regulations concerning airborne particle counting

Regulations Concerning Airborne Particle CountingAirborne Particle Counting

Particle Counting ApplicationsApplications

Two types of activities performed with an airborne particle counter:

Environment

Classification focuses primarily on the environment

Environment

Monitoring focuses on process, people and the environment

PeopleProcess

People as a Contamination SourceShed 5 to 10 million skin cells each dayShed 5 to 10 million skin cells each day

2000 to 5000 microorganisms/cm2 on skinFilter efficiency of clothing or garment varies greatly

2

Classification:FS209 and ISO 14644-1

FED STD 209EISO 14644-1

FS209 and ISO 14644-1

Classification is the process of qualifying the English Metric

1

ISO Class

2

cleanroom environment by the number of particles using a standard method

D i l ifi i f di1 M1.5

10 M2.5

3

4

Determine classification of room according to standards

“ISO Class 5” or “Class 100”

Performed on a regular basis but not frequently

100 M3.5

1,000 M4.5

5

6

6 months, yearly or ???

Standards define minimum number of sample pointsUsually based on area of cleanroom or clean zone

10,000 M5.5

100,000 M6.5

7

8

Standards define minimum amount of air to be sampled

Minimum volumes for statistically valid samples

3

9 Classification is a standardized method

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

Executed on a scheduled basis: daily, weekly, monthly

– 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

4

Not controlled by regulation…but need for trend information

Process MonitoringDetermine readiness of room to carry out designated task

Performed whenever relevant activity occurs – daily work

Minimum number of sample points defined by QAA f l l

Performed whenever relevant activity occurs daily work

Area of cleanroom or clean zoneActivityRisk to product

Frequency and volume of sample points defined by QAF t h t h t lFrequent enough to show controlFrequent enough to manage

financial risk of product contamination N d i d b l i b b i k!

5

contamination Not determined by regulation…but by risk!

Differences

Classification MonitoringFrequency 6 months or annual Daily, weekly, monthly

or continuous

Number of positions By formula By need for dataNumber 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 controlor control

Reporting format By standard In form needed for rapid understanding

6

Differences

Classification Monitoring

Distribution of counts in a room or zone

Uniform or homogenous

Unique at each 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 14644-3ISO 14644 3• Guidance on instrumentation to

be used for testing for compliance with ISO 14644-11999

ISO 14644

10

G l St d d

Electronics

General Standard for all Industries

Electronics• Semiconductor• Flat Panel• Circuit Board• Optical• MEMS/Nanomachines

Life Sciences• Pharmaceutical• Biotechnology• Medical Devices• Hospitals/Pharmacies

ElectronicsLaboratoryOther

Aerospace• Launch Vehicles• Satellites• Commercial/Military Aircraft

Laboratories Life Sciences

Aerospace

• Analytical Laboratories• Universities

Other• Nuclear• Photographic, X-ray films

11

• Automobile Painting

ISO 14644

ISO 14644 consists of the following parts, under the general title Cleanrooms and associated controlled environments:and associated controlled environments:

Part 1: Classification of air cleanliness by particle concentrationPart 2: Monitoring to provide evidence of cleanroom performance by airbornePart 2: Monitoring to provide evidence of cleanroom performance by airborne

particle cleanliness.Part 3: Test methodsPart 4: Design construction and start upPart 4: Design, construction and start-upPart 5: OperationsPart 6: VocabularyPart 7: Separative devices (clean air hoods gloveboxes isolators and miniPart 7: Separative devices (clean air hoods, gloveboxes, isolators, and mini-

environments)Part 8: Classification of airborne molecular contaminationPart 9: Classification of surface cleanliness by particle concentration

12

Part 9: Classification of surface cleanliness by particle concentrationPart 10: Classification of surface cleanliness by chemical concentration

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

• Defines cleanroom classes in a zone• Defines cleanroom classes in a zone

• Establishes minimum sampling volumes p g– 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 Li it

Cl N b f P ti l C bi M t b Mi t Si

ISO 14644-1:1999 Limits

Class 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 1 10 2ISO 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

ISO 5 100,000 23,700 10,200 3,520 832 29

ISO 6 1 000 000 237 000 102 000 35 200 8 320 293

FS 209E Class 100

ISO 6 1,000,000 237,000 102,000 35,200 8,320 293

ISO 7 352,000 83,200 2,930

ISO 8 3,520,000 832,000 29,300

14

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

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

2.0 literMinimum sample volume

Minimum sample time 1 minute

Minimum number of locations

1with 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

15

or FS 209E Class 100)

