FDA Issues New Guidance on cGMP for Combination Products – A Quick Review

In January 2015 the FDA issued a new draft  guidance document regarding the final rule on current good manufacturing practice requirements (cGMP) for combination products that was issued on January 22, 2013 and made effective on July 22, 2013. The guidance describes and explains the final rule, so it is important for all combination product manufacturers to understand the most influential topics that were covered.

In this quick review, you learn the key subjects described in the new guidance document and how it relates to the cGMP regulations for combination products, helping you to more efficiently make changes to your own manufacturing process if necessary in order to better comply with the final rule.

Specific Combination Product Regulations

According to hlregulation.com, “Perhaps most noteworthy in the guidance is FDA’s advice on cGMP compliance for specific types of combination products.” These are products which needed very detailed explanations and guidelines for their proper and safe manufacturing and for your company’s ability to comply with the FDA’s rules for them. They are:

  • Prefilled syringes
  • Drug-coated mesh
  • Drug Eluting Stents (DES)

If your company manufactures any of these products, it is important to pay special attention to Article V of the FDA’s guidance document. There are even hypothetical scenarios which will make the streamlining process easier.

Duties of the Manufacturer

There are also several important requirements described in the new guidance that concern the manufacturer specifically and their duties in making sure that the combination products themselves comply with all cGMP requirements. These include:

  • Ensuring that all parts of the manufacturing process be in compliance with the guidelines, including those carried out by third party companies.
  • Keeping documentation (and having all third parties keep documentation) on their responsibilities as to the manufacturing of the product, making sure the manufacturer of the finished product has access to all documentation.
  • Ensuring that, if and when changes are made to the combination product or any parts of the product, these changes are verified through testing to be valid and safe.
  • Explaining how the quality systems for their combination products are structured when applying to the FDA and how they work (e.g. streamlined approach or both 21 CFR Part 820 and 21 CFR Part 211).
  • Preserving reserve samples of single-entity combination products either in whole or part depending on the product in order to address any issues with the manufacturing process or the product itself.
  • Having assurances (documentation) that those involved in the design process of the combination product had sufficient design control systems.

Manufacturers must comply with these requirements and be sure to adjust their company policies in order to do so.

Clarification of Language

The new guidance clarifies language included in the final rule to address the “meaning” and “significance” for combination products. These are:

  • Manufacture –  any activities involved in the manufacturing of the combination product including, but not limited to: designing, fabricating, assembling, filing, processing, testing, labeling, packaging, repacking, holding, and storage.
  • Manufacturer – an entity that is responsible for any of the above activities.
  • Constituent part – any drugs, devices, and biological products included in combination products.
  • Component – (with respect to drugs) “any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product”, or (with respect to medical devices) “any raw material, substance, piece, part, software, firmware, labeling, or assembly which is intended to be included as part of the finished, packaged, and labeled device”.

This clarification of language may impact your operations, but the language itself has the same meaning as when used in the underlying, referenced regulations (e.g. 21 CFR Part 810, 21 CFR Part 211, etc.).

Other Considerations

A few other considerations pointed out in the guidance document are specifically worth mentioning. These could have an impact on your company as a whole or just on the process of the product’s manufacturing or safety-ensuring measures.

  • CAPA (corrective and preventative actions) must be implemented in all facilities involved with the manufacturing of the combination product.
  • A design history file is required for a combination product to include the combined use of the constituent parts, however, it is acceptable to leverage existing data that may have been generated outside of design controls. Note that design and development plans and design reviews are not required for the currently marketed product since these development activities would have already occurred.
  • Purchasing agreements with suppliers are an important tool in establishing purchasing controls, specifically as it relates to controlling changes.
  • A distinction is made between a drug container closure system and a drug delivery device, the latter of which is considered a combination product. The relevance here is that the device constituent parts or materials that make up the drug delivery device are not subject to 21 CFR Part 211.84.
  • The FDA has included very specific advice on applying the cGMP’s other requirements for specific drugs, devices, biological products, and HCT/Ps to certain combination products.

It is important to understand all critical elements of the FDA’s cGMP guidance and their possible impact on you. The new guidance for combination products may cause you to make changes to your company and/or its processes. Your company will need to follow this new guidance as well as those already established by the final rule (21 CFR Part 4), a how-to guide of compliance with the ruling which you can find via the link provided.