HUMAN DRUG CGMP NOTES EXCERPT

June 1998

If a firm's only operation is performing finished packaging operations for bulk tablet and capsule drug products, must it still maintain separate facilities and equipment for packaging penicillin products?

Reference: 21 CFR Sections 211.42.(d), Design and construction features [Buildings and Facilities], 211.46(d), Ventilation, air filtration, air heating and cooling, and 211.176, Penicillin contamination

Yes. The CGMP regulations explicitly require that operations relating to the manufacture, processing and packaging of penicillin be performed in facilities that are separate from those facilities used for other drugs. The regulations also require separate air-handling systems in facilities used for penicillin products. Furthermore, if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, CGMPs require that the non-penicillin drug be tested for the presence of penicillin. The CGMPs make no exceptions from the foregoing for operations that are limited to repackaging solid oral dosage forms.

It should be noted that the requirement for separate facilities does not necessarily mean that operations relating to penicillin products must be conducted in separate buildings from other drugs. A separate area dedicated to penicillin products within a larger facility may be acceptable if penicillin containment can be established and validated.

Is it acceptable under section 211.176 to release products to market as long as the products are tested and no penicillin is found?

Reference: 21 CFR 211.176, Penicillin contamination

It is not acceptable to release the product when other CGMP requirements have not been met. Although this section prohibits marketing of products found to be contaminated with penicillin, it does not sanction marketing of non-penicillin products based only on test results that show no detectable levels of such contamination. Other CGMP requirements must still be met. For example, there must still be adequate separation of facilities used for operations relating to penicillin production from facilities used for non- penicillins for human use.

Section 211.176 is an additive requirement to 21 CFR 211.42.(d) and 211.46(d), and does not mean that testing a product and finding it free from contamination renders the product marketable when produced under a reasonable possibility of contamination. Firms have inappropriately applied 211.176 as a means to market products that have been produced under adverse CGMP conditions.

FDA would not necessarily condone the shipment of potentially contaminated drugs that happen to test negative for penicillin. Drug products that are prepared, packed and held in a facility whereby they may have become contaminated or were in violation of CGMP, may be subject to regulatory action as adulterated (in the CGMP context). The question is not whether they were physically contaminated or even if they were "pharmacologically perfect". Rather, FDA has the enforcement discretion to decide whether to bring an action against such drugs. This prerogative would be based on factors such as violation significance, proposed corrections, and other case related circumstances. FDA's Office of Chief Counsel has indicated "To prevail on a charge of adulteration based upon a failure to conform to CGMP regulations, the government need not establish that any particular drug is actually deficient as a result." See U.S. vs. Western Serum Co., Inc., 498 F. Supp. 863 (D. Arizona 1980.)

What should investigators look for when inspecting a firm's cleaning validation program?

Reference: 21 CFR 211.67, Equipment cleaning and maintenance; 21 CFR 211.100, Written procedures; 21 CFR 211.160, Laboratory controls; FDA Guide to Inspections of Validation of Cleaning Processes, July, 1993

The objective of cleaning validation is to ensure that a specific cleaning process will consistently clean to predetermined limits so as to prevent contaminants (product or cleaning process related) from adversely affecting the safety and quality of the next product manufactured.

As stated in the Guide to Inspections of Validation of Cleaning Processes, determine if firms have a written, well established and validated cleaning program. Basic steps include the development of a sensitive, accurate and precise analytical method for the determination of an acceptable limit, something necessary for any analytical test method developed in conformance with CGMPs. In addition, as discussed in the guide, determine if firms have and follow specific written procedures as to how cleaning will be performed, as well as how the cleaning validation will be conducted (including sampling procedures and analytical methods). Determine if the validation protocol addresses different sampling surface types, hardest to clean areas, and specific equipment, including utensils. FDA expects the validation studies will be completed in accordance with written protocols and that the final validation report will include the appropriate conclusions with management concurrence. Performing testing of cleaned equipment, in accordance with written procedures, would be consistent with 21 CFR 211.67(b).

Does FDA have impurities acceptance limits for cleaning validation and subsequent cleaning verification?

Reference: 21 CFR 211.67, Equipment cleaning and maintenance; 21 CFR 211.176, Penicillin contamination; International Committee on Harmonization (ICH) Guideline on Impurities in New Drug Substances, Q3A, May, 1997

FDA has always been concerned with the issue of contamination and cross contamination. Such contamination may include not only carry over from a previous product or residual cleaning solvents, but also detergents and surfactants.

Except for penicillin, FDA has not established standard acceptance limits for cleaning validation. Due to the wide variation in both equipment and products produced, it would be unrealistic for the agency to determine a specific limit. In the CGMP context, however, firms need to establish limits that reflect the practical capability of their cleaning processes, as well as the specificity of the analytical test method.

We have found that some firms have incorrectly applied as their acceptance limit the 0.1% impurity identification threshold as discussed in both the ICH impurity guideline and the U.S.P. General Notices. This application of the 0.1% impurity threshold is inappropriate because the limit is intended for qualifying impurities that are associated with the manufacturing process or related compounds and not extraneous impurities caused by cross contamination. It is important that acceptance limits reflect the capability of the cleaning process.

When determining the acceptance limit, relevant factors generally include: (1) Evaluation of the therapeutic dose carryover; (2) toxicity of the potential contaminant; (3) concentration of the contaminant in the rinses; (4) limit of detection of the analytical test method; and, (5) visual examination. While we suggest that these factors be considered, relying only on visual examination would not be scientifically sound.

Should non-pharmaceuticals be manufactured in common equipment with active pharmaceutical ingredients (APIs)?

Reference: FD&C Act, Section 501(a)(2)(b); WHO Good Practices for the Manufacture and Quality Control of Drugs, June 1993

FDA has not specifically addressed this issue in a formal document. However, a fundamental tenet of current good manufacturing practice is that equipment does not contaminate the drugs -- that is, alter drug safety, quality or purity beyond established specifications. If you encounter instances in which non-pharmaceuticals are made in the same equipment as APIs, consider this basic tenet, and evaluate the suitability of using common equipment on a case by case basis.

Some non-pharmaceuticals pose unacceptable risks of cross-contamination and product mix-ups, and should therefore not normally be manufactured in common equipment with APIs. In some cases, in addition to separate equipment, it would be appropriate to use a separate facility for pharmaceutical chemical manufacturing.

This separation is an internationally recognized concept. For example, the World Health Organization (WHO) Guide to Good Manufacturing Practices discusses the use of separate facilities for the production of certain "non-pharmaceutical products." It adds that "the production of technical poisons, such as pesticides and herbicides," should not take place on the "premises used for the manufacture of pharmaceutical products."

As a general principle, the risks posed by unanticipated mix-ups or cross-contamination should be considered with particular emphasis on chemicals: (1) Known to pose any acute or long term toxicity concerns; or, (2) of incompletely characterized toxicity. Toxicological assessments normally include information such as acute data (e.g., LD50 determinations) using different routes of administration, mutagenicity, carcinogenicity, teratogenicity, sensitization, and irritation. Investigators should be aware that lack of toxicological assessments is not uncommon.

These risks are influenced by the nature and intended use of the drug products that will incorporate the API. For example, those risks may be of greater concern when the APIs will be used in dosage forms intended for: (1) Large doses, (2) long term therapy; (3) treating open wounds; (4) injection; or, (5) inhalation.

Even when an API manufacturer considers these issues, and determines that the non-pharmaceutical is "harmless" and can be made in common equipment with APIs, it is important that the manufacturer still follows CGMPs for APIs.