufacturing, just as strictly regulated cGMP syntheses are different from those performed for R&D purposes. Learn more about the market of custom synthesis services, the different kinds of service providers (e.g., cCROS and CMOs) and how you can find the best provider for your projects.

What is custom synthesis? What does a cCRO do? What are the differences between small-scale and large-scale custom synthesis and then what is chemical contract manufacturing? Which contract models are there and which factors (amount, purity, synthesis steps, ...) influence the costs? Find out more in our explainer videos on our youtube channel or read the article below!

What is custom synthesis? How can I find the right supplier?

A Contract Research Organization (CRO) enables the outsourcing of a broad variety of research activities from custom synthesis of small molecules to clinical trials of a new drug, which helps to enliven the commercial research culture toward an international, innovation-based (drug) industry [1].

CROs, with their new epistemic skills and capacities, are both manifestations of the changes in commercial research cultures as well as the vehicles to achieve them.

In contrast to Contract Manufacturing Organizations (CMOs), which produce ten to thousands of tons of fine chemicals on multi-purpose plants, CROs have a lab bench or patient population as their working base. However there is an interface when it comes to the pilot plant, which is needed at a certain stage in both industries.

When discussing CROs, it is important to distinguish between their "medicinal" and "chemical" sub-types (mCRO/ cCRO), since they address different scopes of the value chain toward a new life science product. mCROs are active in the clinical part of drug development, operating in the sphere of physicians, hospitals, and patients, but also dealing with medical devices, diagnostics, and drug administration.
Conversely, cCROs mainly focus on only two aspects of the value chain, namely the small-scale preparation of active ingredients of new drugs and the design and basic development of the manufacturing process. As a result, mCROs attract more attention, and the general public considers the outsourcing of pharmaceutical development to predominantly include tasks such as lead identification, compound screening, lead optimization, or clinical trials. Therefore, the market for contract businesses offering custom synthesis and research services is rather small compared to that of mCROs.

Apart from pure cCROs and pure CMOs, a number of hybrid companies aka Contract Researching And Manufacturing (CRAMs) organizations also exist, offering both chemical contract research and contract manufacturing on scales from mg to tons. The advantage of these big one-stop shops is questionable, since small-sample orders only rarely evolve to industrial scale-up supply (in >90% of the cases projects are terminated at the lab sample stage), i.e., true synergies are rare [2].

Thus, although relying on one CRAM organization may benefit a strong partnership throughout the overall value process, it does not have the same character as the selection of individual highly efficient partners entirely focused on one core business. Such specialized partners not provide only resources but also real scientific/technological input. Custom Synthesis and Contract Research companies are often part of cooperative activities to react to such customer demands. Networks are able to provide both complementary and customized offerings, sharing resources, information, and experience and therefore acting like a "virtual" one-stop shop [3].

Here, the definition and constitution of efficient and effective intersections between these partners is the key to success. The main competence of cCROs is the small-scale synthesis of not (yet) available compounds on an exclusive basis, commonly named Custom Synthesis and Contract Research. The background and the purpose/stage of product development are of (nearly) no importance when searching for a new synthetic route toward a (new) molecule, lead compound, impurity, API, metabolite, or any other compound.
So, with cCROs the focus of all activities is “how to make” a (new) compound (for the first time). Regulatory issues and questions of fine tuning a running large scale production do not dominate here while they also have to be considered to some extent at the back of one’s mind.

The smaller working scale of cCROs compared to that of CMOs is a conceptual limitation of such entities. In addition to the mere delivery of an exclusively made compound, the outline, optimization, process development and "ReDesign" of a synthetic route is also part of the Custom Synthesis and Contract Research business, which comprises entirely new syntheses as well as already established synthetic routes in need of improvement for any reason. In the past, entry barriers for setting up a custom synthesis company were low, e.g., the history of most companies began with individual chemists (often PhD students), occasionally working on their own, preparing samples for pharma companies ("garage companies"). As the scale of  these activities increased, fellow students were hired to allow for expansion.

Today, such an approach is hardly possible in view of the tighter regulations, higher complexity of molecules, and the elevated quality expectations of customers. Today, customers require higher standards of know-how, experiences, infrastructure, quality management systems, safety assessments, and available technologies. On top of that, a track record, references in the industry, seamless and proven intersections to horizontal and vertical partners are mandatory for being able to meet the expectations and requirements in this industry.

Is custom synthesis and contract research a service for big pharma companies only?

Not at all. This service generally is not dependent on any individual industry and does not target one type of customers. While some cCROs specifically aim at serving pharma companies, the nature of this service does not differ substantially among different customer branches. Since cCROs help to make new molecules (in a better way), everybody looking for new molecules is a potential client of this service industry.
Pharma-focused service providers often add some pharma-specific extra features, such as the determination of toxicological or metabolism profiles, but this is beyond the very core of this business. So whether you are a small start-up biotech company, a polymer developer, a specialist in the field of cosmetics or a large specialty chemical production company: outsourcing chemical contract research and synthesis tasks will help you to improve your product development.

How does the outsourcing of research activities improve product development and how can you find the right supplier?

Most customers do outsource their chemical synthesis tasks to benefit from saved time, costs, and resources, additionally taking advantage of extra external scientific and technological input. Customers without own in-house resources logically have to rely on external resources and know-how to realize their projects.

However, clients with own chemistry capabilities also profit from the unbiased approaches and additional contributions of highly skilled and focused third parties. Another, more tactical reason for customers to outsource parts of their product development is the fast on-demand extension of in-house resources in times of very high capacity utilization. The option of an “extended workbench” without the need for heavy investments in own staff and labs is most important to bigger companies with strong own research activities.

