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Regulations Concerning

Airborne Particle Counting

Particle Counting
Applications
Two types of activities performed
with an airborne particle counter:

Environment

Classification focuses primarily on


the 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/cm2 on skin
Filter efficiency of clothing or garment varies greatly

Classification:
FS209 and ISO 14644-1
ISO 14644-1
ISO Class

FED STD 209E


English

Metric

1
2
3

M1.5

Determine
D
i classification
l
ifi i off room according
di to
standards
Performed on a regular basis but not frequently

10

M2.5

100

M3.5

1,000

M4.5

10,000

Classification is the process of qualifying the


cleanroom environment by the number of
particles using a standard method

M5.5

ISO Class 5 or Class 100


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 standardized method


3

Environmental Monitoring
Determine stability of room or zone over time; develop trend data
Executed on a scheduled basis: daily,
daily weekly
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 regulationbut need for trend information


4

Process Monitoring
Determine readiness of room to carry out designated task
Performed whenever relevant activity occurs daily work
Minimum number of sample points
defined by QA
A
Area
off cleanroom
l
or clean
l
zone
Activity
Risk to product
Frequency and volume of sample
points defined by QA
F
Frequent
t enough
h to
t show
h
control
t l
Frequent enough to manage
financial risk of product
contamination

N determined
Not
d
i d by
b regulationbut
l i
b by
b risk!
i k!
5

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

Differences

Distribution of counts
in a room or zone

Classification

Monitoring

Uniform or
homogenous

Unique at each
sample position

Classification

Classification Standards for Airborne Particles


General Air Monitoring Standards before 1999

Classification Standards for Airborne Particles


General Air Monitoring Standards

ISO 14644-1
Classification of air cleanliness

ISO 14644-2
Specifications for testing and
monitoring to prove continued
compliance with ISO 14644-1

1999

ISO 14644
14644-3
3
Guidance on instrumentation to
be used for testing for
compliance with ISO 14644-1

ISO 14644

10

Generall Standard
G
St d d
for all Industries
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

Other
Laboratory

Electronics

Aerospace

Life Sciences

11

ISO 14644
ISO 14644 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
Design, construction and start
start-up
up
Part 5: Operations
Part 6: Vocabulary
Part 7: Separative devices (clean air hoods
hoods, gloveboxes
gloveboxes, isolators
isolators, and mini
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

Classification Standard:
ISO 14644-1:1999
14644 1 1999
Defines cleanroom classes in a zone
Establishes minimum sampling
p g 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:
ISO 14644-1:1999
14644 1 1999 Li
Limits
it
Cl
Class

N
Number
b off P
Particles
ti l per Cubic
C bi Meter
M t by
b Micrometer
Mi
t Size
Si
0.1 m

FS 209E
Class 100

0.2 m

0.3 m

0.5 m

1 m

5 m

ISO 1

10

ISO 2

100

24

10

ISO 3

1,000

237

102

35

ISO 4

10,000

2,370

1,020

352

83

ISO 5

100,000

23,700

10,200

3,520

832

29

1 000 000 237,000


1,000,000
237 000 102,000
102 000

35 200
35,200

8 320
8,320

293

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 6

ISO 9

14

Classification Standard:
ISO 14644-1:1999
14644 1 1999

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

Classification Standard:
ISO 14644-1:1999
14644 1 1999
Minimum Sample Volume
(in liters)

ISO Class 5, 0.5 microns = (20/3520) x 1000 = 5.6 liters


ISO Class 5
5, 5 microns = (20/29) x 1000 = 690 liters
16

ISO 14644-2:2000
Continued compliance
(re-qualification)
Schedule of Tests to Demonstrate Continuing Compliance

Class

Maximum Time
Interval

ISO 5

6 Months

ISO 6, 7, 8, 9

12 Months

Air Pressure
Difference

All Classes

12 Months

ISO 14644-1
Annex B5

Airflow

All Classes

12 Months

ISO 14644-1
A
Annex
B4

Test Parameter

Particle Count
Test

Test Procedure

ISO 14644-1
Annex A

17

Example
ISO 14644-1
14644 1 C
Calculations
l l ti
Vial
Washing
System

Freeze
Dryer 1

5m

Freeze
Dryer 2

8m

5m
Calculations for Number of Points:

Freeze
Dryer 3

Area of clean zone = 80 m


Take the SQRT (80) = 8.94
Rounding
g up
p to next integer
g = 9 sample
p positions
p
4m

