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1、Clean Rooms and Zones: Changing Regulatory Demands; Optimizing Sampling Positions; Automating the EM process,Presented by Joe Gecsey HACH September 2012,Agenda,Forthcoming Changes to ISO 14644-1, -2 Cleanroom Standards Benefits of ISO 21501-4 Calibration Choosing sample positions How automation can
2、make the EM task Easier Simpler More valuable,Classification Standards for Airborne Particles,General Air Monitoring Standards before 1999,Classification Standards for Airborne Particles,ISO 14644-1 Classification of air cleanliness ISO 14644-2 Specifications for testing and monitoring to prove cont
3、inued compliance with ISO 14644-1 ISO 14644-3 Guidance on instrumentation to be used for testing for compliance with ISO 14644-1,General Air Monitoring Standards,ISO 14644,Forthcoming Revisions to ISO 14644-1, -2,1. Frequency of re-certification for “continued compliance”: Now: If zone is ISO Class
4、5, every 6 months If zone is ISO Class 6, every 12 months Proposed: Remove re-certification period Re-certification timeframe will be set by regulatory or advisory committees for a particular industry,2. Eliminate Students T test for sample plans with 1 to 9 sample positions 3. Method of determining
5、 number of sample positions Replace with stated number of minimum sample positions as a look-up chart Based on 95% confidence levels not on SQRT of area May mean a small increase in the number of sample points,Forthcoming Revisions to ISO 14644-1, -2,A.4.1.1 Derive the minimum number of sampling loc
6、ations NL from table 3. Table A.1 shows the number of sample locations related to the area of each cleanroom or clean zone to be classified and provides at least 95% confidence that at least 90 % of the total area does not exceed the class limit. Different levels of confidence and verification can b
7、e specified and agreed upon by the customer and supplier.,4. Remove possibility to classify at 5 micron for ISO Class 5 Limit number of 29 removed Note (e) : Sample collection limitations for both particles in low concentrations and sizes greater than 1 um make classification inappropriate, due to p
8、otential particle losses in the sampling system.” 5. Indicate that single digit limits for ISO Class 1 and 2 create challenges to timely execution Note (b) : These concentrations will lead to large air sample volumes for classification. Sequential sampling procedure may be applied; see Annex D.,Fort
9、hcoming Revisions to ISO 14644-1, -2,6. New label for classification level ACP = Air Cleanliness (by) Particles ACC = Air cleanliness (by) Chemicals SCP = Surface Cleanliness (by) Particles SCC = Surface Cleanliness (by) Chemicals,Forthcoming Revisions to ISO 14644-1, -2,Cleanroom Designations,Air,S
10、urfaces,Particles,Chemicals,ACP,SCP,SCC,ACC,ISO 14644 10 Draft,ISO 14644 9,ISO 14644 - 1, - 2 Draft of Revision,ISO 14644 8,Classification Limits: ISO 14644-1,FS 209E Class 100,Proposed new limits and labels: Classification Limits: ISO 14644-1 (2013),FS 209E Class 100,7. Normative Reference to ISO 2
11、1501-4 2 Normative reference The following normative document contains provisions, which, through reference in this text, constitute provisions of this part of ISO 14644. For dated references, subsequent amendments to, or revisions of, any of these publications do not apply. However, parties to agre
12、ements based on this part of ISO 14644 are encouraged to investigate the possibility of applying the most recent editions of the normative documents indicated below. For undated references, the latest edition of the normative document referred to applies. Members of ISO and IEC maintain registers of
13、 currently valid International Standards. ISO 21501-4:2007 Determination of particle size distribution Single particle light interaction methods-Part 4: Light scattering airborne particle counter for clean spaces.,Forthcoming Revisions to ISO 14644-1, -2,ISO 21501 Additional Tests,Before ISO 21501-4
14、 Size calibration Size resolution False count rate Sampling time,ISO 21501-4 Size calibration Verification of size setting Counting efficiency Size resolution False count rate Concentration limit Sampling flow rate Sampling time Sampling volume,ISO 21501-4 Calibration Standard Delivers:,Improved com
15、pliance Removes ambiguity by providing a single internationally recognized standard method for calibration Harmonization between ISO and GMP guidance Improved unit-to-unit reproducibility Improved counting accuracy All current Met One particle counters from Hach may be calibrated using ISO 21501-4 a
16、t your facility,ISO 21501-4 What to look for on the calibration certificate,Road Map to ISO 21501-4 compliance,Audit your Methods and Equipment Training Standard Operating Procedures (SOPs) Validation (IQ/OQ) Calibration Policies Equipment Upgrade as needed Audit your Calibration Service Factory-tra
17、ined and authorized Correct equipment and standards,Additional information,ISO,Optimizing Sampling of Airborne Particle Counts,What price patient safety?,Injections and infusions for people with suppressed immunological systems Injection straight into bloodstream bypasses most of the bodys defences.
