Resources

Links of Interest

Link of interest in cleaning validation.

1. Canadian Cleaning Validation Guidelines from Health Canada (also available in French).
2. FDA’s cleaning validation guideline a key resource for anyone involved in cleaning validation.
3. Annex 15 to EU GMPs covers cleaning validation among other items
4. FDA’s Q&A for CGMP FDA’s replacement for “Human Drug CGMP Notes.”
5. PIC/S PI 006-3 The basis for Annex 15.
6. 21CFR 210-211 (GMPs) the FDA’s GMP speak frequently about cleaning and sanitizing.
7. CBER Compliance Program 7345.848 CBER Quality System inspection program for biological drugs
8. FDA Process Validation: General Principles and Practices (2011) FDA guideline. Not specific to cleaning validation, but helpful in its validation concepts.
9. ICH Quality Guidelines includes guidelines on analytical method validation and on validation of API manufacturing
10. Active Pharmaceutical Ingredients Committee (APIC) “Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants” (2021)
11. WHO Cleaning Validation Guidance Appendix 3 of Annex 4 is the section on cleaning validation.
12. PIC/S PI 030-1 Aide-Memoire: Inspection of Active Pharmaceutical Ingredients.
13. EMA/INS/GMP/809387/2009 EMEA Update on Revision of Chapters 3 and 5 of the GMP Guide: “Dedicated Facilities” (December 10, 2009)
14. EduraLex Volume 4, EU Guidelines for GMP, Draft Annex 2 Manufacture of Biological Medicinal Substances and Products for Human Use (April 9, 2010)
15. ANVISA Resolution – RDC no. 17, of April 16, 2010 Article 125 (page 20) deals with “segregation” for hormones, cytotoxics, and some antibiotics.
16. EMA’s “Concept Paper on the development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities” (2011)
17. EMA “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities” (November 20th, 2014)
18. EMA Q&A on Limits for Shared Facilities (2018)
19. ICH Q7 Questions and Answers (2015)
20. PIC/S PI 046-1, Guideline on Exposure Limits (2018)
21. FDA “Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance-Equipment” Note: This Q&A has questions and answers related to cleaning validation, including use of TOC.
22. FDA “Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance-Buildings and Facilities” Note: This Q&A has questions and answers related to penicillin.
23. FDA “Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance-Production and Process Controls.” Note: This Q&A has questions and answers related to objectionable organisms.
24. FDA “Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance-Laboratory Controls.” Note: This Q&A has questions and answers related to TOC and penicillin.
25. FDA “Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance-Control of Components and Drug Product Containers and Closures.” Note: This Q&A has questions and answers that are related to pathogenic agents and animal-derived drug ingredients.

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Human Drug CGMP Notes Excerpts (Valid even 20 years later)

June 1995

Policy Questions on Cleaning Validation:

Reference: 21 CFR Sec. 211.67, Equipment cleaning and maintenance; and, Guide to Inspections of Validation of Cleaning Processes, July 1993 (reformatted May 1994).

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.

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.

September 1995

What is the FDA’s current policy with respect to validation of bulk pharmaceutical chemical processes?

FDA expects manufacturers to be actively engaged in a validation program for all of their BPC products, although we have not insisted that validations be completed at this time. This agency policy is delineated in the referenced Compliance Policy Guides. FDA will consider withholding approval of new drug applications based on the lack of process validation when (1) a company has not established or is not following an adequate plan to validate all BPCs; or (2) there is evidence that the process is not validated as demonstrated by repeated batch failures due to manufacturing process variability not attributable to equipment malfunction or operator error.

Reference: Compliance Policy Guides 7132c.08 and 7125.38 (Process Validation Requirements for Drug Products Subject to Pre-Market Approval).

September 1997

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

References: 21 CFR 211.67, Equipment cleaning and maintenance; 211.100, Written procedures; deviations; Guideline on The Preparation of Investigational New Drug Products, 3/91

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 sterilization, 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.

March 1998

Do pharmaceutical manufacturers need to have written procedures for preventing growth of objectionable microorganisms in drug products not required to be sterile? What does “objectionable” mean, anyway?

