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Partnering with the right contractor is one of the most critical decisions a pharmaceutical company can make
The active pharmaceutical ingredient (API) is the foundation of a final drug product and is a crucial consideration when choosing a Contract Development and Manufacturing Organisation (CDMO). To understand API contract manufacturing, first, it is necessary to understand what is meant by an “active ingredient.”
Also called the “bulk active” or “bulk drug substance,” the API is the part of the drug that produces the intended effect in the diagnosis, cure, mitigation, treatment or prevention of disease or that affects the structure or any function of a human or animal. The term includes those components that may undergo a chemical change and be present in a modified form intended to furnish the specified pharmacological activity in a finished drug product.
An API is formulated with other components that don’t perform the intended chemistry or biochemistry in the body. These components are called “inactive ingredients.” Active and inactive ingredients are mixed in various dosage forms (such as tablets, capsules or liquids) to yield a drug product.
The manufacture of APIs is a complex, specialised activity, requiring the expert intertwining of chemistry, biology and engineering. For instance, APIs include substances manufactured by a range of processes, including chemical synthesis, fermentation, recombinant DNA or other biotechnology methods, isolation/recovery from natural sources or through any combination of these processes.
Within the pharmaceutical industry, the entire process of making a drug product is either carried out by the owner of the drug, or by engaging a third party or parties (i.e., CDMOs) to complete the whole manufacturing process, or one or more discrete operations, under contract.
Although some companies are hesitant to outsource because of concerns around data security and quality or issues relating to change management, most drug development companies have realized that the return on investment has been worthwhile and that with the right partner, the advantages outweigh the potential risks.
Outsourcing to CDMOs can also provide companies with access to a flexible workforce comprised of highly-specialized experts. Recently, increased outsourcing to CDMOs has been observed for drug owners from biopharma to pharma companies, from small to large firms, and for early to late-stage development projects.
The quality of APIs has a significant effect on the efficacy (producing the result desired) and the safety of medications. Choosing a CDMO that can provide the right API at the required strength, quality and purity is, therefore, a critical decision for drug development companies.
Favipiravir (T-705, 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a novel low molecular weight antiviral compound. It has shown activity against many types of RNA viruses (all strains of influenza А, В, С, arenovirus, bunyavirus, flavivirus, alphavirus, norovirus,as well as the Zika, Usutu,and Ebola viruses). The generally good tolerance of human patients to favipiravir and the high barrier to the development of resistant viral strains indicate that this drug holds great promise for clinical use around the world. It should be noted that a representative of the Zhejiang Hisun Pharmaceutical company from China has anounced that this company has received marketing authorization from the Chinese government for favipiravir as a possible medication against the coronavirus causing Covid-19.
Favipiravir was first synthesized in 2000 by a route consisting of seven steps. The starting material was 3-aminopyrazine-2-carboxylic acid. The amination step was catalyzed by a costly (S)-(–)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((S)-BINAP), fluorination required using the highly corrosive Olah reagent, while the overall reaction yield was approximately 0.44%.
Improved methodologies for the synthesis of favipiravir have been reported in recent years. In particular, a fourstep method enabled the synthesis of favipiravir from commercially available 3-hydroxypyrazine-2-carboxylic acid, which was subjected to esterification and amidation. The nitration of pyrazine ring was followed by reduction of the nitro group in the presence of Raney nickel, allowing to minimize the amount of byproducts. After the replacement of amino group with a fluorine atom, the overall yield of the target product 1 was 8%.
Edoxaban versus Warfarin in Patients with Atrial Fibrillation
Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known.
We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding.
The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P