cleanroom standards & gmps

COMPLYING WITH INTERNATIONAL CLEANROOM STANDARDS / GMPs

without getting ulcers

Sheesh GulatiMeasureTest Corporation

MULTIPLICITY OF STANDARDS / GUIDELINES

• F.S.209E ) Antique value?• BS 5295 )• IEST RP-CC-034.1• PDA Technical Report 13• USP 797 Sterile compounding• TGA Guidelines for Sterility testing Annex IV• PIC/S• ISO 14644• US FDA cGMP Aseptic Processing• EU GMP Annex 1

RESULT ---- Total Confusion !

WHICH STANDARDS TO FOLLOW?Questions to ask about Standards:

• What is the source of the standard? • Is it required? • Should it be required? Can I eliminate it? • Does the standard reflect current technology? • Is it relevant to my product? • Are there newer standards that are more relevant ? • Is the standard sufficient to achieve the required

performance? • Is it realistic? • Does the standard have a potential negative effect on

the product? • Should additional standards and controls be adopted?

FEDERAL STANDARD 209E OBSOLETE

• F.S.209, for 40 years the main definition of cleanroom classification levels, was officially cancelled in 2001

• Replaced by ISO 14644

• The main differences between FS 209 and ISO 14644 and how the new standards affect the pharma industry is discussed in the next few slides

COMPARISON OF ISO 14644-1 WITH FS 209

ISO 14644-1 FED STD 209E

1

2

3 1 M1.5

4 10 M2.5

5 100 M3.5

6 1,000 M4.5

9

ISO Class English Metric

7 10,000 M5.5

8 100,000 M6.5

ISO 14644-1 adds

• 2 “ultra-clean” classes

– ISO Class 1

– ISO Class 2

• 1 “very dirty” class

– ISO Class 9Total of 9 classes

Counts / cubic metre

Must specify room status

• “as-built” / “at rest” / “in operation”

- specify particle size/concentration

ISO 14644-1 COUNT LEVELSAirborne Particulate Cleanliness Classes (by cubic metre)

CLASS Number of Particles per Cubic Metre by Micrometre Size >=

0.1 um 0.2 um 0.3 um 0.5 um 1 um 5 um

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

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

Old Class 100>

ISO CLEANLINESS LEVELS

Points to note:

• Each successively higher ISO classification allows approximately ten times as many particles as the previous class

• The ratio of particles of size A to size B remains approximately constant for all classes. Example:

Class 4 allows 10,200 particles ≥0.3 µm or 3,520 µm ≥0.5 µm

Class 5 allows 102,000 particles ≥0.3 µm or 35,200 ≥0.5 µm

ISO 14644 CLASSES

A common mistake is to assume that, because sizes of 0.1 micron, 0.2, 0.3, 0.5, 1 & 5 microns are given in the Classification Table, we have to check all these particle sizes.

The considered particle size(s) for which the concentration will be measured, shall be agreed upon by the customer and the supplier. Each larger particle diameter shall be at least 1.5 times the next smaller particle diameter.

In the pharmaceutical industry, normally one checks 0.5 and 5 microns

25 microns particles?The main reason 25 microns was historically required for users is due to the BS 5295 standard [U.K.] that required monitoring at 25 microns. In the USA, the need for 25 microns was muted. Several other EU countries also leaned on the BS 5295 standard before ISO 14644-1 was introduced in 1999, and for a few years after. Note that 25 microns is specified within BS 5295 for the equivalent of ISO Class 8 (Class 100K) and ISO Class 9. These are "dirtier" environments. For BS 5295 Class J (ISO Class 8), the limit was zero per cubic metre and for BS 5295 Class K (ISO Class 9), the 25 micron limit was 500/cubic metre. For cleaner areas below ISO Class 8/Class 100K, the chart in BS 5295 is marked as "NS" for "No Specified Limit".

