Regulations Concerning
Particle Counting Two types of activities performed with an airborne particle counter:
Classification focuses primarily on the environment Monitoring focuses on process, people and the environment Process
People
Peop ople le as as a Cont Contaminatio amination n Source Sour ce 2000 2000 to 5000 5000 micr oor ganisms /cm2 on skin Filter Filter efficiency of clothing or garment garment varies greatly
2
Classification:
ISO 14644-1 ISO Class
FED STD 209E En g l i s h
Me t r i c
1 2 3
1 M1.5
Classification 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”
4
10 M2.5
5
100 10 0 M3.5
6
1,000 M4.5
7
10,000 M5.5
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
8 9
100,000 M6.5
Classification is a standardize standardized d method 3
Environmental Monitoring Determine stability of room or zone over time; develop trend data ,
,
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 show control – Frequent enough to provide provide meaningful trend information
Not controlled by regulation…but need for trend information 4
Process Monitoring Determine readiness of room to carry out designated task – Minimum number of sample points defined by QA rea o c eanroom or c ean zone Activity Risk to product Frequency and volume of sample points defined by QA requen enoug
o s ow con ro
Frequent enough to manage financial risk of product
Not determined by regulation…but by risk! 5
Differences Classification
Monitoring
Frequency
6 months or annual
Daily, weekly, monthly or continuous
Sample volume
By formula
By need for data
Pass/Fail criteria
By table
By need for trend info
Reporting format
By standard
In form needed for rapid understanding
6
Differences
Distribution of counts in a room or zone
Classification
Monitoring
Uniform or homogenous
Unique at each sample position
7
Classification
8
Classification Standards for Airborne Particles General neral Air Monitor oni toring ing Standards tandards – befor before e 1999
9
Classification Standards for Airborne Particles General neral Air Monitor oni toring ing Standards tandards –
ISO 14644-1 •
–
Clas Cl assi sifi fica cati tion on of air cl clean eanli lines ness s
ISO 14644-2 • Spec Specif ific icat atio ions ns for for tes testi ting ng and and monitoring to prove continued compliance with ISO 14644-1
–
1999
ISO 14644-3 • Guid Guidan ance ce on on inst instru rume ment ntat atio ion n to be used for testing for compliance with ISO 14644-1
ISO 14644
10
en er a an ar for all Industries Indust ries Electronics • Semic miconductor tor • Flat Panel • Circ ircuit uit Boa Boarrd • Optical • MEMS MEMS/N /Nan anom omac achi hine nes s Life Sciences • Phar Pharma mace ceut utic ical al • Biot Biotec echn hnol olog ogy y • Medi Medica call Devi Device ces s • Hosp Hospit ital als/ s/Ph Phar arma maci cies es Aeros Aer ospac pace e • Laun Launch ch Vehi Vehicl cles es • Satellites • Comme Commerc rcial ial/Mi /Milit litary ary Aircr Aircraf aftt Laboratories • Analy Analytic tical al Labo Laborat ratori ories es • Unive iversiti sitie es Other • Nuclear • Photo Photogra graph phic, ic, X-ray X-ray films films • Auto Automo mobi bile le Pain Painti ting ng
Other Laboratory
Electronics
Aer ospac osp acee
Life Sciences
11
ISO 14644 ISO 14644 consists of the following parts, under the general title Cleanrooms
Part 1: Classification of air cleanliness by particle concentration particle cleanliness. Part 3: Test methods ,
-
Part 5: Operations Part 6: Vocabulary ,
,
,
-
environments) Part 8: Classification of airborne molecular contamination Part 10: Classification of surface cleanliness by chemical concentration 12
Classification Standard: - :
• Establishes minimum sam lin 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
Classification Standard: - : m ts ass
um er o 0.1 m
FS 209E Class 100
ar c es per
0.2 m
0.3 m
u c
e er y
0.5 m
crome er 1 m
5 m
10
2
ISO 2
100
24
10
4
ISO 3
1,000
237
102
35
8
ISO 4
10,000
2,370
1,020
352
83
ISO 5
100,000
23,700
10,200
3,520
832
,
,
,
29
,
,
ISO 7
352,000
83,200
2,930
ISO 8
3,520,000
832,000
29,300
35,200,000 8,320,000
