Inspections, Compliance, Enforcement, and Criminal in Estigations
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Inpecion Gide > Validaion of Cleaning Pocee (7/93)
U.S. Fd & Dg Adiiai U.S.
Inspections, Compliance, Enforcement, and Criminal Inestigations Home Inpec ion, Complianc Home Complianc e, Enfoc emen, and Ciminal Ciminal Ineigaion Ineigaion Inpecion Inpecion Inpecion Gide
Validation Validat ion of Cleaning Processes (7/93)
GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer an rights, privileges, benefits, or immunities for or on an person(s). I. INTRODUC INTRODUC TION Vaidai f ceaig cede ha geeaed cideabe dici ice agec dce, icdig he Ieci Gide f B Phaaceica Cheica ad he Biechg Ieci Gide, hae bief addeed hi ie. Thee Agec dce cea eabih he eecai eecai ha c ceaig eaig cede (cee (cee ) be ai aidaed. daed. Thi gide i deiged eabih ieci ciec ad ifi b dicig acice ha hae bee fd acceabe ( acceabe). Siae, e ecgie ha f ceaig aidai, a ih aidai f he cee, hee a be e ha e a aidae a ce. I he ed, he e f a aidai aidai ce ce i hehe cieific cieific daa h ha he e cie cie de a eeced ad dc dce e a e ha cie ee ee edee edeeied ied e ci cifi ficai. cai. Thi gide i ieded ce eie ceaig f cheica cheica eide . II. BACKGROUND F FDA eie ha eie be cea i e i hig e, he 1963 GMP Regai (Pa 133.4) aed a f "Eie *** ha be aiaied i a cea a d de ae ae ***." A e e iia iia eci e i ie e ceaig (211.67) a icde i he 1978 CGMP eg ai. Of ce, he ai aiae f eiig cea cea e ie i ee ca i iai ai adeai f dg dc. Hiica, FDA ieiga hae ed f g iaiai de iadeae ceaig ad aieace f eie ad/ d c e. A, A, hiica e aig, FDA FDA a e cceed ab he ca i iai ai f eici eicii i dg dc ih eicii he c-caiai f dg dc ih e eid he. A be f dc hae bee ecaed e he a decade de aca eia eicii c-caiai. Oe e e hich iceaed iceaed FD FDA A aa ee f he eia f c c caiai caiai de iadeae cede a he 1988 eca f a fiihe fii he d dg dc, Cheaie Rei USP. The The b haaceica cheica cheica ed dce he d c had be ce caiae caiae d ih ee f ieediae ad degada f he dci f agica eicide. The c-caiai i ha cae i beieed beie ed hae bee de he ee f eceed e. The The eceed e had be e caiaed caiaed be cae f a ac f c c e he ee f e d. d. D D ha had be e ed e eceed e f f a eicide eicide dci dci ce ee ae ed e ec eceed eed e e ed f he ei afaci afacig g ce. The fi fi did hae a deae c c e hee e d, did d adeae eig f ded e, ad did hae aidaed ceaig cede f he d. Se hie f hi eicide caiaed b haaceica haaceica e e ied a ec d facii facii a a diffee diffee cai f fiihig. Thi eed i he ca i iai ai f he bag e d i ha facii' facii' fid fid bed de ih eicide caiai. Thi Thi i ed c caiai ca iai f dc dced ed a ha ie, a ie hee e ic icide ide ee a a dced. FDA iied a i i ae i 1992 a feig b haaceica aface aface hich afaced afaced e e id dc a e a -eida dc ig c c e ie. Thi Thi fi a a i i-e -e b haaceica facii facii.. FDA cide cide ed he e ia f c-caiai be igif igifica ica ad e a ei h ea h i i he bic bic.. The The fi had ece ece ae d a ceaig aidai ga g a a he ie ie f he ieci ad i a cide cideed ed iadeae b FDA. FDA. Oe f he ea i a cideed iadeae a ha he fi a ig f eidece eidece f he ab ece f he ei cd. The fi fi had e idece, f f TLC TLC e he ie ae , f he ee ce f eide f eaci eaci bdc bdc a d degada f f he ei ce. III. GENERAL REQUIREMENTS FDA eec fi fi ha e ie cede (SOP') dea ii iig g he cea ig cee e d f ai ai iece f eie. If fi fi ha e e ceaig ce f ceaig ceaig be ee dif diffee fee bache f he a e dc dc ad e a dif diffee fee ce ce f ceaig ceaig beee dc
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, . S, - , . B . F F . A (, , .) . FDA FD A . FDA , , . FDA , , . FDA . FDA . T " ." ." I. EALAION EALAION O F CL EANI EANING NG ALIDAION ALIDAION
T , . I . . S S . F , , ? D ? W ? H ? T T . A . D D . I, , , ( ) . . W ( ) , " " " . S S . 1. E D E , - - -- -- (CIP . F , . W , , . . W , . D D . A . I , , . P . . S, S, , , . A ; . T , , . I , . W CIP , . T . T . F , , . S , . W , , . . T . 2. C P W
