The Food and Drug Administration (FDA), the US regulating authority in the sphere of medical devices, issued a compliance program describing the inspections related to CDER-led or CDRH-led combination products. The document provides the requirements for different types of inspections to be performed on the appropriate stages of the medical device`s lifecycle. The Agency states that the present compliance program is intended to cover the regulatory gap existing with the Current Good Manufacturing Practice (CGMP) requirements to combination products.
Combination Products: Regulatory Background
In accordance with the definition set forth in the 21 CFR 3.2(e), a combination product is a product comprised of two or more different types of medical products (i.e., drug and device, drug and biological product, device, and biological product, or all three together). Another important definition related to the combination products is a constituent part, that could be either a drug, or device, or biological product.
According to the document, the scope of this program covers combination products of the following types:
- Single-entity combination products (in this case, the components of the combination product, or its constituent parts are combined), and
- Co-packaged combination products (ones when all components are being included in the same package).
The most important question in the field of combination products is related to the determination of the particular center – the regulatory body responsible for and entitled to perform the assessment of the combination product in question – or the lead center. The FDA states that the lead center should be determined depending on the constituent part of the combination product that provides the primary mode of action. When determined, the lead center would coordinate further regulatory procedures related to placing the combination product on the market and consequent post-market surveillance.
CGMPs for Combination Products
The FDA describes the two ways the compliance with CGMP requirements for combination products could be demonstrated, namely:
- Demonstrating compliance with all applicable CGMPs. In this case, the manufacturer shall demonstrate compliance with CGMP requirements to be applied to each component (constituent part) of the combination product.
- Streamlined approach providing that the manufacturer shall demonstrate compliance with either CGMPs for drug or Quality System requirements for the medical device, and with the certain separate (called-out) provisions from the other set of requirements. Using such an approach, the manufacturer of combination products could maintain compliance with the requirements related to CGMPs for drugs and also with the Quality System requirements for medical devices. The FDA states that CGMPs for drugs should be based on the regulations 21 CFR.820.xxx, while the Quality System requirements for a medical device as a component (constituent part) of the combination products should be based on the regulations 21 CFR 211.xxx.
The Agency also indicates that in case if the combination product in question contains a constituent part that is a biological product, the manufacturer shall also maintain compliance with the requirements set forth under the regulation 21 CFR 600 – 680.
Scope of the Compliance Program
The compliance program for combination products issued by the FDA is intended to describe the regulatory framework related to inspections of manufacturing sites producing single-entity and co-packaged combination products. The requirements set forth in the present document are also based on the CGMPs applicable to drugs, medical devices, and biological products, while the document additionally describes the way the CGMPs should be applied correctly in a case of combination products.
According to the compliance program, the inspection of the facility manufacturing combination products should be based on the practices of the appropriate lead center – the regulatory body responsible for the particular combination product. As it was mentioned previously, the lead center should be determined depending on the constituent part of the combination product representing its primary mode of action. As it is stated by the FDA, most of the manufacturers of combination products apply a streamlined approach described hereabove.
In the terms of personnel, the inspections covered by the scope of the compliance program could be carried out by both investigators specializing in drugs and medical devices, or by a single investigator that has the appropriate qualification in the sphere of combination products and CGMPs associated thereto.
Pre-approval inspections are usually related to the particular combination product its manufacturer intends to place on the market. Such inspection should be carried out in accordance with the base compliance program. The particular CGMPs to be applied will depend on the nature of the combination product subject to review. At the same time, the inspection should also include additional coverage of called-out provisions, such as the requirements on:
- Management controls,
- Design controls,
- Purchasing controls,
- Installation and/or servicing,
- Testing and approval or rejection of components, and others.
The particular called-out provisions to be applied would actually depend on the combination product in question and its regulatory determination.
In accordance with the FDA compliance program, the surveillance inspections should be focused on combination products subject to significant changes or ones based on the complex technologies. At the same time, the Agency also states that the safety and effectiveness concerns would have the highest priority. Such inspections should be also based on the information about complaints associated with the combination product in question.
In case the manufacturing facility subject to review maintains compliance with the CGMP requirements, the abbreviated inspections could be used. At the same time, in case if additional assessment is required, the comprehensive (full) inspection should be carried out.
Summarizing the information provided hereabove, the present compliance policy issued by the FDA describes the way the different types of inspections shall be carried out with regard to manufacturers of the combination products.
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