FDA Viewpoints - Human Drug CGMP Notes

The following extracts have been taken from the FDA's "Human Drug CGMP Notes", which is a memo issued to FDA personnel periodically to provide guidance on CGMP for human use pharmaceuticals.

These extracts supplement the information contained in the previous sections.

"Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?

Yes. Since the publication of the inspection guide on gleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.

We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. But in order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidised under TOC test conditions. This is not a trivial exercise because we know that some organic compounds can not be reliably detected using TOC.

TOC may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit 'background' carbon (i.e. carbon from other sources other than the contaminant being removed) as much as possible. The established limit -- or the amount of residue detected for comparison to the spec -- should correct for the target material's composition of carbon. As for any method, recovery studies are necessary. If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample hold time on accuracy and limit of quantitation."

HUMAN DRUG CGMP NOTES, VOLUME 10, NUMBER 01 (First Quarter, 2002) (March 2002) Brian J. Hasselbalch

QUESTIONS AND ANSWERS:

[Question 5]

[VIP ID: 71450]

"What is the level of detergent residue that would be acceptable to FDA? What is the basis for arriving at this level, if any?

FDA has repeatedly stated that it is the firm's responsibility to establish acceptance limits and be prepared to provide the basis for those limits to FDA. Thus, there is no fixed standard for levels of detergent residue. Any residues must not adversely alter drug product safety, efficacy, quality, or stability."

HUMAN DRUG CGMP NOTES, VOLUME 03, NUMBER 02 (June 1995) Motise's Notebook

Policy Questions on Cleaning Validation:

1)

[VIP ID: 3930]

"If the ability of a procedure to clean a piece of equipment made of a particular material, such as 316 stainless steel, is shown to be acceptable and validated, can that "material" specific cleaning procedure be used without "extensive" validation for other pieces of equipment and compounds?

No. The design of the equipment is a major component of its cleanability. Therefore, firms should have data that relate to a given piece of equipment."

HUMAN DRUG CGMP NOTES, VOLUME 03, NUMBER 02 (June 1995) Motise's Notebook

Policy Questions on Cleaning Validation:

2)

[VIP ID: 3931]

"What cleaning and process validation do the CGMPs require for production of a bio-batch, where only a single lot has been made?

The agency has not articulated its expectations regarding process validation or cleaning validation with respect to bio-batches, per se. The closest relevant document is our Guideline on The Preparation of Investigational New Drug Products. In that document we said:

At early clinical stages, where a single batch of drug product may be produced, and where significant formulation and processing changes may make batch replication difficult or inexact, only limited process validation may be possible. In such cases, limited validation, especially for such critical processes as sterilisation, should be derived, to the extent possible, from product and process analogs. In addition, data obtained from extensive in-process controls and intensive product testing may be used to demonstrate that the instant run yielded a finished product meeting all of its specifications and quality characteristics. It is expected that more comprehensive process validation will be conducted as additional uniform batches are made under replicated conditions.

You may apply these principles to the bio-batch process and cleaning validation. We would expect adequate cleaning to have been performed and documented and that in-process and end product testing would show instant lots to meet specifications."

HUMAN DRUG CGMP NOTES, VOLUME 05, NUMBER 03 (September 1997) Motise's Notebook

Policy Questions:

3)

[VIP ID: 4023]

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

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."

HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 02 (June 1998) Motise's Notebook:

POLICY QUESTIONS:

Purely Speaking: (Impurity Issues) Question 2

[VIP ID: 5906]

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

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)."

HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 02 (June 1998) Motise's Notebook:

POLICY QUESTIONS:

Purely Speaking: (Impurity Issues) Question 1

[VIP ID: 5905]

"Is testing rinse solution alone enough to support residue determinations for cleaning validation?

While it is understood that rinse samples are capable of sampling larger surface areas, particularly ones which are difficult to access, for the purposes of cleaning validation, rinse samples alone would not be acceptable unless a direct measurement of the residue or contaminant has been made. One disadvantage of rinse samples is that the residue or contaminant may not be soluble or may adhere to the equipment. Some firms use both swab samples, where feasible, and rinse samples during the course of their cleaning validation.

For routine equipment cleaning after validation, some firms may be able to justify use of rinse samples to demonstrate the process continues to consistently clean the equipment. FDA has compared rinse samples to that of a "dirty pot analogy." When evaluating the cleaning of a dirty pot, the rinse water is not what is looked at to see if the pot is clean.

The purpose of cleaning validation is to demonstrate that a particular cleaning process will consistently clean the equipment to a predetermined limit; the sampling and analytical test methods should be scientifically sound and provide adequate scientific rationale to support the validation."

HUMAN DRUG CGMP NOTES, VOLUME 06, NUMBER 04 (December 1998) Motise's Notebook

POLICY QUESTIONS:

Question 3 [VIP ID: 5982]

"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?

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-penicillin 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."

HUMAN DRUG CGMP NOTES, VOLUME 07, NUMBER 01 (March 1999) Motise's Notebook

Policy Questions On:

Question 3 [VIP ID: 6005]

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

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."

HUMAN DRUG CGMP NOTES, VOLUME 07, NUMBER 01 (March 1999) Motise's Notebook

Policy Questions On:

Question 4 [VIP ID: 6006]

In document CLEANING PROCESSES AND CLEANING VALIDATION GUIDE (Page 163-167)