293,000
ISO 9
,
ze
14
Classification Standard: - :
Minimum sample volume
2.0 liter
Minimum sample time
1 minute
Minimum number of locations
1 with at least 3 samples total
Note: Typi cal sample volume may be larger than min imum list ed abov e especially f or s maller s ize particles i n very clean areas (better than ISO Class 5 or FS 209E Class 100) 15
Classification Standard: - : n mum (in liters)
amp e o ume
ISO Class 5, 0.5 microns = (20/3520) x 1000 = 5.6 liters , 16
ISO 14644-2:2000 (re-qualification) Schedule of Tests to Demonstrate Continu ing Comp liance Maximum Time Interval Particle Count Test
≤ ISO
5
6 Months
ISO 6, 7, 8, 9
12 Months
Air Pressure Difference
Airflow
ISO 14644-1 Annex A ISO 14644-1 Annex B5
All Classes
12 Months
ISO 14644-1 nnex 17
Example Vial Washing System
Freeze Dryer 1
5m
Freeze Dryer 2
8m
Calcul ations for Number of Points:
a cu a ons
5m
Freeze Dryer 3
Area of clean zon e = 80 m² Take t he SQRT (80) = 8.94 Ro un di n u t o n ex t i nt e er = 9 s am l e o si ti on s 4m
18
Example -
a cu a ons
Vial Washing
Freeze Dryer 1 1
2
3
4
5
6
7
Freeze Dryer 2 Calcul ations for Number of Points:
8
Take the SQRT (80) = 8.94 Rounding u p to next integer = 9 sample positi ons 9
Freeze Dryer 3
19
Example 1
2
Vial Washing
3
4
5
6
a cu a ons 7
8
9
10
Freeze Dryer 1
reeze Dryer 2 • Need to adjust f or equipment in r oom. • Under ISO 14644-1, if you sampl e at 10 or mo re pos ons, you can avo e a e ca c u a on o the UCL (Upper Confidence Limit). Calcul ation of the UCL is on ly m andated when the number of posit ions used is between 2 and 9. • Best to sample near potential problem spots w hich are near entrances and exits and near operator positions.
Freeze Dryer 3
20
Example -
a cu a ons
9
Vial Washing System
1 10 8
Freeze Dryer 1
11 3
4
5
6
7
Freeze Dryer 2 • Need to adjust f or equipment in ro om. • Under ISO 14644-1, if you sampl e at 10 or mo re posit ions, you can avoid the added calculation of the UCL (Upper Confidence Lim it). Calcu latio n of the UCL is on ly mandated when the number of posit ions used is between 2 and 9. • Best to sample near potential problem sp ots which are near entrances and exits and near operator positions.
13
14
Freeze Dryer 3
21
Example -
a cu a ons
1.
Avera e the sam le data values at each
osition
2.
Normalize the average to “ number of particles per cubic meter”
3.
Compare normalized value to the target class limit; normalized limit for the given size and target room classification
e num er o po n s samp e s more then the UCL factor must be applied:
an
u ess
an
,
a) Calculate the standard deviation ’
-
c) Calculate UCL d) Compare to classification limit; UCL must
22
Probable Revisions to ISO 14644-1, -2
23
Revisions to , 14644-2:2000 Revision committee has met in Zurich in the beginning of September 2012; y
n uy
:
in Reno October 2013
• Likely to be end of 2013 before new draft(s) , , • If draft is accepted, then effective late 2014 24
Forthcoming Revisions to 1. Fre uenc 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 eriod • Re-certification timeframe will be set by regulatory or advisory committees for a particular industry • 25
Forthcoming Revisions to -
2. Eliminate calculation of UCL (Student’s T test) for sample plans with 2 to 9 sample positions
26
Forthcoming Revisions to . sample positions – 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 pons
27
A.4.1.1
Derive the minimum number of sampling locations NL from table 3. Table A.1 shows the number of sample locations related to the zone to be classified and provides at least 95% confidence that at eas
o
e o a area oes
not exceed the class limit.
verification can be specified and agreed upon by the customer and supplier. 28
Forthcoming Revisions to . 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 ina ro riate due to otential article losses in the sampling system.” 29
Forthcoming Revisions to . ISO Class 1 and 2 create challenges to timel execution
epace num er vaues w
oe
:
volumes for classification. Sequential sampling procedure may be applied; see Annex D.
