By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Though many topics caught my attention during the FDA’s recent cell and gene therapy town halls, I was struck by the sheer number of questions related to defining, demonstrating, and documenting the quality of our raw materials.
The industry’s focus on raw material quality shouldn’t necessarily come as a surprise, seeing as the FDA itself acknowledged that a common CMC issue causing clinical holds for Phase 1 studies includes “using reagents which are not demonstrated to be of a sufficient safety or quality.” But I daresay the regulators themselves were slightly surprised by just how many questions we posed about our raw material quality, use, and documentation.
It goes without saying that what we put into our products and where we make them can leave unique fingerprints on our therapies’ overall quality. Finding high-quality raw materials and consumables has been a particular challenge in past years, in part thanks to COVID constraints, as well as the general immaturity of the supply-chain for ATMPs.
At the end of the day, the questions posed to the FDA during both the cell and gene town halls indicate that we are trying to better define “phase appropriate” development and understand where our material/vendor selection and qualification need to be more diligent. Unfortunately, as this town hall also demonstrated, there are many caveats to account for and quite a few shades of grey.
Despite the murkiness of the topic in general, there were a few best practices I took away from the FDA’s recommendations. I’ve broken these insights into several different overarching categories below.
Overall Reagent Quality: Trust Vs. Due Diligence
- Though the “GMP” on the label of our reagents may make us feel good about their safety/quality, the FDA gave us a friendly reminder: GMP is not actually a grade indicating overall reagent quality. Rather, it’s a descriptor of the controlled environment in which those reagents were made.
- As we already know, the FDA does not typically investigate reagent manufacturer facilities to affirm they actually are CGMP compliant. In turn, a supplier may say that a reagent is manufactured under cGMP, even if it isn’t. Now, before we start picturing our suppliers as the evil witch from Snow White, it may not necessarily always be a malicious misdirect so much as it could be over confidence about the general “health” of their compliance.
- Long-standing relationships with a supplier whose materials have historically met a sponsor’s specifications can provide the basis for greater trust and, in turn, a sponsor’s reliance on a supplier’s quality, safety, and purity confirmation of analysis (COA) documentation.
- However, please note: Regardless of whether you intend to rely on a (trusted) supplier’s confirmation of quality, safety, and purity, the FDA expects the sponsor will perform at least one identity test on each lot of reagent. Similarly, in the case that a supplier’s documentation is missing critical information about a specific attribute, it’s the sponsor’s responsibility to carry out that additional testing.
- Based on its CGMP for Phase 1 Investigation Products guidance, the FDA acknowledged sponsors can rely on a risk assessment to qualify raw materials to enter Phase 1. However, the agency still recommends the sponsor verify the identity of materials (e.g., components/containers/starting & raw materials) by the start of Phase 2 to be in compliance with the GMP principles outlined in 21 CFR 211.
- In addition to identity, you must also have documentation that these materials conform to the purity, strength, and quality specs, as well, to be in compliance with 21 CFR 211. This may translate to relying upon a vendor’s COA plus the sponsor’s own identity testing OR all the sponsor’s own analysis/confirmation of material or reagent quality/identity.
- And don’t forget that the reagents used in the QC lab demand just as much due diligence as those used in manufacturing. Overall, FDA relied on one of my favorite phrases — “fit for purpose”— when discussing the reagents used in QC; in other words, reagents used should be qualified prior to use.
- The path to more stringent, well-controlled assay performance may call for the use of higher quality reagents. However, FDA acknowledged that in-house reagent qualification could also be sufficient to promote greater control over your assays as you progress through development.
Raw Material Quality Expectations For Clinical Development
- During both town halls, there were a handful of questions centered around the use of research-grade materials in clinical development. Generally speaking, the FDA is not a fan of using research-only reagents/materials to manufacture a clinical-stage product. To do so, the sponsor must provide “significant information” on the manufacturing controls and/or quality control testing/COAs in place ensuring that the material or reagent will be suitable for clinical use.
- In some instances, flexibility may be warranted — for example, in the case of reagents used once to make IPSC clones which will be manipulated further. But as we know well, the agency’s willingness to be flexible ultimately depends upon our/our suppliers’ testing and documentation and our (the sponsor’s) rationale/justifications. And based off agency commentary throughout the past few years, clearly explaining and justifying our data-based rationale is where we tend to fall short.
Oversight of Material Supply (i.e., Plasmids) Into GMP Facilities
- For those specifically working with plasmids (specifically for viral vectors), you’ll likely already know that GMP plasmids are not required for GMP manufacturing of viral vectors. (And yes, viral vectors must be manufactured in a GMP environment.)
- Now that being said, relying on non-GMP plasmids in late-stage development is generally considered “risky business.” Everything I’ve heard suggests that companies are keen on playing it safe in this regard; some companies are even striving to source GMP plasmids for early phase manufacturing.
- The sponsor must align around specifications for the plasmid with the plasmid supplier, as well as with the GMP manufacturing facility. In turn, the GMP manufacturing facility will be able to ascertain that the plasmid meets those specifications when it arrives at the GMP facility. The GMP facility should also have a QMS in place to receive the plasmid (i.e., verify identity and confirm that it meets a sponsor’s specifications).
- Overall, it’s the sponsor’s responsibility to make sure that CGMPs are being followed in their manufacturing facilities and that the data being collected will support their product’s clinical and commercial use.
- For a closer look at how to appropriately manage quality of manufacturing and supply chain in an outsourcing relationship, you can refer to ICH Q10 section 2.7.