In The Field - Pharmaceutical Technology

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Pharmaceutical Technology


Xcellerex will serve as the prime contractor on the first grant, in which the company is collaborating with Dowpharma (Midland, MI), a business unit of The Dow Chemical Company, Biopharm Services (Marlboro, MA), and deltaDOT, Ltd. (London).

On the second contract, Xcellerex is collaborating with Neugenesis Corp. (Burlingame, CA) as the prime contractor, SRI International (Menlo Park, CA), and BioPharm Services. The grant is based on the use of Xcellerex "PDMax" and "FlexFactory" technologies to show the potential of Neugenesis's "NeuBIOS" protein-production platform. Neugenesis and SRI will provide project management and integration systems for the team.
-Patricia Van Arnum

GENERICS

New FDA Guidance on Polymorphic Compounds in Generic Drugs

A new guidance issued by the US Food and Drug Administration on July 9, advises companies on how to treat polymorphic drug compounds—those that exhibit multiple structural forms—in filing abbreviated new drug applications (ANDAs). The bottom line, according to the guidance, is that generic drug products containing the polymorphs be the "same" as the reference listed drug (RLD) in active ingredients, bioavailability, and bioequivalence. The guidance pertains to orally available drugs that are either solid- or suspension-dosage products.


(IMAGE OF CRYSTAL: TU LEE)
Polymorphisms arise when compounds are identical chemically, but not structurally. This can happen when two solids take on different crystalline forms such as graphite and diamond; when molecules are disordered and fail to produce a repeatable crystal lattice, as is the case for the molecules in glass; or when solvent is trapped inside the crystal structure—as in hydrates, where water molecules are found within crystals. The guidance notes that different polymorphisms may alter physical properties of compounds and affect their solubility, which in turn can alter their bioavailability or bioequivalence. In addition, polymorphic forms of a compound may alter the way the compound behaves during production, which again, may alter the finished drug's biological activities. On this latter point, the guidance specifically states, "Since an ANDA applicant should demonstrate that the generic drug product can be manufactured reliably using a validated process, we recommend that you pay close attention to polymorphism as it relates to pharmaceutical processing."

The guidance also emphasizes the effect polymorphisms may have on drug stability, which again, may alter the drug's biological activity. But the guidance goes on to say that "it is the stability of the drug product and not stability of the drug substance polymorphic form that should be the most relevant measure of drug equality." Otherwise, a generic drug can be considered the "same" as the active ingredient in an RLD if the generic compound conforms to the standards set out in a United States Pharmacopeia (USP) monograph, if one exists for that particular drug substance. These standards generally include the chemical name, empirical formula, and molecular structure of the compound. However, the "FDA may prescribe additional standards that are material to the sameness of a drug substance." But as concerns polymorphisms, the guidance goes on to say "...differences in drug substance polymorphic forms do not render drug substances different active ingredients for the purposes of ANDA approvals...." Finally, the guidance reminds ANDA applicants that the biological performance characteristics of a drug are also dependent on the drug's formulation and advises applicants to consider the properties of both the drug substance and formulation excipients, when assessing "sameness."
-Michelle Hoffman


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