This morning, FDA released a pre-publication copy of the final CGMPs for combination products set to publish on Tuesday (http://www.ofr.gov/(X(1)S(iypq0p5wuaxjgpwehgaesfj2))/OFRUpload/OFRData/2013-01068_PI.pdf) and to take effect 6 months after publication.
The notice states that "the rule sets forth a transparent and streamlined regulatory framework for firms to use when demonstrating compliance with CGMP requirements for 'single-entity' and 'co-packaged' combination products." FDA explains in its notice that the “final rule is largely identical to the proposed rule." The general approach of the proposed rule was: "(1) To demonstrate compliance with the specifics of all CGMP regulations applicable to each of the constituent parts included in the combination product or (2) to demonstrate compliance with the specifics of either the drug CGMPs or the QS regulation, rather than both...."
In the preamble to the final rule, FDA notes that these CGMPs apply to all combination products, regardless of when they were approved – some commenters asked FDA to apply these CGMPs only to new combination products approved going forward. FDA declined to take that position but said that it will be issuing guidance on how to comply with these rules and how to bring pre-manufacturing design control requirements into compliance for products already on the market. FDA clarifies that the rules will apply to specification developers and contract manufacturers since both are engaged in “manufacturing” activities; however, FDA notes that these rules will not apply to manufacturers of the underlying components even if those components are later included in a combination product or constituent part of a combination product at another facility.
Some other highlights of the preamble include:
• Drug containers and closures will continue to be regulated under 21 CFR Parts 210 and 211; however, syringes do not constitute drug containers or closures and prefilled syringes are subject to this combination product CGMP final rule.
• FDA declined to revise the definition of “constituent part” or to issue a definition for “component” in the final rule (noting that previously issued definitions exist and will continue to apply).
• Not all of the combination product CGMPs will apply to all product types; e.g., only combination products with an OTC drug must comply with the tamper-evident packaging requirements; similarly, not all combination product CGMPs will apply to all facility types as many, but not all, CGMP requirements are facility specific. Manufacturers must ensure compliance with applicable provisions and requirements.
• FDA rejected one commenter’s proposal that the CGMP requirements applicable to a constituent part come into effect only after that constituent part has been formed. FDA notes that the “trigger” for compliance is whether a facility is conducting manufacturing operations that would be subject to the underlying CGMP requirements.
• Out of specification (OOS) investigations for combination products should appropriately address FDA’s considerations for OOS investigations articulated in Parts 211 and 820, as applicable.
• FDA will discuss batch release testing further in guidance.
• FDA will also provide further information on compliance with stability testing and expiration dating requirements in guidance.
Today, FDA also issued a pre-publication notice (to publish Tuesday) of the release of a Draft Guidance on Submissions for Postapproval Modifications to a Combination Product Approved Under Certain Marketing Applications (approved under a BLA, NDA, or PMA) (http://www.ofr.gov/(X(1)S(iypq0p5wuaxjgpwehgaesfj2))/OFRUpload/OFRData/2013-01069_PI.pdf). The Draft Guidance will provide “tables” to help sponsors determine what type of submission to provide for changes to constituent parts of combination products. The comment period will be open for 90 days following publication on Tuesday. This Draft Guidance is not yet available on FDA's website.
Julie Tibbets is a partner in the Food, Drug & Device practice of Alston & Bird LLP. She can be contacted at julie.tibbets@alston.com or (202) 239-3444.