Regulations Concerning

Transcription

1 Regulations Concerning Airborne Particle Counting

2 Two types of activities performed with an airborne particle counter: Classification focuses primarily on the environment Particle Counting Applications Environment Monitoring focuses on process, people and the environment Process People People as a Contamination Source Shed 5 to 10 million skin cells each day 2000 to 5000 microorganisms/cm 2 on skin Filter efficiency of clothing or garment varies greatly 2

3 Classification: FS209 and ISO ISO ISO Class FED STD 209E English Metric 1 M M M3.5 1,000 M4.5 10,000 M ,000 M6.5 Classification is the process of qualifying the cleanroom environment by the number of particles using a standard method Determine classification i 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 sample 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 9 Classification is a standardized method 3

4 Environmental Monitoring Determine stability of room or zone over time; develop trend data Executed on a scheduled basis: daily, weekly, monthly 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 provide meaningful trend information Not controlled by regulation but need for trend information 4

5 Determine readiness of room to carry out designated task Performed whenever relevant activity occurs daily work Minimum number of sample points defined by QA Area of cleanroom or clean zone Activity Risk to product Process Monitoring Frequency and volume of sample points defined by QA Frequent enough to show control Frequent enough to manage financial risk of product contamination Not determined d by regulation but by risk! 5

6 Differences Classification Monitoring Frequency 6 months or annual Daily, weekly, monthly or continuous Number of positions By formula By need for data Sample volume By formula By need for data Pass/Fail criteria By table By need for trend info or control Reporting format By standard In form needed for rapid understanding 6

7 Differences Distribution of counts in a room or zone Classification Uniform or homogenous Monitoring Unique at each sample position 7

8 Classification 8

9 Classification Standards for Airborne Particles General Air Monitoring Standards before

10 Classification Standards for Airborne Particles General Air Monitoring Standards 1999 ISO Classification of air cleanliness ISO Specifications for testing and monitoring to prove continued compliance with ISO ISO Guidance on instrumentation to be used for testing for compliance with ISO ISO

11 Electronics Semiconductor Flat Panel Circuit Board Optical MEMS/Nanomachines Life Sciences Pharmaceutical Biotechnology Medical Devices Hospitals/Pharmacies Aerospace Launch Vehicles Satellites Commercial/Military Aircraft Laboratories Analytical Laboratories Universities Other Nuclear Photographic, X-ray films Automobile Painting Laboratory Aerospace General Standard d for all Industries Other Electronics Life Sciences 11

12 ISO ISO consists of the following parts, under the general title Cleanrooms and associated controlled environments: Part 1: Classification of air cleanliness by particle concentration Part 2: Monitoring to provide evidence of cleanroom performance by airborne particle cleanliness. Part 3: Test methods Part 4: Design, construction and start-up Part 5: Operations Part 6: Vocabulary Part 7: Separative devices (clean air hoods, gloveboxes, isolators, and minienvironments) Part 8: Classification of airborne molecular contamination Part 9: Classification of surface cleanliness by particle concentration Part 10: Classification of surface cleanliness by chemical concentration 12

13 Classification Standard: ISO : Defines cleanroom classes in a zone Establishes minimum sampling volumes Purpose: Gather a sample volume with theoretically at least 20 particles for a statistically valid sample Establishes minimum number of points to classify area, based on statistical criteria Gather from a valid number of locations for a representative sample of the total air volume 13

14 Classification Standard: ISO : Limitsit Class Number of fparticles per Cubic Meter by Micrometer Size 0.1 m 0.2 m 0.3 m 0.5 m 1 m 5 m ISO ISO ISO 3 1, ISO 4 10,000 2,370 1, FS 209E Class 100 ISO 5 100,000 23,700 10,200 3, ISO 6 1,000, , , ,200 8, ISO 7 352,000 83,200 2,930 ISO 8 3,520, ,000 29,300 ISO 9 35,200,000 8,320, ,000 14

15 Classification Standard: ISO : Minimum sample volume 2.0 liter Minimum sample time 1 minute Minimum number of locations 1 with at least 3 samples total Note: Typical sample volume may be larger than minimum listed above especially for smaller size particles in very clean areas (better than ISO Class 5 or FS 209E Class 100) 15

