Comparison of FDA cGMP Compounding Guidance

Comparison of FDA cGMP Compounding Guidance.


The initial Guidance for Industry cGMP – Interim guidance was issued July 2014 and a link to this document is available here.  A total of 25 comments were received from various organizations which are available for viewing here.  The FDA reviewed these comments and released a Revision 1 (which remains in draft form) Dec 2018.  The comment period for Revision 1 is open now, and closes February 11, 2019.  Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.


On review of the Rev1 of the compounding guidance the first noticeable change is the length of the document, the original version is 28 pages in length, the revision 1 version is now 51 Pages in length.

The Table of Contents in the rev 1 is reordered and expanded.

  • Quality Assurance Activities/Complaint handling (section III.K original) is split into two sections. Quality Assurance Activities is now in section III.A, and compliant handling is in section III.N.
  • Equipment, Containers and Closures (section III.D original) is split into two sections. Equipment is now in section III.E and Containers and Closures is in section III.F.
  • Components (section III.E original) now in section III.G and includes two new subsections. III.G.1 Regulatory policy regarding component supplier qualification testing and III.G.2 Regulatory policy regarding testing for finished project to be used as a source material for processing.
  • Production and process controls (section III.F, sub sections 1 and 2) now in section III.H with subsection 2 changed from Aseptic drug processing to Drug Product Sterilization.
  • A new section and subsections have been added (section III.K, sub sections 1, 2 and 3) for Stability/expiration dating for compounded drug products. Sub section III.K.1 stability program and beyond-use dating, sub section III.K.2 establishing an in-use time for sterile drug products, and sub section III.K.3 in-use time and BUDs for sterile drug products.
  • A new section has been added (section III.M) reserve samples.
  • Appendix A added, which addresses the conditions under which FDA generally does not intent to take regulatory action regarding certain release testing requirements.
  • Appendix B added which addresses conditions under which FDA generally does not intent to take regulatory action regarding stability testing and expiration date requirements.

While this document is still in draft and has not been finalized, it would be prudent for each 503B Outsourcing Facility to perform an assessment of current operations, their quality systems, and standard operating practices against the revision 1 guidance to identify any gaps, shortfalls that which they may need to remediate. A quick review of sections III.A, E, and F identified the following changes (note this list is not all inclusive).

Section III.A Quality Assurance Activities

Better defines the role of the quality unit – Part 211 (21 CFR 211.22) requires that drug producers establish a quality control unit to oversee various aspects of production, including strength as well as sterility assurance activities for sterile products and microbiological quality for non-sterile products.

Clarified FDA expectations with regard to staffing eliminates the discussion that one person can fulfill both roles of production and quality.

Clarified that the quality unit is responsible for the quality of compounded sterile and non-sterile drug products.

Provided additional guidance on sampling and testing and annual review of compounding operations.

Section III.E – Equipment

Expands the definition of equipment to mechanical, electronic, or automated and adds that equipment needs to be designed and located to facilitate operations, cleaning, and maintenance, and equipment may require sanitization or sterilization to prevent contamination (21 CFR 211.63, 21 CFR 211.67).

The revision 1 guidance addresses the use of single use disposable equipment such as pre-use/ post-use checks and suitability of single use disposable equipment by the use of valid COA from the supplier.

Additional considerations for sterile drug products added.

Section III.F Containers and Closures

As part of the selection process, testing of the drug product container-closure system under the proposed storage conditions for the finished product must be performed to verify its ability to meet  established quality specifications of the finished drug product over the expiry period (21 CFR 211.94, 21 CFR 211.166).

Identifies that testing must be performed again if the manufacturer’s specification of the 486 container or closure is changed (21 CFR 211 211.94, 21 CFR 211.166).

Additional considerations for sterile drug products added.

Have a question on the cGMPs applicable for a 503B Outsourcing Facility?  Are you looking to schedule an external assessment or review of your facility?  Please use our Contact Us form to let is know how we can help.

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