Particle Sample Tube Lengths for Pharmaceutical Monitoring
Morgan Polen - VP of Applications Technology, Lighthouse Worldwide Solutions
Airborne ParticleCounters (APC) are used for a variety of purposes in pharmaceuticalcleanrooms for such applications:
·Filter testing
·Cleanroom certification andtesting
·Isolator certification andtesting
·Cleanroom and clean devicemonitoring in Pharmaceutical Manufacturing Facilities
The use of APCsrequires the use of tubing for the sampling of the air, as the APCmay be located some distance from the actual air being sampled. Thetubing is connected to an isokinetic probe that allows for thesampling of air in both unidirectional and non-unidirectionalcleanrooms or clean devices. Per various GMPs, the guidance valuefor this air velocity in these unidirectional environments is 0.45meters/second 20%. Thetubing connects an isokinetic probe to the particle counter.
Various factors impactthe efficiency of particle transport in tubing. Factors such as theclean air velocity, tubing length, tubing material, the number ofbends, the radius of such bends and the tubing diameter need to beconsidered in selecting and using such tubing.
Particle size, particlevelocity and tubing diameter are the key factors in determiningparticle transport efficacies in tubing. Tubing material is asecondary concern. Several common materials are listedbelow.
Materials used for thistesting consisted of:
Bev-A-Line XX Co-extruded tubing consisting of PVC exterior and Hytrel interior. This material has been the particle transport material of choice for years, due to the smoothness of the interior walls (Hytrel).
Stainless Steel Extremely clean, durable and conductive, stainless steel is an excellent material for particle transport. However, stainless steel tubing is inflexible and expensive to install.
Polyurethane Smooth material is chemically resistant and is a lower cost than either Bev-A-Line XX or Stainless Steel.
Within the realm ofpharmaceutical manufacturing, particle counting is performed usingseveral types of instruments, with different particle sampling flowrates:
·1.0 CFM (28.3 LPM) is thetraditional flow rate used for testing filters and certifyingcleanrooms. Some portable and remote particle counters sample airat 1.0 CFM. Nominal transport tubing for this flow rate is ¼”ID.
·50 LPM is an alternate flowrate. One such reason for choosing a higher flow rate is because ofthe requirements of cleanroom certification testing at the 5.0micron particle level. ISO 14644-1 requires a minimum sample volumeof 1000 liters or 1.0 cubic meter. The one cubic meter minimumsample volume is also specified in EU Annex 1. Nominal tubing forthis flow rate is ½” ID.
Pharmaceutical Cleanrooms andParticle Transport
In pharmaceuticalapplications, 0.5 and 5.0 micron particles are monitored as part ofGMP Regulations. It should be noted that although 0.5 micronparticles have a high transport efficacy at 1.0 CFM and 50 LPM flowrates, particles > 1.0 micron do not transport well in tubingregardless of the flow rate and tubing diameter. For applicationswhere 5.0 micron particle monitoring is regulated, keeping tubinglengths as short as possible is recommended.
Looking at theassociated data in Figures 1 and 2, an approximate 20% loss ofparticles 5.0 micron and greater is realized at 10 feet. For thisreason, sample lengths greater than 10 feet should not beconsidered because of the amount of error such sample lengths couldimpose on the measurements.
An additional point ofreference is the latest version of “EU Guidelines to GoodManufacturing Practice, Medicinal Products for Human and VeterinaryUse: Annex 1 Manufacture of Sterile Medicinal Products”. Thisdocument prescribes the use of short sampling tubing.
Item 6 (in Annex 1)States: “Portable particle counters with a short length of sampletubing should be used for classification purposes because of therelatively higher rate of precipitation of particles ≥5.0μm inremote sampling systems with long lengths of tubing. Isokineticsample heads shall be used in unidirectional airflowsystems.”
This reflects upon theuse of tubing for the cleanroom classification but not that of theroutine or continuous monitoring during manufacturing.
The length of tubingfor routing monitoring is also called out in Annex 1, Item 11,where it states: “Where remote sampling systems are used, thelength of tubing and the radii of any bends in the tubing must beconsidered in the context of particle losses in the tubing.”
As Annex 1 states, thelength of tubing as well as the radius of any bends need to beconsidered with particle sampling systems. Of particular importanceare Grade A and Grade B cleanrooms. The maximum allowable number of5.0 micron particles is 20 per cubic meter for Grade A, and 29 forGrade B at Rest. (2900 for Grade B in the operational state). Withsuch low numbers for Grade A and B limits, a greater than 20% lossin 5.0 micron and larger particles represents a considerable riskand should be carefully considered when designing a particlemonitoring system.
Lighthouse WorldwideSolutions recommends that continuous particle monitoring incritical locations (Grade A) be carried out only with particlesample tubing lengths of less than 10 feet or approximately 3meters. For Grade B operations, similar practices should also beconsidered.
Figure 1 illustratesthe effects of particle size on transport efficacy in a 1.0 CFMflow rate particle-counting test.
Figure 2 illustratesthe effects of particle size on transport with a 50 LPM flowrate.
OtherFactors:
As the sample tubingwill retain some particles over time, this accumulation ofparticles can impact the results of continuous monitoring. Suddenrelease of particles (previously suspended on the tube walls) mayresult in an unusually high count outside the actual conditionsinside the cleanroom or clean air device. Sample tube cleaning orreplacement may be considered to limit these sudden unexpected highparticle counts.