Reference: 21 CFR sections 211.113(a) Control of Microbiological Contamination, and 211.111 Time limitations on production subpart F- Production and Process Controls

Yes, the CGMP regulations do require these written procedures. 21 CFR 211.113(a) specifies that appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, be established and followed. This means that even though a drug product is not sterile, a firm must follow written procedures that proactively prevent contamination and proliferation of microorganisms that are objectionable.

The meaning of “objectionable” has several facets that need to be evaluated on a case by case basis by each drug manufacturer. The primary meaning relates to microbial contaminants that, based on microbial species, numbers of organisms, dosage form, intended use, patient population, and route of administration, would adversely affect product safety. Of course, most objectionable would be organisms that pose a threat of patient infection or mortality.

Microorganisms may be “objectionable” by virtue of other problems. For example, microbial content that adversely affects product stability, would be objectionable. Likewise, microorganisms that react with, or potentially damage the integrity of, the container closure system (fermentation creating gaseous pressures that explode a container would be an extreme, though legitimate, example), would be objectionable. Similarly, microbial content that interferes with analytical methods, or active ingredient bioavailability, would be objectionable.

For new drugs, the above considerations will likely have been addressed during the new drug review process and may result in microbial specifications for the end product.

Establishing production time limits is an example of a control to prevent objectionable microorganisms. Per 21 CFR 211.111, when appropriate, time limits for the completion of each phase of production must be established and followed. Where a firm finds it necessary to hold a bulk topical or liquid product for several months until it is filled, the firm might establish a holding time limit to prevent microbial build up that would be objectionable. Validation and control over microbial content of purified water systems used in certain topical products are also examples of such procedures.

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.

December 1998

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

Reference: FDA Guide to Inspections of Validation of Cleaning Processes, July 1993

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.

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.

September 1999

Validation and equipment qualification; when “identical” really isn’t.

Reference: 21 CFR 211.100, Written procedures, deviations; Guideline On General Principles of Process Validation, May, 1987

As explained in the 1987 validation guideline, the general requirement for process validation is contained in section 211.100 of the CGMP regulations which states that “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.”

The validation guideline addresses several general principles of equipment suitability. For example, installation qualification is described as establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. Installation qualification includes examination of equipment design, determination of calibration, maintenance, and adjustment requirements, and identifying critical equipment features that could affect the process and product. Another principle is that equipment is evaluated and tested to verify that it is capable of operating satisfactorily within the required process operating limits and that actual production conditions, including “worst case” situations, are simulated. The guideline cautions that “In assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier…”

The guideline further states that each specific process should be appropriately qualified and validated, noting the inherent danger in relying on perceived similarities between products, processes, and equipment.

The following case illustrates the importance of performing adequate equipment qualification on each piece of processing equipment, and the problems that may result when firms fail to verify equipment supplier representations.

A pharmaceutical firm used two blenders to produce a tablet. Both blenders were from the same equipment manufacturer, had the same model number and same design. Although one blender was older than the other, the supplier told the drug manufacturer that the units were “identical.” The drug manufacturer took the claim at face value and did not include the older blender as part of its process validation.

The drug company marketed about 100 lots of tablets made using the old blender. In testing retain samples, the company found that some lots failed the content uniformity specification.

The firm’s investigation traced the out of specification lots to one of the two “identical” blenders, namely the old one. The pharmaceutical firm’s own investigation found the older blender to have a slightly smaller capacity and different RPM (revolutions per minute) operational characteristics when run at the same settings as the newer blender.

Subsequently, the firm recalled its total production of the product it made using the older blender. This extensive recall involved multiple strengths of product totaling approximately one half million bottles from U.S. and foreign consignees. The firm plans to qualify the old blender using production size lots.

In light of this case study, during your audits of a firm’s process validation, it would be appropriate to determine if the firm’s validation protocol includes equipment qualification for all units of significant equipment, even where multiple units are supposedly “identical.” Moreover, as explained in the validation guideline, the validation should reflect production size lots.

March 2000

Is it acceptable to manufacture penicillin and non-penicillin products in the same facility on a campaign (i.e., the conversion of production facilities to a different product line on a routine basis) basis, with adequate cleaning validation procedures in place?

References:

• 21 CFR 211.42(d) Design, and construction features
• 21 CFR 211.46(d) Ventilation, air filtration, air heating and cooling
• 21 CFR 211.176 Penicillin contamination
• Federal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 148

No, it is not acceptable. The discussion of the comments in the preamble to the regulations state that “…it is important to make clear in these regulations that completely separate air-handling facilities for penicillin and non-penicillin production are required.”. And “…because it is possible for air-handling systems between penicillin and non-penicillin production areas to be interconnected, …the Commissioner finds it necessary to state that any such interconnection would be unacceptable.