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Pcede ad Dceai Eaie he dea i ad ecifici ecifici f he ced e f he (cea (cea ig) ce beig aidae d, ad he a f dcea dcea i eied. We hae e e ge ea SOP, hie he e a ba ch ecd ecd g hee e ha eie eie e e f ecific ecific dc dceai eai f efig each e. Deedig he cei f he e ad ceaig ce ad he abii ad aiig f ea, he a f dceai ecea f eecig ai ceaig e cede i a. Whe e ce ce ceaig ced e a e eied, i i ia ia dce he ciica ciica ceaig e (f eae ceai b dg hei cee). I hi egad, ecific dceai he eie ief hich icde ifai ab h ceaed i ad he i aabe. Hee, f eaie ie ceaig eai, he ee dceai ha he ea ceaig ce a efed ef ed i igh gh b e ffic fficie. ie. Ohe fac ch a hi f cea cea ig, e e ide ee fd a fe cea cea ig, ad aiabii f e e a a dicae he a f dceai eied. F eae, he aiabe eide ee ae deeced fig ceaig, aica f a ce ha i beieed be acceabe, e eabih he effeciee f he ce ad ea eface. Aiae eaai be ade ad he ea eface i deeed a be, e eeie dceai (gidace) ad aiig a be eied. 3. Aaica Aaica Meh d Deeie he ecifici ad eiii f he aaica ehd ed deec eida caia. Wih adace i aaica echg, eide f he afacig ad ceaig cee ca be deeced a e ee. If ee f caiai eida ae deeced, i de ea ha he e i eida caia caia ee afe ceaig. ceaig. I ea ea ha ee f caia geae ha he e ii iii i deeci ii ii f he aaica ehd ehd ae ee i he a e. The fi fi hd chaege he aaica ehd i cbiai ih he aig ehd() ed h ha caia ca be eceed f he eie face ad a ha ee, i.e. 50% ece, 90%, ec. Thi i ecea befe a cci ca be ade baed he ae e. A egaie e a a be he e f aig aig echie (ee be ). 4. Saig Thee ae geea e f aig ha hae bee fd acceabe. The deiabe i he diec ehd f aig he face f he eie. Ahe ehd i he e f ie i. a. Diec Diec Sface Saig Saig - Dee Dee ie ie he e f a ig ig aeia ed ad i iac he e d aa ice he aig aeia a a iefee ie fee ih he e . F eae, eae, he adheie e d i ab ha bee fd iefee iefee ih he aai f ae. Theefe, Theefe, ea ea i he aidai g a, i i ia ia a e ha he aig edi edi ad e (ed f eaci f f he edi) ae aifac aifac ad ca be eadi eadi ed. Adaage f diec Adaage diec aig aig ae ha a ea ha de cea ad hich ae eaa b acceibe acceibe ca be eaaed, eadig eabihig a ee f caiai eide e gie face aea. Addiia, eide ha ae "died " ae ibe ca be aed b hica ea. b. Rie Rie Sae Sae - T adaage f ig ie ie a ae e a e ha a age face face aea a be aed, ad iacceibe iacceibe e e e ha ca be i ie e diaebed diaebed ca be a aed ed a d eaaed. A diadaa ge f ie ae i ha he eide caia caia a be be a be hica ccded i he e i ie. e. A aag haae ca be i hei "di ." I he eaai f ceaig f a di , aica ih died eide, e de a he ie ed ee ha i cea; cea; e a he . Chec ee ha a diec eaee eaee f he eide caia caia ha bee ade f he ie ie ae he i i ed aidae he ceaig ce. F eae, i i acceabe i e ie ae f ae ai (de i ee he cedia e) ahe ha e i f eia caiae. c. Rie Pdci I-Pce C Miig - Idiec eig, ch a cdcii eig, a be f e ae f ie iig ce a ceaig ce ha bee aidaed. Thi d be aica e f he b dg bace aface hee eac ad ceifge ad iig beee c age eie ca be aed ig ie i ae. A idiec e ehd hae bee h ceae ih he cdii f he eie. Dig aidai, he fi hd dce ha eig he ceaed eie gie a acceabe e f he idiec e. . ESTABLISHMENT OF LIMIT LIMITS S
FDA de ied e a cceace ecifi ecificai cai ehd f de ei eiig ig he he a cea ig ce i aidae d. I i i iacica iacica f f FDA d de he ide aiai i eie ad dc ed hgh he b ad fiihed dage f idie. The fi' aiae f he eide ii eabihed hd be gica baed he aface' edge f he aeia ied ad be acica, achieabe, a d eifiabe. eifiabe. I i ia de fie he e ii iii i f he aa i ica ca ehd ehd i de e ea ab e ii. ii. Se Se ii ha hae bee eied b id eeeaie i he ieae i eeai icde aaica deeci ee ch a 10 PPM, bigica acii ee ch a 1/1000 f he a heaeic de, ad gaeic ee ch a iibe eide.
