When separate products are combined, packaged as a unit, or packaged separately but intended for use only with another product, the constituent parts of this combination product retain regulatory status. This rule applies to current good manufacturing practice (CGMP) requirements. If constituent parts of a cross-labeled combination product are manufactured at the same facility, the FDA does not object to a streamlined CGMP operating system used to demonstrate compliance (Notice, 82 FR 3336, January 11, 2017).
Compliance demonstration approaches. Two options are available for manufacturers to demonstrate CGMP compliance for combination products that are made at the same facility. A manufacturer may show that regulations applicable to each separate product have been followed, or use a streamlined approach demonstrating compliance with either drug or device regulations, as well as with specified provisions from the other set. If a biologic is involved, relevant CGMP requirements must be met. Although the FDA would typically consider the streamlined approach not relevant or applicable to combination products, the agency considers this method acceptable when only one facility is involved. If a facility manufactures only one type of part for a combination product, it is only subject to the CGMP regulations for that part.
Demonstrating compliance. Manufacturers must compile documentation showing compliance and make it readily accessible to an FDA inspector. The type of approach chosen should be identified in premarket submissions or the common technical document. In the event that CGMP regulations governing constituent parts conflict, the regulations more specifically applicable will control. The FDA recognizes that some CGMP regulations may not apply to a particular product. In such a case, manufacturers must document justification for determining that certain measures are not appropriate or necessary. Additionally, even if a facility manufacturers only one type of constituent part for a combination product, it should consider the effects of changes in the manufacturing process on the combination part as a whole. Manufacturers are responsible for coordinating CGMP systems across multiple facilities when necessary.
Investigational products. The production of investigational drug used in a phase 1 study is generally exempt from 21 C.F.R. parts 210 and 211 governing CGMPs. The FDA has determined that a combination product with a constituent drug part used for a phase 1 study is also exempt, but the exemption does not apply when the sponsor moves on to phase 2 and 3 studies.
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