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Long-Sought-After Rule on CGMPs for Combination Products Released by FDA

Posted 22 January 2013 | By

The US Food and Drug Administration's (FDA) Office of Combination Products (OCP) has released a new final regulation on the current good manufacturing practices (cGMPs) used in the manufacture of combination products.


Combination products are, as their name implies, a combination of two or more product classes, such as a medical device, biologic and a pharmaceutical product. They are typically regulated by analyzing their constituent parts to determine their primary mode of action, which is then analyzed by the appropriate regulatory center. A pre-filled syringe containing a vaccine, for example, might be regulated by FDA's Center for Biologics Evaluation and Research (CBER), while a drug-coated stent might be regulated by the Center for Drug Evaluation and Research (CDER).

Combination products might also be two devices that are physically separate but are specifically indicated for use with one another or are packaged together.

Because the devices combine two or more products that on their own might be regulated, they are subject to careful scrutiny in regards to their manufacturing.

New Regulatory Framework

FDA said its new regulation "sets forth a transparent and streamlined regulatory framework for firms to use when demonstrating compliance with CGMP requirements for 'single-entity' and 'co-packaged' combination products."

Pharmaceutical and biological products are largely governed by a set of drug quality regulations under CGMP (21 CFR 210-11 and 600-680, respectively), while medical devices are manufactured under Quality Systems Regulation (QSR) regulations (21 CFR 820) and blood- and tissue-based products are regulated under 21 CFR 1271.

If the devices are physically separate, such as those packaged together, then they will follow their own separate product-specific quality regulations, FDA explained.

The application of those rules to single-entity products is considerably more difficult, FDA said, and the agency explained that it wished to put forth a rule that would make the standards unified regardless of which center took the lead on regulating the product.

The New Rule

Regulators called the final rule "largely identical" to the proposed rule, and it contains 11 main sections, the most important of which may be Section 4.4.

The section specifies that good manufacturing practices for combination products can be satisfied by either demonstrating compliance with all applicable regulations on a separate basis, or by meeting either:

  • the CGMP regulation and 21 CFR 820.20 (management responsibility), 820.30 (design controls), 820.50 (purchasing controls), 820.100 (corrective and preventive action, or CAPA), 820.170 (installation) and 820.22 (servicing); or
  • the quality system regulations (QSR) and 21 CFR 221.84 (component, container and closure testing), 221.103 (yield calculation), 211.132 (tamper-evident packaging), 211.137 (expiration dating), 211.165 (testing and release), 211.166 (stability testing), 211.167 (special testing requirements) and 211.170 (reserve samples).

The rule, Current Good Manufacturing Practice Requirements for Combination Products, will come into effect in 180 days (Monday, 22 July 2013).

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