30
Forthcoming Revisions to - ,. ACP = Air Cleanliness (by) Particles ACC = Air cleanliness (by) Chemicals SCP = Surface Cleanliness (by) Particles
31
Cleanroom Designations
Particles
Air
Surfaces
ACP
SCP
ISO 14644 - 1, - 2
ISO 14644 – 9
Draft #2 of Revision
Chemicals
ACC –
SCC –
32
Classification Limits: ISO 14644-1:1999 Number of Particles er Cubic Meter b Micrometer Size 0.1 m
FS 209E Class 100
0.2 m
0.3 m
0.5 m
1 m
5 m
ISO Class 1
10
2
ISO Class 2
100
24
10
4
ISO Class 3
1,000
237
102
35
8
ISO Class 4
10,000
2,370
1,020
352
83
ISO Class 5
100,000
23,700
10,200
3,520
832
29
ISO Class 6
1 000 000
237 000
102 000
35 200
8 320
293
ISO Class 7
352,000
83,200
2,930
ISO Class 8
3,520,000
832,000
29,300
35,200,000 8,320,000
293,000
ISO Class 9
33
Pro osed new limits and labels: Classification Limits: ISO 14644-1 (2014) Numb er of Particles per Cubic Meter by Micro meter Size ISO-ACP
0.1 m
0.2 m
0.3 m
0.5 m
1 m
5 m
10
FS 209E Class 100
2
100
24
10
3
1,000
237
102
35
4
10,000
2,370
1,020
352
83
5
100,000
23,700
10,200
3,520
832
6
1,000,000
237,000
102,000
35,200
8,320
293
7
352,000
83,200
2,930
8
3,520,000
832,000
29,300
35,200,000 8,320,000
293,000
9
34
Forthcoming Revisions to - ,7. Calibration of Instruments to ISO 21501-4 7.1 Part of Appendix A (Normative):
A.2.2 Instrument calibration The instrument shall have a valid calibration certificate; the fre uenc and method of calibration should be based on current accepted practice as specified in ISO 21501-4:2007 . 7.2 Also will be added to Bibliography: ISO 21501-4:2007 Determination of particle size distribution – Single counter for clean spaces. 35
Probable Revisions to New Title for Section:
Cleanrooms and associated controlled — provide evidence of performance by ACP
Focus of 14644-2 will be on methods covering mon or ng o par c es an ey suppor ng parame ers
Probable Revisions to ISO 14644-2
n ro uc on s rev s on o - re ects a philosophical shift that emphasizes mon tor ng over c ass cat on.
37
Probable Revisions to ISO 14644-2
n ro uc on s rev s on o philosophical shift
that .
re ec s a emphasizes
flow of data over time, offering a greater installation."
38
Probable Revisions to ISO 14644-2
n ro uc on "Potential benefits gained from more substantial monitoring are: – – 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
Probable Revisions to ISO 14644-2
n ro uc on "ISO 14644-2 specifies requirements of a monitoring plan, based on a risk assessment of the intended use. The data obtained provides evidence over time of continuing cleanliness by particles (ACP). In some circumstances, relevant regulatory agencies may impose supplementary policies or restrictions. In such , procedures may be required."
40
Probable Revisions to ISO 14644-2
n ro uc on "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 ."
