Contract Manufacturing | Small molecule APIs | CMO

Overview of Small molecule API Manufacturing & more on CMOs & CDMOs offering clinical & contract manufacturing services for small molecule APIs.

Q1. What are small molecules?

Small molecules are chemical compounds with molecular weights below 900 Daltons or ranging from 0.1 to 1.0 kDa obtained through chemical synthesis or from natural products. Due to their small size, they can diffuse across cell membranes and reach intracellular sites of action.

Most of the pharmaceutical finished formulations contain active ingredients as small molecules as they are notably smaller than large molecules (biological molecules) like proteins. Due to their smaller size and simpler chemical structure, small molecule APIs require less sophisticated manufacturing procedures than large molecule APIs, which are more challenging to create. Small molecule APIs can be formulated into oral dosage forms for delivery, which have greater compliance and lower cost of administration compared to injectables.

Moreover, small molecule APIs also have anticipated pharmacokinetic and pharmacodynamic characteristics and drug-drug interactions which facilitate easier dosing. These often have a clearly defined mechanism of action and are designed to target a particular enzyme or receptor to modify a biological pathway or function.

For almost a century, small molecule APIs have been the backbone of the pharmaceutical sector. These comprise approximately 85 to 90% of the pharmaceutical market as they can be formulated into more acceptable dosage forms. Small molecule APIs offer enhanced stability and can be readily formulated into tablets, capsules, suppositories, and inhalation formulations. Additionally, they also have a reasonably high rate of patient compliance due to their stability, low cost, and accessibility.

The market for small molecule API manufacturing is constantly expanding. Several CDMOs and contract manufacturers are providing comparable contract development and manufacturing services. These small molecule API CMOs have years of experience in the commercial manufacturing of complex small molecule drugs and APIs along with clinical trial materials via cGMP manufacturing.

Q2. What are the different steps involved in the development and manufacturing of small molecules?

Small molecule development and manufacturing have transformed the healthcare industry over time, thus enhancing patient outcomes and serving as a simple tool to address both acute as well as chronic ailments.

The manufacture and development of small molecule APIs have undergone significant modification lately. Their synthesis and production have become more complicated in the case of targeted therapies such as cancer requiring specially designed API manufacturing processes and delivery systems.

In comparison to large molecules (biologics), small molecule API manufacturing and development is easier as it is more predictable due to its simplicity, which leads to simpler dosage regimens. Various steps involved in the small molecule API development and manufacturing are outlined below:

Synthetic Route and Process Development: Route scouting and process development are important steps in the chemical development process for small molecule API manufacturing. This ensures the correct method is being utilized for the development and manufacturing of small molecule APIs.

Assessment of Key Starting Material: To guarantee an adequate degree of control, the starting materials for small molecules may need more documentation on the source, origin, supply chain, manufacturing process, and controls implemented.

Scale-up and Commercial Manufacturing: Once the key starting material gets approved it is followed by scale-up for small molecule development and manufacturing from lab to pilot to commercial batches.

Supply Chain: The management of the supply chain for small molecule APIs is a tedious method as it involves sourcing, manufacturing, testing, and distribution processes while maintaining safety, efficacy, and quality.

Small molecule development and manufacturing is still a challenging, multi-step process requiring a variety of raw materials with various chemical transformations, physical and chemical characteristics, and operations. Specialized proficiency of small molecule contract development and manufacturing organizations is necessary to overcome the challenges associated with small molecule manufacturing. Thus, small molecule manufacturers collaborate with chemists, regulatory experts, pharmacologists, and manufacturing specialists to subdue these obstacles corresponding with the development and small molecule API manufacturing.

Q3. What factors are contributing to the increasing demand for small molecule APIs?

Small molecule APIs are the mainstay in the development of various pharmaceutical formulations. They are often utilized as an integral component with biological drugs in combination therapies, which leads to the increased demand for small molecule development and manufacturing. Due to stipulated requirements, there has been a surge in the outsourcing of the manufacture and development of small molecule APIs to small molecule CDMOs and CMOs. Several factors contribute to the increased demand for these complex APIs including:

Pharmaceutical Advancements: The continuous discovery of new drug targets and therapeutic areas fuels the demand for small molecule API development and manufacturing aimed at meeting unmet medical requirements.

