Whitepaper Cross-Contamination Protection in HVAC I N D U S T R Y I N S I G H T S Norman A. Goldschmidt September 30, 2011 Principal, Engineering www.geieng.com
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Whitepaper Cross-Contamination Protection in HVAC Introduction In order to comply with widely established GMP regulations requiring minimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air An evaluation of potential for cross-contamination via HVAC should be part of the risk assessment in multi-product facilities. As outlined in the ISPE Risk MAPP guide, two HEPA filters in series within an air recirculation system (on supply and/or return) can reduce the mass of product in an airstream by an acceptable amount. But this approach is certainly not the only way to achieve an acceptable reduction in airborne contamination. Assuming that the risk potential of the products being processed has been determined, and that the unit operations and engineering controls have been chosen, the mass of a product that could contaminate another product via the HVAC may assessed. By establishing the mass of airborne contaminant product, the reduction in airborne contaminant in the HVAC airstream (due to filtration) and comparing this reduced contaminant mass to the mass of the potentially contaminated product, it is possible to determine the potential concentration per unit dose. Employing the filter efficiency rating (ASHRAE Efficiency %) as an adjustment to the airborne mass of particulate has been proposed as a method to achieve this evaluation; this is generally unsatisfactory as it provides only a rough estimate without the level of assurance desired for these critical calculations. However, by employing a mix of well defined cleanroom testing, Industrial Hygiene and filter classification techniques, it is possible to perform a quantitative assessment of the cross contamination protection, or potential, of an HVAC system - with rigor. Copyright Genesis Engineers 2011 - All rights reserved - Do not reproduce without written permission. 3
Principles The risk for cross-contamination from HVAC exists primarily when a drug product is exposed to the air that has come from a room where a second drug is being processed. This risk is tied to the amount of airborne product emitted by the process and is easily understood for a class of compound on a particular piece of equipment, in a particular room. Assuming that the risk potential of the products (or types of products) being processed has been evaluated; the mass of a product that could contaminate another product via the HVAC may be evaluated by the same method used to evaluate the operator exposure risk: 1. Evaluating the mass or volume of airborne contaminant product in the environment. 2. Evaluating the "protection factor", the reduction in airborne contaminant, afforded by components of the HVAC system. 3. Evaluate the exposure over the potential duration of a batch, accounting for the ventilation parameters within the space. This information alone may be sufficient to evaluate risk, if the quantity of product in the air is sufficiently low. However, a complete analysis would include a further evaluation step: 4. Comparing the contaminant mass to the processed product mass and number of doses to determine potential concentration per unit dose. In the following sections we will discuss the methodology and examples of the protection provided by HVAC components. Methodology The factor of protection from HVAC filtration may be utilized in much the same manner as the protection from Personal Protective Equipment (PPE) is applied to a known airborne contamination level (normally expressed in mcg/m3) to determine if an environment/ppe combination yields and acceptable operator exposure according to the formula: Ambient Concentration mcg/cm 3 x Protection Factor = Exposure mcg/cm 3 The data needed to determine the protection factor from filtration is available from ANSI/ASHRAE standard 52.2 testing performed by filter manufacturers. This standard determines the particle stopping capability of filters by particle size. This method allows for extremely precise assessments where the particle size distribution in an airstream has been characterized. Where empirical data is not available a set of assumptions may be made based upon basic information about common pharmaceutical ingredients in order to arrive at an acceptable approximation. Copyright Genesis Engineers 2011 - All rights reserved - Do not reproduce without written permission. 4
