FMEA (Failure mode and effects Analysis) is a systematic method of identifying and preventing product and process problems before they occur. "Closed" vs. "Open" ampoules maintains high Quality Standards while minimizing Capital expenditures, aiding in the control of drug prices.
FMEA (Failure mode and effects Analysis) is a systematic method of identifying and preventing product and process problems before they occur. "Closed" vs. "Open" ampoules maintains high Quality Standards while minimizing Capital expenditures, aiding in the control of drug prices.
FMEA (Failure mode and effects Analysis) is a systematic method of identifying and preventing product and process problems before they occur. "Closed" vs. "Open" ampoules maintains high Quality Standards while minimizing Capital expenditures, aiding in the control of drug prices.
FMEA (Failure mode and effects Analysis) is a systematic method of identifying and preventing product and process problems before they occur. "Closed" vs. "Open" ampoules maintains high Quality Standards while minimizing Capital expenditures, aiding in the control of drug prices.
Open Ampoules for Manufacture Parenteral Products Using FMEA Charles S. Levine VPCI Closed vs. Open ampoules Open Washed Depyrogenated Filled Flame sealed Terminally sterilized Closed Externally sterilized Opened mechanically or by flame Filled Flame sealed Terminally sterilized Supplier Manufacturer Cooperation Drug Product Manufacturer Sintetica S.A., Lugano, Switzerland Ampoule Manufacturer AR.LA.VE.S. s.r.l. (Aritcoli Lavorazione Vetro Soffiato), Treviglio (BG) Italy Supplier Manufacturer Cooperation Mutual Goals Improved quality of Ampoules Improved quality of Drug Product Reduced scrap during Drug Product Manufacturing Potential for expanded markets for Closed Ampoules Potential for expanded markets for Drug Products manufactured using Closed Ampoules Does the use of Closed Ampoules Benefit the Patient? Maintains high Quality Standards while minimizing Capital expenditures, which aids in the control of drug prices. Presentation outline Risk analysis technique Analysis of Ampoule formation process Analysis of drug product manufacturing process Summary of process enhancements HACCP Conduct a hazard analysis Determine the critical control points Establish critical limits Establish monitoring procedures Establish corrective action Establish verification plan Establish recordkeeping and documentation procedures J.G. Surak, HACCP and ISO development of a food is safety management standard, ASQ, FDC Control, No. 135, 2003. Controlling Risk At each critical control point identify the appropriate method for controlling product quality. 100% inspection Automated Manual Equipment controllers Process validation Periodic sampling and inspection Finished product testing FMEA FMEA (Failure Mode and Effects Analysis) is a systematic method of identifying and preventing product and process problems before they occur.* R. E. McDermott, The Basics of FMEA, 1996 FMEA process Define the process Select a team of experts Develop the FMEA matrix Process function Failure mode Failure effects Failure causes Probability of failure Severity of effects Likelihood of detection Calculate Risk Priority Number (RPN) Take preventive and corrective action Recalculate RPN A. Sahni, Using Failure Mode and Effects Analysis to Improve Manufacturing Processes, 1993 FMEA Failure mode presence of foreign particulate matter Cause of failure Inadequate control of environmental conditions during the formation of the ampoules Failure effect Potential injury to the patient Calculation of Risk Priority Number (RPN) RPN = P X S X D Where P = Probability of Failure S = Severity (Potential harm to patient) D = Likelihood of detection For each variable Scaled from 1 to 5 1 is best case 5 is Worst case Probability of Failure (P) P = 5 failure will occur often P = 1 unlikely to occur Severity (S) S= 5 serious injury to the patient or employee or high cost to the company S= 1 no effect on the patient or employee Likelihood of Detection (D) D = 5 No method to detect Failure D = 1 Failure is immediately detectable Applications of FMEA in the Pharmaceutical Industry, Pharmaceutical Technology, R. Kieffer Drug Product