In this two-part blog we’re discussing air handling systems in pharma; also referred to as HVAC systems. HVAC is an abbreviation for; heating, ventilation and air conditioning. A few basic concepts will be touched upon. These basic concepts include;
- The need and reason for pharmaceutical HVAC systems
- Technical requirements for HVAC systems
- Different types of HVAC systems
- Qualification and monitoring requirements
This part will examine the need and reason for pharmaceutical HVAC systems.
As we all know, there are a number of factors that attribute to the quality of pharmaceutical products. These factors include the personnel, procedures, validation and the manufacturing environment. Any inadequacies in the above factors will lead to sub-standard (non-GMP compliant) products.
The manufacturing environment
Nothing is as critical to product quality as the manufacturing environment. There’s a great deal of environmental factors affecting the product such as light, temperature, humidity, air movement and microbial contamination.
When we have an uncontrolled GMP manufacturing environment it can lead to product degradation. Which in turn leads to product contamination and loss of profits for the company.
We must design GMP manufacturing environments that prevent cross-contamination:
Contamination of a starting material, intermediate product, or finished product with another starting material or product during production.World Health Organization – Glossary
If we want to prevent cross-contamination, we first have to identify where cross-contamination originates from. It’s always easy to point to the personnel in a GMP environment as humans are often the largest source of contaminants in a GMP facility.
But there are many other factors at play, some examples of these factors are;
- Poorly designed air handling systems and dust extraction systems
- Poorly operated and maintained air handling systems and dust extraction systems
- Inadequate procedures for personnel and equipment
- Insufficiently cleaned equipment
We must also make a distinction between “regular” contamination and cross-contamination. When equipment produces dust during production, it’s contaminating the environment and possibly the product, but technically it’s not cross-contaminating when we have dedicated production rooms with proper line-clearance in between production runs.
The problem occurs when lines start crossing. When equipment is used for multiple product types and line-clearance is failing. Or when products cross each other in corridors for example. The image below clearly shows the difference between contamination and cross-contamination.
So, how can we reduce/minimize cross-contamination? Obviously, if you still have a choice, by ensuring a proper GMP compliant design of your facility. If there are man, material, product and waste flows for different products that do not intersect you have eliminated 50% of the problem. The other 50% can be solved by ensuring:
- Proper personnel procedures
- Adequate premises
- Use of closed production systems
- Adequate, validated cleaning procedures
- Appropriate levels of protection of the product
- Correct air pressure cascades
Level of protection
The concept of “Level of Protection” helps you define the environmental requirements from a patient-perspective. Besides this, it helps to prevent contamination and cross-contamination whilst producing under optimal hygiene conditions.
Level of Protection takes the product’s sensitivity to contamination and the “therapeutic risk” into account. In short, your level of protection depends on the product and the environment required to produce safe medicine. It can be illustrated by the line diagram below.
When you’re defining Levels of Protection you have to define the following parameters;
- Air cleanliness requirements (filters type and position, air changes, air flow patterns, pressure differentials, contamination levels by particulate matter and micro-organisms)
- Personnel and material transfer methods
- Permitted operations
- Building design and finishes
All operations within a pharmaceutical facilility must be correlated to well-defined cleanroom classes, and can be included in a hygiene concept. Your hygiene concept should be easy to comprehend and provide a solid overview of “what happens where”. You can use the table below for reference.
|Washing of containers||X|
|Preparation of solution for terminal sterilisation||X|
|Preparation of solutions for aseptic filling||X||X||X|
|Depyrogenisation of containers||X|
|Filling for terminal sterilisation||X|
|Filling for terminal sterilisation||X|
Based on the cleanroom class requirements defined in your hygiene concept, various Levels of Protection have to be created. These must include;
- Correlation between process operations and cleanroom classes
- Type of operation permitted in each Level of Protection
- Definition of cleanroom class (parameters, building materials,
- room requirements, HVAC systems)
- Requirements for personnel and material in the different classes (clothing, training, type of materials, etc.)
- Requirements on entry conditions for personnel and material ( change procedures )
- Number of particles in the air
- Number of micro-organisms in the air or on surfaces
- Number of air changes for each room
- Air velocity
- Air flow pattern
- Filters ( type, position )
- Air pressure differentials between rooms
- Temperature, humidity
Part 1: Conclusion
Air handling systems are the main tool for reaching the required parameters in GMP cleanrooms. But you cannot assess them as a standalone item. HVAC systems in a GMP environment are insufficient to achieve a certain grade of cleanroom class/product quality, they must always be accompanied by additional measures. These measures can include personnel qualification, limiting the amount of operations performed in a room, etc.
In the second part of this post we will the technical requirements, the types of HVAC’s and more.