FDA Guidance on Polymorphic Compounds in Generic Drugs

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The guidance issued by the US Food and Drug Administration  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.

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.”

A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent.

Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand. For this reason, in ANDAs, careful attention is paid to the effect of polymorphism in the context of generic drug product equivalency.

This review ..Adv Drug Deliv Rev. 2004 Feb 23;56(3):397-414……discusses the impact of polymorphism on drug product manufacturability, quality, and performance. Conclusions from this analysis demonstrate that pharmaceutical solid polymorphism has no relevance to the determination of drug substance “sameness” in ANDAs.

Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance “sameness”. These case studies also illustrate the conceptual framework from these decision trees and illustrate how their general principles are sufficient to assure both the quality and the therapeutic equivalence of marketed generic drug products.


ANDAs: Pharmaceutical Solid Polymorphism – Food and Drug   click here


Issues of Polymorphism and Abbreviated New Drug Applications click here


POLYMORPHISM OF DRUGS – Seventh Street Development Group click here

An Overview of Solid Form Screening During Drug  – ICDD..http://www.icdd.com/ppxrd/10/presentations/PPXRD-10_Ann_Newman.pdf


Although polymorph/salt screening should ideally be performed to select the optimum solid form upon selection of the lead compound prior to animal pharmacokinetic (PK) studies, these screening study can be costly and time consuming. But the consequences of late discovery of a thermodynamic form are grave, so there must be a strategy to minimize the risk without spending a large amount of resources.

We find this right strategy based on early BCS classification of new compounds. We tailor the upfront polymorph/salt studies based on the risk in bioavailability, stability and manufacture-ability. Since regulatory agencies worldwide require the use of the same salt across preclinical and clinical studies, for insoluble or unstable compounds, salt screening is done early to enable further compound development.

Once salt is selected, the polymorph screening of the selected salt if soluble may be done a little later after animal study. However it is paramount to confirm 1) the polymorph in use is stable in the toxicological vehicle, 2) no changes of solid forms during shipping and storage, 3) no significant degradation upon storage.

Should there be polymorphic changes such as formation of a hydrate in the animal vehicle resulting in lowered solubility and precipitation of the hydrate, or formation of a hydrate when exposed to humidity during shipping and storage, early discovery of the stable forms will enable consistent animal exposure and avoid study repeats and delays in timelines.

Therefore, although most companies do not perform comprehensive polymorph screening until late in the development cycle, we recommend identification of a thermodynamic stable form within the confine of not only the API manufacture processes but also in the designated animal and human formulations.

For instance, for a drug product manufactured by direct compression, the solidstate properties of the active ingredient will likely be critical to the manufacture of the drug product, particularly when it constitutes the bulk of the tablet mass.

On the other hand, for a drug product manufactured by wet granulation, the solidstate properties of the active ingredient may no longer be important but the potential for polymorphic conversion is high in the presence of high moisture contents. In the context of the effect of polymorphism on pharmaceutical processing, what is most relevant is the ability to consistently manufacture a drug product that conforms to applicable in-process controls and release specifications.

This upfront work is especially critical to insoluble compounds prone to varied oral bioavailability in animal and human.


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