Regulations Concerning

(1)

Regulations Concerning

Airborne Particle Counting

(2)

Particle Counting

Applications

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

People Process

People as a Contamination Source Shed 5 to 10 million skin cells each day Shed 5 to 10 million skin cells each day 2000 to 5000 microorganisms/cm2 _{on skin}

(3)

Classification:

FS209 and ISO 14644-1

FED STD 209E

ISO 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 di

1 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 points

Usually 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

(4)

Environmental Monitoring

Determine stability of room or zone over time; develop trend data Executed on a scheduled basis: daily weekly monthly

Minimum number of sample points defined by QA

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

(5)

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 f l l

Performed whenever relevant activity occurs daily work

Area of cleanroom or clean zone Activity

Risk to product

Frequency and volume of sample points defined by QA

F t h t h t l

Frequent enough to show control Frequent enough to manage

financial risk of product contamination

N d i d b l i b b i k!

contamination

(6)

Differences

Classification Monitoring

Frequency 6 months or annual Daily, weekly, monthly or continuous

Number of positions By formula By need for data 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

or control

Reporting format By standard In form needed for rapid understanding

(7)

Differences

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

(8)

(9)

Classification Standards for Airborne Particles

(10)

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 14644-1

1999

(11)

G

l St

d

Electronics

General Standard

for all Industries

Electronics • Semiconductor • Flat Panel • Circuit Board • Optical • MEMS/Nanomachines Life Sciences • Pharmaceutical • Biotechnology • Medical Devices • Hospitals/Pharmacies Electronics Laboratory Other Aerospace • Launch Vehicles • Satellites • Commercial/Military Aircraft

Laboratories Life Sciences

Aerospace

• Analytical Laboratories • Universities

Other

• Nuclear

• Photographic, X-ray films • Automobile Painting

(12)

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 concentration

Part 2: Monitoring to provide evidence of cleanroom performance by airborne Part 2: Monitoring to provide evidence of cleanroom performance by airborne

particle cleanliness.

Part 3: Test methods

Part 4: Design construction and start up Part 4: Design, construction and start-up Part 5: Operations

Part 6: Vocabulary

Part 7: Separative devices (clean air hoods gloveboxes isolators and mini Part 7: Separative devices (clean air hoods, gloveboxes, isolators, and

mini-environments)

Part 8: Classification of airborne molecular contamination

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

(13)

Classification Standard:

ISO 14644 1 1999

ISO 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

(14)

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

(15)

Classification Standard:

ISO 14644 1 1999

ISO 14644-1:1999

2.0 liter Minimum sample volume

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)

(16)

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

(17)

ISO 14644-2:2000

Continued 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 A

ISO 6, 7, 8, 9 12 Months

Airflow All Classes 12 Months ISO 14644-1

A B4

Difference All Classes 12 Months Annex B5

(18)

Example

ISO 14644 1 C l l ti

ISO 14644-1 Calculations

Freeze Dryer 1 Vial Washing System 5 m Freeze Dryer 2 8 m 5 m Freeze Dryer 3 5

Calculations for Number of Points: Area of clean zone = 80 m²

Take the SQRT (80) = 8.94

Rounding up to next integer = 9 sample positions

4 m

(19)

Example

ISO 14644 1 C l l ti

ISO 14644-1 Calculations

Freeze Dryer 1 Vial Washing System System 1 2 3 4 5 6 7 Freeze Dryer 2

Calculations for Number of Points: Area of clean zone = 80 m²

8

Freeze Dryer 3

Area of clean zone = 80 m² Take the SQRT (80) = 8.94

Rounding up to next integer = 9 sample positions

(20)

Example

ISO 14644 1 C l l ti

1 2 3 4 5 6 7 8 9 10

ISO 14644-1 Calculations

Freeze Dryer 1 Vial Washing System F System Freeze Dryer 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

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.