Certification: ISO 14644-1 versus FS 209E

Minimum sample time not specified 1 minute

Minimum number of samples at each

location

ISO 14644-1

2.0 litre(0.07 cubic

foot)

1 with at least 3 samples total

Parameter

Minimum sample volume

2 with at least 5 samples total

FS 209E

2.83 litre(0.1 cubic foot)

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)

ISO 14644-1 Minimum Sample Time at 1 CFM

Time required (in minutes) at 1 cfm (28.3 lpm) flow rate with 1-minute limit imposed

0.1 um 0.2 um 0.3 um 0.5 um 1 um 5 um

ISO Class 1 70.64 353.20

ISO Class 2 7.06 29.43 70.64 176.60

ISO Class 3 1.00 2.98 6.93 20.18 88.30

ISO Class 4 1.00 1.00 1.00 2.01 8.51

ISO Class 5 1.00 1.00 1.00 1.00 1.00 24.36

ISO Class 6 1.00 1.00 1.00 1.00 1.00 2.41

ISO Class 7 1.00 1.00 1.00

ISO Class 8 1.00 1.00 1.00

ISO Class 9 1.00 1.00 1.00

Cleanroom Certification

Initial and periodic certification• Federal Standard 209E (previously)• ISO 14644-1, -2 (now)• Max time interval for ISO Class 5 is 6 months

Three states• As-built• At Rest• Operational / Dynamic

Averaging of Data from all positions permitted

Certification: FS209E and ISO 14644-1

• Defines Cleanroom classes

• Establishes minimum sampling volumes

• purpose: to gather a sample volume with theoretically at least 20 particles to help with statistical validity of sample

• Establish minimum number of points to classify area, based on statistical criteria

• Certification is also referred to as Classification or validation or Verification

Monitoring vs. Certification (Qualification)

EC or GMP focus: parameters during operation• dynamic or “in operation”

• potential effect on product is critical issue

but Certification is normally done during idle time• infrequent but thorough check of the environment

• “as-built”

• “at rest”

Greatest concern for FDA is for viable microorganisms• Technology is not available today to measure viable

counts in real time• Non-viable counts used as a surrogate

U.S. FDA AND ISO 14644• FDA welcomes new ISO standards as one

harmonised, base-line document on the subject of air cleanliness classification is better than five with small but difficult to reconcile differences

• ISO documents are generic, non-industry specific, written to meet multi-constituent industries, and often the result is the dilution of standards to the lowest common denominator

• A company may meet the criteria of ISO 14644 but that does not mean they are complying with cGMPs. According to FDA, classification of a clean area is based not only on particle concentration but also on microbiological data

“A”

125

119

120

364 >> 121

“B”

3

8

12

238 <<

65

FDA prohibits averaging across positions

FDA says“No !”

for 2 positions in ISO Class 5 (FS 209E

Class 100) ...

Placement of Sample Probes

• No regulatory standards for monitoring

• Not controlled earlier by FS 209E or now by ISO 14644-1, when conducting monitoring of the process

• Costly and not practical to establish monitoring points based on the ISO 14644 formula of square root of area in sq.metres. Risk assessment is very important in determining where to monitor

ISO Class 5: ISO 14644-1 Classification Calculations

8 m

4 m

5 m

5 mCalculations for Number of Points:

Area of clean zone = 80 m²

Take the SQRT (80) = 8.94

Rounding up to next integer = 9 sample positions

Freeze Dryer

1

Freeze Dryer

2

Freeze Dryer

3

Vial Washing System

This process of selecting sample points for verification will be compared later to the process of selecting points for the daily monitoring of the same area.

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

1 2 3 4 5 6

7

8

9

ISO Class 5: ISO 14644-1 Classification Calculations

Freeze Dryer

1

Freeze Dryer

2

Freeze Dryer

3

Vial Washing System

We might place them as shown. But this does not take into account the reality of what is in the room: entrances, exit and machinery. So we need to adjust for these.

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.

1 2 3 4 5 6 7 8 9 10

Freeze Dryer

1

Freeze Dryer

2

Freeze Dryer

3

Vial Washing System

ISO Class 5: ISO 14644-1 Calculations

Freeze Dryer

1

Freeze Dryer

2

Freeze Dryer

3

Vial Washing System

1

2

3 4 5 6 7

8

9

10

11

12

13

14

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.

