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Process Analytical Technologies (PAT) and Non-viable Particle Counting

by Mark Hallworth

Pharmaceutical manufacturing environments have traditionally seen particle counting as a "necessary evil" required to demonstrate compliance to a cleanroom standard. Now, however, Process Analytical Technologies (PAT) changes the focus to the final quality of the product. To reflect this change, continuous facility monitoring is recommended in place of intermittent particle counting using portable monitors. This follows the original intent of PAT:

"To understand and control the manufacturing process, quality cannot be tested into products. It should be built-in or incorporated by design using a system for designing, analyzing, and controlling manufacturing through process measurements of critical quality and performance attributes of materials and processes with the goal of ensuring final product quality."

Portable counters are very useful in demonstrating that a cleanroom is generally compliant with regulatory limits. However, occasional particle counting does not catch all instances of contamination; continuous monitoring provides data useful in trending analyses and is required to ensure that product quality has not been at risk.

The particles of concern (between 0.5 and 5.0 micron in size) are unlikely to enter a cleanroom via the filtration system, given the cleanliness techniques used in a pharmaceutical processing environment. Thus contamination is either a process or personnel issue. These can be very short-lived, such as a broken vial that is cleaned up immediately. In fact, any incident lasting for about a minute or less is unlikely to be detected by a portable particle counter; it would, however, be detected using a continuous monitoring system.

The importance of continuous particle monitoring can be demonstrated through an examination of the two most critical areas within aseptic pharmaceutical manufacture: the area of exposed product (ISO Class 5, GMP Class A) and the immediate supporting areas (ISO Class 7, GMP Class B). In the examples below, portable and continuous monitoring systems are compared in a Class B cleanroom that has an associated Class A zone. A risk classification has been applied that will bias the data according to the perceived risk to product. The results demonstrate that continuous monitoring creates a significant improvement over the use of a portable device in these areas.

In Example 1, a 50 m2 Class B room has a laminar zone (Class A) of an additional 25 m2. A portable particle monitoring system used eight locations in the background and five beneath the laminar zone; each was monitored three times a day for three minutes per location. If the same area were continuously monitored at two locations in the background and three in the laminar zone (sample points assigned in accordance with legislative guidelines and based upon risk assessment), a significant improvement over the difference relative to risk is achieved. Specifically, when compared to continuous monitoring, the Class B portable monitoring system has only a 2.5% confidence rating and the Class A portable monitoring system only a 1.0% confidence rating even though, in both cases, continuous monitoring uses fewer sample locations. Although this analysis is not exhaustive, we can see that continuous monitoring is a far more reliable method of detecting events.

Example 2 shows a similar situation but with a smaller room area and therefore significantly fewer monitoring locations. In this model, the Class B area is 25 m2 and the Class A area is 10 m2. Again, based upon the number of samples measured per day, the confidence rating with the portable system is very low and continuous monitoring results in a significant improvement.

Room Class Monitoring
Method
Room Area (m2) Sample Points(1) Risk to
Final Product Rating (2)
Duration
of
Sample
(min)
Samples Per Day Total
Duration of Sampling (min)
Duration x Risk Difference Relative to Risk (%)

Example 1

B

Portable

50

8

3

3

3

72

216

2.50

B

Continuous

50

2

3

1

1440

2880

8640

 

A

Portable

25

5

4

3

3

45

180

1.04

A

Continuous

25

3

4

1

1440

4320

17280

 

Example 2:  

B

Portable

25

5

3

3

3

45

135

3.13

B

Continuous

25

1

3

1

1440

1440

4320

 

A

Portable

10

4

4

3

3

36

144

1.25

A

Continuous

10

2

4

1

1440

2880

11520

 

(1) Portable based on ISO14644-1

(2) Risk based upon factor: A = 4 Highest; B = 3; C = 2; D = 1 Lowest

The above numbers are functions of time versus number of samples taken; no account is made for operator activity during the sampling periods. It is assumed that an operator maintains normal Standard Operating Procedures (SOPs) during the test period.

This shift to continuous data collection has translated itself into legislative guidance in the revisions of both the EC Guide to Good Manufacturing Practice Revision to Annex 1, September 2003, and the FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, September 2004. The EC guide states "a continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B areas." The FDA states, "we recommend conducting nonviable particle monitoring with a remote counting system. These systems are capable of collecting more comprehensive data and are generally less invasive than portable particle counters." Both guides direct manufacturers to continuously monitor the critical activities within a clean process environment to verify control of these environments.

In practical terms, the collection of more data can be difficult to manage and the connection to improved quality assurance, the driving aim for PAT, can thus become clouded. The design of a continuous monitoring system therefore requires special considerations, such as how operators are to react to out-of-tolerance conditions. For example, alarm systems and pagers can be used to achieve the fastest possible response to failures. Product can then be isolated or quarantined while awaiting microbial support to verify final product quality.

Reporting of data also takes a new direction. Instead of reporting individual sample results, it now looks at trend analysis. In Example 1 above, the total number of samples using the portable monitor was 72; for continuous monitoring the number becomes 2880. The emphasis becomes identifying what events occurred, how long the event lasted, and how the operator reacted to these events. Particle monitoring has thus evolved from snap-shots of an environment into a tool which allows for continuous feedback and improved environmental controls and which has, in turn, prompted changes to SOPs and modifications in the ways cleanrooms are used and managed.

###

The author is the Pharmaceutical Manager for Particle Measuring Systems, Boulder, CO. He has managed the installation and validation of almost 200 facility-monitoring projects in pharmaceutical production facilities and the companys transition to 21CFR part 11 compliant software. He currently lectures for pharmaceutical societies throughout Europe and the US on non-viable particulate monitoring, cGMP compliance (both for FDA and EU approval processes), and facility monitoring systems and the implications of validating those systems to GAMP. He can be contacted at mhallworth@pmeasuring.com. ■

Page last updated: 6 March 2009