Classification Standard: ISO 14644 1 1999

Minimum Sample Volume

ISO 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 microns = (20/29) x 1000 = 690 liters

16

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

ISO 14644-2:2000Continued complianceContinued compliance

(re-qualification)

Schedule of Tests to Demonstrate Continuing Compliance

Test Parameter Class Maximum Time Test Procedure

Particle Count ≤ ISO 5 6 Months ISO 14644-1

Test Parameter Class Interval Test Procedure

Air Pressure All Classes 12 Months ISO 14644-1

Test Annex AISO 6, 7, 8, 9 12 Months

Airflow All Classes 12 Months ISO 14644-1 A B4

Difference All Classes 12 Months Annex B5

17

Annex B4

ExampleISO 14644 1 C l l tiISO 14644-1 Calculations

FreezeDryer 1

Vial Washing System 5 m

FreezeDryer 28 m

5 m

FreezeDryer 3

5Calculations for Number of Points:

Area of clean zone = 80 m²

Take the SQRT (80) = 8.94

Rounding up to next integer = 9 sample positions

18

4 m

g p g p p


FreezeDryer 1

Vial Washing SystemSystem

1 2 3 4 5 6

7

FreezeDryer 2

Calculations for Number of Points:

Area of clean zone = 80 m²8

FreezeDryer 3

Area of clean zone = 80 m²

Take the SQRT (80) = 8.94

Rounding up to next integer = 9 sample positions9

19

ExampleISO 14644 1 C l l ti

1 2 3 4 5 6 7 8 9 10

ISO 14644-1 Calculations

FreezeDryer 1

Vial Washing System

F

System

FreezeDryer 2

• Need to adjust for equipment in room.

• Under ISO 14644-1, if you sample at 10 or more iti id th dd d l l ti f

FreezeDryer 3

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

20

are near entrances and exits and near operator positions.


FreezeDryer 1

Vial Washing System

1

2

8

9

10

Freeze

2

3 4 5 6 711

12Dryer 2

• 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

12

13

FreezeDryer 3

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

14

21

operator positions.


1. Average the sample data values at each position1. Average the sample data values at each position2. 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 thevalue 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 10If the number of points sampled is more than 1 but less than 10,then the UCL factor must be applied:

a) Calculate the standard deviationb) Use Student’s T factor from tablesb) Use Student’s T-factor from tablesc) Calculate UCLd) Compare to classification limit; UCL must

not exceed the applicable limit

22

not exceed the applicable limit

Probable Revisions to ISO 14644-1, -2

23

Revisions to ISO 14644 1:1999ISO 14644-1:1999,

14644-2:2000Revision committee has met

in Zurich in the beginning of September 2012; b WEBEX i J l 2013by WEBEX in July 2013:in Reno October 2013

• Revision process still ongoing• Revision process still ongoing• Likely to be end of 2013 before new draft(s)

submitted for vote vote is recordedsubmitted for vote, vote is recorded,• If draft is accepted, then effective late 2014

24

Forthcoming Revisions to ISO 14644 1ISO 14644-1

1. Frequency of re-certification for “continued1. 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 periodRemove 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

• Or: 1 year if not monitoring !!

Forthcoming Revisions to ISO 14644 1ISO 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

3 Method of determining minimum number of

ISO 14644-1

3. Method of determining minimum number of sample positions

– Replace with stated number of minimum sampleReplace 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 pointspoints

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 cleanarea of each cleanroom or clean zone to be classified and provides

at least 95% confidence that at l t 90 % f th t t l dleast 90 % of the total area does

not exceed the class limit.

Different levels of confidence andDifferent levels of confidence and verification can be specified and

agreed upon by the customer and li

28

supplier.


4 Remove possibility to classify at 5 micron

ISO 14644-1

4. 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, due to potential particle

29

pp p , p plosses in the sampling system.”


