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Best practices to consider when transitioning from research-grade to GMP-grade materials.
Transitioning to reagents labeled GMP (good manufacturing practices) in the development of advanced therapy medicinal products (ATMPs), such as cell and gene therapies, can be complicated and is a potential bottleneck when the urgency for speed is particularly heightened.
In the early discovery and preclinical stages, most materials will be predominantly for research use only (RUO) due to availability, flexibility, and cost benefits. However, once proof of concept has been established and there are sufficient data to support a move to the clinic, there is a real urgency to develop a documented process, get to clinical studies and, ultimately, to market. It is at this point—the transfer from discovery to process development—that the focus shifts to developing a manufacturable process, which will require the implementation of GMP-grade materials.
However, it is also exactly at this point that, if not well planned for, things can begin to go awry. The pressure to move quickly can mean that organizations simply do not have the time to adequately plan and strategize for the change to GMP, which can be especially difficult for smaller and start-up companies that may have only limited commercial manufacturing experience.
So, how can one ensure the transition to GMP runs as smoothly as possible? While the process will be different for each organization, the simple answer is that it is never too early to start thinking about GMP reagents and to evaluate suppliers that can help transition from the research phase to the clinical production phase. Seek out experienced suppliers, think ahead, and perform initial risk assessments to strategize how to make the transition. A good reagent supplier should be able to effectively handle the transition of reagents to a GMP process quickly and easily to avoid significant interruption or delays, as well as provide valuable advice and expertise.
While there is no shortcut to implementing GMP, one way to mitigate road bumps in the transition from RUO reagents to GMP reagents is to start with RUO materials manufactured to a higher standard of quality. Of course, the ideal scenario would be to start with GMP-grade reagents and, therefore, entirely negate the need to transition at all; however, GMP-grade versions of reagent formulations are often not available off the shelf, are more expensive, or—perhaps even more importantly—function differently. One such example is RUO-grade lipid-based transfection reagents used to produce viral vectors. These reagents do not currently have a direct GMP equivalent, yet they typically provide higher yields than GMP-grade alternatives such as polyethylenimine (PEI). At the point in discovery where transfection reagents are commonly implemented, the need is simply to produce enough virus for rapid proof of concept, leading many organizations to choose to use RUO-grade materials here for the benefits of availability, turnaround, and flexibility.
In lieu of using GMP-labeled reagents from the outset, researchers can instead look to suppliers that adhere to International Organization for Standardization (ISO) manufacturing standards. Adherence to ISO standards provides a good foundation of written procedures and training that include manufacturing protocols, raw materials requirements, quality records, product design, certification, and packaging/shipping. Reagents manufactured to an ISO standard will also have the important flexibility needed for high quality preclinical research.
While the common ISO 9001 standard (1) is undoubtedly better than standard in-house manufacturing or no ISO compliance at all, a significant step up from this is a supplier that manufactures RUO reagents under the medical device standard ISO 13485:2016 (ISO 13485) (2). ISO 13485 represents the requirements for a quality management system (QMS) for the design and manufacture of medical devices and is recognized as a harmonized standard by FDA (3,4). The benefits of starting with products manufactured under ISO 13485 standards include traceability, a change control process, and testing, which allow flexibility to continuously improve processes and mitigate costs, such as switching to less expensive enzyme alternatives, and the adjustment of risk controls based on valid statistical quality thresholds (e.g., optimizing functionality testing).
Both the ISO 9001 and ISO 13485 standards are designed to enable the consistent manufacture of safe and high-quality products; however, there are some key differences that facilitate the transition to GMP from ISO 13485. The ISO 13485 standard is for medical devices; therefore, it is more stringent and puts more emphasis on risk management during product realization, as well as having more extensive documentation requirements and being closely linked to regulatory requirements. In fact, using reagents manufactured to ISO 13485 standards can even increase speed to market, and some countries recognize certification to ISO 13485 standards to support regulatory approvals.
