Maintaining Good Cleaning Practices

Transcription

1 Maitaiig Good Cleaig Practices Kathlee Kedrick Validatio Techology Maager NEPDA Meetig o PDA TR29 November 12,

2 The Cleaig Program Life Cycle Cleaig Program Lifecycle Operatios Validatio Maiteace Commissioig Developmet Desig

3 Cleaig Regulatios FDA CFR Title 21 parts 210 ad 211 EMEA Aex 15 EMEA Aex 18 (a) Equipmet ad utesils shall be cleaed, maitaied, ad, as appropriate for the ature of the drug, saitized ad/or sterilized at appropriate itervals to prevet malfuctios or cotamiatio that would alter the safety, idetity, stregth, quality, or purity of the drug product beyod the official or other established requiremets. (b) Protectio of the clea equipmet from cotamiatio before use. 21CFR Part

4 Major Elemets to Maitaiig the Cleaig Process Compliace with Stadard Operatig Procedures (SOP) Visual ispectio of iteral equipmet surfaces prior to use Coductivity verificatio Maiteace Program for Equipmet Prevetative Maiteace Program (PM) Geeral upkeep of equipmet A Cleaig Moitorig Program Samplig Critical parameters A Revalidatio Program Some or all elemets of the origial validatio A Revalidatio Assessmet Program Assessmet of equipmet to verify it is still i a validated state

5 Stadard Operatig Procedures Effective Traiig of Operators The SOPs must be robust ad esure that equipmet is used i the maer it was validated. Operators must comply ad perform the cleaig procedures as validated Eye exams Verificatio of traiig at a specified time icremet Competecy traiig to esure operators uderstad the importace of maitaiig the validated state

6 Visual Ispectio Visual ispectio ca allow detectio of gross cotamiatio cocetrated i small areas that could otherwise go udetected by samplig ad/or aalysis. EU Guidelies to GMP Volume 4 No residue to be visible o the equipmet after cleaig procedures are performed Spikig studies to demostrate level of visibility Visual ispectios coducted per SOP Basically is it clea or ot

7 Cleaig Process Record Keepig Records must be kept showig the equipmet umbers, the date of cleaig, who cleaed it ad who ispected/tested it. Operators are Importat They verify that it passes other aalytical testig such as coductivity They verify the equipmet is visually clea They should be the oes to otice a chage i the iteral surfaces. They ca recommed chages to the procedure They have the most cotact with the equipmet

8 Failure Example Failure to clea ad maitai equipmet ad utesils used i the productio of drug products i order to prevet cotamiatio [21 CFR (a)]. For example, deterioratig equipmet was observed, icludig: tape flakig off fillig equipmet directly above a ucovered hopper cotaiig product to be filled, a leakig gasket i the product trasfer lie durig fillig, ad two leaks i the Purified Water system. While your respose appears adequate, we are cocered about the coditio of your maufacturig facility i that durig the ispectio our ivestigators observed multiple coditios of disrepair.

9 Prevetative Maiteace (PM) Scheduled for defied itervals Ispectio of equipmet for wear Replaces items such as gaskets, diaphragms, valves, etc as ecessary Esures that the equipmet is mechaically soud prior to use Ispectio of spray devices

10 Failure Example Utesils ad equipmet that directly cotact sterile API durig trasfer are iadequate to esure that these APIs are maitaied sterile ad pyroge-free. For example: Several pits/holes were observed i the weld at the ed ad there was a crack observed betwee the hadle ad the ed. These holes ad crack create a challege for sterilizatio.

11 What is Moitorig? Moitorig refers to the routie measuremets take o the cleaig process that serve as idicators of whether the process is i a state of cotrol ( or cosidered from the opposite poit of view, serve as idicators that the process either is ot or may ot be i a state of cotrol). Cleaig Validatio, U.G. Barad, 2005

12 Why Moitor the Cleaig Process? Cotrol over a cleaig process ca be demostrated by a review of all relevat data at specified time icremets. Relevat data icludes sample results ad tredig of those results. Moitorig the cleaig processes esures the process is performed correctly ad also provides a early warig if it is ot performig as validated. Provides additioal reassurace to the visual assessmet ad coductivity verificatio that is performed with each cleaig. Cosistet with the lifecycle approach to validatio (Desig, Formal Validatio Studies, ad Ogoig Cotrols) as well as cotiuous improvemet for maufacturig quality ad efficiecy.

13 Moitorig Cleaig Cycles Temperature, flow, pressure, fluid level, draiage, cleaig aget cocetratio, coductivity, ad ph may play a role i moitorig the cleaig program. The ature of the cleaig method will determie the critical parameters to be moitored durig cleaig. Istrumetatio for moitorig critical parameters should be accurate ad subject to a routie calibratio program.

