Biopharmaceuticals safety profiles

In practice, the regulatory framework governing the first dose of a biopharmaceutical in humans is designed around several fundamental tenets know the safety profile for the test agent, maintain a positive risk-benefit profile in each subject population, and beware of the unknown. 

Formulation design is based on the physical, chemical, and biopharmaceutical properties of a drug substance. A formulation for direct compression is composed of active pharmaceutical ingredients and other inactive ingredients such as fillers, binders, dis-integrants, flow aids, and lubricants. Simplicity is the basis of good formulation design. Minimally, a direct compression tablet formulation must meet requirements for manufacturability, uniformity of dose, physical and chemical stability, appropriate dmg release profiles, and bioavailability. In addition, the formulation must meet many quality standards and special requirements to ensure the efficacy and safety of the product. 

Indeed, for a number of years, it was widely believed that branded biopharmaceuticals were unhkely ever to be threatened by lower-priced, post-patent expiry versions of the products because they are too sensitive and sophisticated to copy safely (see also Part Vll, Chapter 4). The intellectual property is complicated, and could be protected by an extensive array of composition and process-related patents that would extend patent lifetimes practically indefinitely. Moreover, it was widely understood that biopharmaceutical product safety and potency profiles are often exquisitely sensitive to the parameters of the production and purification processes used, and small fluctuations in process specs can result in substantially different biologic activity and immunogenicity. To produce a close copy of such a product, near-exact replication of the innovator company s process may be required. However, biopharmaceutical companies have often chosen to exclude the details in patent filings, preferring to maintain exact process specifications as closely guarded... 

Portola Pharmaceuticals Inc, a US based biopharmaceutical company, are currently undertaking a Phase I study with an in-house oral Syk inhibitor PRT-062607 (structure unknown) to evaluate safety, PK and PD in healthy volunteers, ahead of investigating the drug in chronic inflammatory disease indications. Very scant information is known about the compound, except it is claimed to be highly selective for Syk from profiling in a broad panel of in vitro kinase and cellular assays. 

Safety evaluation programs should normally include two relevant species. However, in certain justified cases one relevant species may suffice (e.g., when only one relevant species can be identified or where the biological activity of the biopharmaceutical is well understood). In addition even where two species may be necessary to characterise toxicity in short term studies, it may be possible to justify the use of only one species for subsequent long term toxicity studies (e.g., if the toxicity profile in the two species is comparable in the short term). 

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