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Check the manne r in which limi limits ts are e stab lished. Unlike Unlike finished pha rm rmaceuticals aceuticals w here the chemi chemical cal identity of residua residua ls are know n (i.e., (i.e., from actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-products which may never have been chemically chemi cally identified. identified. In esta blishing residual limits, limits, it may may not be ade quate to focus only on th e principal reactant s ince other chemical variations may be more difficul difficultt to remove. There are circumstances circumstances w here TLC scree ning, in addition to chemical chemical analyses , may may be ne ede d. In a bulk process, particularly for very poten t chemicals chemicals such as some ste roids, the issue of by-products by-products ne eds to be cons idered if equipmen is not ded icated. The objective of the inspection is to e nsure tha t the ba sis for any limits limits is scientifically scientifically justifiable. I. OHE IE
a. Placebo P roduct In order to evaluate a nd validate cleaning cleaning processes some manufacturer manufacturers s have proc processe esse d a placebo batch in the equipment under esse ntial ntially ly the same o perating parameters parameters us ed for processing product. A sample of the placebo batch is then tested for residual residual contaminati contam ination. on. However, we have documented several signific significant ant issues that need to be addressed when using placebo product product to validat cleaning cl eaning proc processe esse s. One cann ot as sure tha t the contaminate w ill be uniformly uniformly distributed distributed th roughout the system. For example, if the discharge valve or chute o a blender are contaminated, the contaminant would probably not be uniformly dispersed in the placebo; it would most likely be concentrate in the initial discharge portion o f the ba tch. Additionally, Additionally, if if the contaminant or res idue is of a larger particle size, it may not be u niform niformly ly dispersed in the placebo. Some firm firms s ha ve made the a ssumption that a residual conta mi minant nant w ould be w orn off the equipment surface uniformly; uniformly; this is also a n invali conclusion. Finally, Finally, the a nalytical powe r may may be grea tly reduced reduced b y dilution dilution of the conta mi minate nate . Because of such problems, rinse and /or swa samples sampl es should be us ed in conjunction conjunction with the placebo method. b. Detergent If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common comm on problem ass ociated w ith deterge nt use is its composition. Many dete rgent supp liers will not provide specific composition, which makes it diffic difficult ult for the user to e valuate res idues. As with produ ct residues, it is important important a nd it is expected tha t the manufacturer evaluate the e ffi fficiency ciency of the cleaning proces s for the removal of residues. How ever, unlike product residue residue s, it is is expe cted that no (or for for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. Otherwise, a different detergent should be selected. c. Test Test Until Clean Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilized by some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases. Constant retesting and resampling resampl ing can show that the cleaning process is not validated since these retests a ctual ctually ly docum document ent the presence of unacceptable residue and conta mi minants nants from an ineffective clean clean ing process. II. EFEENCE
1) J. J. Rodeh Rodeh amel, "Cleaning an d Maintena nce," Pgs 8 2-87, University University of Wisconsin's Control Proced ures in Drug Production Seminar, Seminar, July July 1722, 1966, W ill illiam iam Blockstein, Blockstein, Editor, Published by the University of Wisconsin, L.O.C.#66-64234. 2) J.A. J.A. Constan ce, "Why Some Dust Co ntrol Exhaust Syste ms Don't Work," Pharm. Eng., January-February, 24-26 (1983). (1983). 3) S.W. S.W. Harder, "The Validation o f Cleaning P rocedures," P harm. Technol. Technol. 8 (5), 29-34 (1984) 4) W.J. Mead, "Mainte nance: Its Inte rrelationship w ith Drug Drug Qua lity lity," ," Pha rm rm.. Eng. 7(3), 7(3), 29-33 (1987). 5) J.A. J.A. Smith, Smith, "A Modified Modified Sw abbing Technique for Validation of Deterge nt Residue s in Cle an-in-Place Systems," Pha rm rm.. Technol. 16(1), 16(1), 60-6 (1992). 6) Fourman, G.L. G.L. and Mullen, M.V., M.V., "Determining "Determining Clea ning Validation Acceptance Lim Limits its for Pha rm rmaceutical aceutical Manufacturing Ope rations," P harm Technol. 17(4), 54-60 (1993). 7) McCormick McCormick,, P.Y. and C ullen, L.F., L.F., in Pha rm rmaceutical aceutical P rocess Validation, 2nd Ed., edited by I.R. Berry Berry and R.A R.A.. Nash, 31 9-349 (1993) Return to: Page Top Top Inspection Start 1
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