Campaign production of penicillin and any non-penicillin product in the same facility and with the same equipment violates the CGMP regulations 211.42(d) and .46(d). A concern is that the cleaning validation process does not include the air handling system throughout the facility. This is important because campaign production has the potential for recontamination of the air handling systems and facilities, and can lead to cross contamination of non-penicillin products with penicillin. The concept of decontamination is broader than a typical cleaning procedure validation, in that sampling is extended to include the environment, as well as surfaces of the facility and equipment that are to be decontaminated.

A facility contaminated with penicillin could not begin non-penicillin production until extensive decontamination and clean-up of the facility is accomplished in accordance with the established procedures, and representative environmental samples demonstrate that the facility conforms with its decontamination protocol/specifications.

Current technology makes decontamination of air handling systems difficult. This is because the decontamination/cleaning procedures would necessitate sampling and residual testing of other parts of the air handling system, to include the ductwork. This would be difficult because the air handling system throughout its length has uneven areas and crevices that create the possibility of penicillin residue build-up, with slough-off at undetermined periods during the non-penicillin production period. Thus penicillin contamination would not be uniformly distributed in the air handling system, and “representative” samples (retain, surface and/or air) may not be an accurate portrayal of the level of contamination.

21 CFR 211.176 indicates that where the possibility of exposure exists, non-penicillin products must be tested for traces of penicillin and not marketed if detectable levels are found. This means that representative samples from all batches of non-penicillin products produced in each campaign must be tested with an acceptable method and found non-detectable for the penicillin product produced prior to the start-up of the non-penicillin campaign.

One case we reviewed demonstrated a positive environmental surface sample from the fan blade of an exhaust hood in the repack room for beta-lactam residue, even though the most recent beta-lactam repackaging operation had been performed more than six months prior to sampling.

Is it acceptable to manufacture penicillin products in the same facility as cephalosporin?

References:

• 21 CFR 211.28 Personnel responsibilities
• 21 CFR 211.42(b),(c)&(d) Design, and construction features
• 21 CFR 211.46(c)&(d) Ventilation, air filtration, air heating and cooling
• 21 CFR 211.67 Equipment cleaning and maintenance
• 21 CFR 211.80(b) Control of components and drug product containers and closures
• 21 CFR 211.176 Penicillin contamination

Beta-lactams are products with a chemical substructure that contains the beta-lactam ring. They have the potential to sensitize and cause allergic response in humans. Hypersensitivity, due to intolerance of beta lactam ingredients, can trigger reactions which range from a rash to life-threatening anaphylaxis. There is evidence that cross-sensitivity exists between penicillins and cephalosporins. Thus, patients who are intolerant of penicillin may also be intolerant of cephalosporins, and further, cephalosporins may induce anaphylaxis in patients with a history of penicillin anaphylaxis.

The immune system is exquisitely sensitive and can distinguish between very subtle changes in chemical composition. Patients may be tolerant of a given drug but intolerant of another drug with closely related chemical structures. There is evidence that patients tolerant of penicillin may be intolerant of cephalosporins. CDER recognizes the considerable potential for cross-sensitivity and the possible life-threatening consequences of unintended exposure. Therefore, although not a specific requirement of sections 211.42 (d), 211.46(d) and 211.176, it is recommended that manufacturing operations for cephalosporins, penems and cephems, be separated from non-beta-lactam products and other beta-lactam drug products. For example cephalosporin type products would be separated from penicillin type products or non-beta-lactam products.

Production of cephalosporin type products can be approached from two different regulatory/compliance perspectives: (1)If cephalosporins are considered to be non-penicillin drugs, they could not be manufactured in a facility lacking adequate separation from penicillin products. (2) For cephalosporin production with other non-beta-lactam drug products, similar health concerns exist for patients sensitive to cephalosporins who should not be exposed to it in a non-beta-lactam product.

For fundamental CGMP reasons and because of the difficulties in demonstrating and validating appropriate sampling and testing methodology for measuring cross-contamination, penicillin production should be performed in facilities separated from non-beta-lactam drug products and other beta-lactam drug products unless adequate separation is demonstrated. We don’t know of a satisfactory shared facility as of today.

