Certificate of Analysis for Investigational Drug

Question 1:

Would you please be able to comment whether it is a requirement for a CRO to request certificate of analysis (COA) from the sponsor prior to conducting clinical trials. It is my understanding that FDA requires COA be submitted to the FDA for IND and ANDA submissions, but are there any regulations stipulating that CRO must have the COA on files (for either ANDA or IND studies) prior to conducting the trial?

Answer 1:

Our regulations for IND submissions do not specifically mention COA. Regulations involving chemistry, manufacturing, and control information can be found at 21 CFR 312.23. If the obligation for this section was transferred to your CRO, then you would be responsible for the information. See 21 CFR 312.52. You can view these regulations at www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm

I can find nothing in our regulation that would apply to the testing of drugs by CROs under an ANDA other than 21 CFR 320.

Question 2:

Thanks for responding to my query; I've found the COA listed as an essential document in the "Guidelines for Good Clinical Practice" section of "Good Clinical Practice: A question and Answer Reference Guide" and briefly referenced in "Guidance for Industry: content and format if INDA for Phase 1 studies of drugs, including well characterized, therapeutic, biotechnology-derived products," section d and also in the "Fundamentals of US Regulatory Affairs" (5th edition) section on generic drugs (Regulatory Affairs Professionals Society), but all sources indicate that COA would be submitted by the sponsor to the FDA, and no mention is made as to whether a CRO is to maintain these records on files..

As a CRO we were requesting COA from the sponsor as an added measure of assuradness in product quality and suitability for release for testing in human subjects, but were wondering if the practice was necessary. An alternative would be to request a product release statement from the sponsor, but this too may be unnecessary if product quality is ascertained by testing that is verified by FDA/CDER at the time of IND/ANDA submission. Please comment on the need for a CRO to obtain this COA/product release statement as an additional proof of test product quality and suitability for use in humans prior to conducting phase 1 clinical trials.

Answer 2:

I'm interpreting your e-mails to mean that your CRO has contracted with the sponsor to be responsible for conducting the Phase 1 studies for the sponsor. Phase 1 studies generally involve the first time an investigational drug is first used in humans.

FDA's regulations for the conduct of investigational studies do not specifically mention "Certificates of Analysis." However, FDA issued a guidance several years ago entitled "Guidance for Industry: Guideline on the Preparation of Investigational New Drug Products (Human and Animal)" (it's electronically available at www.fda.gov/cder/guidance/old042fn.pdf). This guidance explains that FDA expects investigational drug products that will be used in human subjects to be manufactured in compliance with good manufacturing practices (CGMPs). FDA's regulations for CGMPs specify that components of drug products "...be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component..." See 21 CFR 211.84(d)(2).

In Section 8, "Essential Documents for the Conduct of a Clinical Trial," of FDA's official guidance, the ICH E6, "Good Clinical Practice: Consolidated Guidance," section 8.2.16 recommends that "Certificate(s) of analysis of investigational product(s) shipped" be maintained in the sponsor's files, "To document identify, purity, and strength of investigational products to be used in the trial." Here is a link to the complete E6 guidance: www.fda.gov/cder/guidance/959fnl.pdf .

The point of a Certificate of Analysis (COA) is to ensure that the test article is properly characterized, that is, that the test article is of acceptable quality and identity. Although FDA's regulations do not specifically require that you request a COA from the sponsor, the COA would provide documentation that the investigational product is, indeed, of acceptable quality and identity. Thus, although not required by the regulations, your practice of requesting a COA would certainly be in keeping with good clinical practice (GCP). If the product that you are using in the study involves a commercially available drug that you are purchasing from a retail source, then you would want to retain the labeling and other documentation to show the source of the product and its quality (e.g., expiration date).

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