Regulatory Open Forum

Maria,

Based on your question, I presume that this is an 'integral' drug-device combination which is already authorized as a medicinal product (per the medicinal product directive).

The application of medical device regulations (formerly MDD, where the device 'part' would need to comply with Annex I, the Essential Requirements, and currently the MDR, where they device must comply with Annex I, the GSPRs) are only applied at the time of marketing application and/or 'significant' change (ref. MDR Art. 117). More information on EMA expectations for medical devices content in submissions is contained in the recently published guideline as well as the EMA page on medical devices.

To more directly answer your question, follow the manufacturing controls described in the medicinal product MAA/dossier which should include controls for the combination product (e.g. in process/release testing for the 'integral' combination product). From the EU perspective, the manufacturer(s), including any CMO, would still be subject to drug cGMPs as there is no analogous combination product GMP regulation as in the US (21 C.F.R. 4 Subpart A). So, compliance with other aspects of the MDR and/or ISO 13485 are not required. However, again, the manufacturing process and controls that were approved for the medicinal product should be followed (which may include elements specific to the combination product).

As noted above, if the combination product is also approved in other jurisdictions that have their own requirements (the US), the manufacturer would need to meet those as well (i.e. the combination product cGMPs, which could be a 'streamlined' approach based on the drug cGMPs).

Maria,

Based on your question, I presume that this is an 'integral' drug-device combination which is already authorized as a medicinal product (per the medicinal product directive).

The application of medical device regulations (formerly MDD, where the device 'part' would need to comply with Annex I, the Essential Requirements, and currently the MDR, where they device must comply with Annex I, the GSPRs) are only applied at the time of marketing application and/or 'significant' change (ref. MDR Art. 117). More information on EMA expectations for medical devices content in submissions is contained in the recently published guideline as well as the EMA page on medical devices.

To more directly answer your question, follow the manufacturing controls described in the medicinal product MAA/dossier which should include controls for the combination product (e.g. in process/release testing for the 'integral' combination product). From the EU perspective, the manufacturer(s), including any CMO, would still be subject to drug cGMPs as there is no analogous combination product GMP regulation as in the US (21 C.F.R. 4 Subpart A). So, compliance with other aspects of the MDR and/or ISO 13485 are not required. However, again, the manufacturing process and controls that were approved for the medicinal product should be followed (which may include elements specific to the combination product).

As noted above, if the combination product is also approved in other jurisdictions that have their own requirements (the US), the manufacturer would need to meet those as well (i.e. the combination product cGMPs, which could be a 'streamlined' approach based on the drug cGMPs).

Maria,

For Europe your supply chain sounds reasonable and I would not expect that any additional GMP requirements (beyond those for medicinal products) are needed. However, as noted in my original message, any manufacturing controls described in the MAA/dossier should be followed (as authorized for the new pen presentation), and these may occur at various sites/CMOs. [This advice, of course, should not be taken in lieu of a more thorough assessment which would require significantly more information.]

For the US you will need to be compliant with the applicable combination product cGMPs per 21 CFR 4 Subpart A and further described in accompanying guidance. For drug manufacturers this is commonly fulfilled via the streamlined approach as described in 21 CFR 4.4(b) which utilizes the drug cGMPs along with specified sections of the device QSR (GMPs). ISO certification (i.e. 13485) would have no additional value from a US regulatory perspective (though in practice most manufacturers in this situation utilize the relevant sections of ISO 13485 to develop the device-related elements of their QMS, such as Design Controls, and there may be other reasons to pursue a certification).

Maria,

Based on your question, I presume that this is an 'integral' drug-device combination which is already authorized as a medicinal product (per the medicinal product directive).

The application of medical device regulations (formerly MDD, where the device 'part' would need to comply with Annex I, the Essential Requirements, and currently the MDR, where they device must comply with Annex I, the GSPRs) are only applied at the time of marketing application and/or 'significant' change (ref. MDR Art. 117). More information on EMA expectations for medical devices content in submissions is contained in the recently published guideline as well as the EMA page on medical devices.

To more directly answer your question, follow the manufacturing controls described in the medicinal product MAA/dossier which should include controls for the combination product (e.g. in process/release testing for the 'integral' combination product). From the EU perspective, the manufacturer(s), including any CMO, would still be subject to drug cGMPs as there is no analogous combination product GMP regulation as in the US (21 C.F.R. 4 Subpart A). So, compliance with other aspects of the MDR and/or ISO 13485 are not required. However, again, the manufacturing process and controls that were approved for the medicinal product should be followed (which may include elements specific to the combination product).

As noted above, if the combination product is also approved in other jurisdictions that have their own requirements (the US), the manufacturer would need to meet those as well (i.e. the combination product cGMPs, which could be a 'streamlined' approach based on the drug cGMPs).

Maria,

For Europe your supply chain sounds reasonable and I would not expect that any additional GMP requirements (beyond those for medicinal products) are needed. However, as noted in my original message, any manufacturing controls described in the MAA/dossier should be followed (as authorized for the new pen presentation), and these may occur at various sites/CMOs. [This advice, of course, should not be taken in lieu of a more thorough assessment which would require significantly more information.]

For the US you will need to be compliant with the applicable combination product cGMPs per 21 CFR 4 Subpart A and further described in accompanying guidance. For drug manufacturers this is commonly fulfilled via the streamlined approach as described in 21 CFR 4.4(b) which utilizes the drug cGMPs along with specified sections of the device QSR (GMPs). ISO certification (i.e. 13485) would have no additional value from a US regulatory perspective (though in practice most manufacturers in this situation utilize the relevant sections of ISO 13485 to develop the device-related elements of their QMS, such as Design Controls, and there may be other reasons to pursue a certification).

Maria,

Based on your question, I presume that this is an 'integral' drug-device combination which is already authorized as a medicinal product (per the medicinal product directive).

The application of medical device regulations (formerly MDD, where the device 'part' would need to comply with Annex I, the Essential Requirements, and currently the MDR, where they device must comply with Annex I, the GSPRs) are only applied at the time of marketing application and/or 'significant' change (ref. MDR Art. 117). More information on EMA expectations for medical devices content in submissions is contained in the recently published guideline as well as the EMA page on medical devices.

To more directly answer your question, follow the manufacturing controls described in the medicinal product MAA/dossier which should include controls for the combination product (e.g. in process/release testing for the 'integral' combination product). From the EU perspective, the manufacturer(s), including any CMO, would still be subject to drug cGMPs as there is no analogous combination product GMP regulation as in the US (21 C.F.R. 4 Subpart A). So, compliance with other aspects of the MDR and/or ISO 13485 are not required. However, again, the manufacturing process and controls that were approved for the medicinal product should be followed (which may include elements specific to the combination product).

As noted above, if the combination product is also approved in other jurisdictions that have their own requirements (the US), the manufacturer would need to meet those as well (i.e. the combination product cGMPs, which could be a 'streamlined' approach based on the drug cGMPs).