CDMO | CMO | Drug substance (API) development & manufacturing

Overview of biological drug substance or API synthesis, from clinical development to small scale manufacturing, offered by CDMOs, CMOs, & CROs.

Q1. What is API custom synthesis?

API Custom Synthesis:

Custom synthesis refers to the production of desired quantities of APIs and intermediates as well as fine chemicals, small molecules, reference standards, impurities, and other substances exclusively according to a specified scale. The amounts produced during custom synthesis of APIs tend to be small, ranging from a few milligrams to about 10 kg or so, and can be carried out in-house or by contract manufacturers.

Small molecule API manufacturing:

- Small molecule APIs refer to APIs with lower molecular weights and small molecule API manufacturing refers to the drug substance development and manufacture of these molecules. Pharmaceutical product development service providers, with custom manufacturing expertise, can successfully undertake and deliver small molecule API manufacturing.

An active pharmaceutical ingredient (API) is defined by the USFDA as: any substance or mixture of substances intended to be used as active ingredients in medicinal drug products. Active ingredients have direct effects in the diagnosis, cure, mitigation, treatment, and prevention of diseases. Moreover, active ingredients can have a direct effect in restoring, correcting, or modifying physiological functions in human beings.

Intermediates are the building blocks of active pharmaceutical ingredients (APIs) and pharmaceutical intermediates are by-products of API synthesis. Furthermore, these pharmaceutical intermediates are produced during each and every reaction of API development. The intermediates are then used in the production of bulk drugs and also for contract research and development (R&D) purposes by various biopharma and pharma companies.

If it is impossible or impractical for a company to make these molecules and compounds in-house, API & intermediate custom synthesis can be outsourced to contract manufacturers including CDMOs, CMOs, and CROs. CMOs and CDMOs offer contract manufacturing services to produce APIs & intermediates on a small or large scale. Whereas, fully integrated contract research organizations (CROs) offer custom synthesis services for clinical development.

Fully integrated contract research organizations offer custom synthesis expertise and enable the outsourcing of a broad variety of contract research and development activities from small molecule API manufacturing to the full scale clinical development and manufacture of drug substances. Advantages of custom synthesis of APIs: API custom synthesis produces active pharmaceutical ingredients which impart therapeutic effects to treat ailments in patients.

Furthermore, APIs can be mixed together during custom synthesis of APIs to achieve desired effects (if in when a single active ingredient cannot achieve the same).Custom synthesis is essential to the pharmaceutical industry since many of these active pharmaceutical ingredients (APIs) can sometimes be very difficult to find or hard to synthesize. Custom synthesis or drug substance development and manufacture ultimately provides the platform necessary for clients to accelerate time to market for finished dosage forms (FDF).

Q2. What are the steps involved in API / drug substance development?

Drug development begins with API synthesis itself, before undertaking API development, it is well worth considering the level of API and molecule development desired for the substance of interest and outlining the goals for the API synthesis project before going forward.

The API development process, also referred to as the drug substance development process, is a highly challenging task. Contradicting API synthesis goals must be balanced, including the consideration of quality, safety, robustness, costs and time constraints. Furthermore, there are several steps involved in API development and all of them have to be coordinated carefully, following which custom synthesis services can be carried out as planned.

Steps Involved in API Custom Synthesis:

Step 1: Physicochemical Studies

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

Therefore, physicochemical studies provide relevant information for formulation selection for later stages of clinical development and commercial contract manufacturing. Physicochemical studies further anticipate the need for molecular modifications.

Physicochemical studies include:

- Selection of suitable drug substance candidates

- Planning API and drug substance development and manufacturing processes

- Advancement of analytical development services

- Assignment of API retest periods

- Synthetic route scouting of APIs

In the end, the goal is to select an appropriate process chemistry route and also to estimate the quantities of the chosen raw materials required to produce the desired quantity of APIs.

Route Scouting & Route Optimization:

Synthetic route scouting during early stages of process development offers significant benefits by decreasing processing times, reducing the steps involved in process chemistry, improving quality and safety profiles, reducing chemical waste production, and improving scalability.

Route optimization can reduce costs, increase the efficiency of biological drug substance development processes, increase the safety of drug products, and accelerate the drug substance development and manufacturing process altogether.

Custom synthesis and route scouting go hand in hand, lately there has been an increasing trend towards achieving route optimization and all the benefits that it imparts to the pharmaceutical product development process. Contract manufacturers provide such process chemistry, route scouting and route optimization - discovery and development services.

Step 2: The raw materials, chosen during the early stages of drug substance development, are treated in a reactor to obtain the required intermediates.

Step 3: Intermediates are purified to obtain individual drug products via sedimentation, filtration, centrifugation, etc.

Step 4: Physicochemical studies, reactor treatments, and purification are followed by scale-up contract manufacturing services. Scale up is generally defined as the process of increasing batch sizes. In process scale up, a formula is transformed into a viable, robust product by the development of a reliable and practical method of manufacturing that affects the orderly transition from laboratory to routine processing in a full-scale production CDMO facility. This is explored in detail in the subsequent question.

Steps 1 through 4, the development of drug substances via contract manufacturing services, are usually followed by packaging selection, discovery, and development services, and finally commercialization.

