In pharmaceutical, vaccine, and sterile manufacturing, the cleanroom environment is the major predicate for all manufacturing activity: without a proper background environment, no medicine can be produced for patient consumption. Today, there are a myriad of details individually assessed when building a new cleanroom or retrofitting an old one. Examples include construction materials, differential pressures and airflows, ergonomic features, and even lighting. There are reams of specifications for modular walls, air handling units (AHUs), flooring systems—the list goes on. Before the design team dives into those specifications, from the entry to the cleanroom to the exit from it, they must identify the real intentions for, and purpose of, the cleanroom.
The intentions and purpose are the reality of stable, reliant, and compliant operation within a tightly controlled and monitored environment. Different companies call this data by different names, such as Operational Philosophies or User Requirements (User Requirements will be used here). Functionally, this data should be captured in a document during the concept phase of the project, the content of which is agreed upon by the chartering team and is the foundation of all subsequent design activities.
A particular challenge for the Quality role on any project is defining User Requirements that are based on regulatory needs (published requirements, industry knowledge of agency action, or other sources). There are some simple regulatory requirements for airlocks that can inform early design. However, these requirements can often drive teams to focus on minute details before a holistic understanding of the requirements has been developed. For example, an FDA Guidance for Industry1 states: “Air change rate is another important cleanroom 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.
Here is the risk: in doing that, the team has circumvented the appropriate User Requirement process. Whenever that occurs, it is possible to commit to delivering a project at a target cost or on a target schedule without understanding all drivers. To uphold the true intentions and purpose of the cleanroom, the Quality need is that the number of air changes in any room must adequately protect the product. In the airlock example above, if materials are being cleaned, decontaminated, and/or debagged for a demanding and continually-fed process, there is a chance that 20 air changes will not be adequate to maintain an active Grade C specification. Multiple people ripping open plastic bags and spraying disinfectant will certainly create a particle-rich environment.
Further, Annex 1 in the Eudralex2 states: “Adjacent rooms of different grades should have a pressure differential of 10-15 pascals (guidance values).” Increasing differential pressure increases cost, so a project at or above the financial target may be tempted to state that a basic design of 10 Pa between grades meets the requirements. Whereas this is literally true, the real activity must be analyzed to ensure sufficient protection of the controlled environment. If, on one side of the airlock, washed materials are being packaged for sterilization and, on the other side of the airlock, an open transfer of process waste is occurring; a differential pressure of 10 Pa alone may not suffice in overcoming acceptable risk to the process. A true requirement here may have read “the differential pressure between adjacent rooms must be sufficient to ensure protection of critical process functions from support functions.”
The regulations referenced here are atypical as they provide a specific quantified value for the design team to use. More often, a regulation reads like this: “There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mixups during the course of…procedures.”3 Working from an idea such as this can help deliver a project that runs like a clock, with no wasted motion or undue effort spent on manual segregation of materials. But when the question is asked “Does this design meet the regulations?” Quality and the other Users must stand behind the robustness of their design.
Whether qualified or quantified, regulations are only a starting point. They must be met, for sure, but 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.
One of the necessary realities of a cleanroom (but one that is rarely anticipated) is that the doors that lead to production space can be just as damaging to reliable supply as a sterilizing autoclave that fails a vacuum hold once a week. A careful study, starting from the User Requirements and ending with a stable, reliant, and compliant facility must be started at the concept phase of the project and be continually revisited throughout design.
Here is a basic roadmap for obtaining those solutions.
Step 1: Identify Basic Requirements: For any process, people and materials will need to be moved into the controlled space. So, as a basic User Requirement, the entry airlocks must accommodate the number of people and the amounts and types of material needed to produce at stated capacity. At this first level, any special needs should be identified, such as cold-chain management, non-routine gowning needs (e.g., Universal Design for differently-abled personnel), or special containment for live viruses or beta-lactams. In this first step, the Users must make clear that not only must the process run as intended, but the process must have supporting infrastructure to run as required.
Step 2: Quantify Requirements: The need described in Step 1 must now be quantified. Working backward from peak consumption of all materials, the Users can define a steady-state and worst-case schedule for material movement into the controlled environment. Examples of typical items for vaccine and bioprocess manufacturing are bags, bottles, or cell factories, vessels used for storage or movement of liquids, filters, and separation technologies. No single item from this list would pose a problem for an airlock of almost any size. However, the rhythm of production could call for some amount of all of these items to be in the cleanroom at the same time (a real worst-case scenario). If large items are potentially in scope, the working height and width of those items are exceedingly important. If doorways or corridors have insufficient clearance for tanks or carts, demolition and more construction will be required, adding cost and schedule. Having a basic understanding of equipment, tools, and volumes in the late stages of the conceptual design will save hours of difficult discussions later in the project when changes are more expensive.
Personnel movement can be just as complex. Biologic processes can often run for weeks on end and require constant monitoring. Thus, at a shift change, a bolus of people needs to get into the cleanroom as quickly as possible in order to relieve those at the end of their shift. As has been stated often,4 humans are the highest risk for contamination in a cleanroom. The size, air change rate, and air flow direction in a personnel airlock is key to protecting the processing spaces.
Step 3: Additional Characteristics, Links to Other Needs: Now that the variety and amounts of material are known, attention must be paid to the actual activity taking place in the airlock. How is cleaning and disinfection handled? How are the material lot numbers tracked? How will the material be used once it leaves the airlock: immediate use in production or stored in the cleanroom as a kit? The high-level coldchain and containment requirements listed at Step 1 must now be fully detailed as well. Depending on the process, there may be some material that requires a temperature-controlled environment, so a hand-off controlled temperature unit (CTU) may need to fit in the airlock.
In the vaccine industry, the products prevent disease. Every dose released to the market is potentially one more life that will not be affected by measles, human papillomavirus, hepatitis A, or the host of other illnesses vaccines prevent. With that as the driver behind our industry, starving a production system because airlocks are undersized for material transport or personnel movement is inexcusable.
When viewed through a holistic lens of User Requirements, the needs of Operations, the needs of the Process, and the needs of Quality blend into one true requirement for a quality product. Supporting documentation may be found in regulations or in journals such as this, but all of the best guidance in the world is useless until the User Requirements are fully defined by a cross-functional group of stakeholders.
References:
- Guidance for Industry Sterile Drug Products Produced by Aseptic Processing— Current Good Manufacturing Practice, September 2004, p. 7.
- EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products (corrected version); 25 Nov 2008, Item #53.
- U.S. Code of Federal Regulation, 21 CFR 211.42(c)
- See Controlled Environments, v13, No. 9, From the Editor for one recent example.
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