Where only the overall mass of product in an environment is known, the older ANSI/ASHRAE standard test 52.1 or it s Eurovent equivalent can be utilized to effectively understand the mass reduction (and therefore cross-contamination reduction) capability of filters in the HVAC system. In the following examples we demonstrate the effectiveness of this method and the surprising effectiveness of medium efficiency filters at reducing airborne contamination. Example Mass Reduction through Medium Efficiency s Example - Total Mass Reduction from MERV 11 Filtration Size Total Mass units Efficiency Units Mass units 0.1µ 1.0E-01 mcg x 15.000000% mcg/cm 3 = 8.5E-02 mcg/m 3 0.5µ 1.0E+00 mcg x 29.400000% mcg/cm 3 = 7.1E-01 mcg/m 3 1.0µ 1.0E+01 mcg x 48.900000% mcg/cm 3 = 5.1E+00 mcg/m 3 5µ 1.0E+02 mcg x 94.100000% mcg/cm 3 = 5.9E+00 mcg/m 3 10µ 1.0E+03 mcg x 96.700000% mcg/cm 3 = 3.3E+01 mcg/m 3 Total 1.11E+03 44.80 mcg/m 3 Example - Total Mass Reduction from MERV 13 Filtration Size Total Mass units Efficiency Units Mass units 0.1µ 8.5E-02 mcg x 35.000000% mcg/cm 3 = 5.5E-02 mcg/m 3 0.5µ 7.1E-01 mcg x 65.300000% mcg/cm 3 = 2.4E-01 mcg/m 3 1.0µ 5.1E+00 mcg x 81.800000% mcg/cm 3 = 9.3E-01 mcg/m 3 5µ 5.9E+00 mcg x 98.800000% mcg/cm 3 = 7.1E-02 mcg/m 3 10µ 3.3E+01 mcg x 99.800000% mcg/cm 3 = 6.6E-02 mcg/m 3 Total 1.37E+00 mcg/m 3 Example - Total Mass Reduction from MERV 15 Filtration Size Total Mass units Efficiency Units Mass units 0.1µ 1.0E-01 mcg x 50.000000% mcg/cm 3 = 5.0E-02 mcg/m 3 0.5µ 1.0E+00 mcg x 92.500000% mcg/cm 3 = 7.5E-02 mcg/m 3 1.0µ 1.0E+01 mcg x 97.400000% mcg/cm 3 = 2.6E-01 mcg/m 3 5µ 1.0E+02 mcg x 99.500000% mcg/cm 3 = 5.0E-01 mcg/m 3 10µ 1.0E+03 mcg x 99.999999% mcg/cm 3 = 1.0E-05 mcg/m 3 Total 1.11E+03 0.89 mcg/m 3 This simple analysis shows that a MERV 15 (~95% ASHRAE) filter provides a 3 log reduction in contaminants. More importantly, a MERV 11 (~50% ASHRAE ) gives a 1.5 log (20:1) reduction in airborne contamination. Copyright Genesis Engineers 2011 - All rights reserved - Do not reproduce without written permission. 5
Example Mass Reduction through HEPA s In Series Size Mass units Efficiency Mass units 0.1µ 1.0E-01 mcg/m 3 x 99.999% = 1.0E-06 mcg/m 3 0.5µ 1.0E+00 mcg/m 3 x 99.99000% = 1.0E-04 mcg/m 3 1.0µ 1.0E+01 mcg/m 3 x 99.99900% = 1.0E-04 mcg/m 3 5µ 1.0E+02 mcg/m 3 x 99.99990% = 1.0E-04 mcg/m 3 10µ 1.0E+03 mcg/m 3 x 99.99999% = 1.0E-04 mcg/m 3 Total 1.1E+03 mcg/m 3 4.0E-04 mcg/m 3 Size Array Evaluation Example - Total Mass Reduction from HEPA Filtration Example - Total Mass Reduction from HEPA Filtration Mass units Efficiency Mass units 0.1µ 1.0E-06 mcg/m 3 x 99.999% = 1.0E-11 mcg/m 3 0.5µ 1.0E-04 mcg/m 3 x 99.99000% = 1.0E-08 mcg/m 3 1.0µ 1.0E-04 mcg/m 3 x 99.99900% = 1.0E-09 mcg/m 3 5µ 1.0E-04 mcg/m 3 x 99.99990% = 1.0E-10 mcg/m 3 10µ 1.0E-04 mcg/m 3 x 99.99999% = 1.0E-11 mcg/m 3 Total 4.0E-04 mcg/m 3 1.11E-08 mcg/m 3 Unsurprisingly, two HEPA filters in series yield an 11 log reduction in contamination, reducing airborne contamination from about one milligram per cubic meter to about ten femtograms, far below limits of detection or concern for any material we've encountered. Assuming that the return air is representative of the airborne contamination level (normally expressed in mcg/m3) in the room, as measured or calculated... The first step in the process is to determine the Mixed Air concentration and account for differences between the concentration in the airstream coming from the room where the "contaminant" is being processed and any dilution that may take place prior to introduction into the room "being contaminated". Return Air Concentration mcg/cm 3 x % Return Air in supply = Mixed Air mcg/cm 3 The second step is to determine the protection from HVAC filtration according to the formula: Ambient Concentration mcg/cm 3 x Protection Factor = Exposure mcg/cm 3 Copyright Genesis Engineers 2011 - All rights reserved - Do not reproduce without written permission. 6
