Dealing with EC GMP requirement
Thursday, August 25, 2005 08:00 IST
EU inspectors maintain that large particles are potential carriers 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 and/or problems with personnel and procedures. You can expect occasional counts, but investigate trends.
Regarding the minimum sample volume, the change to volume of 1 cubic metre will be for qualification (commissioning & revalidation), not for routine monitoring. One is doing continuous monitoring as mandated, so the volume is indeterminate. At a recent British Parenteral Society meeting it was clarified that this 1 cu.metre was not for each sampling point, but is the minimum volume for the sum of the samples for a particular area. Therefore if 4 sampling points are specified for a room, then each point might need a 0.25 cu.metre sample (not 4 cu.metre each). What is not clear is if each sampling point should take the same sample size, i.e. each point's sample size = 1m3/number of sample points.
EC GMP requirements
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 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: 3501 counts for 0.5 micron & 2 counts for 5 micron particles
Although manifold type sequential monitoring systems are not banned, it will be difficult to justify the use of manifolds after 1st. September 2003, evidence may be expected that manifold systems have documented efficiency at larger particles.
Now that ECD GMP has made it mandatory to have continuous particle monitoring in Grade A areas, let us have a brief look at what this implies. In conventional particle measurement methods, the operator moves a self-contained optical particle counter to the work-station and places an isokinetic probe at a convenient location, usually held in place by a stand.
This conventional particle counter contains a vacuum pump, printer, display, etc and is usually mounted on a lab trolley to facilitate moving about the cleanroom. Drawbacks of stand-alone counter are that it brings additional personnel and equipment into the room resulting in added bio-burden It also lacks consistent sampling programs in timing and location.
Production personnel usually stop all activity and move away when the particle count sample is to be taken. This results in elimination of action that may be generating contamination, thus lowering the particle count. To overcome these shortcomings, continuous monitoring systems using remote sensors are used. A typical remote sensor for the pharma industry is shown in the photo (courtesy Met One, USA) and has the following features:
- 0.3 or 0.5 micron sensitivity at 1 cfm
- Internal Vacuum Pump - 100% Duty Cycle
- Stainless steel case, wall mount style
- Filtered output air
- Removable sensor
- Remote display
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 is 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. It states "regular monitoring should be performed during each shift" and "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". In other words, continuous monitoring is not mandatory but recommended by US FDA in ISO Class 5 areas.
Hepa Filter Testing -- US FDA recommendations
- 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 is sufficient.
We are fortunate to have in India, several cleanroom contractors who can design and construct pharma cleanrooms to international standards, at reasonable prices. They are also able to carry out periodic certification including HEPA filter leak testing. What is now needed is an Indian Cleanroom Society which will impart knowledge and training to the hundreds of cleanroom users spread throughout the country.
(The author is CEO, MeasureTest Corporation, Mumbai)