18、,Why monitor for particles?,Greatest concern is for viable microorganisms Technology is not available today to measure viable counts in real time Total particle counts used as a surrogate (non-viable),100,000 billion bacteria on and in the human body,General Air Monitoring,Viable counts Can be cultu
19、red Will grow into “colonies” requires optimum growth medium requires sufficient incubation Enumerated as CFU = Colony-Forming Units VU = Viable Units,General Air Monitoring,Non-viable counts Sometimes referred to as “total count” Includes all types of airborne material Solid particles Fibers Microo
20、rganisms Skin flakes Droplets,How an airborne particle counter works ,Laser Diode,Detector,Mirror,Particle,Light Trap,Principle: Light Scattering,Relative sizes of particulate matter,Human hair: 50 -100 m,Visible: 35 - 50 m,Bacteria: 1 to 8 m,Skin Flake: about 20 m,Table salt,Skin flake,Bacteria,40
21、m,Relative Sizes of Particulate Matter,Bacterium 2 - 8 m,0.5 m,Virus: 0.001 m,Skin Flake,Fiber,Alumino-silicate with K and Ti,Talc,Particle Counting Applications,What,Particle Counting Applications,Two types of activities performed with an airborne particle counter: Classification focuses primarily
22、on the environment Monitoring focuses on process, people and the environment,People as a Contamination Source Shed 5 to 10 million skin cells each day 2000 to 5000 microorganisms/cm2 on skin Filter efficiency of clothing or garment varies greatly,Classification: FS209 and ISO 14644-1,Classification
23、is the process of qualifying the cleanroom environment by the number of particles using a standard method Determine classification of room according to standards “ISO Class 5” or “Class 100” Performed on a regular basis but not frequently 6 months, yearly or ? Standards define minimum number of samp
24、le points Usually based on area of cleanroom or clean zone Standards define minimum amount of air to be sampled Minimum volumes for statistically valid samples,Classification is a standardized method,Environmental Monitoring,Minimum number of sample points defined by QA Area of cleanroom or clean zo
25、ne Activity Risk to product Frequency and volume of sample points defined by QA Frequent enough to show control Frequent enough to provide meaningful trend information,Determine stability of room or zone over time; develop trend data Executed on a scheduled basis: daily, weekly, monthly,Not controll
26、ed by regulation but needed for trend information,Process Monitoring,Minimum number of sample points defined by QA Area of cleanroom or clean zone Activity Risk to product Frequency and volume of sample points defined by QA Frequent enough to show control Frequent enough to manage financial risk of
27、product contamination,Determine readiness of room to carry out designated task Performed whenever relevant activity occurs daily work,Not controlled by regulationbut by risk!,Three Common Methods of Sampling,Manual: with a handheld or portable particle counter Sequential: with a manifold/scanner and
28、 particle counter Continuous: with portable or remote particle counters,MET ONE 6000 & 7000 Series for production monitoring Grade A & B areas,MET ONE 3400 Series Cleanroom classification Environmental monitoring Short-term online sampling,MET ONE HHPC+ Handheld particle counter Used for troubleshoo
29、ting,Manual Monitoring,Manual Monitoring,Consistently samples fixed positions Samples every position one or more times per hour Can operate 24 hours per day,Sequential Monitoring,Sequential Monitoring,Tubing Transport Loss,Able to detect fast, intermittent events Uses dedicated counter at each sampl
30、e point Avoids effects of long tubing runs,Continuous Monitoring,Continuous Monitoring,Placement of Isokinetic Probes in a Pharmaceutical Filling Area for the Purpose of Monitoring,Number of Sample Probes for Monitoring,No regulatory guidelines No requirements or advice from FS 209E, ISO 14644-1, FD
31、A Guidelines, EU GMP Annex I, etc. when conducting monitoring of the process,2. Sample near points of intervention by operators Examples: Vial turntable Filling needles Stoppering process,1. Sample near exposed product Generally at work height and near exposed product If liquid sterile fill, guidanc
32、e is to sample air approaching the product within 1 foot (12” or 30 cm) of exposed components USA,Placement of Sample Probes,3. Storage or staging areas Exposed product or component Risk of particulate deposition over time,Placement of Sample Probes,Three major determinants of risk 1. Where Product
