Or why it’s hard—but not impossible—to make a silk purse out of a sow’s ear.
It’s been over three decades since manufacturers introduced the first biologic from recombinant DNA—a biosynthetic form of “human” insulin developed by Genentech and marketed under the trade name Humulin.
Today, a growing list of monoclonal antibodies (mAbs)—and more recently fusion proteins—have been redefining how we attack cancer and other chronic diseases, while certain clot-busting drugs have become the standard of care in treating ischemic strokes. Blood factors and some vaccines use recombinant DNA technology, and there are even signs that the struggling field of gene therapy is starting to flex its muscles. In 2012, uniQure’s Glybera became the first gene therapy to be approved in the Western hemisphere—in this case for a rare and inherited lipoprotein lipase deficiency that triggers severe or multiple pancreatitis attacks.
Yet despite their growing popularity, the class of medicines known as biopharmaceuticals—or simply biologics—can be as finicky as Mother Nature herself. Arguably the biggest challenge in making biologics are flagging unwanted host cell proteins (HCPs) that inevitably show up in the finished product like ants at a picnic. Nano in scale, these trace amounts, nonetheless, can be highly immunogenic—and can ultimately sink a potential biopharmaceutical—so manufacturers work hard to identify and control any impurities in the final product.
This has traditionally meant using commercial kits—off-the-shelf generic assays that are readily available and require no preparation—to detect HSPs, loosely defined as any ingredients that are not part of the product. But the “black box effect” associated with this method can be hit or miss, so some drug makers have turned, increasingly, to product-specific assays and, as a backup, mass spectrometry to quantify protein interlopers that can interfere with the drug. This more time-consuming approach brings greater breadth and depth to HCP protein analysis, which is one reason why both the U.S. Pharmacopeial Convention, which establishes written standards for such things as medicines, food ingredients and dietary supplements, and its counterpart, theEuropean Directorate for the Quality of Medicines and HealthCare that publishes the European Pharmacopoeia, are writing new chapters that specifically address how drug developers deal with these HCPs. Both groups are expected to release draft guidelines later this year.
Will the future guidelines signal a dramatic shift for the field, and will the US and European versions be significantly different? My sense is no and no. Both groups tend to be fairly conservative. Moreover, both these bodies communicate with each other so surprises are unlikely. What these recommended standards are likely to do is provide some clarity on how best to develop and validate assays that companies can embrace and which meet regulatory requirements. For instance, the recommendations will, for the first time, specify validated tests and reference standards for quantifying residual E. coli and Chinese hamster ovary (CHO) genomic DNA in biologics derived from recombinant protein. There is also a chapter being written on best practices for developing and validating residual HCP procedures.
Sophisticated labs with extensive expertise in bioanalysis understand well how complex it can be to purify these molecules, so the new standards will probably only reinforce what they have been doing for over a decade. But not every company takes the high road. It’s only been in recent years that biopharmaceutical companies began waking up to the inherent problems in purifying biological products—regardless of whether they were produced by recombinant fermentation or extracted from natural sources—and finding reliable methods of validating the results.
Consider the rocky journey that a human growth hormone (hGH) product took when it reached late-stage testing. Unexpectedly, researchers detected an increased ratio of patients with elevated levels of anti-hGH antibodies related to HCP impurities. A commercial assay used in the study failed to detect a specific HCP that was in the final drug substance. It was only after a more sensitive, process-specific assay became available that the protein was detected and the purification process was optimized, leading to a decline in anti-hGH levels. But to reach this juncture the study also had to be repeated—at significant cost to the company—in order to confirm the lower immunogenicity.
For tips on a more comprehensive system of removing the protein impurities, see my second blog in this package.