Martin Ginty, 蒙特全球制药行业总监：Humidity control for GMP compliant production

Humidity control for GMP compliant production

通过湿度控制实现GMP合规生产

Martin Ginty, 蒙特全球制药行业总监

Martin Ginty, Pharmaceutical industry director of Munters

郑丽丽，蒙特中国制药行业应用工程师

Lili Zheng，Pharmaceutical industry application engineer of Munters

摘要/ Abstract：

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. Humidity can be a problem, and can result in non-compliant production，resulting in a series of problems. According to the temperature and humidity requirements of each production area, we can use different psychrometrics and humidity control methods to control the temperature and humidity in each production area within a reasonable range, so as to ensure that each production link can meet the requirements of GMP operating environment. 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.

药品生产质量管理规范（GMP）要求对于药品的质量和安全性有直接影响的工艺、人员、环境或设备必须在指定范围内进行操作。如果湿度不满足生产工艺的要求，进而会造成生产不合规的情况，产生一系列的问题。我们可以根据各个生产区的温湿度要求，采用不同的焓湿和湿度控制方法，将各生产区的温湿度控制在合理的范围之内，从而保证各个生产环节能够满足GMP的操作环境要求。凭借60多年的制药行业和其他领域生产经验，蒙特可以提供干燥除湿解决方案以及相关专业知识和支持，确保您的生产符合GMP规定。

关键字/Key Words：

GMP  生产工艺 温湿度要求 焓湿和湿度控制 蒙特 干燥除湿解决方案

GMP  production process  Temperature and humidity requirements  Psychrometrics and humidity control    Munters   desiccant dehumidification solutions

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 limits are controlled by the manufacturing team, with countermeasures available in the event of a problem occurring. Any other indirect production or storage processes must also be assessed for possible risk impact.药品生产质量管理规范（GMP）要求对于药品的质量和安全性有直接影响的工艺、人员、环境或设备必须在指定范围内进行操作。这些指定范围由生产团队规定，并且有相应的解决问题的对策。对于药品质量和安全存在间接影响的生产或存储工艺中的任何其它部分，也必须评估可能的风险影响。

Humidity can be a problem, and can result in non-compliant production. Uncontrolled humidity levels can affect production processes and lead to producing out of specification products.
如果湿度不满足生产工艺的要求，进而会造成生产不合规的情况。未经控制的湿度水平会影响到生产工艺，致使生产出不合格的产品。

Some common issues that can arise from poor humidity control are:湿度控制不当造成的一些常见问题有：

 The figure below shows the influence on storage of a variety of materials as relative humidity changes:下图显示了相对湿度变化对于各种物料存储的影响：

The relationship between relative humidity (RH%) and air temperature is important, variations in temperature will also affect RH%. For example, temperature drops or cold surfaces can result in condensation.相对湿度和气温之间的相对关系很重要，气温变化也影响相对湿度。比如，温度下降或表面寒冷会使相对湿度上升，有可能会造成冷凝。

Humidity in manufacturing areas各个生产区的温湿度要求

Look at the following typical conditions found in areas related to solid dosage production:固体药剂生产相关区域的常见温湿度条件见下表：

When RH% levels are correctly maintained for the designated process areas then humidity related issues are unlikely to occur, either to the product or the production equipment itself. The required RH% values for any given process are depend on:若指定工艺和周围区域保持在正确的相对湿度水平，那么就不会给正在生产的物料或者生产设备造成湿度相关的问题。特定工艺所需的相对湿度值取决于多种因素：

{C}o {C}The materials being used (APIs, excipients).所用的物料（原料药、辅料药）。

{C}o {C}The manufacturing space, location, climate, etc.生产空间的地点、气候等。

{C}o {C}Standard Operating Procedures.标准操作规程。

{C}o {C}GMP specified values which may be influenced by other factors.可能受到其它因素影响的GMP特殊规定。

Therefore, in all areas of production, humidity levels should always be carefully considered for optimal product quality. 因此，在所有生产区域中，应始终认真考虑湿度，以达到最佳的产品质量。

Ask yourself: 自问问题：

{C}o {C}Do the RH% levels within my facility exceed GMP specified values at any time?我的设备中的相对湿度是否在任一时间都满足GMP规定要求？

{C}o {C}If they do, for how long? What is the recovery time to return to the specified value?如果超不满足，持续了多长时间？恢复到规定值需要多长时间？

{C}o {C}What is the impact of this and do I need to react to this?这有什么影响，我需要对此采取应对措施吗？

{C}o {C}Is recovery time fixed or variable?恢复时间是固定的还是可变的？

… and maybe you experiencing moisture related production or quality problems:可能您正面临着湿度相关的生产或质量问题：

