Destin A. LeBlanc

Cleaning Validation Technologies

Technical Consulting Services

MARCH 1999

Does FDA have a policy regarding use of the "Matrix" or "Family" approaches to process validation?

Reference: 21 CFR 211.100, Written procedures; deviations; 211.110, Sampling and testing of in-process materials and drug products; May 1987, Guideline on General Principles of Process Validation

No. The CGMP regulations, at section 211.110, require a manufacturer to "validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product." Although some guidance is presented in the May 1987 "Guideline on General Principles of Process Validation," CDER has not published any formal written policy on the "matrix" or "family" approaches to process validation.

Nonetheless, because the general principle is to validate a drug manufacturing "process," in theory it may be possible for a manufacturer that uses the same "process" for several related products to develop a scientifically sound validation plan for that process, rather than different plans for each product manufactured by that process.

We have reviewed several plans that use a "matrix approach," and have received inquiries regarding a "family approach" to process validation. Within these proposals, a "matrix approach" generally means a plan to conduct process validation on different strengths of the same product, whereas the term "family approach" has been used to describe a plan to conduct process validation on different, but similar products. In the cases we're aware of, both approaches generally call for a plan to validate the process using a minimum number of production batches of each strength or product. Either approach may be in accord with CGMP if the study demonstrates that the process is consistent for all the strengths or products involved. It is important that any such validation plan be designed to evaluate all sources of variation in the products manufactured by the process.

Each plan should be evaluated on a case by case basis and it is up to the manufacturer to develop and justify the appropriate matrix according to the specific similarities and differences in the different strengths or different products. For example, if there are significant differences in the equipment or process, we would expect that each strength/product would need to be validated separately.

The agency has not yet established its current thinking about the principles of the matrix or family approach; thus, our limited experience cannot yet be broadly extrapolated to applied CGMP. Those principles are gradually emerging, though, and we anticipate addressing them thoroughly in future guidance documents.

Can a facility that produced penicillin dosage forms be decontaminated and renovated for production of non-penicillin solid dosage forms provided there is no further penicillin production in the renovated facility?

Reference: 21 CFR 211.42(d), Design and construction features; 211.46(d), Ventilation, air filtration, air heating and cooling; 211.176, Penicillin contamination; FDA By-Lines #3, Nov.77, Procedures for the Detection of Residual Penicillins in Drugs; 21 CFR 436.104 Penicillin Activity; and FDA Guide to Inspections of Validation of Cleaning Processes, July 1993.

Yes. However, the decontamination process is extremely difficult and we are unaware of any firm that has successfully decontaminated a penicillin facility and converted it to production of non-penicillin products.

Note that at section 211.176 the CGMP regulations require that if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin product must be tested for the presence of penicillin and not marketed if detectable levels are found using the codified method. Such a reasonable possibility may be present where decontamination has not been conducted effectively. That would put the responsible firm in a position of having to test each and every lot of non-penicllin product for the presence of penicillin.

In sum, while the CGMP regulations would not prohibit decontamination and conversion, the difficulty of cleaning up penicillin residues makes the chore daunting.

Is there an acceptable level of penicillin residue in non-penicillin drug products?

Reference: 21 CFR 211.176, Penicillin contamination; 21 CFR 436.104 Penicillin Activity; FDA By-Lines No.3, Nov.77, A Review of Procedures for the Detection of Residual Penicillins in Drugs.

Any detectable levels of penicillin residue are considered violative because 21 CFR 211.176 indicates that a non-penicillin drug product must not be marketed if detectable levels of penicillin are found when tested according to procedures specified in The Procedures for Detecting and Measuring Penicillin Contamination in Drugs.

The current analytical standard for demonstrating adequate decontamination of facilities, separation within the same building, or measurement of cross-contamination is codified at 21 CFR 211.176 and 436.104 and has a limit of detectability of 0.006 ppm (as Penicillin G using S. Lutea) and a violative detection amount of 0.03 ppm. Note that the latter amount reflects the method's limits with respect to confidence and reproducibility and does not represent a tolerance level. This analytical methodology is limited to the detection of Penicillin G and ampicillin in a limited number of products listed in the referenced method, not including other beta-lactam antibiotics. In situations where this methodology is not workable, it is the firm's responsibility to develop, validate, and use other methodology with similar sensitivity.