A mom-and-pop approach to drug production may be an appealing, alternative option for the manufacture of biopharmaceuticals, argue the authors of a new commentary published in Nature Biotechnology. Rather than being produced on a commercial level, the manufacture of personalized medicines that are developed to target a defined disease biomarker should happen at a patient’s bedside. The authors of the article, who are from the Utrecht University in the Netherlands, essentially suggest adopting a compounding approach for the production of biopharmaceuticals. The pilot program the authors propose would complement, not replace, the commercial manufacture of biologics.

The commercial manufacture of many targeted therapies is a wasteful endeavor, say the authors, and the way biomarkers and genetic material are collected and validated in clinical practices isn’t standardized, making it difficult for FDA-approved targeted therapies to actually reach the right patients. Developers have a hard time identifying the correct biomarkers for a disease, and few drug companies (especially in the case of small biotech companies) have enough resources to launch companion diagnostic tools to adequately measure the levels of a particular biomarker present in any given patient, the researchers write.

Additionally, regulation from FDA constrains how drug makers manufacture drugs once they are approved—the method of manufacture is “baked into” the drug’s approval, and any substantial changes to the way a drug is made may require additional FDA chemistry, manufacturing, and controls (CMC) postapproval. Patent considerations also play into a company’s decision to pursue an investigational drug candidate, the authors note, and patent protection can restrict patient access to a drug. For patients who are close to death, the current timelines for drug development are not feasible, they add.

Drugs that would be good first candidates for the bedside production approach would be biosimilars, the authors suggest, as the profit opportunities for these medications are small, and commercial manufacturers may not pursue their development as a result. To test their hypothesis, the researchers conducted a pilot program in collaboration with an unnamed high cell density perfusion culture system vendor for the production of recombinant human alpha-glucosidase (rhGAA), and they say the resulting product will be tested for safety and efficacy forthcoming in clinical trials. The researchers also plan to donate the clone, production technology, and clinical data to the World Health Organization “to be used for the production in the developing world,” the authors write.

Manufacturing Guidelines Are Too Stringent

The money required to produce medicines in a good manufacturing practice (GMP) setting is prohibitive, the authors note, and patient populations that are characterized as “responders” to a targeted therapy are very small—so small, in fact, that prices for personalized therapies would be unnecessarily high, much like what the industry has seen for drugs developed as orphan therapies. Unlike medications with orphan designations, however, personalized therapies are not guaranteed additional periods of market exclusivity. The targeted therapies that are already on the market range in price from $70,000­­­­­­­–130,000 per treatment cycle. The researchers estimate the cost of producing a biopharmaceutical in a commercial setting can be up to $540,000 per gram, whereas bedside production could reduce the price to upwards of $10,800 per gram.

To combat high prices and long development wait times (approximately 10–15 years to market) that result from traditional drug development, the researchers attest that point-of-care production for individualized therapies, or what they refer to as “magistral production,” may be a better model for drugs that are associated with distinct disease markers. The authors write, “The expertise for producing drugs should no longer be the sole domain of the industry; indeed, many people with expertise in drug R&D are being dismissed by larger drug companies increasingly focused on clinical development and marketing.”

Miniaturization of bioreactors and the recent advancements in the scaling down of cell culture and filtration technologies used to manufacture medications facilitates the benchtop model, the researchers point out. Intensification of perfusion processes upstream also allow for acceptable yields at small scale, and advances in downstream purification, such as flocculation, precipitation, and aqueous two-phase extraction, are now suitable to support bedside purification of products.

Safety Concerns

Schellekens et al. suggest that because many academic centers and health-system pharmacies already produce investigational medications in a magistral manner (and are often protected from patent litigation through a personal use exemption), they are well equipped to produce targeted therapies for small groups of patients. However, the production of such medications in less-controlled environments (i.e., outside of a hospital cleanroom), is a major disadvantage, a fact that the authors acknowledge. In locations outside of the clinical setting, safety concerns surrounding sterility are usually addressed by GMP validation of a plant. But if validation were not required, it may be difficult for investigators in charge of producing a medication to assure the drug’s sterility, a fact that could present a major health threat. The authors say some type of regulation should be in place to handle quality control issues at an institutional level, but do not offer suggestions for who would oversee such operations and if the FDA would then be responsible for monitoring products coming out of these locations.

The authors, however, maintain that the risk presented by inadequate industrial manufacturing of drugs at large scale is more significant than the risk associated with the production of a biotherapeutic for an individual patient. They cite the adverse effects associated with Eprex ® (epoetin alfa) and Vioxx ® (rofecoxib)—which were discovered post-FDA approval—and say these have had more of a global impact than any one adverse result with a single patient. They also say that it is preferable to have health professionals such as pharmacists (rather than plant engineers) manufacture personalized therapies, writing, “The risk of compounding is also minimal compared with industrial production because the medicine is produced by a pharmacist or technician under his direct supervision.”

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