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Authors of a new commentary published in Nature Biotechnology argue that a pilot scale approach to drug production could be an interesting, alternative option in the manufacture of biopharmaceuticals. Personalized medicines that are fabricated to target a particular disease biomarker should happen at a patient’s bedside, instead of being produced on a commercial level. Adopting a compounding approach for the production of biopharmaceuticals was essentially suggested by the authors, from the Utrecht University in the Netherlands. The authors said that the commercial manufacture of biologics would be complemented, but not replaced by this pilot scale idea.
Large scale manufacture of targeted therapies is a futile attempt. The method in which biomarkers and genetic material are collected and validated in clinical practices are not consistent, making it difficult for FDA-approved targeted therapies to actually reach the right patients, say the authors. Drug fabricators have a tough time zeroing down the exact biomarkers for a disease, and few drug companies (especially in the case of small biotech companies) have sufficient resources to kick-start companion diagnostic tools to effectively measure the levels of a particular biomarker present in any given patient.

Stringent Regulations:

Furthermore, regulation from FDA controls the method of manufacture of

drugs once they are approved. The method of manufacture is incorporated in the approval of the drug, and any considerable changes in this may require additional FDA Chemistry, Manufacturing, and Controls (CMC) post approval. Patent considerations also play a major role in company’s idea to pursue an investigational drug candidate since patent protection can restrict patient from accessing a drug. For patients in death bed, the current timelines for drug development are not feasible, the authors add.

Authors suggest that Biopharmaceuticals, are the ones that would be choice of drug for bedside production. But profit expectations from these medications are small, and as a result commercial manufacturers may not go further with their development.

To verify their hypothesis on Biopharmaceuticals, the team conducted a pilot program in collaboration with an undisclosed high cell density perfusion culture system dealer for the manufacture of recombinant human alpha-glucosidase (rhGAA), and they are of the opinion that the resulting product will be tested for safety and efficacy in the forthcoming clinical trials. The researchers are also planning 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.

Producing medicines in a good manufacturing practice (GMP) setting is very expensive and patient populations that are characterized as “responders” to a targeted therapy are so small that prices for personalized therapies go unnecessarily high. The targeted therapies that are already in the market are priced from $70,000–130,000 per treatment cycle. The researchers estimate the cost of producing a biopharmaceutical in a commercial setting can go up to $540,000 per gram, whereas bedside fabrication could reduce the price to $10,800 per gram.

To overcome extreme prices and long wait times for the development (approximately 10–15 years to market) that’s the result of traditional drug development, the researchers indicate that point-of-care production for individualized therapies, or what they refer to as “magistral production,” could be a better model for drugs that are linked with distinct disease markers. The authors said that 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.

Miniature versions of bioreactors and the recent advancements in the scaling down of cell culture and filtration technologies used to manufacture medications facilitate the bench top model. Amplification of perfusion processes upstream also allow for satisfactory yields at small scale, and advances in downstream purification, such as flocculation, precipitation, and aqueous two-phase extraction, are now appropriate to support bedside purification of products.

Safety Concerns:

Schellekens and team suggest that because many academic centers and health-system pharmacies already produce investigational medications in a magistral manner (which are often protected from patent litigation through a personal use exemption), they are well equipped to produce targeted therapies for small groups of patients. But, the production of such medications in less-controlled environments (i.e., outside of a hospital clean room), is a major disadvantage, a reality that the authors acknowledge. In places other than 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 guarantee 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 conclude 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 have 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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