As expected, business strategies of different custom synthesis service providers are subject to variation. Hence, selecting the right outsourcing partner to fit your philosophy as well as complementing your company’s key competences is a challenge. Conditions that may affect your choice include:

• the size of the cCRO,
• the key competence of the cCRO,
• soft factors: location, communication (language), partnership, ownership, trust (confidentially and IP protection),
• track record,
• importance of certificates (ISO 9001, cGMP),
• financial stability.

Generally, when selecting a cCRO fitting your need, you should select a partner that is a specialist in the field where you need support, but not too restricted in his scope to stop in a certain critical phase. For example, you are looking for an expert to provide assistance with the new synthesis of a radio tracer that will later be produced under GMP conditions at your site. If you select an expert for regulated custom synthesis you possibly head one (expensive) step too far, since for a first development, a GMP synthesis is not yet required.
Quite the opposite is true: GMP might be even counterproductive in most such cases as it limits flexibility that is required to find the optimal synthetic route at the beginning of a product development.

This would be the same as partnering with a radiopharma company helping you with the labelling and having know-how on many radiopharmaceuticals. In the first instance, you need experts developing an efficient, nearly waste-free synthesis of the non-radioactive analogue in accordance with the subsequently imposed radiochemical requirements. Consequently, you need to pick an outsourcing partner who is an expert in general synthesis with proven intersections to GMP partners/radio labs and an understanding of the requirements and regulations you are facing. Once this is completed, it might be useful to transfer this optimized route to another CRO (a radio lab) - or, since this is your key competence, do the labeling and GMP synthesis in house.

Another important condition to consider is the offered contract model. Most companies offer contract models that are only based on the resources employed. These “FTE” ("Full Time Employee") options do not guarantee a result (e.g., the delivery of target compounds or final proof of concept for a new synthetic route). Customers will have to pay on the basis of "elapsed working time", even if the compound cannot be delivered. Since this contract model makes sense either for large project volumes of quite predictable chemistry or for really basic research, it is often chosen by larger pharmaceutical companies, who “rent” additional chemical resources for a longer period of time (1-2 years) as an “extended workbench”.

For all other requirements, alternative contract models are more suitable. Some cCROs offer a so-called “FFR/ FFS” (Fee for Results/ Fee for Service) contract option, which means that the whole risk of failing is covered by the supplier and not by the customer. The customer only pays if the service provider can deliver the requested compound. There are several other options, all with their cons and pros. If you want to know more about these options and how they affect the costs for custom synthesis – please find here additional information:

costs & contract options for custom synthesis services

As to finding the right partner for custom synthesis, there are some questions you need to ask:

1. What stage of product development am I at?
2. Am I interested in the molecule (sample) or in a (new) synthetic route?
3. What are my own core competencies?
4. Do I have (all) the resources to handle (all/what) activities on my own?
5. Do I have the chemical know-how?
6. Is the known synthetic route to my molecule already the best approach?
7. Is the synthetic route already scaleable/scaled up?
8. What kind of contract option suits my needs best?
9. Am I willing to cover all chemical development risks on my own?
10. What is the scale for the synthesis? (mg or tons?)
11. Have special technologies - like flow chemistry or enzymes - already been considered/should they be considered for my future production process?
12. What about regulations? Do I need the compound to be synthesized under cGMP conditions (e.g., API synthesis) or do I only need research quality for initial testing?
13. If the compound turns out to be a “hit” and needs to be synthesized in larger quantities, will I be lost with the chosen supplier then?
14. What do I expect from a cCRO with respect to know-how transfer, compound delivery, reliability, independence, stability, track record, and scientific plus technological contribution?

As a chemical Contract Research Organization (cCRO), ChiroBlock is your right partner if you are searching for:

• first samples of sophisticated research reagents (mg-g)
• commercially not available reference compounds and analytical standards
• customized catalysts or building blocks- development of synthetic routes (route scouting)
• search for alternative synthetic routes (e.g., avoidance of certain technologies, hazardous starting materials, protected IP, etc.)
• a more efficient synthetic route (e.g., higher yield, lower costs)
• up-scaling of synthetic routes for larger quantity and reproducible quality (validated lab protocols)
• regular supply with exclusive fine chemicals up to several kg synthesized under strict QM DIN ISO 9001 or IPEC 2006 PQG GMP conditions
• supply of newly developed exclusive compounds up to a few hundred kg per year
• a CRO that is able and willing to transfer the internally developed process to the customer or to third parties (CMOs) via clearly defined interfaces

If you need help in finding the right supplier or still have questions, please contact us and send us your request. ChiroBlock has built up strong partnerships with other specialists operating at different stages of product development (e.g., manufacturers, enzymes specialists, computational chemistry, API synthesis, etc.). Within this strong cluster of excellence, we will find the right partner for you whenever such external expertise is required and whenever your requirements exceed ChiroBlock's strong capabilities.

[1] Sariola, S.; Ravindran, D.; Kumar, A.; Jeffery, R. Big-pharmaceuticalisation: Clinical trials and Contract Research Organisations in India, Social Science & Medicine 131 (2015) 239-246.[2] Pollack, P., Fine Chemicals: The Industry and the Business, Wiley InterScience (2007)[3] Runge, W., Technology Entrepreneurship : A Treatise on Entrepreneurs and Entrepreneurship for and in Technology Ventures, KIT Scientific Publishing, Karlsruhe, Bd 2 (2013)