(21)

Example

ISO 14644 1 C l l ti

ISO 14644-1 Calculations

Freeze Dryer 1 Vial Washing System 1 2 8 9 10 Freeze 2 3 4 5 6 7 11 12 Dryer 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

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

(22)

Example

ISO 14644 1 C l l ti

ISO 14644-1 Calculations

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 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 If the number of points sampled is more than 1 but less than 10, then the UCL factor must be applied:

a) Calculate the standard deviation b) Use Student’s T factor from tables b) Use Student’s T-factor from tables c) Calculate UCL

d) Compare to classification limit; UCL must not exceed the applicable limit

(23)

Probable Revisions to

ISO 14644-1, -2

(24)

Revisions to

ISO 14644 1:1999

ISO 14644-1:1999,

14644-2:2000

Revision committee has met

in Zurich in the beginning of September 2012; b WEBEX i J l 2013

by WEBEX in July 2013:

in Reno October 2013

• Revision process still ongoing

• Likely to be end of 2013 before new draft(s)

submitted for vote vote is recorded

submitted for vote, vote is recorded,

(25)

Forthcoming Revisions to

ISO 14644 1

ISO 14644-1

1. Frequency of re-certification for “continued

1. 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 !! • Or: 1 year if not monitoring !!

(26)

Forthcoming Revisions to

ISO 14644 1

ISO 14644-1

2. Eliminate calculation of UCL (Student’s T test)

for sample plans with 2 to 9 sample positions

(27)

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 points

(28)

A.4.1.1

Derive the minimum number of sampling locations N_L from table 3. Table A.1 shows the number of sample locations related to the area of each cleanroom or clean area 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 d

least 90 % of the total area does not exceed the class limit.

Different levels of confidence and Different levels of confidence and

verification can be specified and agreed upon by the customer and

li supplier.

(29)

Forthcoming Revisions to

ISO 14644 1

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 pp p , p p

(30)

Forthcoming Revisions to

ISO 14644 1

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 execution

y

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.

(31)

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) Chemicals SCC = Surface Cleanliness (by) Chemicals

(32)

Cleanroom Designations

Air Surfaces Particles

ACP

SCP

ISO 14644 – 9 ISO 14644 - 1, - 2 Draft #2 of Revision Chemicals

ACC

SCC

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

(33)

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

(34)

Proposed new limits and labels:

p

Classification 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 100 293,000 9 35,200,000 8,320,000 2,930 8 3,520,000 832,000 29,300 7 352,000 83,200 , , , , ,

(35)

Forthcoming Revisions to

ISO 14644 1 2

7. Calibration of Instruments to ISO 21501-4

ISO 14644-1, -2

7.1 Part of Appendix A (Normative):

A 2 2 I lib i

A.2.2 Instrument calibration

The instrument shall have a valid calibration certificate;

the frequency and method of calibration should be q y

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

(36)

Probable Revisions to

ISO 14644-2

New Title for Section:

ISO 14644 2

Cleanrooms and associated controlled

environments Part 2: Monitoring to

environments — 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 t

(37)

Probable Revisions to ISO 14644-2

I t

d

ti

Introduction

"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

"

(38)

I t

d

ti

"Thi

i i

f ISO 14644 2

fl t

Introduction

"This revision of ISO 14644-2 reflects a

philosophical

shift

that

emphasizes

monitoring over classification

monitoring over classification.

The monitoring process provides a continuing

flow of data over time, offering a greater

assurance

of

the

performance

of

the

assurance

of

the

performance

of

the

installation."

(39)

I t

d

ti

"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

(40)

I t

d

ti

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

(41)

I t

d

ti

"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 "

(42)

I t

d

ti

"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 of periodic 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 necessary to revise the plan when significant changes y p g 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 "

(43)

T bl

f

t

Introduction

T bl

f

t

Annex A (informative)

Monitoring

- Environmental - Process

(46)

Environmental

Monitoring

Understanding stability of particulate levels through trends

Samples taken daily, weekly or monthly

No requirement to monitor as many points as needed for classification

No requirement to sample 1 cubic meter

Consider using viable sample points as guidance in choosing positions and number of sample points in g p p p an area

(47)

Process

Monitoring

In operation or dynamic only

Relates to process and product quality Data may be needed for product release Data may be needed for product release

Often included with Batch Record

Average only count data from same location Average 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

(48)

Cleanroom

Monitoring

No clear guidance from standards or regulation

Number 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

(49)

Cleanroom

Monitoring

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

(50)

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 14644-1

Refers to ISO 14644-1

– Class 100 > ISO Class 5 – Limit restated

3520 counts/m³ for counts 0 5 μm and larger 3520 counts/m for counts 0.5 μm and larger

(51)

FDA’s Guidance for Industry:

