6.2 Equipment/Line/Area Cleaning, Preparation, and Clearance

This page will address various regulatory issues related to this section of the GMP Institute framework.  Click below to view the issues that are relevant to you.

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?

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

How would the CGMPs address the problem of cleanroom operators who are shedders or practice poor aseptic technique?

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.

Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000.

This same text is also reprinted in framework sections 3.1 and 3.2.

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. 

Contact for further information: Edwin Melendez, HFD-322; (301) 594-0095; e-mail: melendeze@cder.fda.gov

Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000.

This same text is also reprinted in framework sections 3.1, 3.2, and 4.3. 

How would the CGMPs address the problem of cleanroom operators who are shedders or practice poor aseptic technique?

References: 
See 21 CFR 211.42(c)(10), Design and construction features; 
211.25, Personnel qualifications; 
211.28, Personnel responsibilities; 
211.113 Control of microbiological contamination; 
Guideline on Sterile Drug Products Produced by Aseptic Processing, June 1987

To protect exposed sterilized product, personnel are expected to consistently maintain sterile gown quality and aseptic method standards. Investigators can use the referenced sections of the CGMP regulations when they encounter the issues of cleanroom employees who appear to be "shedders" or practice poor aseptic technique. The term "shedders" is popularly used to describe individuals from whom high or frequent counts of microorganisms are recovered, as compared to other personnel. In general, firms can prevent, monitor and solve this problem. Here are some principles to keep in mind.

Cleanrooms are defined by their low levels of both viable and nonviable particulates and these levels need to be monitored and kept under control. Humans are a chief source of particulate contamination in the cleanroom, although these contaminants may originate from a number of other sources. 

Firms can take a number of measures to minimize the levels of microbiological contamination introduced by cleanroom operators. Among the widely recognized key measures to control personnel-borne contamination are:

(1) following good hygiene standards;
(2) training in proper gowning techniques; 
(3) maintaining gown quality; and,
(4) following proper aseptic technique.

Per CGMPs, firms monitor and observe performance of individuals to detect problematic trends and ensure adherence to these practices. For example, retraining an individual in proper gowning technique can generally resolve the problem of adverse trends or a high spike in personnel monitoring data.

Nonetheless, despite effective execution of the above-listed measures, some individuals are natural shedders whose presence in a cleanroom may compromise product quality. It is not unusual for firms to reassign such employees to duties outside of the cleanroom.

Note that because some people are found to be shedders, not everyone will be suitable for cleanroom duty. Ultimately, it is such differences among cleanroom personnel which underscore the need to monitor and qualify cleanroom operations on each production shift.

Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov .