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Final FDA Guidance Clarifies Regulatory Classification for Novel Formulation of Pharmaceuticals

Posted 25 April 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has released a new final guidance document regarding how regulators plan to classify pharmaceutical products that are made of solid-state co-crystals, a novel formulation for drugs that raises some equally novel regulatory issues.


Pharmaceutical products are generally comprised of two components: An active ingredient (API) and an excipient, which serves to enhance the product's qualities, including bioavailability, taste, stability and ease of use.

FDA added that pharmaceutical products have traditionally taken several forms: Crystalline, amorphous, or solvate and hydrate forms. An additional and emerging category identified by FDA is solid-state co-crystals, which regulators said conferred several advantages to other forms.

"Co-crystals are composed of an API with a neutral guest compound (also referred to as a conformer) in the crystal lattice," FDA explains in its new guidance, Regulatory Classification of Pharmaceutical Co-Crystals. Another advantage is that unlike salts, "a co-crystal's components are in a neutral state and interact via nonionic interactions," FDA added.

Those two physical differences have opened new opportunities for manufacturers, FDA said, including the engineering of a wider array of solid-state forms that are more bioavailable, stable and easier to process during manufacturing. The principal benefit, regulators added, is that its neutral state allows for it to interact with nonionic functional groups that salt-based drugs need to form.

And while the drug's qualities may be beneficial, it raises a novel regulatory question: How do you regulate a product where the excipient and API are essentially a single, non-separable entity?

New Guidance

In 2011, FDA moved to recognize this emerging type of pharmaceutical formulation, issuing draft guidance on how they should be classified. Now FDA is out with the final version of that guidance, which explains how FDA plans to classify products made from co-crystals, which data will be needed to support a classification, and what those classifications will mean for the submission's approval pathway.

The guidance answers the above question-How should a co-crystal be classified in regulatory terms?-by finding that an API-excipient "should be treated as a drug product intermediate (DPI)."

"Specifically," FDA explained, "it is not regarded as a new API." Rather, regulators see the formulation as just an innovative way to get an already-approved API to the activity site.

FDA said that sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) should submit data to FDA showing that the component API/excipient in the co-crystal form exist in their "neutral states and interact via nonionic interactions." Data should also be submitted to show that there is a "complete dissociation of the API from its excipient" prior to the API reaching the site in the body where it becomes activated.

Any manufacturing facility that makes a co-crystal will still have to meet current good manufacturing practice (CGMP) regulations, FDA added.

FDA: Regulatory Classification of Pharmaceutical Co-Crystals

Federal Register

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