The next step in the process is to determine the ventilation rate or airflow of the room "being contaminated". Mixed Air Concentration mcg/cm 3 x Airflow m 3/ hr= Supply Air Product Rate mcg/hr Then the period of exposure in the room "being contaminated" is accounted for as: Supply Air Product Rate mcg/hr x Exposure Duration mcg / hr= Total Product Exposure mcg Next, an adjustment to determine the exposure per unit is applied, assuming uniform and full airborne contribution to the product "being contaminated" according to the formula: Total Product Exposure mcg / Total Units produced = Max. Potential Contamination/unit Finally, sensitivity analysis should be applied by testing assumptions around filter integrity and upset (e.g. spill) cases, to assure that the system is robust and that non-attainment cases are understood, to set process limits. Example Max. Airborne Cross-Contamination Potential Calculation Starting with an airborne contamination (after dual HEPA filtration) of 1,000 mcg/m3 a 100 m 3 room with a ventilation rate of 20 Air Changes per hour might have a maximum airborne cross-contamination potential as follows... Cross Contamination Potential Calculation Room Airflow Calculation Room Vol units Ventilation Rate units Airflow Units 1000 m 3 x 20 AC/hr = 20,000 m 3 /hr Total Airborne Product Calculation Airflow units Airborne Product Concentration units Airborne Product Rate Units 20,000 m3/hr x 1.10E-08 mcg/m 3 = 2.20E-04 mcg/hr Total Airborne Product Available for Cross-Contamination Airborne Product Rate units Exposure Duration units Total ProdUnits 2.20E-04 mcg/hr x 8 hr = 1.76E-03 mcg As this example shows, the total contamination available in our example case is less than 2 picograms over an 8 hour shift. Further dividing this by the number of units produced in an 8 hour period will likely yield an inconsequential mass/unit. Copyright Genesis Engineers 2011 - All rights reserved - Do not reproduce without written permission. 7
Other Factors to Consider While small particles (<10µ) are of interest in worker safety, due to their greater respirability, large (>10µ) particles are of greater interest in the prevention of cross contamination. This focus on large particles is due to: 1. Large particles represent the great preponderance of the mass of particles suspended in the air. 2. Their lower buoyancy (higher settling rate) makes them more likely to contaminate a product by falling out of an airstream as its velocity decreases in a production room (see graph below). 1.00E+00 Settling Velocities cm/s Size µ 0.1 1 10 100 1.00E-01 1.00E-02 1.00E-03 1.00E-04 1.00E-05 Settling Velocities cm/s The first of these facts is accounted for in our method, which models the mass of the airborne contaminant, not simply the particle count. It would be desirable to apply a reduction factor addressing the second item, accounting for the percentage of available airborne contamination that may be expected to actually settle on critical surfaces and contaminate a dose. However, since the data necessary to support these factors is difficult to obtain and particular to each product, absent the use of computational fluid dynamic models, it is reasonable to neglect this factor and accept the overstatement of potential contamination as a factor of safety. Conclusion The cross-contamination risk inherent in HVAC recirculation can be satisfactorily assessed using readily available information about the product and/or process, the HVAC system configuration and standard component performance information. Using the outlined method we can quantify the maximum cross contamination potential of HVAC system designs providing a rigorous method to assure control of airborne crosscontamination risk. Copyright Genesis Engineers 2011 - All rights reserved - Do not reproduce without written permission. 8