5 Indicate that single digit limits for

ISO 14644-1

5. Indicate that single digit limits for ISO Class 1 and 2 create challenges to timely executiony

R l b l ith “N t (b)” Replace number values with “Note (b)” :

These concentrations will lead to large air sample 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 1 2

6 New label for classification level

ISO 14644-1, -2

6. New label for classification level

ACP = Air Cleanliness (by) Particles

ACC = Air cleanliness (by) Chemicals

SCP = Surface Cleanliness (by) Particles

SCC = Surface Cleanliness (by) ChemicalsSCC = Surface Cleanliness (by) Chemicals

31

Cleanroom Designations

Air Surfaces

Particles ACP SCPISO 14644 – 9ISO 14644 - 1, - 2

Draft #2 of Revision

ChemicalsSCCACC

ISO 14644 10ISO 14644 8 ISO 14644 – 10ISO 14644 – 8

32

Classification Limits: ISO 14644-1:1999

Number of Particles per Cubic Meter by Micrometer Sizep y

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

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

FS 209E Class 100

, , , , , ,

ISO Class 7 352,000 83,200 2,930

ISO Class 8 3,520,000 832,000 29,300

33

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

Proposed new limits and labels:pClassification Limits: ISO 14644-1 (2014)

ISO-ACP

1 10

0.1 m 0.2 m 0.3 m

Number of Particles per Cubic Meter by Micrometer Size

0.5 m 1 m 5 m

3 1,000 237 102 35

2 100 24 10

1 10

6 1,000,000 237,000 102,000 35,200 8,320 293

5 100,000 23,700 10,200 3,520 832

4 10,000 2,370 1,020 352 83

FS 209E Class 100

293,0009 35,200,000 8,320,000

2,930

8 3,520,000 832,000 29,300

7 352,000 83,200

34

,, , , ,

Forthcoming Revisions to ISO 14644 1 2

7. Calibration of Instruments to ISO 21501-4ISO 14644-1, -2

7.1 Part of Appendix A (Normative):

A 2 2 I lib iA.2.2 Instrument calibrationThe instrument shall have a valid calibration certificate;

the frequency and method of calibration should be q ybased 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 4: Light scattering airborne particle

35

particle light interaction methods Part 4: Light scattering airborne particle counter for clean spaces.

Probable Revisions to ISO 14644-2

New Title for Section:

ISO 14644 2

Cleanrooms and associated controlled environments Part 2: Monitoring toenvironments — Part 2: Monitoring to

provide evidence of performance by ACP

Focus of 14644-2 will be on methods covering it i f ti l d k ti tmonitoring of particles and key supporting parameters

Probable Revisions to ISO 14644-2I t d tiIntroduction

"Thi i i f ISO 14644 2 fl"This revision of ISO 14644-2 reflects a philosophical shift that emphasizes

it i l ifi ti "monitoring over classification."

37

Probable Revisions to ISO 14644-2I t d ti

"Thi i i f ISO 14644 2 fl t

Introduction

"This revision of ISO 14644-2 reflects aphilosophical shift that emphasizesmonitoring over classificationmonitoring over classification.

The monitoring process provides a continuingThe monitoring process provides a continuingflow of data over time, offering a greaterassurance of the performance of theassurance of the performance of theinstallation."

38


"Potential benefits gained from more substantial

Introduction

monitoring are:

Faster response to adverse conditions– 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


"ISO 14644-2 specifies requirements of a monitoring plan,

Introduction

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 airbornecleanroom 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 monitoringsituations, appropriate adaptations of the monitoring procedures may be required."

40


"The level of airborne particles measured under a

Introduction

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 "adjacent spaces.

41


"In processes that inherently produce particles as part of

Introduction

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 ofperiodic at rest classification rather than monitoring of airborne particles in operation. Other performance and cleanliness attributes may still be required to be monitoredmonitored.

After a monitoring plan is initially established, it may be necessary to revise the plan when significant changes y p g gare made to the installation or process requirements. It is also prudent to conduct periodic reviews of a monitoring plan based on data obtained "

42

plan based on data obtained.

Probable Revisions to ISO 14644-2T bl f t t

Introduction

Table of contents

1 Scope2 Normative references3 Terms and definitions4 Creating, executing and maintaining a monitoring plan4.1 Principle4 2 Risk Analysis4.2 Risk Analysis4.3 Monitoring plan4.4 Review and approval4.5 Analyzing Data5 Periodic classification

43

Probable Revisions to ISO 14644-2T bl f t t

Annex A (informative)

Table of contents

Matters to consider when developing a monitoring planA.1 General ConsiderationsA.2 Pressure differential monitoringA.3 Airborne particle monitoring systemA.4 Airflow velocity and volume monitoring

Annex B (informative) Matters to consider when setting Warning levelsB.1 Setting levelsB.2 Considerations in setting Warning levels for Pressure DifferentialB.3 Consideration in setting Warning levels for Airborne Particle