{C}o {C}The flow of API and excipients is not as expected. 原料和辅料药的流动性没有达到预期水平。

{C}o {C}Variations when weighing of batches of raw materials or finished product that could be caused by fluctuations in water content.称重一批原材料或成品时，存在可能由于水分含量变化而引起的重量变化。

{C}o {C}Signs of clogging, caking or other obstructions in silos, bins, pneumatic transport pipework and process equipment?有堵塞、结块或其它的料仓、料箱、管道和工艺设备障碍的迹象吗？

{C}o {C}Consideration should be given to moisture-permeable containers for packaging.在包装时应考虑是否使用可渗透水分的容器。

{C}o {C}APIs and excipients that are prone to hydrolytic degradation.容易发生水解降解的原料和辅料药应特别关注。

Even when all of these factors are taken into account, 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?” 即使考虑到所有这些因素，或许也需要溯本求源并自我提问，“生产和存储工艺的相对湿度水平是如何在研发阶段确定的？”

Storage and Warehousing储存和仓储

Deviations from the claimed 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. 与理想温度和湿度条件的偏差必须降到最低，加以控制并记录在文件中。不幸的是，温度和湿度偏差几乎是不可避免的，但是HVAC的自动控制和湿度控制系统可提高响应和恢复的快捷度，而且能提供历史和趋势数据，并对这些重大偏差进行追踪。

The effects temperature or humidity deviations on every item held in storage need to be considered. This can be a daunting task for warehouses to containing hundreds or maybe even thousands of different inventory items, with more new items coming in future. The impact assessment therefore has the potential to become an enormous task.需要考虑温度或湿度偏差对于存储的每种物品的影响。对于仓库来说这是一项艰巨的任务，因为它要包含数百种甚至上千种的不同库存项目，而且未来还会存放新的项目。因此，影响性的评估有可能成为一项艰巨的任务。

It is easier to ensure temperature and humidity are controlled within defined limits, supported by automatically generated logs.使用自动生成日志，更容易确保将温度和湿度控制在规定范围内。

Psychrometrics and humidity control焓湿和湿度控制

There are different ways to try to control humidity.可尝试使用不同的方法控制湿度。

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. So, let’s ignore using untreated outdoor air because of its variability and look at other ways to treat the air either entering or already within the building.使用室外空气通风——通风气流的水分含量必须低于建筑内空气中的含水量才有效，因此，它会受天气变化和季节性条件的影响。所以，我们不使用未经处理的室外空气，因为它具有可变性，并考虑处理进入建筑或者已存在于建筑中空气的其它处理方法。

Heating – This lowers the relative humidity but not the absolute humidity, there is still the same mass of water vapour and the dewpoint is unchanged. This might be a reasonable approach if you need to heat the area for comfort, but it can be relatively expensive.加热——可降低相对湿度，但不会改变绝对湿度，水蒸气的质量不变，结露点也未改变。如果你需要加热某个区域以达到舒适效果，这可能是一种合理的湿度控制策略，但费用相对昂贵。

Cooling– 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, condensation on the cooling coils can lead to corrosion and the wet conditions are a good breeding ground for bacteria and mould.冷却——使用冷却盘管先把空气温度降到露点以下，使冷凝水析出，然后升高气温就可以使相对湿度降低。但是当温度低于10℃时，效率会显著降低。此外，冷却盘管冷凝会造成腐蚀，而且潮湿条件是细菌和霉菌滋生的温床。

Desiccant dehumidification – This reduces both relative and absolute humidity, and also reduces dew-point without being temperature sensitive (operating range is between +40°C to -40°C), while the lower airflows result in energy savings. Multiple energy sources are possible 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. 干燥除湿——可降低相对和绝对湿度，还能降低结露点，同时适用的温度范围广（操作范围在+40℃至-40℃），而且所需风量小，有助于节能。可以使用多种能源，比如电、蒸汽、燃气、低温热水等，所以可以利用可用的公用设施和废热。系统干燥运转能降低因潮湿条件引起的细菌滋生和维护可能性，进而延长设备的使用寿命。而且，这种湿度控制方法可以做到在-70℃结露点（对于某些敏感原料药)进行干燥.

In closing结语

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.凭借60多年的制药行业和其他领域生产经验，蒙特可以提供干燥除湿解决方案以及相关专业知识和支持，确保您的生产符合GMP规定。我们能够提供多种系统，可以应用到研发、试点工厂和各种规格生产区中，确保您在从生产测试和试验的有限生产到全面生产的过程中投入的时间和精力能得到充分利用。