What changes when a project transitions from research laboratory to clinical GMP production environment?
From Research Stage to GMP Production
What changes when a project transitions from research laboratory to clinical GMP production environment?
From the initial discovery phase through development and into commercial production, drug developers encounter numerous hurdles along the product journey. These challenges arise not only in the biological context but also within the regulatory framework. Biopharmaceutical production must follow Good Manufacturing Practice (GMP), a system for ensuring that manufactured products are consistently produced and controlled according to set quality standards.
As a result, the operational environment of a GMP manufacturing site significantly differs from that of a research laboratory.
Why does GMP exist?
Due to some unfortunate historical events, the need for standardized regulations was realized,ultimately leading to the establishment of GMP system as we call it today.
In the early 1900s, there was a real Wild West in medicine with no regulations to protect the public from dangerous products, such as contaminated injections. An unfortunate example is the diphtheria scandal around Jim, a horse that was used to produce diphtheria antitoxin. One day Jim showed signs that he had contracted tetanus and was thereafter euthanized. Due to amix-up in the serum harvesting records, the contaminated serum prepared from him was administered to diphtheria patients. As a result, several children died after receiving the contaminated antitoxin.
In 1937, the Sulfanilamide disaster claimed over 100 lives after a toxic solvent was used in a cough syrup formulation to dissolve the sulfanilamide. At the time, no law required safety studies of new drugs. A chemist working on the cough syrup failed to note that the new formulation contained a toxic solvent, diethylene glycol, causing mass poisoning.
Despite the onset of “The Federal Food, Drug, and Cosmetic Act” in the 1938, history repeated itself in 2007, when a cough syrup containing the same toxic solvent, diethylene glycol, caused the death of nearly 400 people in Panama. The compound had been imported from a Chinese manufacturer under the name TD glycerine, meaning ‘glycerine substitute’. A Spanish intermediary later mislabeled it as glycerine on customs documents, which led to its unintentional use in medicine. Using today’s GMP guidelines in the EU and US, these kindsof mix-ups and inaccuracies should not be possible since GMP specifies identity control of all used raw materials.
Later, in the late 1950s, the Thalidomide tragedy resulted in severe birth defects in more than 10,000 children worldwide after the drug, initially developed as a sleeping pill in Germany,became a popular off-label treatment against morning sickness during pregnancy.
In response to such events, regulations were gradually established to address growing safety concerns. The regulation of clinical studies was established, as well as procedures for regulatory approvals and quality assurance in the development of drugs products. The World Health Organization (WHO) formulated the first GMP guidelines for drugs and medical devices by the end of the 1970s. The European Medicines Agency, known as EMA, was founded in 1995 and it is responsible for assessing and monitoring drug products to maintain and promote public health in the EU. In Europe, GMP inspections are performed by national regulatory agencies that work under the umbrella of the EMA.
Unfortunately, drug-related scandals did not end there. A number of subsequent incidentshave led to ongoing revisions of GMP regulations. As a result, GMP is often referred to as cGMP, where the ‘c’ stands for current reflecting, that best practices must be continuously updated to better protect public health.
What does GMP mean in practice?
Moving from the research stage to GMP production converts into strict requirements forquality and traceability, where there is no room for shortcuts.
Let’s break down the main differences between the research stage and GMP production.
GMP Production Facility
A GMP production facility must be designed to meet both GMP standards and biosafety requirements.
One critical GMP aspect is maintaining cleanroom conditions, which involves keeping the air free of particulates. This is often achieved through specialized ventilation systems, such as single-pass airflow designs that avoid recirculating air.
Unlike in common research laboratories, where personnel can enter wearing standard lab coats through regular doors, GMP cleanrooms require entry through pressured airlocks and the use of specialized protective clothing, including coveralls with hoods and masks.
