QuestionsandAnswersoncGMPaboutequipmentpart

1、8Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance - Equipment..9.Many leading analytical balance manufacturers provide built-in auto calibration features in their balances. Are such auto-calibration procedures acceptable instead o

2、f external performance checks? If not, then what should the schedule for calibration be?Is there a list of CDER-approved drug manufacturing equipment?Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?(updated 5/18/2005)

3、A firm has multiple media fill failures. They conducted their media fills using TSB prepared by filtration through 0.2F m-sterilizing filter. Investigation did not show any obvious causes. What could be the source of contamination?What are the cleaning validation requirements for potent compounds (e

4、.g., compounds that are cytotoxic, mutagenic, or have high pharmacologic activity), and is dedicated equipment required? How do I perform cleaning validation, including for homeopathic drug products?Does equipment need to be clean enough to meet limits based on the most sensitive possible methods of

5、 residue detection or quantification?Do firms need to quantify the total amount of residue remaining on equipment surfaces after manufacturing a product (before cleaning) to support cleaning validation studies?Should laboratory glassware be included in a firms equipment cleaning validation program?1

6、0. What is an acceptable level of detergent residue, and what is the basis for arriving at this level, if any?11.If a procedure s ability to clean a piece of equipment made of a particular material, such as 316 stainless steel, is acceptable and validated, can that-specific ”“ mcleaatenriinagl proce

7、dure beapplied to other pieces of equipment and compounds without extensive validation?12.Is testing rinse solution enough to support residue determinations for cleaning validation?13. Does FDA prefer one type of material over another (e.g., polyvinylidene difluoride over stainless steel) for constr

8、uction of recirculating loops in water for injection (WFI) systems?1. Many leading analytical balance manufacturers provide built-in auto calibration features in their balances. Are such auto-calibration procedures acceptable instead of external performance checks? If not, then what should the sched

9、ule for calibration be?The auto-calibration feature of a balance may not be relied upon to the exclusion of an external performance check (211.68). For a scale with a built-in auto-calibrator, we recommend that external performance checks be performed on a periodic basis, but less frequently as comp

10、ared to a scale without this feature. The frequency of performance checks depends on the frequency of use of the scale and the criticality and tolerance of the process or analytical step. Note that all batches of a product manufactured between two successive verifications would be affected should th

11、e check of the auto-calibrator reveal a problem. Additionally, the calibration of an auto-calibrator should be periodically verified-a common frequency is once a year-using National Institute of Standards and Technology (NIST)-traceable standards or NIST-accredited standards in use in other countrie

12、s.References:*21 CFR 211.68: Automatic, mecha ni cal, and electro nic equipment21 CFR 211.160(b)(4): General requireme nts (Lab Con trols)USP Cha pter Weights and Bala ncesSee also: ASTM sta ndard E 617: Sta ndard Sp ecification for Laboratory Weights and P recisio n Mass Stan dards (this sta ndard

13、is incorpo rated into the USP by refere nee; other widely recog ni zed sta ndards may be acce ptable)2. Is there a list of app roved drug manufacturing equip ment?No. The CGMP regulati ons n either approve nor p rohibit sp ecific equipment for use in manu facturi ng of p harmaceutical p roducts (wit

14、h the exce pti on of asbestos and fiber-releas ing filters, see 211.72). We do not mai ntai n a list of appro ved equipment. Firms are afforded the flexibility to select equipment that best satisfies their p articular n eeds and that is cap able of meet ing the releva nt CGMP requireme nts. Each fir

15、m is res pon sible for select ing all equipment used in their manu facturi ng p rocess to p roduce quality p roduct in accorda nee with CGM P. They are also respon sible for select ing the approp riate inten ded use for the equipmen ts op erati on, and are free to modify sta ndard equipment desig ns

16、 to best suit their p rocess and that are comp atible with the p roduct un der p rocess.The CGMPs require that equipment be of approp riate desig n to facilitate op erati ons for its inten ded use and for clea ning and maintenance (see 211.63 and 211.67) and, that any equipment surface in con tact w

17、ith componen ts, in-p rocess materials, or drug p roducts not be reactive, additive, or absor ptive so as to alter the safety, ide ntity, stre ngth, quality, or p urity of the drug p roduct bey ond the official or other established requireme nts (see 211.65).References:*2121212121CFR 211.63: Equipme