16 Classification Standard: ISO : Minimum Sample Volume (in liters) ISO Class 5, 0.5 microns = (20/3520) x 1000 = 5.6 liters ISO Class 5, 5 microns = (20/29) x 1000 = 690 liters 16

17 ISO :2000 Continued compliance (re-qualification) Schedule of Tests to Demonstrate Continuing Compliance Test Parameter Class Maximum Time Interval Test Procedure Particle Count Test ISO 5 ISO 6, 7, 8, 9 6 Months 12 Months ISO Annex A Air Pressure Difference All Classes 12 Months ISO Annex B5 Airflow All Classes 12 Months ISO Annex B4 17

18 Example ISO Calculations l Vial Washing System 5 m Freeze Dryer 1 8 m Freeze Dryer 2 Calculations for Number of Points: Area of clean zone = 80 m² Take the SQRT (80) = 8.94 Rounding up to next integer = 9 sample positions 5 m Freeze Dryer 3 4 m 18

19 Example ISO Calculations l Vial Washing System Freeze Dryer 1 7 Freeze Dryer 2 Calculations for Number of Points: Area of clean zone = 80 m² Take the SQRT (80) = 8.94 Rounding up to next integer = 9 sample positions 8 9 Freeze Dryer 3 19

20 Example ISO Calculations l Vial Washing System Freeze Dryer 1 Need to adjust for equipment in room. Under ISO , if you sample at 10 or more positions, you can avoid the added d calculation l of the UCL (Upper Confidence Limit). Calculation of the UCL is only mandated when the number of positions used is between 2 and 9. Best to sample near potential problem spots which are near entrances and exits and near operator positions. Freeze Dryer 2 Freeze Dryer 3 20

21 Example ISO Calculations l Vial Washing System Freeze Dryer Need to adjust for equipment in room. 12 Freeze Dryer 2 Under ISO , if you sample at 10 or more positions, you can avoid the added calculation of the UCL (Upper Confidence Limit). Calculation of the UCL is only mandated when the number of positions used is between 2 and 9. Best to sample near potential problem spots which are near entrances and exits and near operator positions Freeze Dryer 3 21

22 Example ISO Calculations l 1. Average the sample data values at each position 2. Normalize the average to number of particles per cubic meter 3. Compare normalized value to the target class limit; normalized value at each and every sample point must be less than the limit for the given size and target room classification If the number of points sampled is more than 1 but less than 10, then the UCL factor must be applied: a) Calculate the standard deviation b) Use Student s T-factor from tables c) Calculate UCL d) Compare to classification limit; UCL must not exceed the applicable limit 22

23 Probable Revisions to ISO , -2 23

24 Revision committee has met in Zurich in the beginning of September 2012; by WEBEX in July 2013: in Reno October 2013 Revision process still ongoing Revisions to ISO :1999, 1: :2000 Likely to be end of 2013 before new draft(s) submitted for vote, vote is recorded, If draft is accepted, then effective late

25 Forthcoming Revisions to ISO Frequency of re-certification for continued compliance : Now: If zone is ISO Class 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 Or: 1 year if not monitoring!! 25

26 Forthcoming Revisions to ISO Eliminate calculation of UCL (Student s T test) for sample plans with 2 to 9 sample positions 26

27 Forthcoming Revisions to ISO Method of determining minimum 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 27

28 A Derive the minimum number of sampling locations N L 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 t area does not exceed the class limit. Different levels of confidence and verification can be specified and agreed upon by the customer and supplier. 28

29 Forthcoming Revisions to ISO Remove possibility to classify at 5 micron only for ISO Class 5 Limit number of 29 removed Replace number with Note (e) : Sample collection limitations for both particles in low concentrations and sizes greater than 1 um make classification inappropriate, p due to potential particle losses in the sampling system. 29

30 Forthcoming Revisions to ISO Indicate that single digit limits for ISO Class 1 and 2 create challenges to timely execution Replace number values with Note (b) : These concentrations will lead to large air sample volumes for classification. Sequential sampling procedure may be applied; see Annex D. 30

31 6. New label for classification level Forthcoming Revisions to ISO , 1-2 ACP = Air Cleanliness (by) Particles ACC = Air cleanliness (by) Chemicals SCP = Surface Cleanliness (by) Particles SCC = Surface Cleanliness (by) Chemicals 31

