In Pharmaceutical, Bio-Pharmaceutical and sterile manufacturing, the clean room environment is the major prerequisite for all manufacturing activity: without a proper movement mechanism & background environment, no medicine can be produced for patient consumption.
The intentions and purpose are the reality of stable, reliant, and compliant operation within a tightly controlled and monitored environment. Tight User Requirements or Design Philosophies must be written or inked down before building Airlocks in clean rooms. The challenge for any Quality unit is to define URS based on regulatory considerations when the facility exports a product in different regulatory areas.
FDA Guidance
FDA Guidance for Industry states:
“Air change rate is another important clean room design parameter. For Class 100,000 ( ISO 8 ) supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically acceptable.” Design requires hard numbers, so there is temptation for the design team to use this statement as a final Quality position—that 20 air changes is acceptable in a Grade C area.”
To design such an air lock one should consider that the quality of product should not get compromised when materials cleaned, Decontaminated, Debagged & when the plant is operated continuously. In such a scenario it is evident that 20 Air changes may not be sufficient to maintain Grade C specifications as multiple particulates are generated by various operations such as debagging, disinfecting etc.
Fit For Purpose
Adjacent rooms of different grades should have a pressure differential of 10-15 pascals (guidance values) and 12.5 Pa between a classified and non-classified room.
This is the EU requirement. Increase of differential pressures might increase the overall costs for constructing many air locks in the facility. One must not get tempted to look about the basic requirement of 10 Pa. This might give a bigger headache when materials are being packed for sterilization process and other open transfers posing a direct risk. A perfect design must fit for the purpose i.e “the differential pressure between adjacent rooms must be sufficient to ensure protection of critical process functions from support functions.”
Regulators will also look for “The separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mix-ups during the course of…procedures.” Quality unit and the other Subject Matter Experts (SME/Users) must stand behind the robustness of their design.
Quality Design
Regulations are only a starting point & must be met. A strong scientific and engineering rationale is what makes a Quality design requirement. When these regulations are laid out in a forum of operational needs and technological/ process requirements, very often a simple, robust, and elegant solution for many problems can be found.
The new concept is that companies are constructing multi-use manufacturing facilities capable of producing two or more products simultaneously. This refers to a situation where a manufacturer of medicinal products produces two or more products within the same facility either concurrently or on a campaigned basis. This must be designed to facilitate for working with live cells and inactivated products which needs strict containment & Regulatory issues for both personnel safety and cross contamination between areas and products.
Cross Contamination
The following key factors are considered to minimize the chance of cross contamination between different production areas, and consequently the product:
- The engineering design;
- Use of functionally closed process systems;
- Air handling systems segregation;
- Procedural separation of production activities;
- Personnel flow, product flow, clean/dirty equipment flow;
- Gowning regime;
- Validated cleaning and changeover procedures.
Airlock Designs
In general, there are three basic airlock designs that can be combined or used individually to protect the clean room and/or prevent cross contamination between two adjacent areas of different process operations served by two different HVAC systems. These three airlock systems are:
- The cascading pressure airlock
- The pressure bubble
- The pressure sink
Cascading Pressure Airlocks
The cascading pressure airlock is used to protect clean areas from adjacent areas with lower required cleanliness. Normally, in this type of airlock, the movement or transfer from the cleaner area to the lower classified area or Hallway which does not pose any issue with cross contamination.
Pressure Bubble
The pressure bubble airlock is used to create a barrier between the clean room where the process resides and the adjacent area or area with lower air classification. As the name implies, this type of airlock is a pressurized space that pushes the air out and into both the areas it protects. This type of airlock creates a barrier between the two spaces it serves, thus preventing cross contamination.
Pressure Sink
The pressure sink airlock is used to create a barrier between the clean room where the process resides and the adjacent area or less classified area. This type of airlock is a negatively pressurized space that pulls the air in from both the process area and the adjacent space thus creating a barrier between the two spaces it serves.
A combination of sink and bubble air lock design is also used for creating a barrier between Potent compound or bio-contained clean areas and the adjacent space.
Good Airlock Design
Identifying Requirements: The basic airlock requirement is where people and materials movement must be properly spaced to accommodate that daily capacities and also for special purposes for movement of equipments during emergency break downs. Some needs such as Col-chain management, special gowning needs, Containment of Bacteria , Live virus , CHO cells, Potent compounds & Beta Lactums. In the basic stages the users must make clear that along with process the supporting infrastructure must run as desired.
Quantify Requirements: A quantification of the above must be done in this phase. The SME’s must work on backward calculation starting from Peak consumption of all working materials and also defining a steady state and worst case schedules for the men and material movements into the controlled areas. These includes how many bags, Vessels, men, Utensils, Disposable and Reusable filters, Sterilized tubing, storage of liquids, toxoids and solutions and different sizes of adjuvant blend material moments along with the frequency of movement based on hours or Half day schedules. If large items are potentially in scope, the working height and width of those items are exceedingly important. Doorways must be sufficiently designed to prevent any breaking down of walls or doors after construction is done. The whole process needs proper knowledge of Tools & equipments used in the production and process operations.
Personnel movement will be just as complex as the movement of materials as it varies from type of operation and product that is manufactured in the facility such as Vaccines & Potent compounds. Vaccine production process may run days or weeks. In such an event the peak movement load and shift change loads must be properly noted. During such events proper lighting, size of airlocks, air change rate and air flow direction in a personnel airlock are the key issues to be focused.
Additional Needs: Now that the variety and amounts of material are known to move thru the airlocks. Large attention must be paid on such activities, Cleaning and disinfection activities, how such activities are handled and how the materials are tracked with lot numbers. Attention must be paid to the actual activity taking place in the airlock. How material enters and leaves the air locks into controlled areas must be clearly stated and usage of any kits for such activities must be stated. Depending on the process, there may be some temperature sensitive material, requires a temperature-controlled environment, so a hand-off controlled temperature unit (CTU) may need to fit in the airlock.
Conclusion
Pharmaceutical and Biopharmaceutical industries are meant to treat diseases and also give immunity for patients from dangerous diseases. A proper design must ensure that clean and sterile products are produced preventing any re introduction of bacteria or allergens or any disease causing materials into the systems, materials and process.
A proper URS and Subject matter expertise is the need of the hour to design, Qualify and operate such Clean room facilities with good airlocks, In one say we would call Air Locks are ventricles of heart. If they fail the whole system collapses.