Counts

44

Monitoring

- Environmental

- Process

45

Environmental MonitoringMonitoring

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 positions and number of sample points in

46

g p p pan area

Process MonitoringMonitoring

In operation or dynamic only

Relates to process and product quality

Data may be needed for product releaseData may be needed for product releaseOften included with Batch Record

Average only count data from same locationAverage only count data from same location– Each point must be below limit– But not necessarily each sample

M b OK d l ALERT ACTION il 3 d 5 h– May be OK to delay ALERT or ACTION until 3rd or 5th consecutive high reading

– Information is about sample point not zone

47

CleanroomMonitoringMonitoring

No clear guidance from standards or regulationNumber of sample points– 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– Assess the potential for product exposure– Consider possible contaminants created by process

– Impact to product– Impact to operators– Impact to operators

48

CleanroomMonitoring

However two guidances are offered:

Monitoring

US FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing- Sterile Drug Products Produced by Aseptic Processing

EU GMP Annex 1U G e- Manufacture of Sterile Medicinal Products

49

FDA’s Guidance for Industry: Sterile Drug Products g

Produced by Aseptic Processing

Initial release: June 1987

New Revision: September 2004

Restates count values in metric format– Cubic foot cubic meterCubic foot cubic meter– 1 cubic meter = 35.31 cubic feet

Refers to ISO 14644-1Refers to ISO 14644-1– Class 100 > ISO Class 5– Limit restated

3520 counts/m³ for counts 0 5 μm and larger

50

3520 counts/m for counts 0.5 μm and larger

FDA’s Guidance for Industry: Sterile Drug Products

F t ti l d t

gProduced by Aseptic Processing

Focus on potential product exposure

Defines two zonesDefines 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 ProcessingAseptic Processing

Pharmaceutical Industry Compliance GuidanceCompliance Guidance

– FDA cGMP Guidance for Industry• Sterile Drug Products

Produced by Aseptic Processing

– EU GMP Annex I (EMEA)• Manufacture of Sterile

Medicinal ProductsMedicinal Products

52

EU GMP Annex 1 is more specificthan FDA cGMP Guidance


53


54

PIC/S Guidance

7. ENVIRONMENTAL AND PERSONNEL MONITORINGAnnex I of the EU/PIC/S Guide to GMP provides the basis

for environmental and personnel monitoring requirements and recommendationsand 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 Worst caseshould not compromise the product quality. Worst case scenarios of simulations tests should also include monitoring activities.

56

PIC/S Guidance

7.2 Non-viable monitoring7.2.1 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 inroom monitoring, the counts should be performed in locations where there is most operator activity. For the filling environment the counts should be performed dj h filli d hadjacent 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 monitoring7.2.1 (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 thefilter rather than the air immediately surrounding the critical zones should be avoided. However the location of the sample device should not compromise the laminarity f h i fl i h i i l I i i l lid i h ldof the air flow in the critical zone. Initial validation should

be checked to confirm that worst case positions have been adequately identified. These may be reconfirmed q y yduring process simulation tests.

58

EU Annex 1:L t t i i (2009)Latest revision (2009)

Classification– Sections 4 through 7g

MonitoringMonitoring – Sections 8 through 17

59

EU Annex 1 Summary:Cl ifi tiClassification

Classification – Sections 4 through 7Classification – Sections 4 through 7

Section 4:“Classification should be clearly differentiated from

operational process environmental monitoring.”

Section 5:“ For classification purposes in Grade A zones, a minimum p p

sample volume of 1 m3 should be taken per sample position.

60

EU Grade Definitions

Grade Activity 0.5 m 5 m 0.5 mA High Risk - filling, open vials, stopper bowls 3 520 20 3 520 20B Aseptic preparations 3 520 29 352 000 2 000

at rest in operationmaximum permitted number of particles/m3 equal to or above

5 m

• Zone grades according to risk of product contamination

C Clean area of less critical operations 352 000 2 000 3 520 000 20 000D 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 rest” vs “In operation”At rest vs In operation

61

EU Annex 1:L i i (2009)

Limits at 5 microns for Grade A

Latest revision (2009)

At Rest In OperationAt Rest In Operation

1 per cubic meter 20 per cubic meter

Grade

At Rest In Operation

Maximum permitted number of particles/m3

equal to or greater than the tabulated sizeGrade

At Rest In Operation

Maximum permitted number of particles/m3

equal to or greater than the tabulated size

0.5 µm 5 µm 0.5 µm 5 µm

A 3 500 1 3 500 1

0.5 µm 5 µm 0.5 µm 5 µm

A 3 520 20 3 520 20

B 3 500 1 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 5000 000 20 000 t d fi d t d fi d

B 3 520 29 352 000 2 900

C 352 000 2 900 3 520 000 29 000

D 3 520 000 29 000 not defined not defined

62

D 3 5000 000 20 000 not defined not definedD 3 520 000 29 000 not defined not defined

EU Annex 1 Summary:Classification

Section 5:Section 5:

“For classification purposes EN/ISO 14644-1 methodology p p gydefines 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 ofof the largest considered particle size and the method of evaluation of the data collected.”