18

Example
ISO 14644-1
14644 1 C
Calculations
l l ti

Vial
Washing
System

Freeze
Dryer 1
1

Freeze
Dryer 2
Calculations for Number of Points:
8

Area of clean zone = 80 m


Take the SQRT (80) = 8.94
Rounding up to next integer = 9 sample positions
9

Freeze
Dryer 3

19

Example
ISO 14644-1
14644 1 C
Calculations
l l ti
1

Vial
Washing
System

10

Freeze
Dryer 1

Freeze
F
Dryer 2
Need to adjust for equipment in room.
Under ISO 14644-1, if you sample at 10 or more
positions,
iti
you can avoid
id the
th added
dd d calculation
l l ti
off
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

20

Example
ISO 14644-1
14644 1 C
Calculations
l l ti
9

Vial
Washing
System

1
10
8

Freeze
Dryer 1

2
11
3

12

Freeze
Dryer 2

14

Freeze
Dryer 3

Need to adjust for equipment in room.


Under ISO 14644-1, 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.

13

21

Example
ISO 14644-1
14644 1 C
Calculations
l l ti
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
10,
then the UCL factor must be applied:
a)
b)
c)
d)

Calculate the standard deviation


Use Students T-factor
T factor from tables
Calculate UCL
Compare to classification limit; UCL must
not exceed the applicable limit
22

Probable Revisions to
ISO 14644-1, -2

23

Revisions to
ISO 14644
14644-1:1999,
1:1999
14644-2:2000
Revision committee has met
in Zurich in the beginning of September 2012;
b WEBEX iin JJuly
by
l 2013
2013:
in Reno October 2013

Revision process still ongoing


Likely to be end of 2013 before new draft(s)
submitted for vote
vote, vote is recorded
recorded,
If draft is accepted, then effective late 2014
24

Forthcoming Revisions to
ISO 14644
14644-1
1
1. Frequency of re-certification
re certification for continued
continued
compliance:
Now:
If zone is ISO Class 5, every 6 months
If zone is ISO Class 6, every 12 months

Proposed:
Remove re
re-certification
certification period
Re-certification timeframe will be set by regulatory or advisory
committees for a particular industry
Or: 1 year if not monitoring !!
25

Forthcoming Revisions to
ISO 14644-1
14644 1

2. Eliminate calculation of UCL (Students T test)


for sample plans with 2 to 9 sample positions

26

Forthcoming Revisions to
ISO 14644-1
14644 1
3. Method of determining minimum number of
3
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

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
area of each cleanroom or clean
zone to be classified and provides
at least 95% confidence that at
l
least
t 90 % off th
the ttotal
t l area d
does
not exceed the class limit.
Different levels of confidence and
verification can be specified and
agreed upon by the customer and
supplier.
li
28

Forthcoming Revisions to
ISO 14644
14644-1
1
4 Remove possibility to classify at 5 micron
4.
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
pp p
, due to p
potential p
particle
classification inappropriate,
losses in the sampling system.
29

Forthcoming Revisions to
ISO 14644-1
14644 1
5. Indicate that single digit limits for
5
ISO Class 1 and 2 create challenges
to timelyy execution
R l
Replace
number
b values
l
with
ith N
Note
t (b) :
These concentrations will lead to large air sample
volumes for classification. Sequential sampling
procedure may be applied; see Annex D.

30

Forthcoming Revisions to
ISO 14644
14644-1,
1 -2
2
6 New label for classification level
6.
ACP = Air Cleanliness (by) Particles
ACC = Air cleanliness (by) Chemicals
SCP = Surface Cleanliness (by) Particles
SCC = Surface Cleanliness (by) Chemicals

31

Cleanroom Designations

Particles

Air

Surfaces

ACP

SCP

ISO 14644 - 1, - 2

ISO 14644 9

Draft #2 of
Revision

Chemicals

ACC

SCC

ISO 14644 8

ISO 14644 10

32

Classification Limits:
ISO 14644-1:1999
Number of Particles p
per Cubic Meter by
y 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

ISO Class 2

100

24

10

ISO Class 3

1,000

237

102

35

ISO Class 4

10,000

2,370

1,020

352

83

ISO Class 5

100,000

23,700

10,200

3,520

832

29

,
,
237,000
,
1,000,000

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 6

ISO Class 9

33

Proposed
p
new limits and labels:
Classification Limits: ISO 14644-1 (2014)
Number of Particles per Cubic Meter by Micrometer Size
ISO-ACP

FS 209E
Class 100

0.1 m

0.2 m

0.3 m

0.5 m

1 m

5 m

10

100

24

10

1,000

237

102

35

10,000

2,370

1,020

352

83

100,000

23,700

10,200

3,520

832

1,000,000 237,000

102,000

35,200

8,320

293

352,000

83,200

2,930

3,520,000

832,000

29,300

35,200,000
,
,
8,320,000
,
,

293,000
,

34

Forthcoming Revisions to
ISO 14644
14644-1,
1 -2
2
7. Calibration of Instruments to ISO 21501-4
7.1 Part of Appendix A (Normative):

