Can a facility that produced penicillin dosage forms be decontaminated and renovated for production of non-penicillin solid do Author：noor | Size：46.00 K | View：339 | Page：3Can a facility that producedpenicillin dosage forms be decontaminated and renovated for production ofnon-penicillin solid dosage forms provided there is no further penicillinproduction in the renovated facility? Reference: 21 CFR 211.42(d), Design andconstruction features; 211.46(d), Ventila...
Can a facility that producedpenicillin dosage forms be decontaminated and renovated for production ofnon-penicillin solid dosage forms provided there is no further penicillinproduction in the renovated facility? Reference: 21 CFR 211.42(d), Design andconstruction features; 211.46(d), Ventilation, air filtration, air heating andcooling; 211.176, Penicillin contamination; FDA By-Lines #3, Nov.77, Proceduresfor the Detection of Residual Penicillins in Drugs; 21 CFR 436.104 PenicillinActivity; and FDA Guide to Inspections of Validation of Cleaning Processes,July 1993. Yes. However, the decontamination processis extremely difficult and we are unaware of any firm that has successfullydecontaminated a penicillin facility and converted it to production ofnon-penicillin products. Note that at section 211.176 the CGMPregulations require that if a reasonable possibility exists that anon-penicillin drug product has been exposed to cross-contamination withpenicillin, the non-penicillin product must be tested for the presence ofpenicillin and not marketed if detectable levels are found using the codifiedmethod. Such a reasonable possibility may be present where decontamination hasnot been conducted effectively. That would put the responsible firm in a positionof having to test each and every lot of non-penicillin product for the presenceof penicillin. In sum, while the CGMP regulations wouldnot prohibit decontamination and conversion, the difficulty of cleaning uppenicillin residues makes the chore daunting. Contact for further info: Edwin Melendez,HFD-322, 301-594-0095; e-mail; email@example.com Is there an acceptable level ofpenicillin residue in non-penicillin drug products? Reference: 21 CFR 211.176, Penicillincontamination; 21 CFR 436.104 Penicillin Activity; FDA By-Lines No.3, Nov.77, AReview of Procedures for the Detection of Residual Penicillins in Drugs. Any detectable levels of penicillin residueare considered violative because 21 CFR 211.176 indicates that a non-penicillindrug product must not be marketed if detectable levels of penicillin are foundwhen tested according to procedures specified in The Procedures for Detectingand Measuring Penicillin Contamination in Drugs. The current analytical standard fordemonstrating adequate decontamination of facilities, separation within thesame building, or measurement of cross-contamination is codified at 21 CFR211.176 and 436.104 and has a limit of detectability of 0.006 ppm (asPenicillin G using S. Lutea) and a violative detection amount of 0.03 ppm. Notethat the latter amount reflects the methods limits with respect to confidenceand reproducibility and does not represent a tolerance level. This analyticalmethodology is limited to the detection of Penicillin G and ampicillin in alimited number of products listed in the referenced method, not including otherbeta-lactam antibiotics. In situations where this methodology is not workable,it is the firms responsibility to develop, validate, and use other methodologywith similar sensitivity. Contact for further info: Edwin Melendez,HFD-322, 301-594-0095; e-mail: firstname.lastname@example.org; Dr. Richard Adams,HFD-643, 301-827-5849; e-mail: amailto:email@example.com How can one obtain a copy ofthe procedures for detecting and measuring penicillin contamination in drugs? References: 21 CFR 211.176, Penicillin Contamination; FDA By-Lines No.3, Nov. 77, A Review ofProcedures for the Detection of Residual Penicillin in Drugs. The bioassay referenced in 21 CFR 211.176can be used whenever there exists a reasonable possibility that anon-penicillin drug product has been exposed to cross-contamination withpenicillin. The non-penicillin drug product should be tested for the presenceof penicillin and not marketed if detectable levels are found when testedaccording to procedures specified in "Procedures for Detecting andMeasuring Penicillin Contamination in Drugs", which is incorporated byreference. Copies are available from the Division of Pharmaceutical Analysis,(HFD-923), Center for Drug Evaluation and Research, Food and DrugAdministration, 8301 Muirkirk Road, Laurel, MD, 20703. To request copies of theprocedure contact: Valarie A. Flournoy, Tel 301-827-8236, FAX301-827-8073, E-Mail FLOURNOY@CDER.FDA.GOV. For further information contact: EdwinMelendez, 301-594-0098, firstname.lastname@example.org Can section 21 CFR 436.104(Penicillin Activity) continue to assist in determining residues of penicillincontamination in non-penicillin drugs? Reference: 21 CFR 211.176, PenicillinContamination; FDA By-Lines No.3, Nov.77, A Review of Procedures for theDetection of Residual Penicillin in Drugs. No, it can not. Section 436.104 was in part21 CFR 436. Parts 429 through 460 existed for the purpose of enforcing Section507 of the FD&C Act "Certification of Antibiotics". This sectionof the Act was repealed by FDAMA (FDA Modernization Act). Therefore, section436.104 was deleted from the CFR and does not exist any longer. Section 436.104 (methodology for penicillinactivity) is derived from the original tests for penicillin contamination infoods and drugs published in FDA By-Lines No.3 (Nov.1977). The FDA codifiedmethod continues to exist because it still is required in 211.176 – "…suchdrug product shall not be marketed if detectable levels are found when testedaccording to procedures specified in ‘Procedures for Detecting and MeasuringPenicillin