Clinical Manufacturing – How It Works

July 4, 2022

The drug development process includes five main stages:

Discovery and Development
Preclinical Research
Clinical Research
Regulatory Agency Review
Regulatory Agency Post-Market Safety Monitoring

Clinical research is the third stage of the drug development process. Drugs being tested during this stage are not necessarily manufactured in the same way or at the same facilities as products intended for commercial production.

In this article, we’ll discuss the basics of clinical manufacturing, including:

What clinical manufacturing is
Current Good Manufacturing Practice (cGMP) guidelines
The differences between clinical and commercial manufacturing
The benefits of specialized clinical trial manufacturing services

What Is Clinical Manufacturing?

Clinical manufacturing, also known as clinical trial material manufacturing (CTM), focuses on producing drugs for use in clinical research. Manufacturing can take place at different scales, allowing greater flexibility as development programs evolve.

One of the first steps in clinical manufacturing is to create a development plan and timeline that provides a roadmap for the manufacturing and clinical trial process. This planning should take place before an Investigational New Drug (IND) application or Investigational Medicinal Product Dossier (IMPD) is formally submitted.

To maintain the integrity of clinical manufacturing, consistency is essential. Following cGMP guidelines and implementing appropriate quality controls are key factors in producing consistent clinical trial materials, even when formulations and dosages may still evolve.

Implementing appropriate cGMP principles as early as possible in drug development can help protect the safety of clinical trial participants while establishing a foundation for a robust quality management system (QMS) and the gradual integration of manufacturing processes.

Current Good Manufacturing Practice (cGMP) Guidelines

During new drug development, clinical project teams often need to determine when and to what extent current Good Manufacturing Practice (cGMP) requirements should be applied.

cGMP requirements apply to many types of drugs during clinical development, including vaccine products, recombinant and non-recombinant therapeutics, small-molecule drugs, gene therapies, and other medicinal products. For recombinant products specifically, understanding how protein expression works can help clarify the manufacturing controls involved.

However, the applicable GMP requirements can vary depending on the type of product, stage of development, and applicable regulatory framework.

GMP is a system designed to ensure that products are consistently produced and controlled according to established quality standards. It aims to minimize risks in pharmaceutical manufacturing that cannot be eliminated through testing the final product alone.

In this article, we focus on FDA and EMA requirements and guidance.

FDA Regulations and Guidance

FDA cGMP regulations for drugs are published in Title 21 of the U.S. Code of Federal Regulations, including Parts 210 and 211 (21 CFR 210/211). Certain investigational drugs manufactured for use in Phase I clinical studies may be exempt from compliance with 21 CFR 210/211 under the applicable provisions; however, this exemption does not apply to:

An investigational drug used in a Phase I study once it is available for use in a Phase II or Phase III study.
A drug lawfully marketed as a monograph drug or under an FDA-approved marketing application.

Additional guidance on cGMP for investigational drugs used in Phase I clinical trials is provided in the FDA’s Guidance for Industry on Current Good Manufacturing Practice for Phase 1 Investigational Drugs. According to 21 CFR 210.2(c), the cGMP regulations formally apply to drugs used in Phase II and Phase III studies.

EMA Regulations and Guidance

The European Medicines Agency (EMA) coordinates inspections to verify compliance with applicable standards and plays an important role in harmonizing GMP activities at the European Union (EU) level.

The Agency has a coordinating role in GMP inspections of manufacturing sites for medicines whose marketing authorization in the EU is submitted through the centralized procedure or as part of a referral procedure.

Manufacturers of medicines intended for the EU market must comply with applicable GMP requirements, regardless of where they are located. GMP requirements are designed to ensure that medicines:

Are of consistent and appropriate quality
Are suitable for their intended use
Meet the requirements of the applicable marketing authorization or clinical trial authorization

Several EU legal instruments establish the principles and requirements for GMP, including:

Regulation No. 1252/2014 and Directive 2003/94/EC, applying to active substances and medicines for human use
Directive 91/412/EEC, applying to medicines for veterinary use

In addition, Directive 2001/83/EC and Directive 2001/82/EC contain related provisions.

Clinical Manufacturing and Commercial Manufacturing: What’s the Difference?

The main difference between clinical and commercial manufacturing is the level of flexibility required. Clinical manufacturing needs to accommodate evolving formulations, dosages, batch sizes, and development requirements.

Commercial drug manufacturing, by contrast, typically involves established processes and batches produced according to defined specifications. During clinical development, individual batches may differ as the formulation and manufacturing process are refined, making flexibility particularly important.

One common challenge for clinical trial materials is coordinating the supply chain. Components may come from different facilities or even different continents. This becomes particularly important when a biologic is part of the clinical trial supply, as materials may need to be stored within defined temperature ranges and protected from contamination or other conditions that could affect product quality.

Shipments must therefore be carefully monitored. Temperature excursions and unfavorable environmental conditions can affect sensitive clinical materials, potentially compromising product quality and the integrity of clinical research. Because clinical trial materials are distributed to trial sites rather than directly to patients, they must be stored under appropriate conditions until they are ready for use.

Quality assurance can also be more complex during clinical development. Commercial manufacturing generally involves established products, packaging, and processes, whereas clinical trial materials may be produced in smaller batches while the manufacturing process continues to evolve. Careful planning is therefore important. Considering cGMP requirements early can help minimize risks and support development milestones rather than requiring compliance measures to be added later in the process.

Benefits of Specialized Clinical Trial Manufacturing Services

Working with a specialized CDMO such as 53Biologics can provide pharmaceutical companies with manufacturing expertise and support throughout clinical development. Experienced CDMOs can help navigate cGMP requirements and establish processes that support the transition from clinical trial manufacturing toward later-stage and commercial-scale production.

53Biologics also offers rapid process development services, working with discovery-stage pharmaceutical companies to develop laboratory-scale processes suitable for preclinical testing. As programs advance, we can provide trial formulations suitable for animal studies, toxicology studies, and cGMP clinical trial materials for Phase I research.

More than 98% of proteins handled by 53Biologics have shown improvements in production and/or recovery yields.

Learn More About Clinical Manufacturing

If you are considering a specialized CDMO for clinical trial supply manufacturing, 53Biologics can support your program with expertise in biologics development and manufacturing. Contact us to discuss your project and clinical manufacturing requirements.