Counting the cost
Innovation in computerised distributed monitoring systems now enables pharmaceutical companies to meet the challenges of Annex 1 without punitive costs, according to Ken McWilliam.
Innovation in computerised distributed monitoring systems now enables pharmaceutical companies to meet the challenges of Annex 1 without punitive costs, according to Ken McWilliam.
The revised Annex 1 of the EC Guide to Good Manufacturing Practice (GMP) created new challenges for particle counting by introducing widespread continuous monitoring using larger sample volumes.
Responding to the requirement to demonstrate compliance with particulate levels in cleanrooms has historically involved the extensive use of manifold systems where a central particle counter measured sequentially from many ports. This allowed savings to be made as a single particle counter and pump could be shared among many sample locations, with critical areas able to be monitored using portable counters that moved between operations.
Counting problems
These traditional approaches, however, came at a price:– with the manifold system, particle loss – particularly at 5µm size – became significant where long tubing runs were used. Of course, these particles were not "lost", but had merely settled in the tube, from where they could be disturbed by vibration at a later date and appear as a spurious high count in an "at rest" area.
Another problem introduced with manifold-based systems is that it is impossible to detect when a cap has been inadvertently left on a sample point after sanitisation; all the system sees are particle counts of zero, which is a highly desirable but erroneous outcome. Even the portable counter had its drawbacks as it often relied on paper printouts as evidence of compliance during each stage in the process. These had to be manually annotated, collated and attached to the batch report after the process was complete.
The emergence of distributed systems that can be "daisy chained" from a central PC enables a network of continuous monitoring particle counters to be implemented at reasonable cost. Small counters can be mounted close to the point of measurement – in a laminar flow, for example – thus avoiding the potential for particle loss in long lengths of sample tubing. Each counter typically requires a vacuum supply, DC power and communications to be "plumbed in".
Traditionally, these counters are networked using RS485 or Ethernet, where each particle counter must be set to a unique address every time maintenance work or calibration is carried out. If the wrong address is set within the device, particularly when several are being calibrated at the same time, results may still be gathered, but from the wrong locations.
An innovative approach adopted by Pharmagraph, with its CPC range of Continuous Particle Counters, circumvents this problem and allows the CPCs to be readily swapped. Here, the particle counter is housed in a small stainless steel box that can easily be unclipped from its location. A quick disconnect umbilical connects the counter to the network via a "Smart Socket". This subtle but important innovation permits all CPCs in the system to have the same address, thereby allowing them to be interchanged by maintenance engineers, or even cleanroom operators themselves, with no additional set-up.
The Smart Socket connects to a small "outstation" in the plant area that contains electronics to control the local vacuum pump, detect inadvertent capping of the sample probe, and provide local indication of "fault", "in-compliance" or "out of compliance" situations. It is the outstation that defines the location of the counter, not an address held within the counter itself.
"Plug and play"
When a counter needs to be changed, it is simply unplugged and its replacement plugged in; no switch settings have to be changed, no Ethernet IP address has to be set, and no programming needs to be carried out using a separate PC.
In large installations where a number of continuous monitoring locations are called for, the maintenance associated with the individual vacuum pumps can increase the cost of ownership. Further flexibility with the Smart Socket approach allows centralised control panels with solenoid-operated vacuum valves and robust duty and standby pumps to be used.
This eliminates the regular maintenance of the large number of individual vacuum pumps, often sited in awkward locations, and replaces it with planned maintenance of the duty and standby pumps. Combined with the simple swap-out capability of CPCs, this approach can dramatically minimise downtime while eliminating the chance of erroneous addressing of the counters.
Corrective action
It is vital that operators within a cleanroom know as soon as possible that a process may have become non-compliant. This allows the cause of high particle counts to be investigated and corrective action to be taken, making loss of production minimal. Annex 1, however, calls for sample volumes of one cubic metre to be taken, and with most particle counters sampling at one cubic foot per minute, this would take more than 35 minutes to achieve, which is longer than some operations themselves.
Recent introductions to the marketplace offer sampling at higher flow rates, but this still takes around 20 minutes.
It is impractical to sample at one cubic metre per minute or anywhere close to this as it would be highly intrusive to the production process, so how do you asses the particulate levels per cubic metre when you cannot sample a cubic metre in a reasonable time? The obvious answer is to set the actual sample volume to one cubic metre and wait for each sample to complete. Unfortunately, results then become available relatively infrequently (every 20 to 35 minutes, depending on the instrument), which may cause an entire batch to be rejected.
A second solution adopted by many instrument suppliers is simply to scale up the counts measured for a given sample volume to the equivalent count per cubic metre. The problem here is that a relatively short-lived high count will be scaled up to a value that is out of compliance, whereas that specific count might contribute very little to the complete cubic metre sample.
An alternative approach available within Pharmagraph's CPC instruments is to use a "walking window accumulation" technique. This method continuously accumulates the individual particle counts measured over each cubic foot to produce a new result every minute that represents the true count over the last cubic metre of sampled air. This allows the earliest detection of particle counts that will inevitably come out of compliance when the full cubic metre is sampled, and effectively combines the advantages of the first two approaches; a full cubic metre is being sampled and yet results are available every minute.
As is often the case with new or revised regulations, there is a phase during which different interpretations are made as each new monitoring system is installed. In the longer term the rules become better understood and definitions refined; in the meantime, flexible innovative solutions are required to help maintain GMP compliance while minimising production downtime.