Sterile Drug Products

F t ti l d t

g

Produced by Aseptic Processing

Focus on potential product exposure Defines two zones

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”

(52)

Guidances for

Aseptic Processing

Pharmaceutical Industry Compliance Guidance Compliance Guidance

– FDA cGMP Guidance for Industry

• Sterile Drug Products Produced by Aseptic Processing – EU GMP Annex I (EMEA) • Manufacture of Sterile Medicinal Products Medicinal Products

EU GMP Annex 1 is more specific than FDA cGMP Guidance

(53)

Guidances for

Aseptic Processing

(54)

Guidances for

Aseptic Processing

(55)

PIC/S Guidance

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

for environmental and personnel monitoring requirements and recommendations

and recommendations.

Some specific additional guidance is given below on air borne microbial and non-viable particle monitoring, intervention monitoring and staff training.

(56)

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 case should not compromise the product quality. Worst case scenarios of simulations tests should also include

(57)

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 the counts should be performed in room 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 h

adjacent to the filling zone and where components are exposed in such way as to detect operator activity within these areas.

(58)

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 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

f h i fl i h i i l I i i l lid i h ld

of 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 y

(59)

EU Annex 1:

L t t

i i

(2009)

Latest revision (2009)

Classification

– Sections 4 through 7

g

Monitoring

– Sections 8 through 17

(60)

EU Annex 1 Summary:

Cl

ifi ti

Classification

Classification – 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}

(61)

EU Grade Definitions

Grade Activity 0.5 m 5 m 0.5 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

at rest in operation maximum 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 20 000 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

(62)

EU Annex 1:

L

i i

(2009)

Limits at 5 microns for Grade A

Latest revision (2009)

At RestAt Rest In OperationIn 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 size

Grade

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

D 3 5000 000 20 000 not defined not defined

(63)

EU Annex 1 Summary:

Classification

Section 5: Section 5:

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

(64)

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)

(65)

EU Annex 1 Summary:

Monitoring

Monitoring: Sections 8 through 17

Section 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 ”

(66)

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 system interventions, transient events and any system

deterioration would be captured and alarms triggered if alert limits are exceeded.

(67)

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 for sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.”

• It is not necessary to sample 1m3 _{during verification}

or monitoring

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

classification classification.

(68)

Monitoring Positions:

Risk-based Approach

Lyo 1 Vial Sterilizing Tunnel 4 5 1 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 g y p product is not fully stoppered (6,7)

(69)

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 lyophilized points established for a lyophilized product would not be needed.

(70)

ISO 14644 ISO 21501

d

ISO 14644, ISO 21501 and

EU GMP Annex 1

Sampling of Airborne Particle Counts

I A ti M f t i P

(71)

Air Particle Counter Calibration

ISO 21501 and ISO 14644 the link to GMP

ISO 21501 and ISO 14644 - the link to GMP

• Regulators inspect to EU GMP, which calls up ISO 14644

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”

(72)

Proposed wording in -1 -2

Proposed wording in 1, 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 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.

(73)

ISO 21501-4: Additional Tests

Before ISO 21501-4

Si 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

(74)

ISO 21501-4 Calibration Standard Delivers:

• Improved compliance

– Removes ambiguity by providing a single internationally recognized standard method for calibration

recognized 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 be calibrated using ISO 21501-4 at your facility

(75)

ISO 21501-4

ISO 21501 4

(76)

ISO 21501-4

(77)

ISO 21501-4

ISO 21501 4

What to look for on the calibration certificate

“Hach certifies that the calibration performed

complies with the complies with the

requirements of ISO 21501 . . .

(78)

Online and

Portable Particle Counters

First particle counters designed for ISO 21501 compliance

for ISO 21501 compliance

MET ONE 3400 Cleanroom classification to ISO14644 Cleanroom classification to ISO14644 Portable sampling for environmental validation MET ONE 6015P

Grade A & B automated monitoring Internal vacuum pump

MET ONE 6000 _{MET ONE 7000}

MET ONE 6000

Grade A & B automated monitoring Small and compact

MET ONE 7000 Grade A & B automated monitoring

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ADDITIONAL INFORMATION

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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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Thank you !

[email protected]

+1 541 210 0194

Presented by

Grants Pass, Oregon USA

Joe Gecsey

HACH

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