[ HOW-TO GUIDE ]

How to Set Up cGMP for a Combination Product

Choose the operating system for a drug–device or biologic–device product and prove it meets both sets of requirements.

What a how-to is not

A how-to is SPEQ’s practitioner method, not a procedure. It does not replace your own SOP, it is not a validated approach, and the judgement calls in it belong to your quality unit.

21 CFR Part 4 lets a manufacturer of a single-entity or co-packaged combination product meet the drug cGMPs and the device QMSR through one operating system: either base, plus the named provisions from the other. The work is in choosing the base, mapping every called-out provision to a procedure, and extending complaint handling and safety reporting to cover both constituent parts.

WORK THROUGH THESE STEPS IN THE TEMPLATE
Combination Product cGMP Compliance Plan
Each step below has a place in SPEQ’s structured, regulator-aligned template for this procedure. Open the template →
THE STEPS
  1. 1

    Confirm the type and the lead centre

    Establish whether the product is single-entity, co-packaged or cross-labelled under 21 CFR 3.2(e), and record its primary mode of action and lead centre. If the assignment is unclear, file a Request for Designation before any premarket application; FDA answers within 60 days of filing, or the sponsor’s recommendation stands.

  2. 2

    Choose the base operating system

    Pick drug cGMP (Parts 210/211) or the QMSR (Part 820) as the base. The usual choice is the system that matches the dominant manufacturing activity at the site where the constituent parts come together. Record the decision and the reasoning.

  3. 3

    Map the called-out provisions

    On a drug base, map the ISO 13485 clauses and QMSR sections §4.4(b)(1) names: management responsibility, design and development with risk management, purchasing, data analysis and improvement, complaint handling, installation and servicing. On a device base, map the eight drug sections §4.4(b)(2) names, including stability, expiration dating, testing and release, and reserve samples.

  4. 4

    Handle separate sites

    Until the constituent parts arrive at the same facility, each part’s manufacturer complies with the requirements for its own type in full. Write that into the supplier quality agreements and audit against it.

  5. 5

    Extend complaints and safety reporting

    Make sure one complaint can generate every report Part 4 Subpart B requires — for example five-day and malfunction reports for a device constituent, field alert reports for a drug constituent — on the right timelines, without duplicating a report already filed.

  6. 6

    Join up change control

    Assess every change for its effect on both constituent parts: a device-component change can alter drug stability or dose delivery, and a formulation change can alter device performance.

COMMON PITFALLS
  • !Creating design history for the device constituent after the design was frozen, to satisfy an inspection rather than to control the design.
  • !Treating device shelf-life testing as drug stability.
  • !Using FDA’s 2017 guidance for the device-side provisions without noting it predates the QMSR.
  • !Assuming the lead centre decides which cGMPs apply.
REGULATORY BASIS
GO DEEPER

How to Set Up cGMP for a Combination Product: frequently asked questions

Common questions on set up cgmp for a combination product.

Do we have to use the streamlined approach?

No. Section 4.4(a) allows compliance with every applicable set of cGMP regulations in full, or the streamlined approach in 4.4(b). The streamlined approach is usually less duplication for a site that makes the combined product.

Does a co-packaged kit need the streamlined system at the kitting site?

Part 4 applies to co-packaged combination products. Once the constituent parts are at the same facility, the operating system there must meet the base requirements plus the called-out provisions; before that, each part’s own manufacturer meets the requirements for its type.

What changed when the QMSR took effect?

From 2 February 2026, the device provisions a drug-based system must meet are named as ISO 13485 clauses, incorporated through §820.7, plus certain QMSR sections, replacing references to the former Quality System regulation.

RELATED HOW-TO GUIDES
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WHERE NEXT

  1. DO ITOpen the Combination Product cGMP Compliance Plan template →The structure these steps fill in.
  2. UNDERSTAND ITCombination Products: Jurisdiction and cGMP →The principles behind the procedure.
  3. ALL GUIDESBrowse all 127 how-to guides →

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