Is GMP Grade Good Enough?

Many suppliers of raw materials for mRNA production loosely use the term “GMP grade” on their products. In nodding to good manufacturing practices (GMP), the term gives the impression that all materials comply with strict consensus standards across the industry. The problem? “GMP grade” is not well defined for product quality measures, and raw materials sold under that banner can expose companies to costly risks.

There are no standardized product quality attributes required for an mRNA raw material to be classified as GMP grade. Most, but not all, mRNA materials sold as GMP grade are of good analytical quality and animal origin-free, but beyond that there are significant differences. It is very rare for suppliers to make the full suite of quality support documents available, follow ICH Q7 GMP guidelines, or have a validated manufacturing and testing process specific to each product.

Raw materials with product quality attributes such as item-specific product stability and manufacture in facilities that are free from β-lactams and ingredients of animal origin are more common; however, it is still possible to buy GMP-grade mRNA raw materials that lack those features. The upshot is that raw materials sold under the same GMP-grade designation possess a wide range of quality attributes.

Does that matter? All GMP-grade materials are sold as being suitable for use in the production of mRNA therapeutics and vaccines. With many process development scientists focusing on subsets of product quality attributes such as analytical quality, use of animal origin-free materials, and cost, GMP-grade raw materials can meet the criteria used by those buyers.

The problem lies among product quality attributes that are excluded from many definitions of GMP grade, which are often overlooked by buyers. These attributes decrease the chances of a therapeutic or vaccine avoiding expensive, time-consuming pitfalls as it moves through development, the regulatory approval process, and into commercial production. To mitigate these risks, process development scientists can look for materials with product quality attributes that go beyond those typically seen in GMP-grade products.

Companies that prioritize cost over product quality attributes when choosing mRNA materials should do so with their eyes open, with awareness of the mid- and long-term risks associated with their short-term savings. A seemingly simple choice, out of the innumerable choices made during mRNA development and production, can have far-reaching ramifications with the potential to harm large pharmaceutical companies and small biotech firms alike.

Some of the risks stem from the use of verified, rather than validated, processes to make raw materials. Materials produced using a verified process can meet specifications for one batch of materials but may show considerable lot-to-lot variability. Validated methods are critical to achieve the excellent consistency needed for large-scale, routine manufacture of a drug. Manufacturers take risks on quality when they source raw materials made using verified processes. At some point, they may find that a lot does not meet requirements for their use or regulatory approval.

“If they reject a lot of starting material, they may have to wait for the next batch to be made for six or eight weeks. That’s going to cost them tens of millions of dollars because they went with a cheaper supplier who isn’t delivering all these quality metrics. Or, even worse, they’re going to make a batch and then find out that there’s some impurity in it that wasn’t in the last batch,” said Darwin Asa, PhD, Global Market Development Manager, Nucleic Acid Therapeutics at Thermo Fisher Scientific.

Some companies have learned the hard way of the risks associated with GMP-grade raw materials. A developer of an mRNA vaccine against SARS-CoV-2 used a lower-quality grade restriction enzyme, saving money and enabling it to quickly produce material for a phase I/II clinical trial. However, the decision had severe consequences. Before signing off on a clinical trial, regulatory agencies asked for proof that the vaccine used an animal origin-free enzyme that was fully traceable from its source.

The supplier was unable to meet the request, delaying the project by 18 months and counting, and forcing the vaccine developer to resynthesize clinical trial material. With the project being stalled, the decision to use a cheaper enzyme cost the company hundreds of millions of dollars in lost revenue.

This case shows the importance of starting with the end in mind when choosing mRNA raw materials. By focusing on supplies of high quality, security, and scalability early in the process, companies can reduce the risk of expensive, time-consuming delays down the line. Thermo Fisher Scientific is fully focused on helping its customers insulate from such risks.

The Thermo Scientific TheraPure GMP* product portfolio of enzymes and nucleotides is differentiated from GMP-grade raw materials provided by other suppliers. The manufacturing quality and documentation for TheraPure GMP products go well beyond analytical quality and include the use of animal origin-free materials, product-specific stability data, impurity profiles, and use of verified compendial test methods, where applicable. TheraPure GMP products are all manufactured using validated processes and are tested by validated methods according to ICH Q2 guidelines.

While some raw material buyers overlook such attributes, the costly setbacks seen already in the short history of the mRNA modality show their importance. For mRNA manufacturers that want to mitigate risk, product quality attributes are essential guarantees about the consistency and performance of the raw material.

Manufacturers that choose Thermo Fisher as their raw material supplier can benefit from more than just the most comprehensive set of product quality attributes in the industry; they will also gain access to the support of a company with proven records of raw materials used in approved mRNA products.

Through its work on supporting SARS-CoV-2 vaccines, Thermo Fisher has learned what technical support its partners need and established a supply chain with manufacturing sites that has the resilience to cope with unforeseen disruptions. Now mRNA manufacturers need to decide whether to rely on a tried-and-tested partner or take chances on GMP-grade materials that can expose them to significant risks.

* “TheraPure GMP” refers to the quality level of the raw, ancillary, or starting materials to be used for further manufacturing. TheraPure GMP products are manufactured in facilities with ISO 9001-certified quality management systems that operate in accordance with relevant good manufacturing practice (GMP) principles, as outlined in ICH Q7 or equivalent guidance documents or standards.