A Closer Look at FDA’s Final Rule for 21 CFR Part 4 – Current Good Manufacturing Practices for Combination Products

On January 22, 2013 the FDA published the Final Rule for “Current Good Manufacturing Practices for Combination Products” in the Federal Register.  This rule is designated 21 CFR Part 4, and becomes effective July 22, 2013. The history of this rule goes back to October of 2004, when FDA released a guidance document regarding the application of cGMPs to combination products.  This guidance provoked differing interpretations, which resulted in inconsistent or varying application of the various cGMP requirements, which FDA felt could affect product safety and public health.  FDA also observed that the absence of clear cGMP requirements for combination products was leading some manufacturers to develop and document practices that were redundant and overly burdensome.  FDA released the proposed rule in September of 2009, which resulted in the final rule that was recently released.

Within the preamble and the rule, FDA defines the combination products that are governed by this regulation: combinations of drug/device, biologic/device, drug/biologic or drug/device/biologic are all covered by this rule.  A combination of like products (i.e. drug/drug) are not covered by this rule, and respective existing cGMP regulations apply in those cases.

The good news is that Part 4 does not create any new cGMP requirements; FDA believes there are many similarities to the existing requirements.  It does clarify which cGMP rules need to be enforced based on the conditions under which the combination product is produced and marketed.  The existing cGMP rules that apply to combination products are:

- Drug products – 21 CFR Part 210 and 211

- Medical devices – Quality Systems (QS) Regulation – 21 CFR Part 820

- Biologic products – 21 CFR Part 600 through 680 (where cGMPs are applicable)

- Human cell, tissue and cellular & tissue-based products – 21 CFR Part 1271

How each of these these existing rules apply to combination products depends on the specific circumstances under which the combination product is produced, packaged and marketed.  In the case where the constituent parts are manufactured and marketed as separate products, and are also cross labeled to create a combination product, they remain separate for the purpose of applying cGMP regulations, and need to be manufactured under separate drug, device or biologic cGMPs.

21 CFR Part 4 gives companies two options for single entity and co-packaged combination products, including investigational products.  The first is to demonstrate compliance with the specifics of all cGMP regulations applicable to each of the constituent parts included in the combination product.  The second option is to demonstrate compliance with either the specifics of the drug cGMPs or the device Quality Systems regulation, rather than both, when the combination contains both a drug and device under certain conditions.  If the second option is chosen, compliance with specified provisions from the other of these two sets of cGMP requirements must be demonstrated. 

If a single entity or co-packaged drug/device combination product is produced under a cGMP system that complies with the drug regulations, it also must satisfy the following provisions of the device Quality Systems regulation:

- 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

If the above are satisfied, no additional compliance with the device Quality Systems regulation need to be made. 

If a single or co-packaged drug/device combination product is produced under a system that complies with the device Quality Systems regulation, it must also satisfy the following provisions of the drug cGMP regulations:

- Section 211.84 – Testing and approval or rejection of components, drug product containers and closures

- Section 211.103 – Calculation of yield

- Section 211.182 – 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

- Section 211.167 – Special testing requirements

- Section 211.170 – Reserve samples

Again, upon demonstrating the above requirements have been satisfied, no additional compliance with the drug cGMPs need to be made.

If the combination product includes a biologic product, in addition to the above conditions, the applicable cGMP regulations found in 21 CFR Parts 600 through 680 and 1271 apply.

Now that the finalized regulation has been published, FDA is planning to publish additional clarifying guidance documents.  One of the clarifying guidance documents they point to in the preamble to the rule outlines how to comply with the rule and pre-manufactured design control requirements for combination products that are already on the market and may not have all of the required documentation.

Sparta Systems Enterprise Quality Management System, TrackWise, is uniquely positioned to assist companies producing and marketing combination products manage their cGMP processes.  TrackWise is in use as the pillar EQMS systemin more pharmaceutical, medical device and biologic companies than all other quality systems combined.  TrackWise can be configured to meet the unique and different requirements of the various conditions defined in 21 CFR Part 4.  To discuss your needs, please contact us via e-mail at: insidesales@spartasystems.com or reach out directly to your Account Executive.

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