63

EU Annex 1 Summary:Classification

Section 5 (continued)“F l ifi ti EN/ISO 14644 1 th d l“For classification purposes EN/ISO 14644-1 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

• Currently based on SQRT of Area (M^2)

Sample Volume (B,C,D)

• Proposed – Based on lookup table

64

EU Annex 1 Summary: MonitoringMonitoring

Monitoring: Sections 8 through 17Section 8:“Clean rooms and clean air devices should be routinely y

monitored in operation and the monitoring locations based on

a formal risk analysis study– a formal risk analysis study and – the results obtained during the classification of rooms and/or

l d i ”clean devices”

65

EU Annex 1 Summary: Monitoring

Section 9

Monitoring

• “The Grade A zone should be monitored at such a frequency and with suitable sample size that all interventions transient events and any systeminterventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded.

= “continuous” !!!

66

EU Annex 1 Summary: Monitoring

Section 12:

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 forsampling 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 1m3 during verification or monitoring

• Particle counters used for monitoring may have the same or different flow rate from those used for classification

67

classification.

Monitoring Positions: Risk-based Approach

Lyo 1Vial

Sterilizing Tunnel

4

51

Tunnel

3

7

2

Lyo 2

6

• Monitoring must follow the workflow, covering areas where product is exposed – Annex 1 (2009)− Where open vials exit de-pyrogenation – human interaction (1)

Lyo 3

− 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

68

g y pproduct is not fully stoppered (6,7)

Monitoring Positions: Risk-based Approach

4

Vial Washing System

1

2 3

In a filling operation for which the final product remains liquid, some points established for a lyophilizedpoints established for a lyophilized product would not be needed.

69

ISO 14644 ISO 21501 dISO 14644, ISO 21501 and EU GMP Annex 1

Sampling of Airborne Particle CountsI A ti M f t i PIn Aseptic Manufacturing Process

70

Air Particle Counter CalibrationISO 21501 and ISO 14644 the link to GMPISO 21501 and ISO 14644 - the link to GMP• Regulators inspect to EU GMP, which

calls up ISO 14644calls 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 -2Proposed wording in 1, 2

A.2.2 Airborne particle counter calibrationThe 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 ISObe 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 21501-4Si lib ti

ISO 21501-4 Si lib ti• Size calibration • Size calibration

• Verification of size setting• Counting efficiency

• False count rate

• Counting efficiency• Size resolution• False count rate

• Sampling Flow Rate• Concentration limit• 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 calibrationrecognized standard method for calibration– Harmonization between ISO and GMP guidance

I d it t it d ibilit• Improved unit-to-unit reproducibility

• Improved counting accuracy• Improved counting accuracy

All current Met One particle counters from Hach may

74

be calibrated using ISO 21501-4 at your facility

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

75

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

76

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

“Hach certifies that the calibration performed

complies with thecomplies with the requirements of ISO 21501 .

. .

77

Online and Portable Particle CountersPortable Particle Counters

First particle counters designedfor ISO 21501 compliancefor ISO 21501 compliance

MET ONE 3400Cleanroom classification to ISO14644Cleanroom classification to ISO14644

Portable sampling for environmental validationMET ONE 6015PGrade A & B automated monitoring

Internal vacuum pump

MET ONE 6000 MET ONE 7000

78

MET ONE 6000Grade A & B automated monitoring

Small and compact

MET ONE 7000Grade A & B automated monitoring

Sealed enclosure for wash downAutomatic vacuum control

78

ADDITIONAL INFORMATION

[email protected]

79

Road Map to ISO 21501-4 compliance

Audit your Methods and Equipment ud you e ods a d 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

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+1 541 210 0194Presented by

Grants Pass, Oregon USA Joe Gecsey

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Regulations Concerning Airborne Particle CountingAirborne Particle Counting

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