Manufacturing Process Description Product Epinephrine 1mg/ml (1ml in a 2ml Ampoule) Glass Type I Flint Filling process Clean Fill (not aseptic) Sterilization Terminally sterilized (overkill cycle) Leak test Vacuum Hold 100% inspection Automated What is the difference between a Closed and Open Ampoule? Sealed during transport and preparation for delivery into Filling area Sealed at the glass manufacturer with a slight overpressure The internal surfaces of the ampoule are not cleaned or depyrogenated at the Drug Product manufacturer Process Control shifts from the Drug Product manufacturer to the Glass manufacturer Risk Analysis Objective Minimize the risk that the use of Closed Ampoules versus Open Ampoules increases the risk of foreign particulate matter. Analyzing Risk Ampoule Forming Process Establish risk assessment team Osiris Donghi, Technical Director, ARLAVES Sergio Randisi, Director QA, ARLAVES Augusto Mitidieri, Director QA, Sintetica Charles Levine, Consultant, VPCI Detailed process definition Identify potential hazards and critical control points Analyzing Risk Drug Product Manufacturing Process Establish risk assessment team E. Giudice, Production Supervisor, Sintetica B. Ricardi, Manager QA, Sintetica N. Caronzolo, Manager QC, Sintetica A. Angelini, Qualified Person, Sintetica A. Mitidieri, General Manager, Sintetica C. Levine, consultant, VPCI Closed Ampoule Forming Process (2003) Ampoules are formed and cut from the glass tubing The ampoules exit the forming machine as open ampoules Cooled from approximately 300C to ambient temperature Score break Station Ampoule Chilling (approximately 4C) Ampoule sealing station Ampoule annealing oven Ampoule annealing oven Heating phase 140 to 590C Cooling phase 590 to 70C Bacterial endotoxin reduction 3 log Ampoule Forming Line CLevine_info.pdf Supplier of Type I Glass Tubing Schott Rohrglas, Bayreuth, Germany Kimble Italiana, Montelungo, Italy Tubing Specifications Densocan tubing from Schott Length 1500 mm Sealed at both ends with a vent hole (>0.5mm) Glass Particle specification (sample selection according to ANSI/ASQC z1.4 1993/DIN ISO 2859-1, simple random sample, test level II, normal test Particle size ( 0.2 0.5 mm) Maximum number of particles 4 AQL 0.65 Particle size (>0.5 mm) Maximum number of particles 1 AQL 0.65 Tubing Performance 20 ampoules are produced from each 1.5m tube 20mm at each end of the tube are automatically discarded The tubing is heated to 1200 o C to form ampoules Self Ignition Temperatures Polyvinyl Chloride - 507 o C Polyethylene - 488 o C Cellulose - 260 o C National Fire Protection Association (NFPA) Higher Risk Process Steps Transporting open ampoules to the cooling tunnel (RPN=18 ) Filtration of the air supplied to the cooling tunnel (RPN=12 ) Filtration of the air at the refrigeration Station (RPN=12 ) Proximity of the score brake station to the ampoule sealing station (RPN=24 ) Control of the vacuum level at the score brake station (RPN=12 ) Maximum possible value of RPN is 125 Critical Control Points Process step Transporting open ampoules to the cooling tunnel Filtration of the air supplied to the cooling tunnel Filtration of the air at the refrigeration Station Proximity of the score brake station to the ampoule sealing station Control of the vacuum level at the score brake station Critical control point None Roughing filters only Roughing filters only None None Corrective Actions Process step Transporting open ampoules to the cooling tunnel Filtration of the air supplied to the cooling tunnel Filtration of the air at the refrigeration Station Proximity of the score brake station to the ampoule sealing station Control of the vacuum level at the score brake station Corrective Action Install protective barrier Install F8 (EN779) filters Install F8 (EN779) filters Relocate score brake station and install separation barrier Install low vacuum alarm Recalculation of RPN Ampoule Forming Process 6 12 Control of the vacuum level at the score brake station 6 24 Proximity of the score brake station to the ampoule sealing station 6 12 Filtration of the air at the refrigeration Station 6 12 Filtration of the air supplied to the cooling tunnel 12 18 Transporting open ampoules to the cooling tunnel RPN (2004) RPN (2003) Process step Closed Ampoule Manufacturing Process (2004) Ampoules are formed and cut from the glass tubing Ampoules are transported in a protective barrier Cooled from approximately 300C to ambient temperature with F8 filtered air Ampoule Chilling (approximately 4C) with F8 filtered air Ampoule sealing station Score break (vacuum system equipped with low level alarm) Ampoule annealing oven Ampoule forming Line 1- Cooling Tunnel (open Ampoules) 2- Refrigerated Air (cool Ampoules to 4 o C) 3- Ampoule Sealing Station 4- Transport Belt (Closed Ampoules) 5 Vacuum Control System 6- Score Break Station 1 2 3 4 6 5 Drug Product Manufacturing Process (2003) Receive and release of ampoules Prepare ampoules for clean room filling process Prepare drug product solution Fill ampoules Terminally sterilize drug product 100% inspection Prepare Ampoules for Clean Room Filling Process Remove plastic wrap from modules Reject any damaged modules Autoclave ampoules in a double door jacketed steam autoclave Fill Ampoules Visually inspect each tray of ampoules for defective ampoules The filling system automatically opens the ampoule (inverted) Fills the drug product Seals the ampoule Visually inspect each tray of filled ampoules for defective seals Periodically remove samples for fill volume, seal dimensions and cosmetic inspection Terminally Sterilize Drug Product Load the ampoules in the inverted orientation Overkill sterilization cycle at 121 o C Post-vacuum hold cycle (leak test) 100% inspection Automated inspection for Low Fill Volume (leakers) Particulate matter Higher Risk Process Steps Opening ampoules (generation of glass particles) (RPN= 18) Filling ampoules in a Class C environment Airborne particles related to facility design (RPN=12) Airborne particles related to personnel gowning (RPN=18 ) Ampoule leak test (RPN=10 ) Critical Control Points Process Step Opening ampoules (generation of glass particles) Filling ampoules in a Class C environment Airborne particles related to facility design Airborne particles related to personnel gowning Ampoule leak test Critical Control Point Exhaust Interlock Monitoring P Change Filling Room Operators Clothing daily Cycle Review Corrective Actions Process Step Opening ampoules (generation of glass particles) Filling ampoules in a Class C environment Airborne particles related to facility design Airborne particles related to personnel gowning Ampoule leak test Corrective Actions Validate interlock Increase Environmental Monitoring Frequency Convert to single-use disposable gowns Trend PM rejects Demonstrate sensitivity of leak test (Validation) Recalculation of RPN Drug Product Manufacture 5 10 Ampoule leak test 12 18 Airborne particles related to personnel gowning 6 12 Airborne particles related to facility design 12 18 Opening ampoules (generation of glass particles) RPN (2004) RPN (2003) Process step Ampoule Leak Test Process 140 minutes at 0.2 Bar (Inverted Orientation) 100% automated fill volume inspection Ampoule Leak Test Validation Establish Fill Volume Sensitivity Label Claim 1.0ml Challenged with ampoules filled with 0.80ml 0.90ml 0.95ml 10 of 10 rejected with 0.95ml Ampoule Leak Test Validation Create 20 ampoules each with holes using Lasers 10m 20m 30m Ampoules with 10m were empty after the leak test cycle Particulate Matter Reject History 041249 0.2% 262 132371 04069 030537 041249 0.9% 1187 130257 04068 030537 0.9% 1217 128676 04067 030250 0.8% 293 35599 03122 030537 0.8% 1104 129985 03168 030537 0.7% 902 129688 03167 030537 0.6% 740 129461 03166 030250 7% 7428 111861 03099 030227 030250 6% 8225 128151 03098 030227 4% 4779 125570 03097 Ampoules Lot No. % N particulate matter rejects Number Inspected Batch No. Customer Complaint Frequency No Complaints received for particulate matter Summary FMEA is a tool that can identify those processes that represent the greatest risk for failures of various types. FMEA is also a tool that can evaluate an overall control program to ensure that limited quality resources are being utilized in the most cost-effective manner. Grazie per Tutti Augusto Mitidieri, General Manager, Sintetica, S.A. Osiris Donghi, Technical Director, ARLAVES Sergio Randisi, Director QA, ARLAVES Franco DeVecchi, VPCI