HUMAN DRUG CGMP NOTES EXCERPT

September 2000

How can one obtain a copy of the procedures for detecting and measuring penicillin contamination in drugs?

Reference: 21 CFR 211.176, Penicillin Contamination; FDA By-Lines No.3, Nov. 77, A Review of Procedures for the Detection of Residual Penicillin in Drugs.

The bioassay referenced in 21 CFR 211.176 can be used whenever there exists a reasonable possibility that a non-penicillin drug product has been exposed to cross-contamination with penicillin. The non-penicillin drug product should be tested for the presence of penicillin and not marketed if detectable levels are found when tested according to procedures specified in “Procedures for Detecting and Measuring Penicillin Contamination in Drugs”, which is incorporated by reference. Copies are available from the Division of Pharmaceutical Analysis, (HFD-923), Center for Drug Evaluation and Research, Food and Drug Administration, 8301 Muirkirk Road, Laurel, MD, 20703. To request copies of the procedure contact:

Valarie A. Flournoy, Tel 301-827-8236, FAX 301-827-8073, E-Mail FLOURNOY@CDER.FDA.GOV.

Can section 21 CFR 436.104 (Penicillin Activity) continue to assist in determining residues of penicillin contamination in non-penicillin drugs?

Reference: 21 CFR 211.176, Penicillin Contamination; FDA By-Lines No.3, Nov.77, A Review of Procedures for the Detection of Residual Penicillin in Drugs.

No, it can not. Section 436.104 was in part 21 CFR 436. Parts 429 through 460 existed for the purpose of enforcing Section 507 of the FD&C Act “Certification of Antibiotics”. This section of the Act was repealed by FDAMA (FDA Modernization Act). Therefore, section 436.104 was deleted from the CFR and does not exist any longer.

Section 436.104 (methodology for penicillin activity) is derived from the original tests for penicillin contamination in foods and drugs published in FDA By-Lines No.3 (Nov.1977). The FDA codified method continues to exist because it still is required in 211.176 – “…such drug product shall not be marketed if detectable levels are found when tested according to procedures specified in ‘Procedures for Detecting and Measuring Penicillin Contamination in Drugs,…”. The elimination of 436.104 does not change anything for the following reason: In the By-lines, the test sensitivity is stated to be 0.01 units/ml as penicillin G, using S. lutea, equivalent to 0.006 PPM. The ‘standard response line’ cited at 436.104 covers a range of concentrations equivalent to 0.003 to 0.120 PPM, as penicillin G. However, the test method as cited in 211.176 has always indicated a limit of sensitivity of 0.006 PPM. We always indicate that the sensitivity should be at 0.006 PPM and not necessarily 0.003 PPM. So nothing has changed because the By-lines also covers a range of concentrations which can be used as ‘standard response lines’ similar to 436.104.