Process Development & Optimization for APIs

Overview of process development & process optimization of APIs (drug substances), intermediates, small molecules, fine chemical, etc. by CDMOs & CROs.

Q1. What is API process development?

The term ‘process’ in the pharmaceutical industry is broad and can apply to the process development work that leads to the efficient, reproducible, economical, safe and environmentally friendly synthesis of active pharmaceutical ingredients (APIs), small molecules, etc. in a regulated environment.

Process development is the strategy via which a manufacturing process is identified for a drug substance or drug product from an early stage through scale-up and tech transfer to commercialization.

Contract development and manufacturing companies need development scientists to understand and control the processes used to make a diverse range of products, including food, drug substances (for e.g. small molecules), drug products, cosmetics and paints.

Thoughtful process development reduces project risks, facilitates a robust and flexible manufacturing process, and allows a high quality drug substance or drug product to be consistently produced on target, on budget and on time, meeting the expectation of customers.

Generally, process development studies for active pharmaceutical ingredients (APIs) such as small molecules provide the basis for process improvement, process validation, continuous process optimization, etc. They anticipate and identify contract development and manufacturing steps during the early development stage which could affect the quality of a drug, in order to control these variables during commercialization.

Advanced process development of APIs is carried out by development scientists who devise new production processes or refine existing ones to achieve process optimization. They further devise test methods to assess production processes in order to ensure process validation.

- Process Optimization: Process optimization encompasses widely varying activities whose principal goal is to reduce costs by eliminating process steps, improving yields, shortening cycle times and producing higher-quality drug substances or drug products.

- Process Validation: Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (for e.g. the process of API development and manufacturing) will consistently produce a product meeting its predetermined specifications and quality characteristics.

A CDMO for API process development services, with small to large scale custom API capabilities, can complete process development of APIs and achieve process optimization via various pharmaceutical API CDMO services.

A CDMO for API process development may provide the following pharmaceutical API CDMO services; advanced process development, scale up, commercialization, analytical development, route development and route optimization, synthetic chemistry services (for e.g. synthetic process development), process safety assessment, early phase API process development, etc.

It is imperative to consider the level of small to large scale custom API capabilities required for producing drug substances of interest and outlining the goals for an API development and manufacturing project.

Q2. What are the different process considerations for API development?

Some process considerations for API development (drug development) include:

- Solvent Selection

The solvent system from which an active pharmaceutical ingredient (API) is crystallized, influences solubility, growth and nucleation kinetics, impurity purging, polymorph control, solvation propensity and crystal morphology. Early stages of development are recognized as ideal for detecting benefits and issues regarding the use of solvents.

- Process Safety

Most large pharmaceutical companies conduct process safety assessments that are accountable for the understanding of the thermal hazards associated with reagents, chemicals, and reactions at hand. Process safety assessments in the pharmaceutical industry are important components of active pharmaceutical ingredient (API) development through its life cycle from discovery to commercialization.

- Process Scale-Up Issues

It is important for R&D chemists to identify potential plant issues and to attempt to address these concerns suitably at the R&D stage. Laboratory studies can help address many issues a priori to avoid surprises that might occur in the plant scale-up batches.

- Critical Process Parameters

A CDMO for API process development needs to understand as much as possible about the process. This includes the Critical Process Parameters (CPPs), or the key variables affecting the production process. CPPs are monitored to detect changes in production operations and product output quality or changes in Critical Quality Attributes, such as temperature, the time it takes for a reaction, crystallization and agitation speed, and other factors.

- Chemical Compatibility Studies

Physical and chemical excipient compatibility with the API is a key consideration during preformulation to ensure that the chosen excipients do not compromise drug stability and safety.

- Cost

As a prospective drug candidate is advanced from the stage of discovery lead optimization through preclinical development and into clinical development, there are many short-term cost of good (CoG) factors that should be taken into consideration. CoG estimates are an important tool for developing active pharmaceutical ingredients (APIs), thus serving a crucial and strategic need during early development.

- Environmental Friendliness

These days, R&D chemists are expected to use environmentally benign green chemistry routes for producing active pharmaceutical ingredients (APIs). Ideally, high yielding processes should be developed so that byproducts are not pollutants or can be treated to eliminate pollution.

Other notable process considerations for API development include documentation, process adaptability, determining scale up factor, stimulating R&D plant environments, defining cleaning procedures, collecting stability data for APIs or drug substances, etc.

Q3. What are the different pharma API CDMO services from process development to commercialization?

The ultimate goal of drug substance synthesis research is to translate the laboratory method of making milligram amounts of active pharmaceutical ingredients (APIs) to a production process on a kilogram to ton scale, while maintaining high quality and reproducibility at the lowest cost.