14 Data Aalysis 16 UCL Average Lie Performace Data 4 2 LCL Haford PI Forum

15 Idetifyig Treds Oe poit outside the cotrol limits Two out of Three poits two stadard deviatios above/below average Four out of Five poits oe stadard deviatio above/below average Seve poits i a row all above/below average Te out of Eleve poits i a row all above/below average Seve poits i a row all icreasig/decreasig. Haford Forum

16 Tredig I all cases, treds should be ivestigated to determie the special cause(s) A circle or a shift i the baselie is a tred Geerally, short term shifts are left circled, log term shifts have a ew baselie Remember the goal is Predictio of Future Performace Haford Forum

17 Tred Idetificatio Iitial Idicatio of Tred Oct-98 Dec-98 Feb-99 Apr-99 Ju-99 Aug-99 Oct-99 Dec-99 Feb-00 Apr-00 Ju-00 Aug-00 Oct-00 Dec-00 Feb-01 Apr-01 Ju-01 Aug-01 Average = 9.5 (Oct 98 - Oct 00) Haford PI Forum 2 of 3 at 2 stadard deviatios above average, circled

18 Idetifyig a Tred Report the tred Search for Special Causes Compare detailed data durig the tred to previous stable time iterval Cosider Corrective Actio Maagemet ecessary steps

19 Moitorig Cleaig Cycles Optios for moitorig Periodic Samplig (TOC, Bioburde, Edotoxi, Coductivity) Moitor Critical Operatig Parameters (temperature, flow, pressure) Moitorig ca occur usig equipmet that is i-lie or off-lie but esure that it is accurate ad i a routie calibratio program. Cleaig procedures should be moitored at appropriate itervals after validatio to esure that these procedures are effective whe used durig routie productio. Equipmet clealiess ca be moitored by aalytical testig ad visual examiatio, where feasible.

20 Automated vs. Maual Cleaig Automated Cleaig Maual Cleaig May ot require o-goig verificatio if the system is desiged, istalled, ad validated appropriately Periodic Verificatio Required Verifies how appropriate the traiig is ad how well the operator ca perform the cleaig Semi-automated Cleaig Depedet o the reproducibility of the system Collected sample data should be aalyzed

21 Verificatio vs. Revalidatio Verificatio Revalidatio Performed as part of cleaig moitorig Could require portios of the iitial cleaig validatio to be repeated Samplig ca be less aggressive - Fewer areas - Idirect vs direct samplig Samples that are required ca be more aggressive tha verificatio (Rise vs Swab) Ca iclude aspects of both verificatio ad validatio May be triggered by a chage to equipmet or cleaig procedures

22 Chage Cotrol May Impact all of the cleaig process Stadard Operatig Procedures (SOP) Assay methods Equipmet Detergets Times Ay chages to items determied durig PQ as impactig to the cleaig process must be evaluated ad ultimately approved.

23 Failure Example SOP XXXX, was revised May 17, 2004 to remove the requiremet for [redacted] after use/prior to cleaig if iactivatio time ad temperature requiremets were met durig the iactivatio process. These ew cleaig procedures were ot validated to establish the impact of the chages o the cleaig process.

24 Chage Cotrol Chages must be pre-approved If the maiteace required is deemed a chage The chage cotrol team determies the level of testig that is required This could iclude - New cleaig samples (TOC, Coductivity, Bioburde, Edotoxi, etc) - Verificatio of flow rates - Cofirmatio of pathways - Verificatio of spray coverage A validated process ca be easy to maitai if a efficiet ad effective chage cotrol program is i place.

25 Revalidatio Assessmet Paper Exercise SOP Govered Frequecy Based o Ratioale Criticality of the equipmet could determie if its assessed aually or every three years, for example. Assessmets Ca Iclude Review of ope ad closed work orders Review of related chage cotrols P&ID walk dow of equipmet Review of related SOPs for updates that could affect the validated state Assessmets provide reassurace that the equipmet has remaied i a validated state.

26 Summary Cleaig Program Lifecycle Operatios Validatio Maiteace Commissioig Developmet Desig

27 Summary Compliace with Stadard Operatig Procedures (SOP) Visual ispectio of iteral equipmet surfaces prior to use Coductivity verificatio Maiteace Program for Equipmet Prevetative Maiteace Program (PM) Geeral upkeep of equipmet A Cleaig Moitorig Program Samplig Critical parameters A Revalidatio Program Some or all elemets of the origial validatio A Revalidatio Assessmet Program Assessmet of equipmet to verify it is still i a validated state

28 Thak you!! Questios????