Contamination Control: PDA: A Global Particles, Bio ...

1 PDA: A Global AssociationContamination control : particles , Bio- Contamination , bioburden and Endotoxins in Aseptic DrinkwaterF Ziel Head of Aseptic processing technologies & GMP Compliance. Chairman of Parenteral 2014 Munich ConferenceContentsContamination control & Cross Contamination control .< WHATS NEW >In knowledgeIn GMPC ontamination control : particles , Bio- Contamination , Endotoxins: Strategies, Principles, Disinfection, Techniques, monitoring, bioburden , Sterility, Endotoxin testingThrough phases of establishing control to formal state of controlInitiatives: following on from QMS, QbD, QRM, PAT, CPV and Q-Metrics the EU GMP Annex 1 is in process for revision.

2 Under review for Annex 1 are control Strategies for manufacturing Sterile Drug products/ Practice Guidance:The PHSS have published a Bio- Contamination Life cycle Technical monograph reviewed by the MHRA before publication. The PDA are preparing a Technical Report on Cleaning and s new in Industry, Pharmacy requirementsWhat s new in regulatory expectations and initiatives2 Gowned operators generate microorganisms so following Quality by Design principles a physical separation barrier between the process/ product and the most contaminating source people with Isolators, RABS is required particularly in Aseptic processing that is increasing with new biological products.

3 Environmental monitoring is limited in recovery with limited sample sizes and sample areas/ volumes meaning we only have an indication not absolute values on Contamination levels; trends (much data) are needed to indicate state of single measuring event has little value on its own. We are still learning about disinfection and developing new approaches: Manual, Semi-automatic and Automatic. Isolators are typically decontaminated with vH2O2 VHP (bench mark), other automated gaseous disinfection processes may apply, and still there is not widespread knowledge in this area: An understanding of Science, Process and Microbiology are key to efficacy, efficiency and GMP compliance.

4 Despite being an established process the industry still has problems with Moist heat sterilisationWhat s New: KnowledgePhotographs courtesy of F Ziel of Resident and Transient micro-flora in Controlled EnvironmentsControlled EnvironmentMicrofloraon Hand transferMicrofloraon Materials in transferMicrofloratransfer from Surrounding EnvironmentControlled Zones4 Containment & Cross Contamination control51 Biologicalsafety rooms and cabinets: Biological safety Levels Rooms BL1,2,3,4 & Class 1,2,3 cabinets Containment of Biologically hazardous, toxic, pathogenic organisms, products/substances for operator protection.

5 Requirements detailed in Biosafety AP1 Active Pharmaceutical Ingredient containment: API Powder containment including non sterile products Containment levels referenced in API micro-grams by cubic metre for operator protection. Powder containment in Isolators (turbulent flow) and closed systems. 3 Aseptic and Toxic containment in Aseptic processing of sterile medicines, drugs and drug substances. Using Isolator technology with Safe Change Filter barrier containment and CIP / decontamination features Product and operator protection to including containment for cross Contamination control4 Aseptic and non pathogenic biological product containment in Aseptic processing of sterile medicines, drugs and drug substances.

6 Product protection and containment for cross Contamination control using Isolator Asepticprocessing with product protection Product protection using Barrier Separation Technology (Isolators and RABS).Pharmaceutical Containment HierarchyClassified Area ZonationUnclassif ied Areas / z onesAsept ic core EU Gr ad e A I SO 5 in operationEU Grade B in operationI SO 7 in operationEU Grade C in operationEU Grade D : at RestISO8: In OperationISO8 in operationEU Grade C at RestISO7 in operationCleanroom sRA BSIsolatorsBFSAir Flow and Pressure Cascade6 control Targets.

7 Total particulate & Microbiological levelsEU : DAISO5B : ISO 7C : ISO8<1cfu = 0 cfu10050 n/a200 cfu Settle plates max cfu. Contact plates max cfu. Glove prints max cfu. Active air cfu/ cubic ParticlesViable & Non viable >3520 ( micron)20 (5 micron)3520000 ( )29000 (5 )352000 ( )2900 (5 )3520000 ( )29000 (5 ) at Rest.<In Operation>Microbiological Contamination as colony forming units > (cfu)<In Operation>5025 n/a100 cfu55 510 cfuPersonal & Material TransfersControlled Direct input Utilities / services WFI & HVACISO 14698 FDA <797> & <1116>3 log3log3/6 log3 logAir flow & Pressure Cascade directionGMP Annex 1 > ISO 14644 Parts 1 & 27 Do we really understand what the differences are between Isolators and RABS with all the configuration variants and what is best for a given application.

8 Do we understand the Contamination control attributes of Barrier Separation Technology and how they are applied for Contamination control . Do we understand how containment applies for Pharmaceutical applications, other than APIs; powder particle containment that are well characterized. Could we finally be making progress with implementation with RMM/ RTM?What s New in Contamination Control: Barrier Separation TechnologyA-ISO5B ISO7 RABS8 Open & Closed Design RABS Open & Closed Operation RABSOpen & Closed Operation Using Open or Closed Design : Combination or Physical and Aerodynamic or Active Air managementActive Air management +veAir over spill limited to transfer portsTransfer port closed after useSIP- AIP GIP*Open Design RABSC losed Design RABSSIP- AIP or GIPA-ISO5 Open Operation RABSBest practice.

9 Closed Operation RABSOpen barrier door operator interventions are risk assessed, justified, controlled and monitored. Airflow protection at open set up and last Bio-decontamination step barrier doors remain closed for complete aseptic processing operation. Interventions only by barrier gloves for operators & controlled access ports for in place. AIP= Aseptic/assembly-GIP=Gassing in Place. A-ISO5B ISO7*VHP-GIP of Biological Reduction101 Sterilisation: Moist Heat, Dry Heat Gamma irradiation, ETO Penetrative processes fully referenced in pharmacopeia's delivering a defined sterility assurance level (SAL)2 Automated Surface Sterilisation Non-chemical based automated surface sterilisation Chemical based automated Gaseous Surface Sterilisation in combination with residue free cleaning to prevent chemical Contamination transfer to products3 Automated Gaseous Disinfection (airborne and surfaces) examples include Hydrogen peroxide vapour vH2O2/ VHP4 Semi-automated aerosol/ foggerdisinfection (airborne and surfaces)

10 Examples include Dry fog, nebulisers5 Surface Manual Disinfection Processes; In-process efficacy qualification Surface Manual Disinfection Procedures: Laboratory qualified efficacy. in-process qualification of agent application via procedures (SOPs). EM used to monitor impact on microbial controlBiological Reduction HierarchyRegulationProductFacilityProces sOperationsSeparation Barrier Technology selectionHolistic Decision making Separation Barrier Technology selectionUse a control strategy to consider each area for key requirements / issues that influence the Barrier Technology: Isolator or RABS selection.