Although ISO 9001 is focused on continuous improvement and customer feedback, ISO 13485 centers on establishing processes, policies and procedures, and the ability to consistently demonstrate that products are fit for purpose. ISO 13485 also has a high level of risk management that requires processes to be in place for all stages of product manufacturing as well as training and staff supervision, project site specifications, and prevention of contamination. Importantly, as part of the evaluation process for design and development, clinical evaluation must be performed in line with regulatory requirements. Contamination control and product cleanliness are also taken into consideration, as well as product status related to measurement and monitoring. Additionally, information from post-market surveillance (production and post-production) creates the feedback system required by regulatory agencies to demonstrate the consistency and effectiveness of the quality system.
Starting with RUO reagents manufactured to ISO 13485 standards and then making the transition to GMP manufacturing with the same supplier delivers advantages such as reduced costs, rapid process transition and fast delivery timelines, and accelerated scale-up by ensuring proper risk controls, traceability requirements, change control, and appropriate testing.
Manufacturing needs differ for different applications and purposes, and the transition to GMP will have unique challenges for different groups. For example, an academic team may face challenges related to regionally distributed research teams and limited to no manufacturing experience. Small biotech companies might be under particularly high pressure due to funding restraints and the market need for speed, while larger biotechs and pharma organizations could have challenges related to cost savings and buying vs. making decisions. Therefore, one of the most impactful ways to prevent headaches down the road is to make sure the chosen suppliers not only have the required experience and expertise but, importantly, understand the larger picture and constraints beyond that of a reagent or assay alone.
When selecting a supplier for RUO-grade materials, there are several key manufacturing considerations to help provide a smooth transition to GMP reagents. Ensuring that the supplier has a strong background in manufacturing biological products with robust quality systems, such as certification of ISO 13485 compliance, already in place delivers both reliable assistance in developing reagents and a seamless transition between reagent grades. The supplier should be able to provide lot-to-lot consistency by performing the quality control (QC) and analytical tests necessary to ensure product specifications are met. The manufacturing organization should also have a technical background in design and development processes, and ideally, experience of making large numbers of different buffers and reagents packaged in a variety of container types.
It is also important to assess from the outset the supplier’s forward capabilities to meet future needs. It is easier to transition from RUO to GMP reagents with a single supplier because that supplier will have the proper documentation in place, like the device master record (DMR) and design history file (DHF) specific to a product and its particular manufacturing requirements. However, choosing a vendor who cannot meet future GMP reagent supply needs may force a change of manufacturer when GMP manufacturing is required, which could cause significant delays and added cost.
“Trust but verify” open-door auditing is necessary in GMP production. Make sure a supplier’s manufacturing team accommodates on-site process or product spot audits. Audits are especially important for new GMP production processes to identify and address issues before they become a headache. The importance of excellent technical support should also not be underestimated. A good supplier should be able to both customize and even improve on specifications to facilitate scale up at GMP.
One of the major differences between RUO and GMP manufacturing is the quality and testing of raw materials. How raw material sourcing and testing is done can limit the available selection of materials for reagent production. A good manufacturer should be able to access a wide range of testing and validation methodologies to provide a wide selection of raw materials. In addition, a supplier that negotiates purchase of raw materials and that has the ability to hold or store finished product will decrease the pressure on logistical teams and can speed the transition while decreasing inventory management costs.
While transitioning from use of RUO reagents to GMP requires more controls, planning ahead by selecting the right manufacturer for RUO reagents can help ease the process, avoid bottlenecks, and be cost-effective. Look to start RUO reagent production with a supplier that is FDA registered and has a QMS that is certified as being ISO 13485:2016 compliant. Also, be sure to verify the necessary scientific and manufacturing expertise—from raw material qualification and testing to logistics.
1. ISO, “ISO 9000 Family—Quality Management,” iso.org, accessed Sept. 15, 2020.
2. ISO, “ISO 13485:2016—Medical Devices—Quality Management Systems—Requirements for Regulatory Purposes,” iso.org, March 2016.
3. FDA, “FDA Update—Transition to ISO 13485:2016,” FDA.gov, December 5, 2018.
4. HHS/FDA, RIN: 0910-AH99 (Office of Information and Regulatory Affairs, Silver Spring, MD, reginfo.gov, accessed Sept. 15, 2020.
Bella Neufeld is scientific director at Teknova, an ISO 13485-certified and GMP reagent manufacturer.
Vol. 33, No. 10
When referring to this article, please cite it as B. Neufeld, "Avoiding the GMP Bottleneck," BioPharm International, 33 (10) 2020.