For this series of blog posts, we’re going to discuss Good Manufacturing Practice (GMP) and why is it important in the biotech industry.

What is GMP?

GMP is a set of regulations (enforced by the FDA) that are aimed at controlling the production quality of drugs, medical devices, blood, and some food products. Given the history of medical practice, the first drafts of GMP are fairly recent. They were published on July 21, 1978, two years after the enactment of the Medical Device Amendments of 1976. The regulations cover not just guidance for life science based manufacturing, but also the facilities involved in manufacturing, processing, packaging and storage of a drug or medical device.

GMPs exist today because consumers usually have no means to detect (through smell, touch, or sight) if a drug product is safe or if it will work. As a result, the consumer has to wholeheartedly trust the manufacturer of drug products and medical devises. A consumer receiving a prescription or taking a blood test, should not have to worry about if the function or final clinical result is valid. If the products are not made properly then the consumer is at risk. The government recognized this throughout the decades and acted to establish these regulations for protecting consumer safety and health.

How GMP is used for cell therapy?

The FDA classifies cell-based products as drugs. As a result, the production of cell-based products fall under this set of regulations to ensure such products are safe and effective.  Cell therapy products are being positioned to have the potential to cure diseases and they tend to be highly variable.  They are not a purified molecule or peptide and are functionally more complex in their interaction in the body. For some cases of cell therapy, the final action is relatively unknown, as compared to a purified drug.  For these reasons, the manufacture of cell based products under GMP is critical.

GMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Since GMPs were written well before the emergence of cell therapies, the industry (and FDA) have been working feverishly to agree to basic regulations. In all, the goal to establish GMP criteria is to protect patients during clinical trials and the public of approved products.

Within the regulations, the minimum requirements for the manufacturing of cell-based products are described as they pertain to the individual parts and components of a drug manufacturing process. In carrying out these GMP requirements, systems-based processes emerge. Some of the systems that come out of the guidelines provided by GMPs are:

  1. Quality Systems
  2. Facilities and Equipment Systems
  3. Materials Systems
  4. Production Systems
  5. Packaging and Labeling Systems
  6. Laboratory Control Systems

These are the bare essentials when it comes to cell-based product manufacturing. In designing, monitoring, and controlling these systems for manufacturing, GMPs provide a framework with which manufacturers can run their operations. Not all manufacturers will have to implement the same complete set of systems and requirements due to the varying nature of their respective operations, but there are basic expectations associated with the production of cell-based drug products.

Cell-based products are produced by culturing cells harvested from a source tissue. These production runs can go on for extended amounts of time, up to weeks or months for varying cell types. In that time, a lot can go wrong; however, GMPs help assure that the product has the right identity, strength, quality, and purity. This is important because cell therapy, seen as a drug product, brings with it many variabilities and the FDA wants assurances that what is produced is safe and effective.

Quality Systems

In order to adequately run the production process for cell-based products, the systems used need to confer control over the entire process. Quality systems such as the widely recognized ISO standards help manufacturers achieve quality policies and objectives for their products. These policies and standards need to be based in sound science in order to facilitate the production quality products.

Quality systems typically call for manufacturers to standardize and document processes in order to provide key insights into past and present production runs. With a good quality system, manufacturers can track the quality of their manufacturing inputs and outputs and adjust as idiosyncrasies arise in their processes. It is ultimately the function of the quality system to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products.

Facilities and Equipment Systems

To do the job right, you need the right tools… and facilities and equipment. If a manufacturer’s facilities and equipment are not adequate for the job, odds are the product will reflect that in its quality. Even more so with cell-based products.

To culture cells, aseptic techniques are essential. Some would say, here companies have to go beyond minimal procedures to guard against contamination.  With these manufacturing processes, procedures need to be performed inside cleanrooms in order to facilitate the optimal aseptic techniques and conditions.  Most companies begin with small batches of production and scaling up a cell-based product has complex manufacturing requirements. More robust systems are required and well with controls in the operational procedures.

Material Systems

Tohave the right product, you must begin with right starting material. As with most manufacturing, the starting materials used to produce the products need to be qualified, and validated. Cell-based drug products are derived from quality of the starting tissue source. If the starting material is not within the acceptable standards, the characterizations of the product will likely shift or change completely. This goes true for the materials used for the manufacturing process as well.

Production Systems

This system refers to the complete system of procedures, facilities and equipment, organization and personnel, inputs and outputs associated with the production of a cell-based drug product. This is distinct from a quality system. It is through the coordination of each of these components that a product is produced.

Established procedures and process controls used for drug production need to be clearly defined and adhered in order to assure that the drug products are what they’re represented to be. These procedures, along with any changes, need to be drafted, reviewed, and approved by the appropriate teams and approved by the quality control team. These written procedures and process controls need to be closely adhered to when performed so that consistency is maintained across production runs. Production and process control functions are to be documented at the time of performance, and any deviation from the written procedures need to be recorded and justified.  Reliable records and reports are generated with these practices. It’s through a good production system that conformity and reliability stem.

Packaging and Labeling Systems

Strict control needs to be exercised over packaging and labeling. Operations need to be designed to assure that correct labeling and packaging take place. Prevention of mix-ups and mislabeling is a critical aim of the system.

Cell-based drug products must be packaged and labeled properly in order to maintain product quality. Since cell-based products are prone to environmental factors like temperature and light, the packaging used to deliver the product from the production site to the user must be able to provide the necessary conditions to ensure product viability. For instance, cell-based products for immediate use typically required temperature-controlled packaging. On top of that, some products have additional requirements. In the case of OTC drug products, tamper-evident packaging is required to ensure consumer safety.

Laboratory Control Systems

This system of control is established off scientifically sound and appropriate specifications, standards, sampling plans, and test procedures to assure that the final product conforms to product standards of identity, strength, quality, purity. Batch testing, stability testing, animal testing, and other special testing requirements are used in the determination of conformance. Once all the testing requirements are fulfilled, the cell-based product is released for patient use.

Last Thoughts

The GMP regulations define the minimum standards for drug manufacturing. It’s usually well advised to implement these minimums. However, with cell-based product manufacturing, additional systems and layers are required to further assure product quality. That’s where the flexibility of the regulation is so crucial to manufacturers, for without that discretion to design and improve production processes, drug manufacturing can quickly turn into a big, messy endeavor. GMPs help avoid that and help manufacturers design the best systems and processes for their products.  These permits the freedom to implement comprehensive, modern quality systems and risk management approaches that exceed the minimum standards.

Biblio

  1. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM407991.pdf