A.2.2
A
2 2 IInstrument calibration
lib i
The instrument shall have a valid calibration certificate;
the frequency
q
y 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
particle light interaction methods-Part
methods Part 4: Light scattering airborne particle
counter for clean spaces.
35

Probable Revisions to
ISO 14644-2
14644 2
New Title for Section:

Cleanrooms and associated controlled


environments Part 2: Monitoring to
provide evidence of performance by ACP

Focus of 14644-2 will be on methods covering


monitoring
it i off particles
ti l and
d key
k supporting
ti parameters
t

Probable Revisions to ISO 14644-2

I t d ti
Introduction
"This revision
"Thi
i i off ISO 14644
14644-2
2 reflects
fl
a
philosophical shift that emphasizes
monitoring
it i over classification."
l
ifi ti "

37

Probable Revisions to ISO 14644-2

I t d ti
Introduction
"This revision
"Thi
i i
off ISO 14644-2
14644 2 reflects
fl t a
philosophical
shift
that
emphasizes
monitoring over classification.
classification
The monitoring process provides a continuing
flow of data over time, offering a greater
assurance of the performance of the
installation."

38

Probable Revisions to ISO 14644-2

I t d ti
Introduction
"Potential benefits gained from more substantial
monitoring are:

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

Probable Revisions to ISO 14644-2

I t d ti
Introduction
"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
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
situations,
procedures may be required."

40

Probable Revisions to ISO 14644-2

I t d ti
Introduction
"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
spaces."

41

Probable Revisions to ISO 14644-2

I t d ti
Introduction
"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
at rest classification rather than monitoring of
airborne particles in operation. Other performance and
cleanliness attributes may still be required to be
monitored.
monitored
After a monitoring plan is initially established, it may be
necessaryy to revise the p
plan when significant
g
changes
g
are made to the installation or process requirements. It is
also prudent to conduct periodic reviews of a monitoring
plan based on data obtained
obtained."
42

Probable Revisions to ISO 14644-2

T bl off contents
Table
t t
Introduction
1
Scope
2
Normative references
3
Terms and definitions
4
Creating, executing and maintaining a monitoring plan
4.1
Principle
42
4.2
Risk Analysis
4.3
Monitoring plan
4.4
Review and approval
4.5
Analyzing Data
5
Periodic classification

43

Probable Revisions to ISO 14644-2

T bl off contents
Table
t t
Annex A (informative)
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

Monitoring
- Environmental
- Process

45

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
g positions
p
and number of sample
p points
p
in
choosing
an area
46

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
M be
b OK to delay
d l ALERT or ACTION untilil 3
3rd
d or 5
5th
h
consecutive high reading
Information is about sample point not zone

47

Cleanroom
Monitoring
No clear guidance from standards or regulation

Number of sample points


Positions of sample points

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

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

49

FDAs Guidance for Industry:


Sterile Drug
g 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 = 35.31 cubic feet

Refers to ISO 14644-1


Class 100 > ISO Class 5
Limit restated
3520 counts/m
counts/m for counts 0
0.5
5 m and larger
50

FDAs Guidance for Industry:


Sterile Drug
g Products
Produced by Aseptic Processing
F
Focus
on potential
t ti l product
d t 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
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

Guidances for
Aseptic Processing

53

Guidances for
Aseptic Processing

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
and recommendations.
recommendations
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
should not compromise the product quality
quality. Worst case
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
room monitoring,
monitoring the counts should be performed in
locations where there is most operator activity. For the
filling environment the counts should be performed
adjacent
dj
to the
h filling
filli zone and
d where
h
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
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
off the
h air
i flflow iin the
h critical
i i l zone. IInitial
i i l validation
lid i should
h ld
be checked to confirm that worst case positions have
been adequately
q
y identified. These may
y be reconfirmed
during process simulation tests.

58

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

59

EU Annex 1 Summary:
Cl
Classification
ifi ti
Classification Sections 4 through 7
Section 4:
Classification should be clearly differentiated from
operational process environmental monitoring.
Section 5:
purposes
p
in Grade A zones, a minimum
For classification p
sample volume of 1 m3 should be taken per sample
position.