41
Probable Revisions to ISO 14644-2
n ro uc on "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 airborne particles in operation. Other performance and cleanliness attributes may still be required to be . After a monitoring plan is initially established, it may be necessar to revise the lan when si nificant chan es are made to the installation or process requirements. It is also prudent to conduct periodic reviews of a monitoring ." 42
Probable Revisions to ISO 14644-2
a e o con en s Introduction 1
Scope
2
Normative references
3
Terms and definitions
4
Creating, executing and maintaining a monitoring plan
4.1
Principle
. 4.3
Monitoring plan
4.4
Review and approval
4.5
Analyzing Data
5
Periodic classification
43
Probable Revisions to ISO 14644-2
a e o con en s Annex A (informative) Matters to consider when developing a monitori ng 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 Pressur e Differential B.3 Consideration in setting Warning levels for Airb orne Particle Counts
44
Monitoring - Environmental - Process
45
Environmental 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 choosin ositions and number of sam le oints in an area 46
Process In operation or dynamic only Relates to process and product quality
Often incl uded with Batch Record
– Each point must be below limit – But not necessarily each sample –
ay e to e ay consecutive high reading
or
unt
r or t
– Information is about sample point not zone
47
Cleanroom No clear guidance from standards or regulation –
um er o samp e po n s
–
Positions of sample points
It is necessary to consider the purpose of monitoring within the specific manufacturing context. – –
Consider possible contaminants created by process – Impact to product –
48
Cleanroom However two guidances are offered: US FDA Guidance for Industry: EU GMP Annex 1 - Manufacture of Sterile Medicinal Products
49
FDA’s Guidance for Industry: Sterile Dru Products Produced by Aseptic Processing Initial release: Jun e 1987 New Revision: September 2004 Restates count values in metric format – – 1 cubic meter = 35.31 cubic feet
– Class 100 > ISO Class 5 – Limit restated ³
.
50
FDA’s Guidance for Industry: Sterile Dru Products Produced by Aseptic Processing ocus on po en a pro uc exposure 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
Guidances for Pharmaceutical Industry
– FDA cGMP Guidance for Industry • Sterile Drug Products Produced by Aseptic Processing – EU GMP Annex I (EMEA) • Manufacture of Sterile
EU GMP Annex 1 is more specific than FDA cGMP Guidance 52
Guidances for
53
Guidances for
54
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 . Some specific additional guidance is given below on air borne microbial and non-viable particle monitoring, intervention monitoring and staff training.
55
PIC/S Guidance 7.1 Air Borne Microbial and Non-Viable Particle Monitoring 7.1.1 It is important to state that the monitoring activity itself . scenarios of simulations tests should also include monitoring activities.
56
PIC/S Guidance 7.2 Non-viable monitoring 7.2.1 The location chosen for monitoring should be checked to ensure that the positions reflect the worst case. For , 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
PIC/S Guidance 7.2 Non-viable monitoring 7.2.1 (continued) Monitoring with sampling probes located in such a way that they monitor the air from the HEPA critical zones should be avoided. However the location of the sample device should not compromise the laminarity of the air flow in the critical zone. Initial validation should be checked to confirm that worst case positions have been ade uatel identified. These ma be reconfirmed during process simulation tests.
58
EU Annex 1: atest rev s on Classification – Sections 4 through 7
– Sections 8 through 17
59
EU Annex 1 Summary: ass ca on
Section 4: “Classification should be clearly differentiated from operational process environmental monitoring.” Section 5: “ For classification purposes in Grade A zones, a minimum sample volume of 1 m3 should be taken per sample position.
60
EU Grade Definitions
at rest in operation maximum permitted number of particles/m3 equal to o r above Grade A B C D
Activity High Risk - filling, open vials, stopper bowls Aseptic preparations Clean area of less critical operations Clean area of less critical operations
0.5 m 3 520 3 520 352 000 3 520 000
5 m 20 29 2 000 20 000
0.5 m 3 520 352 000 3 520 000 not defined
5 m 20 2 000 20 000 not defined
• • Particle count measurements at 0.5 m and 5 m • “
”
“
”
61
EU Annex 1: atest rev s on Limits at 5 microns for Grade A 1 per cubic meter 20 per cubic meter
3
Maximum permitted permitted number number of partic les/m 3 Maximum particles/m equal to to or or greater greater than than the the tabulated equal tabulated size size
Grade 0.5 µm µm 0.5
5 µm µm 5
0.5 µm µm 0.5
5 µm µm 5
A A
3 500 520 3
20 1
3 500 520 3
20 1
B
3 500 520
29 1
352 000 350
900 22 000
C
352 000 350
900 2 000
520 000 000 3 500
29 000 000 20
no
e ne
no
e ne 62
EU Annex 1 Summary: Classification
“For classification ur oses EN/ISO 14644-1 methodolo defines both the minimum number of sample locations and the [minimum] sample size based on the class limit evaluation of the data collected.”