Furthermore, if necessary, other sections of the CGMP regulations i.e., 211.28; 211.42(b) & (c); 211.46(c); 211.67; and 211.80(b) could be applied to control contamination between beta-lactam and non-beta-lactam drug products. In summary the Agency considers the separation of production facilities for sensitizing beta-lactam based products to be current good manufacturing practice.

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.

2nd Quarter 2001

Should equipment be as clean as the best possible method of residue detection or quantification? Must a firm quantify the amount of residue on equipment surfaces in support of validating the cleaning procedure? Should lab glassware be included in a firm’s equipment cleaning validation program?

No, no, and mostly no. The CGMPs require that equipment be cleaned to prevent contamination that “would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements” (see 211.67(a». The preamble indicates that this phrase was added to account for the fact that absolute cleanliness is neither valuable nor feasible in many circumstances for multi-use equipment. The answer to the question “how clean is clean?” cannot, therefore, be “it depends on the method of detection.” If the method of detection determined levels of contamination, advances in the sensitivity of detection methods would necessitate correspondingly ever-lower limits and ever-increasing wash cycles. So, how clean should equipment be? It should be as clean as can reason- ably be achieved, to a residue limit that is medically safe and that causes no product quality concerns (other than the fact of the contaminant’s presence), and that leaves no visible residues. Reason- ably avoidable and removable contamination is never acceptable.

In validating the original cleaning procedure, a firm need not quantify the level of chemical contamination remaining after manufacturing a product and before cleaning during validation exercises. The firm must, however, ensure that they validate the proposed cleaning procedure as for routine use, and not pre-clean or otherwise attempt to make it easier for the procedure being validated to meet its cleaning objectives. For example, batches significantly smaller than full-scale would not offer sufficient assurance that the cleaning procedure could reliably remove residues to below acceptable levels after full-scale production. A validated cleaning procedure may be relied upon as long as the material being cleaned was manufactured at similar scale and manner as during validation. Also, equipment stored unclean for a longer time than during validation should be sampled to demonstrate that the cleaning procedure was effective. Once cleaned by a validated procedure, a firm generally should not be expected to analytically examine equipment surfaces to demonstrate cleanliness (see the Dec. 1998 Notes article). Hand cleaning methods may be an exception to this general rule because of inherent variability in operator compliance and abilities. Usually, visual inspection of equipment surfaces, including hard to clean nooks and crannies, along with rinse water testing would suffice.

Do not expect lab glassware to be included in the processing equipment cleaning validation program. Glassware must, of course, be clean and the CGMPs consider lab equipment to be included in the scope of 211.67. The assurance of cleanliness is best assessed by inspecting laboratory procedures for the use of non-dedicated glassware and other equipment, method validation (ruggedness, e.g.), and the absence of extraneous or interfering data in the results of sample analyses. Lab cleaning procedures may include repetitive rinses with the solvent used to prepare the analyte and oven drying. The equipment need not be swabbed or otherwise tested to ensure removal of potentially contaminating residues. A firm may elect to sample its glassware for residual contamination to exclude or explore the possibility of interference in the case of particularly sensitive analyses or highly difficult to clean compounds. The possibility of carryover contamination affecting a method’s performance or integrity of the results is generally considered to have a low risk to product or consumers. Contaminated lab equipment, however, should not be a frequent excuse for rejecting or discarding aberrant results. We expect that firms maintain lab equipment in a clean and sanitary manner so as to provide confidence in the results of analysis.

References:

• Preamble to the Good Manufacturing Practices for Human and Veterinary Drugs, Federal Register, September 29, 1978, pages 45040-1, paragraphs 167-175https://www.fda.gov/cder/dmpq
• 21 CFR 211.67
• Guide to Inspections of Cleaning Validation, 1993
• Human Drug CGMP Notes editions Dec. 1998, Sep. 1998, Sep. 1997, Jun. 1995

1st Quarter 2002

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 cleaning 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 oxidized 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 use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because 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 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 holding time on accuracy and limit of quantitation.

References:

• 21 CFR 211.67: Equipment cleaning and maintenance.
• USP 25, <643> Total Organic Carbon
• Guide to Inspections of Cleaning Validation, 1993