Here could be a distribution of sample points that would both provide a good view of the cleanroom particulate values, and, importantly, be defended against any regulatory challenge. Note that there are more points suggested than the minimum calculation.

ISO Class 5: ISO 14644-1 Calculations

Placement of Isokinetic Probes in a Pharmaceutical Filling Area for the Purpose of Monitoring—

What you won’t find in any book !

EU Annex I: Selecting Monitoring Positions ISO Class 5

Presence of lyophilizers indicate vials may not be fully stoppered so the holding position near “5”represents some risk

Position “6” provides evaluation of Grade B zone and probably early indication of pressure balance problems due to proximity to doors

Positions “7” and “8” are needed because loading area in front of lyophilizers should be Grade A if product is not fully stoppered

1

2

3 4

5

6

7

8

Freeze Dryer

1

Freeze Dryer

2

Freeze Dryer

3

Vial Washing System

EU Annex I: Selecting Monitoring Positions

If this were a filling operation for which the final product remains liquid i.e. freeze dryers were not present, some points would not be needed.

1

2

3 4

5

Vial Washing System

Placement of Isokinetic Probes in a Life Science Manufacturing Area (ISO Class 7 or 8)

Example: Cleanroom Area ISO Class 7 or 8 Classification

175 feet (53 m)

100 ft (30 m)How to choose

sampling points?

This is a large area of 30 metres by 53 metres, and rated as an ISO Class 7 or Class 8 (FS209E Class 10K or 100K).

ISO Class 7: ISO 14644-1 verification

175 feet (53 m)

100 ft (30 m)

Entry plane (m2): 1590 m2

SQRT (1590) = 39.87

Minimum sample points = 40

Following the ISO 14644-1 methods, we would determine that the minimum number of sample points to carry out a formal verification would be 40.


175 feet (53 m)

100 ft (30 m)


SQRT (1590) = 39.87


6x7 grid = 42

But this is not an easy number to set up for a grid pattern in a rectangular area so forty-two positions might be a better choice.


175 feet (53 m)

100 ft (30 m)


SQRT (1590) = 39.87


6x7 grid = 42

The sample positions would be at work height in the middle of each rectangle.

Example: ISO 14644-1 Calculations

1. Sum and average values at each position2. Calculate the mean of averages3. Result must be less than

– a) the limit for the given size and – b) target room classification

If the number of points sampled is more than 1 but less than 10, then the UCL factor must be applied:• Calculate the standard deviation• Use Student’s T-factor from tables• Calculate UCL• Compare to classification limit• UCL must not exceed the applicable limit

ISO Class 7: Selecting MonitoringPositions

175 feet (53 m)

100 ft (30 m)

Work Station 1

Work Station 2

Work Station 3

Work Station 4

Storage

In the real world, monitoring positions will be affected by the physical layout of the area and the activities that occur within it. Also entry and exit points should be considered.

ISO Class 7: Selecting MonitoringPositions

175 feet (53 m)

100 ft (30 m)

Work Station 1

Work Station 2

Work Station 3

Work Station 4

Storage

Monitoring should focus on the product exposure and vulnerability: “Where in the process is my product that most vulnerable to contamination because of a) the length of time it sits exposed to ambient air, b) the nature of the process step, or c) the effectcontamination might have on the next step [for example, a coating process].

Where to monitor – PIC/S recommendations

Pharmaceutical Inspection Convention, GenevaRecommendation on the Validation of Aseptic Processing

states:Ensure that location chosen for non-viable monitoring

reflects the worst caseFor room monitoring, counts should be performed in

locations where there is most operator activityFor the filling environment,counts should be performed

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

Where to monitor -- PIC recommends

• Avoid monitoring in such a way that the probes monitor the air from the HEPA filter rather than the air immediately surrounding the critical zones

• Location of the sample device should not compromise the the laminarity of the air flow in the critical zone

FDA GMP:

• Measurements should be taken with the particle counting probe oriented in the direction of oncoming airflow and at the sites where there is most potential risk to the exposed product

Where to monitor?