18、nt desig n, size, and locati onCFR 211.65: Equi pment con structionCFR 211.67: Equipment clea ning and maintenanceCFR 211.68: Automatic, mecha ni cal, and electr onic equipment CFR 211.72: Filters3. Can Total Organic Carbon (TOC) be an acce ptable method for detecting residues of contaminants in eva

19、luating cleaning effectiveness?Yes. Since the p ublicati on of the inspection guide on clea ning validati on in 1993, a nu mber of studies have bee n p ublished to dem on strate the adequacy of TOC in measuri ng con tam inant residues.TOC or TC can be an acce ptable method for mon itori ng residues

20、routi nely and for clea ning validati on. In order for TOC to be fun cti on ally suitable, it should first be established that a substa ntial amount of the con tam in at ing material(s) is orga nic and contains carb on that can be oxidized un der TOC test con diti ons. This is an imp orta nt exercis

21、e because some orga nic compounds cannot be reliably detected using TOC.References:*TOC use may be justified for direct surface sam pie test ing as well as in direct (rinse water) sam pie testi ng. In either case, because TOC does not ide ntify or dist in guish among differe nt compounds containing

22、oxidizable carb on, any detected carb on is to be attributed to the target compoun d(s) for comparing with the established limit. Thus, a firm should limit backgro und carb on (i.e., carb on from sources other tha n the con tam inant being removed) as much as p ossible. If TOC samp les are being hel

23、d for long p eriods of time before an alysis, a firm should verify the impact of sample holdi ng time on accuracy and limit of qua ntitati on.21 CFR 211.67: Equipment clea ning and maintenan ce.21 CFR 211.160(b): Ge neral requireme nts (Laboratory Con trols) USP 643 Total Orga nic CarbonGuide to Ins

24、p ecti ons of Clea ning Validati on, 19934. A firm has mult iple media fill failures. They conducted their media fills using TSB (try ptic soy broth) prep ared by filtration through 0.2 micron sterilizing filter. Investigation did not show any obvious causes. What could be the source of contaminatio

25、n?A firm rece ntly had multi pie media fill failures. The media fill runs, simulati ng the filli ng p rocess duri ng p roducti on, were con ducted in side an isolator. The firm used TSB (non-sterile bulk po wder) from a commercial source, and prep ared the sterile soluti on by filteri ng through a 0

26、.2 micro n sterilizi ng filter. An inv estigati on was laun ched to trace the source of con tam in ati on. The in vestigati on was not successful in isolat ing or recoveri ng the con tam in at ing orga nism using conven ti onal microbiological tech niq ues, in clud ing the use of selective (e.g., bl

27、ood agar) and non selective (e.g., TSB and tryp tic soy agar) media, and exam in ati on un der a microsc ope. The con tam inant was eve ntually ide ntified to beAchole plasmalaidlawii by using 16S rRNA gene seque nee. The firm subseque ntly con ducted studies to confirm the p rese nee ofAchole plasm

28、alaidlawii i n the lot of TSB used. Therefore, it was not a con tam inant from the p rocess, but from the media source.Achole plasmalaidlawii bel ongs to an order of mycop lasma. MycopI asma contain only a cell membra ne and have no cell wall. They are not susce ptible to beta-lactams and do not tak

29、e up Gram stai n. In dividual orga ni sms are p leom orp hic (assume various sha pe from cocci to rods to filame nts), vary ing in size from 0.2 to 0.3 micr ons or smaller. It has bee n show n thaAchole plasmalaidlawii is cap able of pen etrati ng a 0.2 micro n filter, but is retai ned by a 0.1 micr

30、o n filter (see Sun daram, et al.). Achole plasmalaidlawiiis known to be associated with ani mal-derived material, and microbiological media is ofte n from animal sources. En vir onmen tal mon itori ng of mycopi asma requires selective media (PPLO broth or agar).Resolution:For now, this firm has dec

31、ided to filter prep ared TSB, for use in media fills, through a 0.1 micron filter (n ote: we do not expect or require firms to rout in ely use 0.1 micro n filters for media prep arati on). In the future, the firm will use sterile, irradiated TSB whe n it becomes available from a commercial supp lier

