API CDMO | Drug Substance Development

Overview of API Custom Development & leading CMOs, CDMOs offering custom synthesis & contract manufacturing services for APIs & Intermediates.

Q1. What is Custom API Development?

An active pharmaceutical ingredient (API) is any substance or a mixture of substances used in a finished pharmaceutical drug product to provide pharmacological action. Custom API development refers to the production of desired quantities of APIs exclusively on a specified scale as per the customer's requirement.

Drug substance development and manufacturing is the foundation on which pharmaceutical products are built. A company can use either a traditional approach or an enhanced approach to drug substance development, or a combination of both. The amounts produced during the synthesis of APIs tend to be small, ranging from a few milligrams to about 10 kilograms, and this can be carried out in-house or by manufacturers.

Custom development is essential to the pharmaceutical industry as many active pharmaceutical ingredients (APIs) are sometimes very difficult to find or are hard to synthesize. Custom synthesis provides a platform to the clients to accelerate time to market for finished dosage forms (FDF).

The requirements for complex chemicals to facilitate new innovations in drug development pose challenges for all drug development firms. The need for custom drug substance development and manufacturing in the pharmaceutical and biotechnology industries continues to expand.

There are many active pharmaceutical ingredients (APIs), such as small molecule APIs, high potency APIs, small molecules, cytotoxic compounds, biological drug substances and large molecules such as peptides that require complex procedures for their synthesis. Companies prefer to outsource them to contract development and manufacturing organizations and contract manufacturing organizations.

These pharmaceutical companies offer drug substance development services and custom API development and manufacturing along with pharmaceutical drug products. Custom drug substance development companies offer various services, including process and analytical validation, quality control and quality assurance, kilo scale, pilot scale and commercial production. Fully integrated contract development & manufacturing organizations offer drug substance manufacturing and enable the outsourcing of a broad variety of contract development activities from cytotoxic compounds, peptides, biological substance, small molecule drug substance manufacturing to the full scale clinical and commercial manufacturing.

Q2. What are the steps involved in drug substance development and manufacturing?

The API development process is a highly challenging task. There are several steps involved in API development and manufacturing and all of them have to be coordinated carefully.

Steps involved in API development and manufacturing are noted below:

Route scouting: Synthetic route scouting during the early stages of process development provides significant benefits by reducing the processing time, decreasing the number of steps involved in process chemistry, improving the quality and safety profiles, reducing the production of chemical wastes and improving the scalability to accelerate the drug substance development and manufacturing process overall.
Process development: To combat the increasing complexity in API synthesis, the right process development method should be used from the lab scale to pilot scale.
Technology transfer: A proven technology transfer protocol is necessary. It ensures that the API manufacturer receives complete information about the chemistry, including all materials, processes and analytics.
Scale-up: Physicochemical studies, reactor treatments and purification are followed by scale-up. Scale up is generally defined as the process of increasing batch sizes. The early stage development phase, which is generally 100-1000 times smaller in quantity (milligrams) when compared to the production batch, takes place during the laboratory scale stage. A pilot plant is used to test the behavior of a product during small-scale API development and manufacturing, before proceeding with large-scale production. Pilot labs often use kilo lab units to achieve low volumes.
Process validation: Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, to establish scientific evidence that a process is capable of consistently producing a high-quality pharmaceutical product.
Commercial drug substance manufacturing: It can be very challenging to take Active Pharmaceutical Ingredients (APIs) from the preclinical stage to clinical development and then to commercial scale production. The final stage of scale-up (kilogram stage) is the production scale. Production batches are always referred to as the 100X batch and this is the scale at which drug substance manufacturing organizations run during routine product marketing.
Supply chain management

Q3. What are the steps one should consider before undertaking active pharmaceutical ingredient (API) synthesis?

Drug development begins with the synthesis of an API and preclinical research to determine the efficacy and safety of the drug. An active pharmaceutical ingredient (API) synthesis process is a related series of operations that results in the preparation of an active pharmaceutical ingredient. A significant part of the quality of the finished pharmaceutical product is dependent on the quality of the active pharmaceutical ingredients (APIs) used in the formulation.

The key factors driving the growth of the active pharmaceutical ingredients (APIs) market are the increasing drug research and development activities for drug manufacturing, the growing importance of generics and the increasing number of biopharmaceuticals. The most important reason in favor of generics is the fact that they are far less expensive to manufacture than their branded counterparts.

Contract Manufacturing Organizations (CMOs) have gained prominence amid the increasing cost of manufacturing drugs and the rise in chronic diseases. API suppliers who can secure their supply chains, from raw materials through to ingredients, are likely to see a considerable increase in demand from pharmaceutical firms.The trend of outsourcing work to CMOs by big pharmaceutical firms is expected to grow in the future, and this will result in a growth in demand for quality APIs.

Proper profiling of your drug is the first step that you should consider before undertaking API synthesis. This includes considering its toxicology, which will have an impact on the facilities required and controls to be put in place to meet all safety and hygiene standards.

The second step is to choose the route that will have the best efficiency. Before starting your experiments, you should first focus on important things like which reagents to use and how to make the process as efficient as possible.

The third step involves preparing for scale-up, which includes at least three kilo scale-up trials of the process while still in the lab, before heading into the far more costly cGMP drug substance manufacturing facility for commercial processing. The last step involves developing a sound synthetic route process. While there are many things to consider and multiple steps to undertake in selecting a synthetic process for a drug candidate, the best CMOs focus on chemical yield, cycle time, number of chemical steps and convergence, etc.

Q4. Which are the leading pharmaceutical companies offering API Development contract Services?

There are various pharmaceutical organizations, such as contract pharmaceutical development and manufacturing organizations (CDMOs) that have the capabilities to offer active pharmaceutical ingredient development or API development services. The leading companies offering custom API development services are mentioned below.

Ofichem - API Development Services

With over 45 years of experience in the production of niche APIs, Laboratory Ofichem develops, produces & distributes APIs worldwide. It can safely & simultaneously produce a broad range of active pharmaceutical ingredients (APIs) for the human & veterinary pharmaceutical markets.

Pfizer CentreOne - API Contract Manufacturing Services

Pfizer CentreOne, a global API contract manufacturing and active pharma ingredient development organization, offers contract manufacturing services for intermediates, small molecules, large molecules and biological drug substances for clinical & commercial manufacturing.

Minakem - HPAPI & API development services

Minakem provides HPAPI development & API contract manufacturing services. Its facility in Louvain-la-Neuve pioneered the utilization of containment technology for the development of highly active pharmaceutical ingredients (HAPI) as well as cytotoxic compounds for clinical & commercial manufacturing.

Polpharma - Active Pharmaceutical Ingredient Development Services

Polpharma provides API contract manufacturing and development services for API synthesis & contract manufacturing services for FDFs. It has compliant and FDA-approved multipurpose facilities which offer an individual approach to each CDMO project.

Phyton Biotech LLC - Plant-based drug substance development services

Phyton offers comprehensive development and API contract manufacturing services for plant-based small molecules, extracts and recombinant products for use in traditional Chinese medicines (TCMs), cosmetics, agriculture as well as food & pharmaceutical industries.

Solara Active Pharma Sciences - Custom API development services

Solara offers contract research, manufacturing & active pharmaceutical ingredient development services across the entire value chain of a new chemical entity, from the preclinical phase to commercial production. It provides drug substance development services with custom active pharmaceutical ingredient (API) synthesis and API integration services.