Where to monitor in ISO Class 5 (Class 100) / Grade filling room

General wisdom is to monitor wherever an operator is known to breach the sterile zone with his arm or body

Typically this may be the following 3 areas : de-scrambler table, near the filling needle mechanism, and the stoppering process

Some filling machines often incorporate these functions in a more compact area and thus only one or two positions are practical

1. Sample near to exposed product• Generally near work height and exposed product• If liquid sterile fill, guidance is to sample air approaching the product within 12” (30 cm) of

exposed Do Not measure directly above critical point

• Starves the are of air• Creates turbulence

Measure to one side, close to critical location

Placement of Sample Probes

Less than 12 inches (30 cm)

2. Sample near to points of intervention by operators

Examples: • Descrambler table• Filling needles• Stoppering process

Probe Sampling Positions

Isokinetic probe on an Accumulation Turntable provides monitoring of rotary in-feed turntable after sterilization zone.

Adjustable mount (optional) allows fine tuning of sampling position.

Probe shown with Cap in place

Probe Sampling Positions

Iso kinetic sampling under the HEPA Filter in a Shrouding Machine

Isokinetic probe cups can be mounted up to 3 metres from the counter

Each probe is connected to the counter via a Hytrel non shedding tubing.

EC GMP Guide Annex 1 – Sterile products

Version effective September 2003 stated:• Limit of 5 micron particles for Grade A is 1

per cu.metre in operation and for Grade B at rest

• Continuous measurement system should be used for Grade A areas (and recommended for Grade B)

• For routine testing, total sample volume should not be <1 m³ for Grade A & B areas; preferably also in Grade C areas

REVISION OF EU-GMP GUIDEComments:

Research on size distribution of particles in a cleanroom has shown that when 3500 particles of 0.5 micron are present per cu.metre, it will contain more than one particle of 5 micron. The well established, and confirmed, size distribution curve used in the ISO standard predicts 29 particles.

Therefore this stipulation was illogical and led to protests from industry

EU-GMP ANNEX 1 2003 REVISIONS

• The use of the word "continuous" was misleading; the right interpretation was “periodic automated sampling”

Sampling intervals of 5 to 10 minutes are all right, whereas 35 to 40 minutes would be too long.

• The regulators feel that there should be zero 5 micron particles in the room, but realise that there can be occasional "outliers". However, they expect people to react to trends of frequent or high readings. So, the occasional count of "1" or "2" should not stop the line. Constant readings of say 20, should cause an investigation.

CLASSIFICATION ACCORDING TO 0.5 MICRON

If we were just considering 0.5 micron particles, both ISO and US FDA would permit a sampling volume of

Vs = 20/Cn.m x 1000 where Vs = Volume in litres, Cn.m = number of particles/m3 for the relevant class

Therefore Volume of sample = 20/3520 x 1000 = 5.68 litres

With a particle counter of flow rate 1 cfm (28.3 lpm), time taken would be less than 1 minute, so we would run the particle counter for just 1 minute.

1 PARTICLE OF 5 um IN QUALIFICATION

Now let us see what happens if we were to consider 5 micron particles also.Using the same formula, volume per location according to ISO 14644 would be :20/29 x 1000 = 690 litres

At sampling rate of 1 cfm (28.3 litres/mim), this would take only 24 minutes

Which is still quite reasonable

BUT WHAT HAPPEN WITH EC GMPLIMIT OF ONE PARTICLE OF 5 um

Volume required per location would be:20/1 x 1000 = 20,000 litres

Time required per location at sampling rate of 28.3 l/min = 706 minutes = 12 hours approx!This made Certification of your cleanroom much more expensive and time consuming.

Latest 2008 revision therefore relaxed limit to 20 particles instead of 1 particle of 5 microns/cu.metre

EU GMP LATEST REVISION 2008

On 14th February 2008, the European Commission updated Volume 4 of EU Guidelines to the GMPs for medicinal products for Human and Veterinary use

This revised Annex 1 will come into operation on 1st. March 2009 except for the provisions on capping of freeze-dried vials, which should be implemented by 1st. March 2010.