32、. (Firms autoclave is too small to p ermit p rocess ing of TSB for media fills, so this was not a viable op ti on.) The firm will con ti nue mon itori ng for mycop lasma and has revalidated their clea ning p rocedure to verify its removal. In this case, a thorough in vestigati on by the firm led to

33、a determ in atio n of the cause of the failure and an approp riate corrective actio n.References:*21 CFR 211.113: Con trol of microbiological co ntami natio n21 CFR 211.72: Filters21 CFR 211.84(d)(6): Testi ng and appro val or reject ion of componen ts, drug p roduct container, and closuresSun daram

34、, S., Eise nhuth, J., Howard, G., Bran dwe in, H. App licati on of membra ne filtratio n for removal of diminu tive bioburde n orga ni sms in p harmaceutical p roducts and p rocesses. PDA J. P harm. Sci. Tech nol. 1999 Jul-Aug; 53(4): 186-201.Kong, F., James, G., Gordon, S., Zekyn ski, A., Gilbert,

35、G.L. Sp ecies-s pecific PCR for ide ntificati on of com mon con tam inant mollicutes in cell culture. Appl. Environ. Microbiol. 2001 Jul; 67(7): 3195-200.Murray, P., Baro n, E., P faller, M., Te nover, F., Yolke n, R. Ma nual of Cli nical Microbiology ASM P ress, Sixth Editi on.5. What are the clea

36、ning validati on requireme nts for potent compounds (e.g., compounds that are cytotoxic, mutage nic, or have high p harmacologic activity), and is dedicated equipment required?Sep arati on or dedicatio n of equipment and facilities for the manu facture of potent compounds is not sp ecifically requir

37、ed by CGMP regulatio ns. However, manu facturers should ide ntify drugs with such risks and defi ne the con trols n ecessary to elim in ate risk of p roduct cross-c on tam in atio n in non dedicated equipment and facilities. Such con trols in clude proper clea ning, clea ning validati on, and other

38、con tam inant con trols. Firms must validate that clea ning p rocedures are adequate to en sure that cross-c on tam in ati on does not occur. CGMP regulati ons establish requireme nts to guide devel opment and executi on of clea ning validati on plans.In desig ning a facility, firms should carefully

39、 evaluate manu facturi ng p rocesses to determ ine the best p rocedural con trols and floor plan op timiz ing the flow of materials, equipment, and people to help p reve nt p roduct con tam in ati on.Refere nces: 21 CFR 211.42: Desig n and con struction features 21 CFR 211.67: Equipment clea ning an

40、d maintenance6. How do I p erform clea ning validati on, in cludi ng for home op athic drug p roducts?21 CFR 211.67(a) requires that any equipmen t, i nclud ing dedicated and mult ipurpose equipmen t, is “ clea ned, maintain ed, and, as ap phate for the n ature of the drug, san itized an d/or steril

41、ized at approp riate in tervals to p reve nt malf un cti ons or con tam in ati on that would alter the safety, ide ntity, stre ngth, quality, or pu rity of the drug p roduct bey ond the official or other establishe d requirements. ” You must therefore ensure that residues(e.g., active in gredie nts,

42、 clea ning age nts) are adequately removed from p roduct con tact surfaces of all equipment duri ng p roduct cha ngeovers an d/or betwee n p roduct ion camp aig ns, depending on the types of materials and surfaces in use.Clea ning p rocedures should be well-docume nted and con siste nt for their int

43、en ded use. Clea ning validati on p rograms should p rovide assura nee that residues are effectively removed from p roduct con tact surfaces, and manu facturers should select test methods that dem on strate their effective ness. FDA does not pro vide exte nsive guida nee on con duct ing clea ning va

44、lidati on but does recomme nd con sult ing guideli nes p ublished by various trade and pro fessi onal associati ons for additi onal in formatio n (e.g., I ntern ati onal Society for Pharmaceutical Engin eeri ng, Paren teral Drug Associati on).Refere nee: 21 CFR 211.67: Equipment clea ning and mainte

