How to comply with 21 CFR Part 4

The 21 CFR Part 4 final rule may seem like old news, but most of the combination products industry is still unclear what to focus on in order to be in compliance with the final ruling. Since the regulation went into effect in July, 2013, every combination products manufacturer is at risk to an audit. Here’s a quick guide to get you on the right path to full compliance before the auditors knock on your doors.

First, a quick review of combination products

Combination Products are products comprised of two or more types of medical products. These products can be a combination of a drug and a device, a biologic and a drug or a biologic and a device – or a combination of all three. There are three kinds of combination products:

  • Single Entity – for example, a drug eluting stent
  • Co-Package – for example, a first-aid or surgical kit
  • Cross-Labeled – for example, certain light-emitting and light-activated drug-devices

The purpose behind the 21 CFR Part 4 final rule

The purpose of this regulation was to help identify and clarify which rules apply to combination products and to ensure that companies understood how to satisfy the CGMP requirements for combination products in a manner that ensures manufacturing of a safe and effective product while avoiding redundant regulatory requirements.

Prior to this final rule, manufacturers of combination products had to guess at what regulation(s) applied to their specific product. Part 4 clarifies this confusion by requiring that single-entity or co-packaged combination products must comply with the specifics of all relevant regulations.

What’s included

21 CFR Part 4 focuses mostly on co-packaged and single entity combination products since these are comprised of combined products and as a consequence they are being made in the same facility and at some point being put in the same product, making the manufacturing process more complex.

The rule does not go into any great detail on cross-labeled combination products because their logic is pretty straightforward. The basic notion is that since they are manufactured separately to be marketed separately, each constituent part can be regulated separately for CGMP purposes.

How to comply with 21 CFR Part 4

The good news is that you don’t need to use dual quality systems to comply with 21 CFR Part 4. You have the option to use a streamlined approach because although the FDA’s view is that drugs, devices and biological products do not lose their individual regulatory identities when they become constituent parts of a combination product, they do recognize that 21 CFR 210 and 211 (for drugs and biologics) and 21 CFR 820 (for devices) are similar in most respects.

Under this streamlined approach, a manufacturer may choose to operate under and comply with either 21 CFR 210/211 or 21 CFR 820, as an alternative to both, provided that additional specific aspects of the other CGMP framework also are incorporated. Here’ the breakdown:

Drug/Biologics Manufacturer

If you are currently a drug and biologics manufacturer, and you are producing a combination product, you would begin with the quality foundation of the drug GMPs from 21 CFR 210/211 and then you would follow specific Quality System Regulations (QSRs) from 21 CFR 820 to cover the medical device requirements for your single-entity or co-packaged drug-device combination product. These are:

  • Section 820.20: Management responsibility
  • Section 820.30: Design controls
  • Section 820.50: Purchasing controls
  • Section 820.100: Corrective and preventive action
  • Section 820.170: Installation
  • Section 820.200: Servicing

Medical Device Manufacturer

If you are currently a medical device manufacturer, and you are producing a combination product, you would start with a robust quality foundation for medical device QSRs from 21 CFR 820 to ensure that your quality system is maintaining good control over the design and manufacture of the product and then you would overlay some of the drug GMPs from 21 CFR Part 210-211 to cover the pharmaceutical requirements. These are:

  • Section 211.84: Testing and approval or rejection of components, drug product containers, and closures
  • Section 211.103: Calculation of yield
  • Section 211.132: Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.
  • Section 211.137: Expiration dating
  • Section 211.165: Testing and release for distribution
  • Section 211.166: Stability testing (including forced degradation studies)
  • Section 211.167: Special testing requirements
  • Section 211.170: Reserve samples

Final thought

You do have a choice. You can put dual quality systems in place – but with the alternative streamlined approach option there is really no good reason to do so. The streamlined approach is less costly, less prone to errors, less frustrating to employees and it is more efficient. It’s a win-win.