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. In addition, 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. Just because one does not see an issue doesn’t mean there isn’t a problem. 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 products that don’t meet specification.
Some common issues that can arise from poor humidity control are:
Figure 1 shows the influence on storage of a variety of materials as relative humidity changes. Storage in this sense is not just restricted to warehousing, but also applies to any material, object, or equipment that remains stationary in a fixed location for extended periods. So, think of this also 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, as variations in temperature also will affect the RH%. For example, a sufficiently large drop in air temperature can result in water vapor condensing out. Alternatively, cold surfaces will cause condensation to form if the surface temperature drops below the dew point of the air around it.
Humidity in Manufacturing Areas
In pharmaceutical manufacturing, quality and consistency are key. Consider the following typical conditions found in areas related to solid dosage production:
|Weighing, Mixing||68 to 72°F (20 to 22°C)||35 to 40% RH|
|Compression||68°F (20°C)||25 to 35% RH|
|Pan coating||53 to 203°F (12 to 95°C)||10 to 70% RH|
|Filling and Packing||68°F (20°C)||10 to 35% RH|
|Storage||68 to 77°F (20 to 25°C)||45% RH|
Figure 2: Typical conditions in solid dosage production.
From Figure 2, 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 produced or the production equipment itself.
Of course, the actual required RH% values for any given process are dependent upon many factors, including:
Often, issues can arise when there has been some change made to the manufacturing conditions, such as a new product formulation, the use of different fillers, or adding staff on the plant floor. Introducing a few extra tons of materials or adding additional personnel in the space will alter the load on the air handling system and result in humidity issues.
Therefore, in all areas of production, humidity levels always should be carefully considered, not just to suit the material being produced, but also to take into account any other effects arising from unexpected RH% levels that could occur and potentially disrupt production.
So, the questions that pharmaceutical manufacturers must ask themselves are:
Bearing all of the preceding points in mind, take a moment to consider if you are experiencing moisture related production or quality problems in production areas. Issues may arise based on a number of factors:
Figure 3: The angle of repose of a powder or granulate is the steepest angle of descent or dip relative to the horizontal plane to which a material can be piled without slumping. Often a measurement is taken in pre-production as a quality check to ensure material is flowing as it should.
Even when taking all of these factors into account, more radical action might be needed. It may be appropriate 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?”
In some cases, the environmental conditions for producing a new product are adopted from a similar, existing product already in production based on the assumptions that:
Storage and Warehousing
It is important to consider a pharmaceutical product’s exposure to humidity throughout the entire production process. In storage and warehousing, deviations from the desired temperature and humidity conditions must be minimized, 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 also can provide historical and trend data to track these excursions.
Although minor deviations probably have no significant impact, it’s important to consider the effects of temperature or humidity deviations on every item held in storage. This can be a daunting task, as it is not unusual for warehouses to contain hundreds or even thousands of different inventory items.
It also is worth considering that new items will be added in the 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. 72°F/22°C at 50% RH) supported by automatically generated logs. Keep in mind that varying air handling strategies may be necessary based on the location and local environment of each storage facility.
Psychrometrics and Humidity Control
There are different ways to control humidity, or more correctly, to attempt to control humidity.
One way is using outdoor air for ventilation. With this method, the 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.
Thus, for the most part, we should ignore using untreated outdoor air because of its variability. Instead, let’s review more effective ways to treat the air either entering or already within the building. These methods include:
Once a target RH range is specified for a facility, those set points should be maintained for quality and consistency in production. Implementing an effective humidity control strategy in pharmaceutical production and storage will ensure year-round GMP compliance and enhance product safety.
About the Author
Martin Ginty is Global Pharmaceutical Industry Manager for Munters, a provider of air treatment solutions for humidity and climate control. He has more than 20 years of experience in implementing national and international level automation and HVAC projects.
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