A CDMO for API development (drug development) with small to large scale custom API capabilities provides a range of pharmaceutical API CDMO services which enable API development and manufacturing. These pharmaceutical API CDMO services, from the early development stage to commercialization, are explored in detail below.

Physicochemical Studies

In this stage of the API development process, the physicochemical properties of a drug substance are characterized and established. Every drug substance has intrinsic chemical and physical properties which need to be considered before API development can be conducted at a larger scale.

Route Scouting

Process research (sometimes referred to as route scouting) is an analytical development tool to design and demonstrate new synthetic routes or methodologies with a focus on IP, safety, costs, atom efficiency, quality and delivery to meet the goal of sustainability in the pharmaceutical industry.

Process or Route Development

Process development is a mature field in the pharmaceutical industry encompassing execution via optimization of a disclosed procedure focused on manufacturing and delivery. It offers significant benefits by decreasing processing times, improving quality and safety profiles (via process safety assessments), reducing chemical waste production, and improving scalability.

Process development further helps in identifying small to large scale custom API capabilities and custom synthesis technologies required to successfully carry out API production from a small scale, all the way up to commercialization.

Process or Route Optimization

Route development and route optimization can be achieved by outsourcing API production to a well equipped CDMO for API process development. Route optimization can reduce costs, increase the efficiency of drug substance development, increase the safety of drug products, and accelerate the drug substance development and manufacturing process altogether.

Scale up

As the development of a new drug substance progresses, the batch sizes manufactured generally increase. Scale up is generally defined as the process of increasing batch sizes. On the way from laboratory to market, scale-up is part of product research and development (R&D) and optimization.

In process scale up, a formula is transformed into a viable, robust product by the development of a reliable and practical method of API manufacture. The possibility of manufacturing a drug substance at commercial-scale should be considered as a possibility when new formulations are in the R&D phase. Any processes involved in fabricating the drug must be scalable in terms of safety and efficacy, and economic factors must also be considered.

API Manufacturing Process

The API manufacturing process involves weighing and measuring API starting materials, selected during the early stages of analytical development, followed by treating them in reactors (custom synthesis technologies) to obtain pharmaceutical intermediates which are used to produce the API formulation.

The intermediates obtained via the reactor treatment are then purified via filtration and other processes to give the required drug substances. A CDMO for API development and manufacturing may possess small to large scale custom API capabilities including reactor treatments, API purification, API manufacturing processes, etc.

Commercialization

Commercialization is a process that involves the transition of an idea or invention to market as a new product that includes stages such as idea generation, research and development (R&D), product development and marketing of pharmaceutical products.

The contract development and manufacturing of drug substances is usually followed by packaging, late stage analytical development, and ultimately commercialization. A CDMO for API development may support synthetic process development and commercialization activities by offering regulatory support and other outsourcing services.

Q4. Which are the leading pharma companies for outsourcing API process development services?

A CDMO for API development provides various pharmaceutical API CDMO services including synthetic chemistry services, analytical development, early phase API process development, advanced process development, process safety assessment, scale up, commercialization, etc. Some of the leading CDMOs for API process development services are listed below.

Menadiona

Menadiona delivers cost-efficient synthesis, process development of APIs and life-cycle management solutions to customers within the pharmaceutical value chain. Their R&D laboratory team is not only developing new processes, they also work in process optimization and offer early phase API process development along with other synthetic chemistry services .

Menadiona’s aim when developing new processes is to face and fix “scaling-problems” at the pilot plant stage which disposes of 7 reactors with capacities from 20L to 1.500L made from 3 different materials (Hastelloy, Stainless Steel and Glass lined), 2 centrifuges with capacities of 60L and 400L, and dryers.

PMC Isochem

PMC Isochem offers cGMP & non cGMP industrial exclusive custom synthesis technologies and provides tailor made outsourcing services from development to production, including analytical development, route selection, process development (synthetic process development of APIs) as well as process optimization.

PMC Isochem's knowledge and management tools ensure an optimized timing for projects. It delivers substantial improvements in manufacturing and creates additional value by reducing operating costs and secures sourcing of raw materials, based on total transparency with customers.

Minakem

Minakem has the expertise, flexibility and the resources to provide a full range of pharmaceutical custom development services. Minakem's custom development capabilities include route scouting, process development, process optimization and scale up (early development stage to late stage, small to large scale), clinical batch supply, synthesis & purification of analytical reference standards, etc.

Farmak A.S

Farmak's priority is the development of processes that are used in the production of active pharmaceutical ingredients (APIs), intermediates, and specialized chemicals which are sold not only on the Czech market, but also and especially in foreign markets.

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