60

EU Grade Definitions

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

at rest
in operation
maximum permitted number of particles/m3 equal to or above
5 m
0.5 m
0.5 m
5 m
3 520
20
3 520
20
3 520
29
352 000
2 000
352 000
2 000
3 520 000
20 000
3 520 000
20 000
not defined
not defined

Zone grades according to risk of product contamination


Particle count measurements at 0.5 m and 5 m
At
At rest
rest vs In
In operation
operation

61

EU Annex 1:
L
Latest
revision
i i (2009)
Limits at 5 microns for Grade A
1 per cubic meter 20 per cubic meter
At Rest
Rest
At

In Operation

Maximum permitted
permitted number of particles/m3
Maximum
equal to
to or
or greater
greater than
than the
the tabulated
tabulated size
equal
size
3

Grade

0.5 m
m
0.5

5 m
m
5

0.5 m
m
0.5

5 m
m
5

A
A

3 500
520
3

20
1

3 500
520
3

20
1

3 500
520

29
1

352 000
350

2 000
900

352 000
350

2 000
900

3 500
520 000

29 000
20

520 000
335000
000

29 000
20

nott d
defined
fi d

nott d
defined
fi d
62

EU Annex 1 Summary:
Classification
Section 5:
For classification p
purposes
p
EN/ISO 14644-1 methodology
gy
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

EU Annex 1 Summary:
Classification
Section 5 (continued)
F classification
For
l
ifi ti purposes EN/ISO 14644
14644-1
1 methodology
th d l
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

EU Annex 1 Summary:
Monitoring

Monitoring: Sections 8 through 17


Section 8:
Clean rooms and clean air devices should be routinelyy
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
l
d
devices
i

65

EU Annex 1 Summary:
Monitoring
Section 9
The Grade A zone should be monitored at such a
frequency and with suitable sample size that all
interventions transient events and any system
interventions,
deterioration would be captured and alarms triggered if
alert limits are exceeded.
= continuous !!!

66

EU Annex 1 Summary:
Monitoring
Section 12:
The sample sizes taken for monitoring purposes using
automated systems will usually be a function of the
sampling rate of the system used
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 1m3 during verification
or monitoring
Particle counters used for monitoring may have the
same or different flow rate from those used for
classification
classification.
67

Monitoring Positions:
Risk-based Approach
4

Vial
Sterilizing
Tunnel

Lyo 1

1
5

7
2

Lyo 2
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)

Lyo 3

Loading
g area in front of lyophilizers
y p
must be Grade A if
product is not fully stoppered (6,7)

68

Monitoring Positions:
Risk-based Approach
4

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

ISO 14644
14644, ISO 21501 and
d
EU GMP Annex 1
Sampling of Airborne Particle Counts
I Aseptic
In
A
ti Manufacturing
M
f t i Process
P

70

Air Particle Counter Calibration


ISO 21501 and ISO 14644 - the link to GMP

Regulators inspect to EU GMP, which


calls up ISO 14644

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

Proposed wording in -1
1, -2
2
A.2.2 Airborne particle counter calibration
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
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
Size
Si calibration
lib ti

False count rate


Sampling Flow Rate
Sampling Time

ISO 21501-4
Si calibration
Size
lib ti
Verification of size setting
Counting efficiency
Size resolution
False count rate
Concentration limit
Sampling flow rate
Sampling time
Sampling volume

73

ISO 21501-4 Calibration Standard Delivers:


Improved compliance
Removes ambiguity by providing a single internationally
recognized standard method for calibration
Harmonization between ISO and GMP guidance

Improved
I
d unit-to-unit
it t
it reproducibility
d ibilit
Improved counting accuracy
All current Met One particle counters from Hach may
be calibrated using ISO 21501-4 at your facility
74

ISO 21501-4
21501 4
What to look for on the calibration certificate

75

ISO 21501-4
What to look for on the calibration certificate

76

ISO 21501-4
21501 4
What to look for on the calibration certificate

Hach certifies that the


calibration performed
complies with the
requirements of ISO 21501 .
..

77

Online and
Portable Particle Counters
First particle counters designed
for ISO 21501 compliance

MET ONE 6015P


Grade A & B automated monitoring
Internal vacuum pump

MET ONE 6000


Grade A & B automated monitoring
Small and compact

MET ONE 3400


Cleanroom classification to ISO14644
Portable sampling for environmental validation

MET ONE 7000


Grade A & B automated monitoring
Sealed enclosure for wash down
Automatic vacuum control

78

78

ADDITIONAL INFORMATION

ISO21501@hach.com

79

Road Map
to ISO 21501-4 compliance
Audit
ud you
your Methods
e ods a
and
d Equipment
qu p e
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 you !
jgecsey@hach.com
+1 541 210 0194
Presented by

Grants Pass, Oregon USA

Joe Gecsey
HACH
Life Science
Applications

81

Regulations Concerning
Airborne Particle Counting