Q3. How can drug substances be developed from milligram procedure to Kilogram process?

Custom synthesis services to go from preclinical to clinical development and then to commercial scale production can be challenging. The development process has to be carefully managed and clearly defined. This is achieved during the scale up phase of API & molecule development.

Pharmaceutical process scale-up deals with a subject vitally important to the contract research & development industry—the procedures of transferring the results obtained via discovery and development services, explored above, from laboratory scale to the pharmaceutical pilot unit, and finally to production scale. Fully integrated contract manufacturers, for API and molecule development, have the custom synthesis expertise to provide scale up services at the laboratory and pilot scale of drug development

- Laboratory Scale: The early stage development phase, generally 100-1000 times lesser in quantity (milligrams) as compared to the production batch, takes place during the laboratory scale stage of formulation scale-up.

- Pilot Plant: It is used to test the behavior of a product during small scale custom API development and manufacturing, before proceeding with large scale production. Pilot labs often use kilo lab units to achieve low volume, test batches of active pharmaceutical ingredients.It is also an important stage for hazard identification and toxicity testing of drug products in a quality controlled testing laboratory. The pilot plant stage is where a lab scale formula is transformed into a viable product by using practical custom synthesis services and manufacturing procedures.

Production Scale: The last stage of scale-up (kilogram stage) is the production scale. Production batches are referred to as the 100X batch and this is the scale at which fully integrated contract research organizations, and more importantly contract development and manufacturing organizations, run during routine marketing of product.

Q4. What is the role of quality by design (QbD) approach in drug substance development and manufacturing?

Quality by design studies, which can be applied to a wide range of drugs, are usually implemented during the pilot plant stage of drug substance development. This discovery & development service can be used to validate analytical methodology, assess variability, perform method optimization of sample collection time intervals, and provide other information in a small number of subjects before proceeding with a full-scale bioequivalence study prior to commercialization.

The role of quality by design (QbD) in drug substance development and manufacturing:

Quality by design processes permit derisked scale up during drug substance development and manufacture with process optimization. When we look at the quality by design (QbD) approach, quality signifies the suitability of a drug substance for its intended use and includes attributes such as the identity, strength, and purity of products.

Significance of QbD:

- Ensures predefined standards of quality.

- Enables custom synthesis expertise

- Ensures product quality with effective control strategies.

Benefits of QbD:

- Eliminates batch failures during custom API development and manufacturing.

- Minimizes deviations and costly investigations.

- Enables regulatory intelligence monitoring.

- Enables better drug substance development and manufacturing decision making.

- Invests in future activities.

- Functions as small scale feasibility studies.

Q5. What is the difference between a chemical synthetic drug and a biologic drug substance?

Active pharmaceutical ingredients based on its sources can be divided into two major categories, including chemical synthetic drugs and natural chemical drugs.

Chemical Synthetic Drug:

A drug is typically manufactured through chemical synthesis, which means that it is made by combining specific chemical ingredients in an ordered process. The steps outlined in the custom synthesis of APIs, in question two, pertain to chemically synthesized APIs, whereas biologically sourced APIs are produced via fermentation.

Non-biologic, conventional drugs, increasingly called "small-molecule drugs," have an easily identifiable structure that can be replicated with 100% confidence in scores of manufacturing sites, across the globe.

Biologic Drug Substance:

A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules. Many biologics are produced using recombinant DNA technology.

Biologics are medications targeted to specific genotypes or protein receptors and can cost thousands of dollars monthly and require special handling, as they are often less stable than chemically derived drugs and require controlled temperature and light, as well as protection from jostling when in liquid form.

Natural chemical drugs, based on its sources, can be divided into two categories including biochemical drugs and plant chemical drugs. Antibiotics are generally made by microbial fermentation, which is a biochemical process.

Q6. What are the various considerations for biologic drug substance and drug product testing?

Ways to Ensure Regulated and Quality Controlled Development and Manufacture of Drug Substances:

In the context of globalization, APIs are sourced in a worldwide market and the risk of sourcing substandard or contaminated products is high. A proper system of regulation for drug substance development services can promote the constant sourcing of active ingredients of appropriate quality and thereby safeguard public health interests.

Biological drug development consists of two fundamental components: the drug substance (DS) development, which can include custom API manufacture, process development, and scale-up; and the drug product (DP) development, which includes the filling of the drug substance into the primary container.

Biological drug substances and drug products are assessed on the basis of preset standards set by regulatory agencies like the FDA and ICH against the development and manufacture of drug substances. Furthermore, cGMP guidelines for custom API development and manufacturing as well as other drug substance development services, can be used to ensure the quality APIs or drug substances.

Another standard, set by the FDA, that is used to assert the quality of APIs is the process validation guideline, which covers early drug substance development services through to finished dosage form (FDF) assessments.

As seen above, a significant part of the quality of a finished pharmaceutical product (FPP) is dependent on the quality of the active pharmaceutical ingredients (APIs). Therefore, it is important for companies (in-house manufacturers and contract manufacturers) to adopt the outlined strategies and comply with the regulations imposed on the development and manufacture of drug substances, to ensure not only the quality of the starting materials, but the overall quality of the end product that ultimately reaches consumers.

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