32 Cleanroom Designations Air Surfaces Particles ACP SCP ISO , - 2 Draft #2 of Revision ISO Chemicals ACC SCC ISO ISO

33 Classification Limits: ISO :1999 Number of Particles per Cubic Meter by Micrometer Size 0.1 m 0.2 m 0.3 m 0.5 m 1 m 5 m ISO Class ISO Class ISO Class 3 1, ISO Class 4 10,000 2,370 1, FS 209E Class 100 ISO Class 5 100,000 23,700 10,200 3, ISO Class 6 1,000,000, 237, ,000 35,200 8, ISO Class 7 352,000 83,200 2,930 ISO Class 8 3,520, ,000 29,300 ISO Class 9 35,200,000 8,320, ,000 33

34 Proposed new limits and labels: Classification Limits: ISO (2014) Number of Particles per Cubic Meter by Micrometer Size ISO-ACP 0.1 m 0.2 m 0.3 m 0.5 m 1 m 5 m , ,000 2,370 1, FS 209E Class ,000 23,700 10,200 3, ,000, , ,000 35,200 8, ,000 83,200 2, ,520, ,000 29, ,200,000, 8,320,000, 293,000 34

35 Forthcoming Revisions to ISO , Calibration of Instruments to ISO Part of Appendix A (Normative): A Instrument calibration i The instrument shall have a valid calibration certificate; the frequency and method of calibration should be based on current accepted practice as specified in ISO : Also will be added to Bibliography: ISO :2007 Determination of particle size distribution Single particle light interaction methods-part 4: Light scattering airborne particle counter for clean spaces. 35

36 Probable Revisions to ISO New Title for Section: Cleanrooms and associated controlled environments Part 2: Monitoring to provide evidence of performance by ACP Focus of will be on methods covering monitoring i of particles and key supporting parameters

37 Probable Revisions to ISO Introduction ti "This revision i of ISO reflects a philosophical shift that emphasizes monitoring i over classification." 37

38 Probable Revisions to ISO Introduction ti "This revision i of ISO reflects a philosophical shift that emphasizes monitoring over classification. The monitoring process provides a continuing flow of data over time, offering a greater assurance of the performance of the installation." 38

39 Probable Revisions to ISO "Potential benefits gained from more substantial monitoring are: Introduction ti Faster response to adverse conditions Ability to Trend data over time Additional parameters in conjunction with airborne counts Integration of data from multiple instruments Enhanced knowledge of installation and process allows more effective risk analysis Reduction in operation costs and product losses" 39

40 Probable Revisions to ISO Introduction ti "ISO specifies requirements of a monitoring plan, based on a risk assessment of the intended use. The data obtained provides evidence over time of continuing cleanroom or clean zone performance related to airborne cleanliness by particles (ACP). In some circumstances, relevant regulatory agencies may impose supplementary policies or restrictions. In such situations, appropriate adaptations of the monitoring procedures may be required." 40

41 Probable Revisions to ISO Introduction ti "The level of airborne particles measured under a monitoring plan may typically be higher than the level observed during the at-rest classification process. The observed values may fluctuate considerably due to factors such as, but not limited to, the number of personnel present, the rate of air flow or exchange, the operation of instruments or machinery, and activities in adjacent spaces. " 41

42 Probable Revisions to ISO Introduction ti "In processes that inherently produce particles as part of the process and where these particles are not a threat to the process or product, it may be appropriate to rely on periodic at-rest classification rather than monitoring of airborne particles in operation. Other performance and cleanliness attributes may still be required to be monitored. After a monitoring plan is initially established, it may be necessary to revise the plan when significant changes are made to the installation or process requirements. It is also prudent to conduct periodic reviews of a monitoring plan based on data obtained. " 42

43 Introduction Probable Revisions to ISO Table of contents t 1 Scope 2 Normative references 3 Terms and definitions 4 Creating, executing and maintaining a monitoring plan 4.1 Principle 4.2 Risk Analysis 4.3 Monitoring plan 4.4 Review and approval 4.5 Analyzing Data 5 Periodic classification 43

44 Annex A (informative) Probable Revisions to ISO Table of contents t Matters to consider when developing a monitoring plan A.1 General Considerations A.2 Pressure differential monitoring A.3 Airborne particle monitoring system A.4 Airflow velocity and volume monitoring Annex B (informative) Matters to consider when setting Warning levels B.1 Setting levels B.2 Considerations in setting Warning levels for Pressure Differential B.3 Consideration in setting Warning levels for Airborne Particle Counts 44

