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

2
 Classification:
FS209 and ISO 14644-1

ISO 14644-1 FED STD 209E Classification is the process of qualifying the
ISO Class English Metric cleanroom environment by the number of
1 particles using a standard method

2
Determine
D i classification
l ifi i off room according
di to
3 1 M1.5 standards
“ISO Class 5” or “Class 100”
4 10 M2.5 Performed on a regular basis but not frequently
6 months, yearly or ???
5 100 M3.5
Standards define minimum number of sample points
6 1,000 M4.5 Usually based on area of cleanroom or clean zone
Standards define minimum amount of air to be
7 10,000 M5.5 sampled
Minimum volumes for statistically valid samples
8 100,000 M6.5

9 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 regulation…but 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 regulation…but
l i b byb 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

6
 Differences

Classification Monitoring

Distribution of counts Uniform or Unique at each

in a room or zone homogenous sample position

7
Classification

8
 Classification Standards for Airborne Particles

General Air Monitoring Standards – before 1999

9
 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
– ISO 14644
14644-3
3
• Guidance on instrumentation to
be used for testing for
1999 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 Other
• Pharmaceutical
Laboratory Electronics
• Biotechnology
• Medical Devices
• Hospitals/Pharmacies
Aerospace
Aerospace
• Launch Vehicles
• Satellites
• Commercial/Military Aircraft
Laboratories Life Sciences
• Analytical Laboratories
• Universities
Other
• Nuclear
• Photographic, X-ray films
• Automobile Painting

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
mini-
environments)
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 0.2 m 0.3 m 0.5 m 1 m 5 m

ISO 1 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

FS 209E
ISO 5 100,000 23,700 10,200 3,520 832 29
Class 100

ISO 6 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

ISO 9 35,200,000 8,320,000 293,000

14
 Classification Standard:
ISO 14644-1:1999
14644 1 1999

Minimum sample volume 2.0 liter

Minimum sample time 1 minute

Minimum number of 1
with at least 3 samples
locations 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

Maximum Time
Test Parameter Class Test Procedure
Interval

≤ ISO 5 6 Months
Particle Count ISO 14644-1
Test Annex A
ISO 6, 7, 8, 9 12 Months

Air Pressure ISO 14644-1

All Classes 12 Months
Difference Annex B5

ISO 14644-1
Airflow All Classes 12 Months
A
Annex B4

17
 Example
ISO 14644-1
14644 1 C
Calculations
l l ti

Vial
Freeze
Washing
Dryer 1
System 5m

Freeze
8m
Dryer 2

5m
Calculations for Number of Points:
Area of clean zone = 80 m² Freeze
Take the SQRT (80) = 8.94 Dryer 3
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
Freeze
Washing
Dryer 1
System
1 2 3 4 5 6

Freeze
Dryer 2
Calculations for Number of Points:
8
Area of clean zone = 80 m²
Take the SQRT (80) = 8.94
Rounding up to next integer = 9 sample positions Freeze
9 Dryer 3

19
 Example
ISO 14644-1
14644 1 C
Calculations
l l ti
1 2 3 4 5 6 7 8 9 10

Vial
Freeze
Washing
Dryer 1
System

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. Freeze
• Best to sample near potential problem spots which Dryer 3
are near entrances and exits and near operator
positions.

20
 Example
ISO 14644-1
14644 1 C
Calculations
l l ti

9
1
Vial 10 Freeze
Washing
8 Dryer 1
System
2

11
3 4 5 6 7

12 Freeze
Dryer 2
• Need to adjust for equipment in room.
• Under ISO 14644-1, if you sample at 10 or more 13
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. Freeze
14
• Best to sample near potential problem spots Dryer 3
which are near entrances and exits and near
operator positions.

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) Calculate the standard deviation
b) Use Student’s T-factor
T factor from tables
c) Calculate UCL
d) 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 (Student’s 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
classification inappropriate, potential p
particle
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 -22

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
Air Surfaces

Particles 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 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

FS 209E
ISO Class 5 100,000 23,700 10,200 3,520 832 29
Class 100

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

ISO Class 9 35,200,000 8,320,000 293,000

33
 Proposed
p new limits and labels:
Classification Limits: ISO 14644-1 (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

1 10

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

FS 209E
Class 100 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

9 35,200,000
, , 8,320,000
, , 293,000
,

34
 Forthcoming Revisions to
ISO 14644
14644-1,
1 -22
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 pplan 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

choosingg positions
p and number of sample
p points
p in
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

EUUG
GMP Annex e 1
- Manufacture of Sterile Medicinal Products

49
 FDA’s 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/m³
counts/m for counts 0
0.5
5 μm and larger

50
 FDA’s 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 airi 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:
“ For classification p
purposes
p 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 or above
Grade Activity 0.5 m 5 m 0.5 m 5 m
A High Risk - filling, open vials, stopper bowls 3 520 20 3 520 20
B Aseptic preparations 3 520 29 352 000 2 000
C Clean area of less critical operations 352 000 2 000 3 520 000 20 000
D Clean area of less critical operations 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
At Rest In Operation
Maximum permitted number of particles/m3
Maximum permitted 3
Grade
equal
equal to
to or
or greater
greater than
than the
the tabulated size
tabulated size
0.5 µm
0.5 µm 5 µm
5 µm 0.5 µm
0.5 µm 5 µm
5 µm

A
A 3 500
3 520 20
1 3 500
3 520 20
1
B 3 500
520 29
1 352 000
350 2 000
900

C 352 000
350 2 000
900 3 500
520 000 29 000
20
D 335000
520 000
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 1464414644-1
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

Vial
Sterilizing 1 Lyo 1
5
Tunnel
7

2 3

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) 6

− 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

Vial
Washing 1

System

2 3

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 ISO 21501-4

• Size
Si calibration
lib ti • Si calibration
Size lib ti
• 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
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 3400

Cleanroom classification to ISO14644
MET ONE 6015P Portable sampling for environmental validation
Grade A & B automated monitoring
Internal vacuum pump

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
ADDITIONAL INFORMATION

ISO21501@hach.com

79
 Road Map
to ISO 21501-4 compliance
 Audit
ud you
your Methods
e ods aand
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

Joe Gecsey
Grants Pass, Oregon USA
HACH
Life Science
Applications
81
 Regulations Concerning
Airborne Particle Counting