LSUG 2011 Revised CR 2

Monitoring Compressed Air/Gas for Particles

1 FDA: Air (CDA) or Gas that contacts Product

2 Air (CDA) or Gas that contacts Product Frequency of sampling and target levels for CDA/Gases

It would seem that the authorities have not established a periodicity for sampling of compressed gas sources. In cases where there is concern that there might be some risk, it may be wise to sample gas sources on a quarterly basis and to set an expectation of an ISO 7 level in non- sterile applications; for sterile areas, a target of ISO 5 or better should be used. Many customers look for an ISO 4 level in sterile gas supplies and this should be achievable with most commercially available filter methods. This higher target level is, however, one of choice, rather than one dictated by regulation (but does add some safety margin).

Also, for sterile areas, a more frequent - monthly or even weekly - sampling may help minimize any lengthy period of heightened risk due to a system failure.

3 MET ONE 3400 for CDA/Gas testing

Ordering a Particle Counter for Gas Sampling The new 3400 gas option, together with the appropriate High Pressure Diffuser (HPD), makes gas monitoring straight-forward. The user simply selects the required gas from a pull-down list on the 3400 interface; the sample flow is automatically adjusted to ensure that a calibrated flow rate is maintained to specification. Ordering a new 1 CFM 3400 with gas calibration is likewise straight-forward. Four versions are available, and include gas calibrations for these gases: Air, N2, and CO2.

2088900-06 3413 0.3 micron, 1 CFM, GASES 2088900-07 3413 0.3 micron, 1 CFM, GASES, WIFI 2088900-08 3415 0.5 micron, 1 CFM, GASES 2088900-09 3415 0.5 micron, 1 CFM, GASES, WIFI For the 1 CFM counters listed above, select the 2080732-13 HPD. Note that HPD versions are available for other flow rates when CDA and/or N2 are the only gases to be sampled. 4 MET ONE Diffusers for CDA/Gas

5 Cleanrooms: Setting Alerts and Actions; Continuous Monitoring; Agenda

• ISO 14644-1: Revisions

• EU GMP ANNEX 1

• What affects Particle Concentration in a cleanroom

• What can be readily controlled to affect concentration

• What are the current trends and dialog that will likely change historic mainstays of cleanroom design

• Setting ALERT and ACTION levels for best effect

• Continuous monitoring for particle counts

7 Measuring Particles: 2 intentions

Classification Monitoring

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

Classification Monitoring

9 Monitoring

10 Two types of Monitoring !!!

“EM” Intermittent Process Control • Daily, weekly, • Continuous during monthly, quarterly process/setup • General 1 to 3 • Frequent consecutive samples each time samples, often at 1- • Static or dynamic minute intervals • General need is to • Watching for show consistency heightened risk due over time – trend to contamination • CAUTION: • “Normal” operations Conditions and sources can cause brief must be identical to spikes in counts draw any conclusions

11 Setting ALERT and ACTION levels for best effect

12 Setting Warning Level(s)

1. Particle Count data sets are difficult to deal with • Often “0” is a target value • Cannot use common methods to establish range • Cannot use methods based on SD (Standard Deviation)

2. Normal activity must not cause a “false alarm” • How do readings change with normal operator actions?

13 Setting Warning Level(s)

3. May not wish to react on very first elevated value • Often need to wait for repeated occurrences – May be consecutive readings - or not

4. Decision of best method based related to understanding best indication of potential “loss of control”

14 Key Take-away #2

In very clean areas with low particle concentration: A) Particle counts can jump with normal activity and then return quickly to low values B) Avoiding nuisance alarms is important C) Generally cannot use common statistical strategies for setting ALERT and ACTION levels

15 Guidances for Aseptic Processing Pharmaceutical Industry Compliance Guidance

– FDA cGMP Guidance for Industry • Sterile Drug Products Produced by Aseptic Processing

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

EU GMP Annex 1 is more specific than FDA cGMP Guidance 16 Guidances for Aseptic Processing

FDA joined PIC/s in January 2011

17 PIC/s Interpretation of Annex 1

"Monitoring, on the other hand, does not need to be performed according to EN ISO 14644-1

18 Setting Warning Level(s)

You must understand your process !!

PIC/s: A formal risk analysis study based on experiments and analysis of the monitoring data (over at least 6 month operation) should provide a basis for the determination of frequencies and limits.

19 Setting Warning Level(s)

You must understand your process !!

PIC/s: Frequencies and limits should be process-based and the results of the initial qualification and on going monitoring should be taken into account when setting operational alert and action limits. These limits and sample locations should be periodically reviewed for on-going validity of the risks initially considered. Those frequencies and limits should be process-based and the results of the qualification should be taken into account.

20 Setting Warning Level(s)