It clearly outlines three phases that need to be performed: Certification: Each cleanroom and clean air device should first be

classified Monitoring: the cleanroom should then be monitored to verify that

conditions are being maintained relative to product quality Data Review: Ensure that the data accrued from the monitoring be

reviewed in the light of risk to finished product quality.

http://www.pmeasuring.com/support/papers/particlemonitoring/pharmaceutical/app41

EU GMP LATEST REVISION 2008

The maximum permitted airborne particle concentration for each grade is given in the following table

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

At rest In operation

Grade 0.5 µm 5.0µm 0.5 µm 5.0µm

A 3 520 20 (ISO 5 = 29)

3 520 20

B 3 520 29 352 000 2 900 (ISO 7 =2930)

C 352 000 2 900(ISO 7 = 2930)

3 520 000 29 000(ISO 8 = 29,300)

D 3 520 000 29 000(ISO 8= 29,300)

Not defined

Not defined

EU GMP 2008 REVISIONContinuous Discontinued?

The new revision does not specifically mention Continuous Measurement Systems are mandatory, but it is implied :

“For Grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly”

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

EU Annex 1: March 2009 Changes

Grade Maximum permitted number of particles/m3 equal to or above

0.5 µm 5 µm 0.5 µm 5 µm

A 3 500 1 3 500 1

B 3 500 1 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 5000 000 20 000 not defined not defined

At Rest In Operation

ExistingEffective Sept. 2003

At Rest In Operation

Grade Maximum permitted number of particles/m3 equal to or above

0.5 µm 5 µm 0.5 µm 5 µm

A 3 520 20 3 520 20

B 3520 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

NewEffective Mar. 2009

5 µm limits for Grade A & B0 1 per cubic meter

5 µm limits for Grade A1 20 per cubic meter

Why measure 5 um particles ?

EU inspectors maintain that large particles are potential carriers (hitch-hikers), of or are, viable organisms themselves.

If these particles are present in an aseptic environment, they represent an increased risk of contamination of the sterile product.

Large particles do not transport well in tubing runs exceeding 3 metres (10 feet). Keep tubing runs from the sample site to the particle counter as short as possible to avoid particle loss.

5 micron counts can be an indicator of:• Problems with the physical plant• Problems with personnel and procedures

SEQUENTIAL MANIFOLD SYSTEMS

1. Although manifold type sequential monitoring systems are not banned, it will be difficult to justify the use of manifolds after 1st.September 2003. Evidence might be expected that manifold systems had documented efficiency at larger particles… “the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing.”

2. “I believe that our intention was not to ban cyclical sampling. By continuous we meant throughout the filling run. But we would expect, again, for the sampling regime to be documented; the rationale explained and justified. … if you had a cyclical manifold and it was sampling in the Grade A zone once every 45 minutes, then you might have a bit of a problem justifying that. If it is sampling, for example, every 5 minutes, the justification would be very much easier to write.”– Paul Hargreaves, MHRA

Tubing Transport LossTubing Transport Loss

0102030405060708090

100

2 7 13 19 26 30

Length of tubing (meters)

% Loss

0,1 µ0,5 µ0,7 µ1 µ3 µ5 µ10 µ

Why EC GMP doesn’t like Manifolds

EU Annex 1 2008 Revision SummaryFor verification (classification of room)Section 3: (Enhanced definition of at rest)

“The “at-rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present.”

Section 4:“Classification should be clearly differentiated from operational process environmental monitoring.”

Section 5:“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”

“For classification purposes in Grade A zones, a minimum sample volume of 1 m3 should be taken per sample position.”

