FDA Issues Draft on cGMP Regulations for "Combination Products"

On 23 September 2009 the US Food & Drug Administration (FDA) has issued proposals for Current Good Manufacturing Practice Requirements for Combination Products (21 CFR 4) in the Federal Register Vol 74, Number 183.

What are Combination Products? The answer to this question can also be found in the text. They are products comprised of one of various combinations of a medical device (21 CFR 820), a medicinal product (21 CFR 210/211) and/or a biological product (21 CFR 600-680). The text also specifically covers products possibly going into the combination products as human cells or are based on tissue (HCT[sol]Ps, 21 CFR 1271). The new regulations are based on industry comments on a FDA draft on this subject from 2004.

The guidance comprises 17 pages with 9 chapters and various subchapters. The following is a short description with an evaluation of the draft.

In general, the respective cGMP regulations for the products going into the combination product have to be fulfilled. However, the FDA is aware of the analogy in the GMP regulations for medicinal products (21 CFR 210/211) and those for medical devices (Quality System Regulations, 21 CFR 820) - as in the guidance mentioned above. "Single-Entity and Co-Packed Combination Products" are used as an example for an explanation in chapter II (Description). Using this example the draft explains that complying with GMPs for medicinal products (21 CFR 210/211), it is "only" necessary to comply with the following items in 21 CFR 820 to make sure that the combination product is also in compliance:

  • 21 CFR 820.20 Management responsibility
  • 21 CFR 820.30 Design control
  • 21 CFR 820.50 Purchasing controls
  • 21 CFR 820.100 CAPA
  • 21 CFR 820.170 Installation
  • 21 CFR 820.200 Servicing

Vice versa, applying Quality System Regulations, QSR, 21 CFR 820, it is "only" necessary to comply with the following items in 21 CFR 211 to make sure that the combination product is also in compliance:

  • 21 CFR 211.84 Testing and approval or rejection of components, containers, and closures
  • 21 CFR 211.103 Calculation of yield
  • 21 CFR 211.132 Tamper-evident packaging for over the counter human drug products
  • 21 CFR 211.137 Expiration dating
  • 21 CFR 211.165 Testing and release for distribution
  • 21 CFR 211.166 Stability testing
  • 21 CFR 211.167 Special testing requirements
  • 21 CFR 211. 170 Reserve samples

The FDA calls this integrative approach a "streamlined approach" respectively current good manufacturing practice operating system. The respective assignments are only supposed to be understood as a rule, though - justified deviations are possible and depend on the product or the process. For instance, a combination product with medicinal product parts and only available on prescription does not have to additionally fulfil 21 CFR 211.132 (Tamper-evident packaging for over the counter human drug products) as it is not available over the counter. This "streamlined approach" is recommended for all combination products - for one reason to avoid duplicate documentation as the authority mentions.

A specific subchapter describes requirements for combination products containing cells or tissue. This part refers to part 1271 of the CFR as well as to the greater legal regulations ("PHS-Act"). The de facto standards are 21 CFR 210/211 and 820, though.

Another subchapter refers to the regulations to be applied to the manufacture of a combination product at different facilities. In the FDA's view it is quite difficult here to implement the "streamlined approach".

Further, inspection potentials and "Enforcement" are described in great detail. The FDA expects that 300 manufacturers in the US will be affected by these new regulations and offers to comment the draft. The regulations become effective 180 days past the publication date of the final document.

Closing the new 21 CFR 4 is introduced with its four chapters. Contents of these chapters were thoroughly discussed earlier though.

The entire document is available here.

Sven Pommeranz
On behalf of the European Compliance Academy (ECA)

Go back

GMP Conferences by Topics