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GMP compliance in pharmaceutical manufacturing requires that any process, person, environment or equipment with direct impact on the quality and safety of the product being produced must operate within specified limits. These specified limits should be under the direct control of the manufacturing team, with countermeasures available in the event of a problem occurring. In addition to this, any other part of the production or storage processes that have an indirect impact must also be assessed for possible risk impact.
Humidity may not seem like an obvious cause of problems, or something that could even result in production being non-compliant, but this can and does occur. Many phenomena are influenced by the relative humidity level, and they can cause production processes to be less efficient, less predictable and more prone to producing out of specification products.
Some common issues that can arise from poor humidity control are:
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The figure below shows the influence on storage of a variety of materials as relative humidity changes. Bear in mind that storage in this sense is not restricted to just warehousing but also applies to any material, object or equipment that is stationary in a fixed location for extended periods. So think of this in the context of equipment and fittings within a pharmaceutical manufacturing plant.
Figure 1. Effect of RH% on materials in static locations.
It is important to note the relationship between relative humidity (RH%) and air temperature, variations in temperature will also affect the RH%. For example, a sufficiently large drop in air temperature can result in water vapour condensing out. Alternatively, cold surfaces will cause condensation to form if the surface temperature drops below the dewpoint of the air around it.
Looking at this from another angle, consider the following typical conditions found in areas related to solid dosage production:
Production area |
Temperature |
Humidity |
Weighing, Mixing |
20 to 22°C° |
35 to 40% RH |
Compression |
20°C |
25 to 35% RH |
Pan coating |
12 to 95°C |
10 to 70% |
Filling and Packing |
20°C |
10 to 35% RH |
Storage |
20 to 25°C |
45% RH |
From the table above, if the RH% levels therein are correctly maintained for the designated process and surrounding areas then no humidity related issues are likely to occur, either to the material being produced or the production equipment itself.
Of course, the actual required RH% values for any given process are dependent on many factors:
Therefore, in all areas of production, humidity levels should always be carefully considered, not just to suit the material being produced but to also take into account any other effects arising from unexpected RH% levels that could occur and potentially disrupt production.
So, the questions that pharmaceutical manufacturers have to ask themselves are:
Bearing all of the preceding points in mind, take a moment to ask yourself if you are experiencing moisture related production or quality problems in your production areas:
Even when all of these factors are taken into account, more radical action might need to be considered. Perhaps you need to go right back to the start and ask, “How was the RH% level for production and storage processes determined in the R&D phase?” Because it can sometimes be that the environmental conditions for producing a new product are adopted from a similar, existing product already in production based on the assumptions that:
Deviations from the desired temperature and humidity conditions must be minimised, controlled and documented. Unfortunately, temperature and humidity excursions are almost inevitable, but automated control of HVAC and humidity control systems will improve response and recovery, and can also provide historical and trend data to track these excursions.
Although minor deviations probably have no significant impact, however the effects temperature or humidity deviations on every item held in storage need to be considered. This can be a daunting task, as it is not unusual for warehouses to contain hundreds or maybe even thousands of different inventory items. It is also worth considering that new items will be added in future, which will require some form of assessment. The impact assessment therefore has the potential to become an enormous task.
It is easier to ensure temperature and humidity are controlled within defined limits (e.g. 22°C @ 50%R.H.) supported by automatically generated logs..
There are different ways to control humidity, or more correctly, to attempt to control humidity.
Using outdoor air for ventilation - Ventilation air must have a lower moisture content than the air within the building to be effective and is therefore at the mercy of changing weather and seasonal conditions.
For the most part, we should ignore using untreated outdoor air because of its variability. So let us look at other ways to treat the air either entering or already within the building.
This will lower the relative humidity but absolute humidity remains unchanged, there is still the same mass of water vapour and the dewpoint is unchanged. This might be a reasonable humidity control strategy if you need to heat the area for comfort, but in energy terms it can be relatively expensive.
Using cooling coils to reduce the air temperature below its dewpoint will lower the RH% after cold air is re-heated, and it will also reduce absolute humidity. However, efficiency falls significantly at air temperatures below 10°C. In addition to this, the inevitable condensation that forms on the cooling coils can become a maintenance issue if they are prone to corrosion. Finally, the wet conditions are a good breeding ground for bacteria and mould, which are definitely not wanted anywhere near pharmaceutical production.
This reduces both relative and absolute humidity, and also reduces dew-point while not being temperature sensitive (operating range is between +40°C to -40°C). Lower airflows can be used when compared to other methods of air treatment, resulting in energy savings. This form of humidity control is also very flexible when considering using multiple energy sources e.g. gas, steam, LPHW, etc. so available utilities and waste heat can be used. The system runs dry which reduces the possibility of microbial growth and maintenance arising from wet conditions, which can also translate to longer equipment life. Furthermore, this form of humidity control can dry down to a -70°C dewpoint which may be required for sensitive APIs.
With over 60 years of experience in pharmaceutical and other areas of manufacturing, Munters can provide desiccant dehumidification solutions as well as expertise and support to ensure your production remains GMP compliant. We are able to provide scalable systems that can be deployed in R&D, pilot plant and full scale manufacturing areas, ensuring that your investments of time and effort can be leveraged as you move from limited production for testing and trials through to full production.
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