EU Annex 1 2008 Summary

For monitoring (for example, with an FMS system)

there is no minimum volume or time period for each sampleIn Annex I, the only statements are to

• encourage a continuous sampling system for the Grade A areas• encourage a continuous sampling system for the Grade B areas,

although not so necessary as for Grade A• indicate that the sample rate can be different than that used to

qualify the area

Section 12 states:"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.“i.e. you do not need to sample minimum 1 cu metre during monitoring

DEALING WITH 1 CU.METRE REQUIREMENTDURING CLASSIFICATION

Increased sampling frequency of low air volume is preferable to high air volume at low frequency

In other words, 35 readings of 1 minute at 1 cfm are preferable to 1 reading of 35 minutes

Action limit for 1 cu.metreSingle readings: If all readings are below 1/35 of the

limjt, the limit will never be exceededMultiple readings: If some of the single readings exceed

the 1/35 of cu.metre limit, it has to be checked whether the result of sampling 1 cu.metre air volume would have exceeded the limit

DEALING WITH 1 CU.METRE REQUIREMENTDURING CLASSIFICATION

Action limit for 1 cft readings:

Readings below 1/35 of the 1 m3 requirement are acceptable

• 100 counts/cft for 0.5 micron• 0 counts/cft for 5 microns

Any reading exceeding 1 m3 requirement is not acceptable:

3521 counts for 0.5 micron & 21 counts for 5 micron particles

SUGGESTED PARTICLE MONITORING REGIME

• Sample size and frequency should be based on likelihood of finding a contamination event

• A long sample time --and hence large volume – could allow a short term even to be diluted by a low subsequent count rate

• A short sample time alone might cause you to think a false or spurious count is a real major contamination event

• Correlation with media fill data? Usually unlikely

• Correlation with an activity ? Highly likely

SUGGESTED PARTICLE MONITORING REGIME

Considering the >= 5 micron particles,• EU GMP limit is 20 per cu metre• 1 cu metre takes about 36 minutes to sample at I cfm

i.e. 28.3 lpm• If we wait 36 minutes before evaluating a sample, we

could miss an event• If we only look at a small sample of 1 cft (28.3 litre),

then 1 real or false particle would imply 35/cu metre= FAILING the 20 limit

• So we should look simultaneously at each 28.3 litresample and a cumulative 1000 litre (1 m3) sample

EU GMP -- VIAL CAPPING ISSUES• Relates to freeze dried products, liquid and

solid fill applications• Concerns were raised by inspectors when

seeing mis-placed stoppers re-seated by hand or even stoppered by hand when missing

• Partially stoppered freeze dried vials “maintained under Grade A conditions at all times”

• Non-freeze dried vials “protected with a Grade A air supply”. Is protected the same as maintained?

EU GMP – VIAL CAPPING

• Containers should be closed by appropriately validated methods. Containers closed by fusion e.g. glass or plastic ampoules should be subject to 100% integrity testing. Samples of other containers should be checked for integrity according to appropriate procedures

• Partially stoppered freeze drying vials should be maintained under grade A conditions at all times until the stopper is fully inserted

• The container closure system for aseptically filled vials is not fully integral until the aluminium cap has been crimped into place on the stoppered vial

EU GMP – VIAL CAPPING• As the equipment used to crimp vial caps can generate

large quantities of non viable particulates, the equipment should be located at a separate station equipped with adequate air extraction

• Vial capping can be undertaken as an aseptic process using sterilized caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped.

EU GMP – VIAL CAPPING• Note that a Grade A air supply is differentiated

from a Grade A environment

• Vials with missing or displaced stoppers should be rejected prior to capping. Where human intervention is requires at the capping station, appropriate technology should be used to prevent direct contact with the vials and to minimize microbial contamination

• This part of Annex 1 will be effective from 1st.March 2010

Interference from capping operation

Sample probe to demonstrate air quality before

capping process

Less

th

an30

5 mm

Unidirectional air shower

Higher sample probe for

monitoring during capping operation

Interpreting EU GMP Annex 1 –

the PHSS Best Practice Guide(Pharmaceutical & Healthcare Sciences Society,

U.K.)

Advice on Best Practice for Cleanroom Monitoring

None in Annex 1– What system to use?– Where to locate monitoring points?– How do we deal with 5μm counts?– 1m3 volume during manufacture?– Powder fill applications?

FDA cGMP– “areas where product is at most potential risk”– “not more than 1 foot away from the work site”

Advice on Best Practice for Cleanroom Monitoring

What was lacking was practical advice on how to implement these continuous monitoring systems. There is none in Annex 1 and ISO14644 is for room classification only.