63
EU Annex 1 Summary: Classification Section 5 (continued) or c ass ca on purposes - me o o ogy 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 loc ation s
Sample Volume (B,C,D)
• Currently based on SQRT of Area (M^2) • Proposed – Based on lookup table
64
EU Annex 1 Summary:
Monitoring: Sections 8 through 17 Section 8: “Clean rooms and clean air devices should be routinel monitored in operation and the monitoring locations based on – and – the results obtained during the classification of rooms and/or c ean ev ces
65
EU Annex 1 Summary:
Section 9 • “The Grade A zone should be monitored at such a frequency and with suitable sample size that all , deterioration would be captured and alarms triggered if alert limits are exceeded.
= “continuous” !!!
66
EU Annex 1 Summary:
Section 12: • “The sample sizes taken for monitoring purposes using automated systems will usually be a function of the . 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 1m3 during verification or monitoring • Particle counters used for monitoring may have the same or different flow rate from those used for . 67
Monitoring Positions: Risk-based Approach 4
Vial Sterilizing
Lyo 1
1 5
7 2
3
Lyo 2 •
Monitori ng mu st foll ow the work flow, covering areas where product is exposed – Annex 1 (2009) −
Where open vials exit de-pyrogenation – human interaction (1)
−
Where vials are fil led (2,3)
−
Surroundin g Grade B backgro und (4)
─ Where the vials are partially stoppered (5)
6
Lyo 3
─ Loadin
area in front of l o hilizers must be Grade A if produc t is not f ully s toppered (6,7)
68
Monitoring Positions: Risk-based Approach 4
Vial Washing System
1
2
3
In a fill ing o peration f or whi ch the final produc t remains li quid, some produ ct wou ld not be needed.
69
, an EU GMP Annex 1 Sampling of Airborne Particle Counts n sep c
anu ac ur ng
rocess
70
Air Particle Counter Calibration •
Regulators inspect to EU GMP, which
•
Next revision ISO 14644 will refer to ISO 21501-4
•
ISO 21501-4 states – “Instruments that conform to this part of ISO 21501 are used for the classification of air cleanliness in cleanrooms and associated controlled environments in accordance with ISO 14644-1”
71
- , A.2.2 Airborne particle counter calibration The airborne particle counter shall have a valid calibration certificate; the frequency and method of calibration should 21501-4:2007 . NOTE: Some airborne particle counters cannot be calibrated to all of the required tests in ISO 21501-4:2007.
72
ISO 21501-4: Additional Tests Before ISO 21501-4 •
ze ca
ra on
ISO 21501-4 •
ze ca
ra on
• Verification of size setting • Size resolution • False count rate
• False count rate • Concentration limit
• Sampling Flow Rate
• Sampling flow rate
• Sampling Time
• Sampling time • Sampling volume
73
ISO 21501-4 Calibration Standard Delivers: • Improved compliance – Removes ambiguity by providing a single internationally – Harmonization between ISO and GMP guidance
• Improved unit-to-unit reproducibility
All current Met One particle counters from Hach may be calibrated using ISO 21501-4 at your facility 74
What to look for on the calibration certificate
75
What to look for on the calibration certificate
76
What to look for on the calibration certificate
“Hach certifies that the calibration performed requirements of ISO 21501 . ..
77
Online and First particle counters designed
MET ONE 3400 MET ONE 6015P Grade A & B automated monitoring Internal vacuum pump
Grade A & B automated monitoring Small and compact
Portable sampling for environmental validation
Grade A & B automated monitoring Sealed enclosure for wash down Automatic vacuum control
78
78
ADDITIONAL INFORMATION
[email protected]
79
Road Map to ISO 21501-4 compliance
Audit our Methods and E ui ment
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
80
Thank ou !
[email protected]
+1 541 210 0194 Presented by
Grants Pass, Oregon USA
Joe Gecsey HACH Life Science Applications
81