45 Monitoring - Environmental - Process 45

46 Environmental Monitoring Understanding stability of particulate levels through trends Samples taken daily, weekly or monthly No requirement to monitor as many points as needed for classification No requirement to sample 1 cubic meter Consider using viable sample points as guidance in choosing gpositions and number of sample points in an area 46

47 Process Monitoring In operation or dynamic only Relates to process and product quality Data may be needed for product release Often included with Batch Record Average only count data from same location Each point must be below limit But not necessarily each sample May be OK to delay ALERT or ACTION until 3rd or 5th consecutive high reading Information is about sample point not zone 47

48 No clear guidance from standards or regulation Number of sample points Positions of sample points Cleanroom Monitoring It is necessary to consider the purpose of monitoring within the specific manufacturing context. Assess the potential for product exposure Consider possible contaminants created by process Impact to product Impact to operators 48

49 Cleanroom Monitoring However two guidances are offered: US FDA Guidance for Industry: - Sterile Drug Products Produced by Aseptic Processing EU UGMP Annex 1 - Manufacture of Sterile Medicinal Products 49

50 FDA s Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Initial release: June 1987 New Revision: September 2004 Restates count values in metric format Cubic foot cubic meter 1 cubic meter = cubic feet Refers to ISO Class 100 > ISO Class 5 Limit restated 3520 counts/m³ for counts 0.5 μm and larger 50

51 Focus on potential ti product exposure FDA s Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Defines two zones Critical (similar to Grade A) Controlled (similar to Grade C or D support areas) Monitor at 0.5 microns Sample point location Not more than 1 foot away from the work site, within the airflow, and during filling/closing operations 51

52 Guidances for Aseptic Processing Pharmaceutical Industry Compliance Guidance FDA cgmp Guidance for Industry Sterile Drug Products Produced by Aseptic Processing EU GMP Annex I (EMEA) Manufacture of Sterile Medicinal Products EU GMP Annex 1 is more specific than FDA cgmp Guidance 52

53 Guidances for Aseptic Processing 53

54 Guidances for Aseptic Processing 54

55 PIC/S Guidance 7. ENVIRONMENTAL AND PERSONNEL MONITORING Annex I of the EU/PIC/S Guide to GMP provides the basis for environmental and personnel monitoring requirements and recommendations. Some specific additional guidance is given below on air borne microbial and non-viable particle monitoring, intervention monitoring and staff training. 55

56 PIC/S Guidance 7.1 Air Borne Microbial and Non-Viable Particle Monitoring It is important to state that the monitoring activity itself should not compromise the product quality. Worst case scenarios of simulations tests should also include monitoring activities. 56

57 PIC/S Guidance 7.2 Non-viable monitoring The location chosen for monitoring should be checked to ensure that the positions reflect the worst case. For room monitoring, the counts should be performed in locations where there is most operator activity. For the filling environment the counts should be performed adjacent to the filling zone and where components are exposed in such way as to detect operator activity within these areas. 57

58 PIC/S Guidance 7.2 Non-viable monitoring (continued) Monitoring with sampling probes located in such a way that they monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones should be avoided. However the location of the sample device should not compromise the laminarity of the air flow in the critical i zone. Initial i validation i should be checked to confirm that worst case positions have been adequately identified. These may be reconfirmed during process simulation tests. 58

59 EU Annex 1: Latest t revision i (2009) Classification Sections 4 through 7 Monitoring Sections 8 through 17 59

60 EU Annex 1 Summary: Classification Classification Sections 4 through 7 Section 4: Classification should be clearly differentiated from operational process environmental monitoring. Section 5: For classification purposes p in Grade A zones, a minimum sample volume of 1 m 3 should be taken per sample position. 60

61 EU Grade Definitions at rest in operation maximum permitted number of particles/m3 equal to or above Grade Activity 0.5 m 5 m 0.5 m 5 m A High Risk - filling, open vials, stopper bowls B Aseptic preparations C Clean area of less critical operations D Clean area of less critical operations not defined not defined Zone grades according to risk of product contamination Particle count measurements at 0.5 m and 5 m At rest vs In operation 61