Continuous – what, for example, does the word continuous mean? Monitoring – where should we locate the monitoring points and how

many should there be?5micron – what do we do if we see 5micron counts. How many are

acceptable before we initiate and action limit1 cubic metre – it is not clear as to whether we should try to sample a

complete cubic meter during each manufacturing batch. Some aseptic manipulations are complete in a matter of minutes and itcurrently takes at least 20 minutes to capture 1cubic metre of air with a modern counter.

Powder – are we really supposed to monitor for particles during a powder fill?

Scope & Aims of PHSS Special Interest Group

Scope:– Cleanroom non-viable air particle monitoring– EU GMP Annex 1

Aims:– Collate best practice from Industry, Healthcare and regulatory

bodies– Publish monograph :

Best Practice for Particle Monitoringin

Pharmaceutical Cleanrooms

Best Practice Document – the team

AstraZenecaBio ProductsBoehringer-IngelheimBoots Contract ManufacturingCardinal HealthGlaxoSmithKlineHach Ultra AnalyticsIpsen BiopharmParticle Measurement TechniquesWyethMHRA Regulatory Inspectors (EMeA)

Best Practice Document ContentsChanges to EU GMP Annex 1 – published 2008, ‘live’ March

2009System DesignOperationsMaintenance and CleaningTrainingAppendix A – Worked exampleAppendix B – Manifold and Remote Particle Monitoring

SystemsAppendix C – Examples of particle loss in transport tubingAppendix D – Isokinetic probesAppendix E – Validation and risk assessment standards

and guidelines

UK PHSS Best Practice monitoring

Grade A areas monitored continuously using dedicated particle counters.

Grade B areas (background for a Grade A) use dedicated particle counters.

Other Grade B areas and Grade C areas may be monitored by manifoldsystems to check that they are under control.(Note: There are no limits for the ‘in operation’ state in Grade D areas.)

Corridors and change areas may be checked on a routine basis using portable particle counters or monitored using manifold systems.

Enhanced monitoring should be provided in certain Grade C and D areas, for example in biologicals sites where low grade areas can potentially contribute a significant bioburden (to the point of sterility failure).

Appendix B – dedicated counter Grade A

VialSterilizing

Tunnel

CentralVacuumPump

KeyRemoteCounter

VacuumTubing,Power& Data

CentralSoftwareSystem

Appendix B – dedicated counter Grade A

VialSterilizing

Tunnel

Key

RemoteCounter

(Built-in Pump)

Power& Data

VacuumTubing

CentralSoftwareSystem

0.5μ 0.5μ

0.5μ

0.5μ

0.5μ

Appendix B – Manifold for Grade B & C

VialSterilising

Tunnel

ParticleCounter

Controller Manifold

KeySampleProbe

VacuumTubing

VialSterilising

Tunnel

ParticleCounter

Controller Manifold

KeySampleProbe

VacuumTubing

VialSterilising

Tunnel

ParticleCounter

Controller Manifold

KeySampleProbe

VacuumTubing

FDA ASEPTIC PROCESSING CGMP GUIDANCE

After over 15 years, US FDA published on 27th. September 2002, a Concept Paper entitled “Sterile Drug Products produced by Aseptic Processing & and invited comments

Subsequently issued as Draft GMP guidance in August 2003 and final CGMP in September 2004

New topics include guidance for personnel qualification, cleanroom classifications under dynamic conditions, environmental monitoring, isolators, blow-fill-seal systems

Appendix 1 reiterates FDA’s view that isolators should not be located in unclassified rooms and suggests Class 100,000 (ISO Class 8) background


• Air classification given in Table 1 of Buildings & Facilities only gives number of particles of 0.5 micron and larger per cft/cu.metre. Also dynamic state only. In this respect it differs from EU GMP as no mention is made of 5 micron particles

• “Regular monitoring should be performed during each shift”

• “Non-viable particulate monitoring with a remote counting system is generally less invasive than the use of portable particle counting units and provide the most comprehensive data”


• Air changes - For Class 100,000 (ISO Class 8) supporting rooms, at least 20 air changes per hours is typically acceptable, for higher cleanliness classes “significantly higher air change rates”

• Air velocity: “air in critical areas should be supplied at a velocity sufficient to sweep particulate matter away from the filling/closing area and maintain laminarity.

