FDA Inspection of a Combination Product Manufacturing Facility

What is a Combination Product?

The term “combination product”, as defined by the FDA in a 21 CFR 3.2(e), includes:

1. A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;

3. A drug, device, or biological product packaged separately that according to its investigational plan, or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or

4. Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

Combination product companies must maintain a quality system that satisfies both 21 CFR 820 quality system regulations and 21 CFR 211 good manufacturing practices for finished pharmaceuticals. RQMIS can support compliance with both sets of regulations and understands which quality system regulations and standards need to take precedence when manufacturing such products. RQMIS has the complex understanding required to navigate this area; with our combined experience in both the medical device and the pharmaceutical industries, RQMIS can effectively target and address discrepancies among the various regulations and standards.

THE SITUATION

A European company that manufactures a long-term implant containing an antibiotic (considered by the FDA as a Combination Product) is faced with its first FDA inspection. In response, the company requests that RQMIS support the audit by conducting a 21 CFR 820/211 gap analysis to determine its audit readiness. The client was familiar with RQMIS through premarket submissions and requested additional support from our Quality group to determine the level of compliance of their quality system and to upgrade it where needed. The client already had a certified EN/ISO13485:2013 compliant system: Part of the manufacturing occurred in a clean room, specifically the packaging of a sterile catheter, and an aseptic filling process was used to create the combination product.

THE SOLUTION

RQMIS aided the manufacturer in upgrading their quality system and supported them during the FDA inspection. In three months, RQMIS accomplished the following:

• Became the U.S. agent for the client
• Performed a baseline audit of their operation
• Educated the manufacturer on requirement specifics and compliance (EN/ISO13485 and 21CFR820/211)
• Transitioned systems from EN/ISO13485:2013 to EN/ISO13485:2016
• Identified and addressed gaps in the Quality System (QS)
• Drafted updates and updated the QS
• Made significant updates to design control, CAPA, and process validation systems
• Audited and rebuilt the Design History File (DHF)
• Attended and supported the FDA inspection
• Facilitated effective communication between the manufacturer and the FDA during and following the audit

RQMIS enabled the manufacturer to complete a successful audit of their combination product manufacturing facility. The audit resulted in a finding of only four minor observations, and a VAI (voluntary action indicated) rating.