45、nance7. Does equipment n eed to be clea n eno ugh to meet limits based on the most sen sitive p ossible methods of residue detecti on or qua ntificati on?“would alterNo. cGMPs require that equipment be clea ned to p reve nt con tam in atio n that the safety, ide ntity, stre ngth, quality, or p urity

46、 of the drug p roduct bey ond the official or other established requireme nts” (see 21 CFR 211.67). The p reamble to the CGMPregulati ons (see 43 FR 45014) in dicates that this p hrase was added because absolute clea nii ness for multiuse equipment is n either valuable nor feasible in many circumsta

47、 nces. The degree of clea nIi ness n eeded, therefore, cannot depend on the method of detecti on because impro veme nts in method sen sitivity would n ecessitate ever-lower limits and everin creas ing wash cycles. Equipment should be as clea n as can be reas on ably achieved to a residue limit that

48、is docume nted to be safe, causes no p roduct quality concerns, and leaves no visible residues. Con tam in ati on that is reas on ably avoidable and removable is n ever con sidered acce ptable.Refere nces: 21 CFR 211.67: Equipment clea ning and maintenance P reamble to the Curre nt Good Manu facturi

49、 ng P ractice final regulati ons (43 FR45014, Sept 29, 1978), htt p://cder/dm pq/preamble.txt8. Do firms n eed to qua ntify the total amount of residue rema ining on equipment surfaces after manu facturi ng a p roduct (before clea ning) to support clea ning validati on studies?No. In vali

50、dat ing origi nal clea ning p rocedures, firms n eed not qua ntify the level of chemical con tam in ati on rema ining after manu facturi ng a p roduct and before clea ning. Firms must, however, en sure that they validate prop osed clea ning p rocedures as for routi ne use and should not p re-clea n

51、or otherwise atte mpt to make it easier for the p rocedures being validated to meet their clea ning objectives.For exa mp le, batches sig nifica ntly smaller tha n full-scale would not offer sufficie nt assura nee that the clea ning p rocedure could reliably remove residues to acce ptable levels aft

52、er full-scale p roducti on. The material being clea ned should be manu factured at a similar scale and manner as duri ng validatio n. Also, firms should sample equipment that is stored un clea ned for a Ion ger time tha n validated to dem on strate that their clea ning p rocedures are effective.Once

53、 equipment surfaces are clea ned by validated p rocedures, firms gen erally are not exp ected to an alytically exam ine them after each clea ning. (Ma nual clea ning methods may be an exee pti on to this gen eral rule because of in here nt variability in op erator comp lia nee and abilities.) Howeve

54、r, a residue-m on itori ng p rogram whose freque ncy and methods have bee n determ ined by risk assessme nt is recomme nded.Refere nee: FDA Guide to Insp eeti ons: Validati on of Clea ning Processes9. Should laboratory glassware be in cluded in a firms equipment clea ning validati on p rogram?No. FD

55、A does not expect laboratory glassware to be in cluded in the p rocess ing equipment clea ning validati on p rogram . Glassware must, of course, be clea n, and CGMP regulatio ns con sider laboratory equipment to be in cluded withi n the scope of 21 CFR 211.67.Clea nii ness is best assessed by inspec

56、ting laboratory p rocedures for the follow ing: Use of non dedicated glassware and other equipment Method validati on (eg, rugged ness) Absenee of extraneous or interfering data in the results of sample analysesLaboratory clea ning p rocedures may in clude rep etitive rin ses with the solve nt used

57、to prepare the an alyte, followed by ove n drying. The equipment n eed not be swabbed or otherwise tested to en sure removal of poten tially con tam in ati ng residues. A firm may elect to samp le its glassware for residual con tam in atio n to exclude or explore the po ssibility of in terfere nee i

58、n the case of p articularly sen sitive an alyses or difficult-to-clea n compoun ds.The po ssibility of carryover con tam in ati on affecti ng a methoderforma nee otstegrity ofthe results is gen erally con sidered of low risk to the p roduct and con sumers, with the exee pti on of potent compoun ds. Con tam in ated laboratory equipment, however, should not be a freque nt excuse for reject ing or discard ing aberra nt results. Glassware that is not prop erly clea ned can make it difficult to determ ine if the source of aberra nt an alytical results is related to the un clea n glassware or