Increasing Disease Prevalence: The rising prevalence of chronic and infectious diseases, and other health conditions necessitates increased demand in the development and small molecule API manufacturing.

Customized Treatments: Advances in personalized medicine drive the demand for these complex APIs. Several small molecule manufacturers and contract developers formulate precision medicine tailored to specific patient populations.

Regulatory Standards: Stringent regulatory standards necessitate innovation in small molecule development and manufacturing. Small molecule manufacturers can sometimes manufacture complex APIs following stringent cGMP specifications thus assuring safety, reliability, quality, and consistency.

Outsourcing Patterns: The rising trend among pharmaceutical companies to outsource small molecule API manufacturing to specialized contract development and manufacturing organizations (CDMOs) is driving the demand for their services and APIs.

Technological Innovations: Advances in high-throughput screening, combinatorial chemistry, synthetic chemistry, and production technologies enable complex small molecule API manufacturing more efficiently, further boosting its demand.

Expiration of Patents: As patents expire for branded drugs, there is a growing demand for their generic versions which are often based on small molecule APIs.

Simpler Dosing Regime: Small molecules possess better PK/PD and are stable and orally bioavailable, thus contributing to their increased demand.

These factors individually or collectively raise the demand for small molecule manufacturing in the pharmaceutical sector. CDMO for small molecule active pharmaceutical ingredients often fulfills this rising demand for manufacturing these complex APIs apart from the small molecule API CMOs.

Q4. What are the leading CMOs / contract manufacturers offering small molecule manufacturing services?

Various pharmaceutical organizations, such as contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs), can offer small molecule manufacturing services. These are also known as small molecule API manufacturers that can produce and scale up complex molecules.

Small molecule contract development and manufacturing organizations offer drug substances that are in greater demand as a result of their success in treating a variety of illnesses and disorders, and the ease of the small molecule manufacturing process. Special expertise of small molecule API CMOs and CDMOs caters to the research, development, and cGMP clinical and commercial manufacturing.

Recently, CDMOs for small molecules have gained importance because of increased R&D costs and the requirement for special competencies and small molecule API development and manufacturing services they offer. Due to this reason, there has been a surge in outsourcing small molecules to CDMOs.

Some of the top small molecule contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) with GMP contract manufacturing capabilities are explained below.

Aspen API: Aspen API is a small molecule CDMO offering contract development and manufacturing services. It is a contract manufacturer for small molecule APIs, steroids, narcotics, complex small molecule high-potency APIs (HPAPIs), peptides, etc, and offers up-scaling and commercial manufacturing services for small molecule active pharmaceutical ingredients.

EUROAPI: EUROAPI is a CDMO for small molecule active pharmaceutical ingredients that offers complex small molecule API development and manufacturing services along with cGMP manufacturing. It has six commercial manufacturing facilities, offering 2,000 m³ cGMP for organic synthesis and 6,000 m³ for microbial fermentation to produce complex small molecules.

Axplora: Axplora is a small molecule CDMO that offers custom manufacturing of APIs and small molecule APIs. It is a contract manufacturer that provides API development and manufacturing services for drug substances and high potency APIs (HPAPIs).

Polpharma: Polpharma API offers contract development and manufacturing services for small molecule drug substances. It is a small molecule API manufacturer that has +70 years of experience in custom manufacturing of APIs and high potency APIs (HPAPIs, scale-up, and cGMP manufacturing of small molecule APIs in volumes ranging from kilos to tens of tons.

Evonik: Evonik is a CDMO for small molecule active pharmaceutical ingredients that offers manufacturing of APIs, high potency APIs (HPAPIs), and advanced intermediates along with small molecule custom manufacturing services. It is a contract manufacturing organization (CMO) that provides small molecule cGMP manufacturing for clinical and commercial supply.

Bachem AG: Bachem is a CDMO for small molecule active pharmaceutical ingredients that offers manufacture and development of small molecule APIs. It is a small molecule API manufacturer that produces drug substances from the gram scale to annual quantities of tens of tons.