33、or Components are vulnerable 2. Activity - Introduction of contaminants by personnel - Introduction of contaminants by process equipment - Affect on protective airflow patterns 3. Potential for Deposition over time - Where components are stored or held,Placement of Sample Probes,One last considerati
34、on: Will you do something with the data ? If you are not going to react to the data, dont sample ! Never, ever, ever “for information only” !,Placement of Sample Probes,Selecting Monitoring Positions,Presence of lyophilizers indicate vials may not be fully stoppered so the holding position near “5”
35、represents some risk Position “6” provides evaluation of Grade B zone and probably early indication of pressure balance problems due to proximity to doors Positions “7” and “8” are needed because loading area in front of lyophilizers should be Grade A if product is not fully stoppered,1,2,3,4,5,6,7,
36、8,Freeze Dryer 1,Freeze Dryer 2,Freeze Dryer 3,Vial Washing System,If this were a filling operation for which the final product remains liquid, some points would not be needed.,1,2,3,4,5,Vial Washing System,Selecting Monitoring Positions,1,3,2,Selecting Monitoring Positions,About 4 meters,Selecting
37、Monitoring Positions: RABS,Selecting Monitoring Positions: RABS,Placement of sample point, counter and tubing,Concerns: Must be able to remove Must be able to sterilize; autoclaving preferred Must not interfere with work flow Must be able to sample in area with poor flow characteristics; vertical or
38、ientation,Selecting Monitoring Positions: Isolators,Holding or Temporary Storage Area,Selecting Monitoring Positions,Monitoring Powder Fill,Section 9 of Annex 1: “For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly, e
39、xcept where justified by contaminants in the process that would damage the particle counter or present a hazard, e. g. live organisms and radiological hazards. In such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Monitoring during si
40、mulated operations should also be performed.,Interference from Product: Powder Filling,Exposed product or vials/ampoules,Unidirectional air bathing the exposed product during manufacturing,Sample probe to demonstrate air quality before filling process,Less than 305 mm,Recommendations: Powder Fill Li
41、ne,Inlet HEPA Filter,Outfeed,from,tunnel,= Position of monitoring during filling,= Positions of monitoring at rest,?,Interference from Process: Capping,Annex 1 (2009): Paragraph 120. Vial capping can be undertaken as an aseptic process using sterilised caps or as a clean process outside the aseptic
42、core. Where this latter approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped.,FDA Aseptic Guidance (2004): If stoppered
43、vials exit an aseptic processing zone or room prior to capping, appropriate assurances should be in place to safeguard the product, such as local protection until completion of the crimping step.,Stoppered vials,Grade A Unidirectional air bathing the stoppered product,Capping Machine,Interference fr
44、om Process: Capping,Isokinetic probes,Minimize turbulence Matching air flow with particle counter flow rate Different size openings for counters with different flow rates Oriented to intersect air flow,80 - 120 fpm (0.4 - 0.6 m/sec),0.1 to 3 cfm (2.83 to 80 lpm),Isokinetic probes,Optimizing Sampling
45、 of Airborne Particle Counts,EU Annex 1 2009,“The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded.,Note: Revision of EU Annex 1
46、 2003 completed, effective date of 01 March 2009,= “continuous” !,FDAs Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing,Contains Nonbinding Recommendations Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations would be of a
47、ppropriate particle quality when it has a per-cubic-meter particle count of no more than 3520 in a size range of 0.5 m and larger when counted at representative locations normally not more than 1 foot away from the work site, within the airflow, and during filling/closing operations. This level of a
48、ir cleanliness is also known as Class 100 (ISO 5). We recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is most potential risk to the exposed sterilized product, containers, and closures. The particle counting probe should be placed in an orientat
49、ion demonstrated to obtain a meaningful sample. Regular monitoring should be performed during each production shift. We recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters. From Section IV. Buildings and Facilities, Sub-part A, Critical Area Class 100 (