• A velocity of 90 to 100 ft/min +-20% is recommended

90 to 100 ft/min air velocity?

• The 90 to 100 fpm +/- 20% value should be a "guideline value" (in MCA terminology) or "informative" (in ISO terminology).

• The magic of 90 fpm has been known to be a fallacy within the cleanroom industry for over 25 years.

• This value is based on a simple calculation that a 5 um particle would stay airborne (settle less than 2 feet) over a distance of 20 feet in a horizontal flow cleanroom.

• The true test is airflow pattern testing

U.S.FDA ASEPTIC PROCESSING CGMP

Differential pressure should be monitored continuously throughout each shift and frequently recorded

“We recommend conducting non-viable particle monitoring with a remote counting system”

Airflow velocities are measured 6 inches from the filter face or at a defined distance proximal to the work surface, for each HEPA filter

Samples from Class 100 (ISO Class 5) environments should normally yield no microbiological contaminants

FDA GMP -WEAKNESSES

Dynamic Classification Expected“ …… the final room or area classification should be

derived from data generated under dynamic conditions”.

CommentsThis is very difficult in practice, and facilities are normally classified under static conditions as per ISO 14644.Various factors outside the control of cleanroom contractors make classification in operational mode difficult such as gowning practice, microbial control, etc.

FDA GMP -WEAKNESSESSterility Expectations“Air monitoring of critical areas should normally yield nomicrobiological contaminants”also “Samples from Class 100 environments should

normally yield no microbiological contaminants”

Comments:Attaining a “sterile state” in an aseptic processing facility is impossible. Personnel are always present in manned cleanrooms performing various activities including microbial sampling. Detection of micro-organisms occasionally is inevitable and need not be a cause for action against product.

AIR CHANGESDescribing airflow in terms of air changes per hour is common

for non-unidirectional flow rooms (ISO classes 6 through 9) and high-bay installations.

Since the airflow in these rooms is non-uniform, attempting to directly measure the average air velocity is not feasible. The average velocity may be calculated, however, using volumetric measurements from the terminal filters. This velocity is then converted into an equivalent room air changes per hour (AC/H).

• It is worth noting that in the UK GMP ('Orange Guide') the room air change requirements have been removed in the latest edition.

EU Annex 1 vs. FDA Guideline

In operationAt restIn operation

States to be monitored

Critical = AControlled = C, D

Grades A, B, C, DGrade B as surrounding Grade A

Room Classes

0.5 micron5 micron0.5 micron

Sizes monitored

FDA GuidelineEU Annex 1

FDA does not require classification of final stage of changing room to be the same as the room into which it leads

FDA CGMP -- HEPA FILTER TESTING

• HEPA filter integrity testing should be performed

twice a year

• DOP /PAO challenge and scanning with aerosol

photometer is recommended (DOP not banned)

• Concentration of poly-dispersed aerosol should be

“appropriate for the accuracy of the photometer”

(previously FDA had suggested 80 to 100 ug/L which

was too high. Normally 20ug/L sufficient)

EN 1822 - European Standard for Filters

HEPA Filter efficiency tested at MPPSLeak Testing also at MPPSEfficiency as low as 85% rated as HEPAParticle Counter and CNC only, no photometersA suitable 0.1 micron sensitivity particle counter

would also require a dilutor and the total cost would be around $ 20,000 i.e. double that of a photometer

TIME TO CHANGE

OLD TERMINOLOGY NEW TERMINOLOGY Laminar flow Unidirectional Flow

Clean Room Cleanroom (one word)

Class 100, Class 1000 Class 5, Class 6 etc Micron Micrometre Static/dynamic At rest/operational Air pattern/smoke Airflow visualisation

cleanroom standards & gmps

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