Stepping from the world of laboratory or animal research into that of in vitro diagnostics (IVD)—where reagent quality can impact critical medical decisions—involves figuring out a lot more than simply how to scale up production. Regulations and certifications, quality control and quality assurance, documentation, and even the ability to multiplex are all impacted by the transition from research use only (RUO) to IVD.
For oligonucleotides, the industry is essentially segmented by how the oligos are to be used: research, diagnostic, and therapeutic applications, says Roman Terrill, J.D., business unit leader for clinical and commercial manufacturing at Integrated DNA Technologies.
While there may be some overlap between the first two, oligos sourced as active pharmaceutical ingredients—for antisense or RNA interference, for example—are “almost a completely separate conversation.”
This distinction is evident in the separate tracks at next month’s “TIDES” conference, Terrill noted, where he and Chad Gerber will participate in a panel discussion entitled “The Oligo Supply Chain for Diagnostics—Getting your Research to the Market.”
Design and development require the flexibility to tweak things—optimize the oligos, adjust reagent concentrations, and generally change the reaction conditions. For the RUO market, “they want it to function as intended, they want it quick, and they want it cheap,” explains Gerber, director of GMP manufacturing and commercial services for Biosearch Technologies.
But as companies scale up for commercial and IVD production, they need to know when to get things locked down. Yes, they still want competitively priced oligos, but they also have the luxury of better forecasting, enabling them to plan and test well in advance. As Gerber notes, “lot-to-lot consistency becomes a top priority.”
“The FDA and insurance companies that manage reimbursement issues are demanding more and more that oligos used in laboratory-developed tests be manufactured as analyte specific reagents (ASRs) and not labeled as research use only,” comments Terrill.
“The ASR standard is not new, but I think it’s fair to say that the practice of CLIA labs purchasing ASR-labeled oligos, rather than RUO-labeled oligos, has intensified within the last several months. And the oligo industry has responded broadly, by providing customers with a choice.”
To use the ASR label, oligo manufacturers have stringent process and procedure controls that assure a consistency not necessarily found in RUO products. The FDA’s good manufacturing practice (GMP) for medical devices documents control, design control, and change control, among other things.
“We have a quality system catered to managing these controls” for commercial and IVD uses, says Gerber. For example changes in supplies, manufacturing equipment, protocol, or anything else that could possibly affect the form, fit, or function of the final product is documented and coordinated with the customer through the change control procedure.
Many manufacturers in both the research and diagnostic spheres will maintain distinct systems and facilities for each. “At IDT, for example, we have an entirely separate internal facility, with its own dedicated instruments and own dedicated HPLC and analytical systems, that is directed at making the oligos that are GMP and labeled for use in diagnostics.
“That facility is registered with the FDA and has an ISO 1345 certification, rather than ISO 1901 2008 certification, which is for research,” Terrill says. At the end of the day it’s a separate business, with completely separate management, quality personnel, and even sales infrastructure.
As a rule RUO may use batch processing with a less documented process. In addition, typically a research customer will order lower purity oligos, which utilize faster and cheaper purification processes.
“This may be adequate for research applications,” Gerber explains. “But if they want GMP oligos, they may decide to increase the purity requirement.” For that, HPLC is required, yielding a product that is more consistent lot-to-lot—since it’s the impurities that will often vary.
Biosearch works to understand and alleviate concerns that its GMP customers may have with regard to purity and contamination. Those anxious about genomic contamination can request that their oligos be prepared under a laminar flow hood, for example, while those worried about the presence of other oligos can order dedicated HPLC columns and a full purification system decontamination and cleaning between runs, with an accompanying validation package to back it up.
To transition customers from RUO to IVD, customers can have their oligos “manufactured under the same processes, staff, and equipment as GMP,” Gerber says of Biosearch’s PilotDx™ program. Other companies may have similar programs.
“Now you can evaluate and do final product optimization—it’s manufactured with a reduced batch record, so it doesn’t have the same pedigree as material fully manufactured under GMP. However, PilotDx manufacturing allows us to make oligos cheaper and quicker while optimizing our manufacturing process in anticipation for scaling up to full-blown GMP production.”