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FDA Releases New Requirements for Combination Products

FDA released a final rule on current good manufacturing practices (cGMP) requirements for combination products to set a more transparent and streamlined framework for regulatory compliance. Following the rule’s release in January, FDA held a webinar, “Current Good Manufacturing Practices for Combination Products Final Rule,” providing a primer on the regulatory approaches to combined products and answering key questions asked during the proposed rule process.

What’s a combination product?

A combination product is defined simply as a product comprising two or more types of medical products, that has been classified into three categories by FDA: single-entity, co-packaged and cross-labeled. Biological products may also meet the definition of combination product and be regulated as drugs, devices or biological products.

The rule states: if the device is a cross-labeled combination product, it’s subject to the cGMP requirements applicable for drug devices. Co-packaged or single-entity combination product subject to cGMP and Quality Systems regulations can implement either the drug cGMPs (at 21 CFR 210 and 211) or device QS (at 21 CFR 802) rather than both, if the manufacturer also implements the specified provisions in the other of these cGMP requirements.

What are the main questions regarding the new rule?

Scope of cMGP requirements

Q. Does the rule create any new cGMP requirements?
A. No, this rule merely classifies how to comply with existing cGMP requirements and offers a mechanism to streamline compliance.

Q. Do facilities that are not otherwise subject to cGMPs become subject to them because of this rule?
A. No, this rule does not change to whom cGMP requirements apply.

Device v. container closure system

Q. Should delivery devices be treated as mere container closures or as prefilled devices?
A. Prefilled devices, so all manufacturing considerations can be appropriately addressed.

Design controls

Q. Do design controls apply to the combination product as a whole or just device constituent part(s)?
A. The combination product, to ensure appropriate selection of the constituent parts and appropriate evaluation of their interactions and interrelationships.

Product testing

Q. Can the product testing and release requirements called out with the drug cGMPs be applied throughout the manufacturing process for the combination product?
A. Yes, as appropriate to confirm the product meets its specifications performs properly.

Reserve samples

Q. Do reserve samples of the combination product need to be kept, or only of the drug constituent part?
A. Reserve samples should include the drug constituent part and the device constituent part/portion(s) of it that come into direct contact with the drug.

Biological product and HCT/P cGMP requirements

Q. Why doesn’t the rule offer a similar streamlining option for biological product and HCT/P cGMPs?
A. These cGMPs address distinct issues. Biological cGMPs augment other cGMPs to address biological product issues and current good tissue practice requirements address communicable disease risk.