62 EU Annex 1: Latest revision i (2009) Limits at 5 microns for Grade A 1 per cubic meter 20 per cubic meter At Rest In Operation Grade Maximum permitted number of particles/m 3 equal to or greater than the tabulated size 0.5 µm 5 µm 0.5 µm 5 µm A B C D not td defined d not td defined d 62

63 EU Annex 1 Summary: Classification Section 5: For classification purposes p EN/ISO methodology defines both the minimum number of sample locations and the [minimum] sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected. 63

64 Section 5 (continued) EU Annex 1 Summary: Classification For classification purposes EN/ISO methodology defines both the minimum number of sample locations and the [minimum] sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected. Number of locations Sample Volume (B,C,D) Currently based on SQRT of Area (M^2) Proposed Based on lookup table 64

65 Monitoring: Sections 8 through 17 EU Annex 1 Summary: Monitoring Section 8: Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean devices 65

66 Section 9 EU Annex 1 Summary: Monitoring 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. = continuous!!! 66

67 Section 12: EU Annex 1 Summary: Monitoring The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices. It is not necessary to sample 1m 3 during verification or monitoring Particle counters used for monitoring may have the same or different flow rate from those used for classification. 67

68 Monitoring Positions: Risk-based Approach 4 Vial Sterilizing Tunnel 1 5 Lyo Monitoring must follow the workflow, covering areas where product is exposed Annex 1 (2009) Where open vials exit de-pyrogenation human interaction (1) Where vials are filled (2,3) Surrounding Grade B background (4) Where the vials are partially stoppered (5) Loading area in front of lyophilizers must be Grade A if product is not fully stoppered (6,7) 6 Lyo 2 Lyo 3 68

69 Monitoring Positions: Risk-based Approach Vial Washing System In a filling operation for which the final product remains liquid, some points established for a lyophilized product would not be needed. 69

70 ISO 14644, ISO and EU GMP Annex 1 Sampling of Airborne Particle Counts In Aseptic Manufacturing Process 70

71 Air Particle Counter Calibration ISO and ISO the link to GMP Regulators inspect to EU GMP, which calls up ISO Next revision ISO will refer to ISO ISO states Instruments that conform to this part of ISO are used for the classification of air cleanliness in cleanrooms and associated controlled environments in accordance with ISO

72 A.2.2 Airborne particle counter calibration Proposed wording in -1, -2 The airborne particle counter shall have a valid calibration certificate; the frequency and method of calibration should be based on current accepted practice as specified in ISO :2007. NOTE: Some airborne particle counters cannot be calibrated to all of the required tests in ISO :

73 ISO : Additional Tests Before ISO Size calibration ISO Size calibration Verification of size setting Counting efficiency Size resolution False count rate False count rate Concentration limit Sampling Flow Rate Sampling flow rate Sampling Time Sampling time Sampling volume 73

74 ISO Calibration Standard Delivers: Improved compliance Removes ambiguity by providing a single internationally recognized standard method for calibration Harmonization between ISO and GMP guidance Improved unit-to-unit t reproducibility Improved counting accuracy All current Met One particle counters from Hach may be calibrated using ISO at your facility 74

75 ISO What to look for on the calibration certificate 75

76 ISO What to look for on the calibration certificate 76

77 ISO What to look for on the calibration certificate Hach certifies that the calibration performed complies with the requirements of ISO

78 First particle counters designed for ISO compliance Online and Portable Particle Counters MET ONE 6015P Grade A & B automated monitoring Internal vacuum pump MET ONE 3400 Cleanroom classification to ISO14644 Portable sampling for environmental validation MET ONE 6000 MET ONE 7000 Grade A & B automated monitoring Grade A & B automated monitoring Small and compact Sealed enclosure for wash down Automatic vacuum control 78 78

79 ADDITIONAL INFORMATION 79

80 Audit your Methods and Equipment Training Standard Operating Procedures (SOPs) Validation (IQ/OQ) Calibration Policies Equipment Upgrade as needed Audit your Calibration Service Factory-trained and authorized Correct equipment and standards Road Map to ISO compliance 80

81 Thank you! Presented by Grants Pass, Oregon USA Joe Gecsey HACH Life Science Applications 81

82 Regulations Concerning Airborne Particle Counting