Contamination in Drugs,…". The elimination of 436.104 does notchange anything for the following reason: In the By-lines, the test sensitivityis stated to be 0.01 units/ml as penicillin G, using S. lutea, equivalent to0.006 PPM. The ‘standard response line’ cited at 436.104 covers a range ofconcentrations equivalent to 0.003 to 0.120 PPM, as penicillin G. However, thetest method as cited in 211.176 has always indicated a limit of sensitivity of0.006 PPM. We always indicate that the sensitivity should be at 0.006 PPM andnot necessarily 0.003 PPM. So nothing has changed because the By-lines alsocovers a range of concentrations which can be used as ‘standard response lines’similar to 436.104. For further information contact: EdwinMelendez, 301-594-0098, email@example.com What do the CGMPs mean by separatefacilities? Must the buildings be totally separated, or are the CGMPs satisfiedwhen the floors are physically separated with separate air filtration unitsinstalled? References: 21 CFR 211.42(d) Design, and constructionfeatures21 CFR 211.46(d) Ventilation, airfiltration, air heating and cooling21 CFR 211.176 Penicillin contaminationFederal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 142 CGMP regulations [21 CFR 211.42(d) and211.46(d)] require separation of penicillins from non-penicillins duringprocessing. The discussion of the comments in the preamble to the regulationsnote that "…isolation of penicillin production operations…can be achievedby sealing off…the two operations." "…does not necessarilymean…separate buildings." Thus, there can be a "building within abuilding"- i.e. two buildings are not required. However, there mustbe total separation of operations, meaning every aspect of the operations mustbe separate. Adequate separation should include physical barriers and separateair handling systems. Personnel and equipment from the penicillin facilityshould not enter the non-penicillin facility. These should operate with wellestablished written procedures and controls. The separation should be audited,procedures validated, and where necessary monitored. Even with separation, if any possibility ofcontamination exists, the non-penicillin products must be tested (21 CFR211.176). An example of possible contamination could be inadequate controlsover movement of equipment or personnel. Section 211.176 requiresnon-penicillin products to be tested for traces of penicillin where thepossibility of exposure exists, and not marketed if detectable levels ofpenicillin are found. While this section prohibits marketing ofproducts found to be contaminated with penicillin, it does not sanctionmarketing of non-penicillin products based only on test results that show nodetectable levels of such contamination. Other CGMP requirements must still bemet. For a discussion on this issue, please review the article "Is itacceptable under section 211.176 to release products to market as long as theproducts are tested and no penicillin is found?" published in "HumanDrug CGMP Notes" (Volume 6, Issue 2, June 1998). Cross contamination issues have been aconcern for a number of years, and continue to be problematic. In onepenicillin cross-contamination case reviewed it was demonstrated how anon-penicillin facility was contaminated by a separate penicillin facilitylocated in the same manufacturing campus. This occurred due to lack of controlsregarding movements of personnel, equipment and materials. In another case,CDER concurred with a district recommendation to withhold approval on asensitizing beta-lactam manufacturing facility that was adjacent to anotherdrug processing building, due to the lack of containment controls which ensuredagainst cross contamination of the other drugs. Is it acceptable to manufacturepenicillin and non-penicillin products in the same facility on a campaign(i.e., the conversion of production facilities to a different product line on aroutine basis) basis, with adequate cleaning validation procedures in place? References:21 CFR 211.42(d) Design, and constructionfeatures21 CFR 211.46(d) Ventilation, airfiltration, air heating and cooling21 CFR 211.176 Penicillin contaminationFederal Register, 9/29/78 (Vol.43, No.190, Book 2) Preamble to the CGMPs at comment 148 No, it is not acceptable. The discussion ofthe comments in the preamble to the regulations state that "…it isimportant to make clear in these regulations that completely separateair-handling facilities for penicillin and non-penicillin production arerequired.". And "…because it is possible for air-handling systemsbetween penicillin and non-penicillin production areas to be interconnected,...the Commissioner finds it necessary to state that any such interconnectionwould be unacceptable." Campaign production of penicillin and anynon-penicillin product in the same facility and with the same equipmentviolates the CGMP regulations [211.42(d) and .46(d)]. A concern is that thecleaning validation process does not include the air handling system throughoutthe facility. This is important because campaign production has the potentialfor recontamination of the air handling systems and facilities, and can lead tocross contamination of non-penicillin products with penicillin. The concept ofdecontamination is broader than a typical cleaning procedure validation, inthat sampling is extended to include theenvironment, as well as surfaces of thefacility and equipment that are to be decontaminated. A facility contaminated with penicillincould not begin non-penicillin production until extensive decontamination andclean-up of the facility is accomplished in accordance with the establishedprocedures, and representative environmental samples demonstrate that thefacility conforms with its decontamination protocol/specifications. Current technology makes decontamination ofair handling systems difficult. This is because the decontamination/cleaningprocedures would necessitate sampling and residual testing of other parts ofthe air handling system, to include the ductwork. This would be difficultbecause the air handling system throughout its length has uneven areas andcrevices that create the possibility of penicillin residue build-up, withslough-off at undetermined periods during the non-penicillin production period.Thus penicillin contamination would not be uniformly distributed in the airhandling system, and "representative" samples (retain, surface and/orair) may not be an accurate portrayal of the level of contamination. 