Cross Contamination 3 - Routes by which cross contamination occurs
Leaving aside mix up, where product A is mixed with product B, and mis-labelling where product A is labelled as product B to have cross contamination the active material in Product A has to get into Product B.
Three routes for contamination to leave Product A and reach product B are examined and the degree of transfer quantified and evaluated. Obviously the numbers vary according to the scenario that is considered but the figures give an order of magnitude evaluation.
Design of the facility and , as important, operations should follow.
Three routes are possible:
Transfer in the air: Particles are carried in the air and drop into another product. Designers take great care to design the appropriate environments and to ensure that air flows act to contain dust.
Transfer by physical means: People carry material from process A to process B, by, for example not changing gloves as they move from one process to another.
Transfer by Cleaning failure: Contact parts are not cleaned appropriately and residues are left from making product A and get into product B.
Which is the biggest risk?
We have imagined each scenario and made some rough calculations. Based on this the risks are, from worst to best
Transfer by physical means. Depends on events but 3 to 297mg could be transferred on unchanged gloves if staff went from one process to another. So change discipline is really important.
Transfer by cleaning failure. Uncleaned or poorly cleaned contact parts are likely to transfer all of the contamination to the following process. Its difficult to imagine anyone deliberately not cleaning equipment but it is possible to imagine a mistake, especially if the surface contamination were not visible. So systems to ensure cleaning takes place should be in place. Also manual cleaning cannot be reproduced time after time. So mechanical cleaning wins out. How much contamination, well it depends on the event. A failure to clean at all could result in the transfer of large amounts, Visible surface contamination is ~ 1 - 4 milligrams/ cm2 or 10-40 micrograms per rm2.
Transfer in the air. Any release is likely to be much release and also transitory as the HVAC filters clean the air. We calculated that a release of 100g of active material might only result in nanograms of contamination to an open process in another room.. Closed processes would avoid even this.
In designing facilities there has, historically, been huge focus on air changes, environments and airflow. The data suggests that there are significantly worst risks in the way the facility is operated and in maintaining procedures.
Scenario, Assumptions & Calculations
Transfer in the air
We think that handling active powders would be riskier than handling granule. First because granules usually contain inert excipients so gram for gram they contain less active material than powders which could be composed of 100% of active. Also small particles can remain in air for far longer than larger, granules. Granules tend to settle so fast that they are unlikely to remain in the air or travel far.
Dust cloud. Larger particles settle relatively quickly.
|Scenario 1: Escape of active powder and transfer in an airstream||
|100g of material is dropped||100g|
|Larger (heavier particles) settle relatively quickly so only smaller (lighter particles) get into HVAC system. Say 25% mass. No local extract, no local guard filters on return air system.||25g|
|Air filtration at 99.995% efficiency.(ie.0.005% pass filter)||0.0025g|
|Particles are mixed in HVAC unit and distributed through the system. They settle slowly, only a portion will settle as they pass over an open process. So most will miss the open process. Say 10%||0.00025g|
|The open process represents only a small 'target' compared to the floor area available for settlement. Portion of open process are compared to floor area of facility, say 5m2 in 1,000m2, ie 0.5%||0.0000125g|
The residual contamination will be removed by the next recycling of the air.
Where the process involves granule the size of the granule is such that it will settle quickly. Most material will end up on the floor rather than enter the HVAC system. Some fine material may be generated in processes so some small particles may exist at this stage of the processing. The material likely to be transferred is probably ~50 fold less.
- Powder handling is greatest risk
- Air filtration and air changes are key in mitigating a release
- Closed process to prevent release, and,
- Closed process to prevent deposit of contaminants mitigate cross contamination
Transfer by physical means
In this scenario we imagined that a person wearing gloves handled an active, that the gloves became contaminated and, without changing gloves, that person placed his hands in intimate contact with another product.
How much material can be left on gloves and how quickly will it drop off into another process? We found some industrial hygiene papers that gave some data to help with the calculations.
Contamination on hands after wearing gloves from improper change procedures.
Contamination on arms from sleeves.
|Scenario 2: Physical Transfer on hands||
|Powder on a surface, assume visible contamination, 1-4mg/cm2. Could be worse.||1mg/cm2|
|Transfer onto gloves, varies with repeated contact||3-37%|
|Portion of surface of glove contaminated, from research, 40%, Area of glove 2,000cm per hand,||40% x 2,000cm2|
|Material transferred to pair of gloves, mg||24-297mg|
|Transfer to next batch depends on circumstance, say 10 to 100%||2.4 - 297mg|
Transfer by cleaning failure
This depends so much on the circumstances that the outcome is variable. However if contact parts are contaminated then almost all that contamination is likely to be transferred in to the next batch that uses those parts. Scenario:
Scenario 3: Parts are not washed before reuse
Processes can create particles on machine parts.
|Assume that residue is not visible to staff, ie. less than 1-4mg/cm2, say 1mg/cm2||1-mg/ cm2|
|Area contaminated, May be considerable granule feed hopper, shaker boxes etc||10,000cm2|
|Percentage of material that gets into next batch||100%|
|Material into next batch||
However if the parts are grossly contaminated, ie the equipment has not be cleaned of residues at all, then teh contamination could be in grams..
- System to ensure cleaning takes place is paramount. Failure inevitably leads to cross contamination.
- Transfer of dirty parts to any central cleaning area should avoid any potential to drop material into common areas. Parts should be bagged for transit
- Cleaning should be effective and reproducible. This suggests that mechanical cleaning is used rather than manual cleaning