The specific level of control depends on the cleanroom classification. Regardless, personnel working in GMP environment must be adequately trained, familiar with GMP requirements, and highly aware of potential contamination sources, such as skin flakes, textile fibers, and hair.
GMP-grade Raw Materials
In the early development and preclinical stages, research-grade materials are typically used due to lower cost and easier availability. However, once production advances to clinical study phases, all raw materials and consumables must be manufactured and documented according to an established quality system.
Unlike in academic settings, where reagents like sodium chloride may be used without extensive documentation, GMP production requires materials with a complete and verifiable history. In practice, CDMOs are responsible for sourcing GMP-grade materials, which involve rigorous auditing and qualification of material suppliers.
Additionally, GMP regulations impose strict controls on the receipt, testing, release, and storage of raw materials. Storage conditions must be carefully monitored, inventory must be accurately tracked, and materials can only be released for production after quality assurance has confirmed that they meet all specifications.
GMP Equipment
Laboratory and manufacturing equipment, such as bioreactors, analytical instruments, and filling lines, among others, are not GMP-certified in themselves, simply because of the diversity in the biopharmaceutical manufacturing processes.
The basic rule is that the equipment used in GMP manufacturing needs to be suitable for its purpose and comply with applicable technical rules. It must be easy to clean and must not have any negative impact on the quality of the product.
Unlike in research laboratories, where methods like ultracentrifugation perform well at a small scale, GMP production requires replacing some of these techniques with alternative technologies, as they are difficult to scale up and challenging to clean. For this purpose, CDMOs have process development teams that support clients in the technical transition andupscaling to GMP grade.
GMP Processes
In a GMP environment, biopharmaceutical manufacturing must be carried out under strict procedural and operational controls, which differ significantly from the flexible workflows in academic research environment.
One core GMP process requirement is dedicated manufacturing. Unlike in research settings, where multiple processes can run in parallel, only one product may be produced in a givenroom at a time under GMP conditions. This segregation helps minimize cross-contamination risks but also increases the production costs.
GMP also demands comprehensive process standardization and documentation, as well as trained personnel. All steps in production must be pre-defined in writing and strictly followedand recorded during execution. To ensure the robustness of the process before initiating the full-scale GMP production, manufacturers typically run pre-GMP batches, such as engineering batches or consistency batches. These are essential to confirm that the process behaves as expected under GMP conditions and to identify any necessary adjustment in advance.
GMP Analytics
Analytical methods used in GMP production must be validated and performed strictly according to Standard Operating Procedures (SOPs), which precisely define how each analysis must be performed.
Unlike in academia, where protocols can be adjusted and modified as needed, the GMP environment allows no room for on-the-fly changes. Once a method is developed and validated, it must be followed exactly as documented. In addition, all associated analytical software systems must meet data integrity regulations, ensuring the reliability and security of results.
GMP-manufactured biopharmaceuticals must also comply with predefined quality control specifications, which may include parameters such as bioburden limits, endotoxin levels, concentration, pH, and osmolality. If a batch fails to meet these specifications, it cannot be released. In GMP manufacturing, quality assurance operates independently and must issue a certificate of analysis before a qualified person can authorize release of the product (in Europe).
Furthermore, GMP requires stability studies for both drug substance and final product to establish appropriate storage conditions and to determine the product’s shelf life.
Summary
Although operating under GMP standards is time-consuming and resource-intensive compared to working in a research setting, it is necessary for patient safety. These legally enforced GMP regulations require biopharmaceutical manufacturers to take proactive measures that ensure product safety, quality, and efficacy. GMP encompasses every aspect of the production process, from facility design and raw material sourcing to equipment validation, process control, IT systems, personnel training, and sanitation.
Moreover, GMP manufacturing is limited in terms of flexibility, as any spontaneous modifications must be avoided in favor of fully documented, pre-approved procedures. But in the end, the added complexity in manufacturing processes is worth it – no-one wants to live through another Sulfanilamide disaster or Thalidomide tragedy.