21 CFR 211.176 indicates that where thepossibility of exposure exists, non-penicillin products must be tested fortraces of penicillin and not marketed if detectable levels are found. Thismeans that representative samples from all batches of non-penicillin productsproduced in each campaign must be tested with an acceptable method and foundnon-detectable for the penicillin product produced prior to the start-up of thenon-penicillin campaign. One case we reviewed demonstrated apositive environmental surface sample from the fan blade of an exhaust hood inthe repack room for beta-lactam residue, even though the most recentbeta-lactam repackaging operation had been performed more than six months priorto sampling. Is it acceptable to manufacturepenicillin products in the same facility as cephalosporin? References: 21 CFR 211.28 Personnel responsibilities 21 CFR 211.42(b),(c)&(d) Design, andconstruction features21 CFR 211.46(c)&(d) Ventilation, airfiltration, air heating and cooling21 CFR 211.67 Equipment cleaning andmaintenance21 CFR 211.80(b) Control of components anddrug product containers and closures21 CFR 211.176 Penicillin contamination Beta-lactams are products with a chemicalsubstructure that contains the beta-lactam ring. They have the potential tosensitize and cause allergic response in humans. Hypersensitivity, due tointolerance of beta lactam ingredients, can trigger reactions which range froma rash to life-threatening anaphylaxis. There is evidence thatcross-sensitivity exists between penicillins and cephalosporins. Thus, patientswho are intolerant of penicillin may also be intolerant of cephalosporins, andfurther, cephalosporins may induce anaphylaxis in patients with a history ofpenicillin anaphylaxis. The immune system is exquisitely sensitiveand can distinguish between very subtle changes in chemical composition.Patients may be tolerant of a given drug but intolerant of another drug with closelyrelated chemical structures. There is evidence that patients tolerant ofpenicillin may be intolerant of cephalosporins. CDER recognizes theconsiderable potential for cross-sensitivity and the possible life-threateningconsequences of unintended exposure. Therefore, although not a specificrequirement of sections 211.42 (d), 211.46(d) and 211.176, it is recommendedthat manufacturing operations for cephalosporins, penems and cephems, beseparated from non-beta-lactam products and other beta-lactam drug products.For example cephalosporin type products would be separated from penicillin typeproducts or non-beta-lactam products. Production of cephalosporin type productscan be approached from two different regulatory/compliance perspectives: 1) If cephalosporins are considered to benon-penicillin drugs, they could not be manufactured in a facility lackingadequate separation from penicillin products. 2) For cephalosporin productionwith other non-beta-lactam drug products, similar health concerns exist forpatients sensitive to cephalosporins who should not be exposed to it in anon-beta-lactam product. For fundamental CGMP reasons and because ofthe difficulties in demonstrating and validating appropriate sampling andtesting methodology for measuring cross-contamination, penicillin productionshould be performed in facilities separated from non-beta-lactam drug productsand 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 sectionsof 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-lactamand non-beta-lactam drug products. In summary the Agency considers theseparation of production facilities for sensitizing beta-lactam based productsto be current good manufacturing practice. Contact for further information: EdwinMelendez, HFD-322; (301) 594-0095; e-mail: firstname.lastname@example.org If a firms only operation isperforming finished packaging operations for bulk tablet and capsule drugproducts, must it still maintain separate facilities and equipment forpackaging penicillin products? Reference: 21 CFR Sections 211.42.(d), Design andconstruction features [Buildings and Facilities], 211.46(d), Ventilation, air filtration, airheating and cooling, and 211.176, Penicillin contamination Yes. The CGMP regulations explicitlyrequire that operations relating to the manufacture, processing and packagingof penicillin be performed in facilities that are separate from thosefacilities used for other drugs. The regulations also require separateair-handling systems in facilities used for penicillin products. Furthermore,if a reasonable possibility exists that a non-penicillin drug product has beenexposed to cross-contamination with penicillin, CGMPs require that thenon-penicillin drug be tested for the presence of penicillin. The CGMPs make noexceptions from the foregoing for operations that are limited to repackagingsolid oral dosage forms. It should be noted that the requirement forseparate facilities does not necessarily mean that operations relating topenicillin products must be conducted in separate buildings from other drugs. Aseparate area dedicated to penicillin products within a larger facility may beacceptable if penicillin containment can be established and validated. Contact for further info: Barry Rothman,HFD-325, 301-594-0098, e- mail: email@example.com