Cleanrooms for the Manufacture of Sterile Drug Products
By Jeffery N. Odum, Gilbane Process
The cleanroom is an integral part of the manufacturing process required to produce sterile drug products. While many of the advances in cleanroom design have been the result of issues related to the semiconductor industry, the pharmaceutical industry has many unique and challenging issues for the cleanroom designer. Even though both industries define Federal Standard 209E as a design basis, significant product and regulatory issues must be addressed when developing the design of a cleanroom for a pharmaceutical or biotech facility that will produce sterile drug products through aseptic manufacturing.
Design basis
The primary focus of cleanroom design and operation in the semiconductor industry is to decrease the size and number of particles that can deposit on circuits and damage or destroy the finished product. Focusing on particle removal, area classifications from 209E of Class 10 or Class 1 are the norm.
Sterile drug products typically require cleanroom classifications of Class 100,000 to Class 100, which are far less stringent than those found in the semiconductor industry. But the focus of sterile drug product cleanrooms is the removal of particles classified as viable organisms– those organisms which can reproduce (colony forming) under the proper environmental conditions.
Parenteral products are defined as those drugs that are injected directly into the blood stream, bypassing the body`s defense mechanisms, normally triggered through the digestive system when taking oral medications. To be effective and to prevent any reactions within the patient, these drugs must be sterile–free from any viable organisms. So, while the pharmaceutical and biotech industries may be less concerned with removing all particulate matter, the composition of contaminants must be carefully monitored and controlled. A simple analogy would be that while a cleanroom consistently operating at 10 particles/ft3 is a success by Federal Standard 209E, if only one of those particles is a colony-forming unit, the room would be a failure.
Regulatory issues
Another differentiation of the sterile product cleanroom comes from the regulatory requirements of the pharmaceutical industry. The manufacture of human drug products is regulated under the Food, Drug and Cosmetic Act. The legal basis of the Food and Drug Administration`s (FDA) enforcement powers is derived from this federal law. In turn, the FDA`s enforcement processes are derived from regulations issued by the agency under the Code of Federal Regulations (CFR). For pharmaceutical manufacturing facilities whose purpose is “the manufacture of drug products for human use,” these are found in CFR 21, parts 210 and 211, known as current Good Manufacturing Practices (cGMPs).
So how does all this relate to cleanroom design? Within the GMPs, there are specific guidelines related to the design and operation of cleanrooms. Specific examples taken from the GMPs are:
“Aseptic processing, which includes as appropriate: Temp erature and humidity controls…an air supply filtered through HEPA filters under positive pressure…a system for monitoring environmental conditions.” [1]
“Adequate ventilation…” [2]
“Floors, walls and ceilings of smooth, hard surfaces that are easily cleanable. [3]
“Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature…” [4]
The biotech industry now brings with it another set of concerns related to the safe handling and release of genetically engineered organisms. The National Institute of Health (NIH) issues biological containment guidelines for dealing with these types of organisms. For example, a cleanroom can be considered “secondary containment” for a closed manufacturing process. The designers must then resolve the conflict between the use of positive room pressurization for cleanliness under GMP and negative room pressurization for containment purposes under “event” conditions, as defined by NIH biocontainment standards.
Since many biotech products are heat sensitive, product stability requirements may require specific temperature and humidity levels during processing and storage. The need for cleaning and sanitizing to meet GMPs will also have an impact on cleanroom finishes, based on the cleaning regime required.
Compliance to GMPs is not a matter of choice. Compliance must be validated through written documentation that is auditable by the FDA and controlled by the facility operator. The FDA`s legal powers of inspection, proscription and punishment add significant costs to cleanroom projects, due to the expenses related to validation. These can range anywhere from three to ten percent of the total installed cost of the project.
Design Issues
Cleanroom design for sterile drug product manufacturing relies on criteria defined in relation to the products(s) being manufactured and the process(es) used to produce them. Early in the programming of cleanroom spaces, decisions must be made regarding the classification of rooms. These decisions are impacted by:
the number of products in the facility
types of products
asepticity of the environment
process support requirements, such as sterilization of incoming and outgoing materials, gowning requirements and pressurization levels
temperature and humidity requirements
containment considerations.
Still today, the majority of pharmaceutical process operations involve significant interaction of employees inside the cleanroom to perform the various manufacturing, quality control, validation and maintenance functions. Because of this, the importance of the filtration system, the control of temperature, and the pressure differentials between spaces are important.
People are the largest generator of particles inside this type of cleanroom. The airflow and filtration system of the cleanroom must provide sufficient air changes for particle removal under operational as well as static conditions. One critical aspect in the design of the airflow system is to maintain low face velocities for return air. By limiting the space available for return air, as a function of room layout and equipment placement, the designer can create situations resulting in excessive turbulence in Class 10,000 and 100,000 areas, as well as early flow separation and turbulence in Class 100 areas, where final product filling operations routinely occur.
As gowned personnel work in these areas, they tend to perspire, causing them to shed particles and bacteria from their skin, increasing bioburden levels within the cleanroom. The HVAC system must be designed to control temperature and humidity to eliminate this situation as much as possible.
Because of the dependence on people in pharmaceutical process operations, there is also significant personnel and equipment movement between cleanroom areas which, in many cases, will be operated at different classification levels. Air pressure differentials are used to isolate and/or contain critical spaces. The effective use of cascading pressures–from high (critical) to low (less critical)–and personnel and equipment airlocks is required to maintain the standard 0.05″ wg. recognized in the United States.
Containment areas are normally designed to operate at negative pressures relative to surrounding areas in order to reduce the spread of organisms in case of the failure of a primary containment system. Since most GMP operations are executed under positive pressure, if a containment area is located within a cleanroom, a zone of negative air pressure will be required. If these two air zones were to come in contact, the GMP (cleanroom) zone would become depressurized, contaminating the entire area. The integrity between these two air spaces is also important during decontamination of the containment area, to ensure a tight shutoff of the air supply and exhaust.
Construction issues
GMP requirements for cleanliness and maintaining clean conditions dictate the use of cleanroom materials and finishes that are smooth, hard, chemically inert, and which provide acceptable resistance to process and cleaning chemicals. Particular attention should also be paid to impact strength, wear, and particle generation characteristics. The major concerns of material selection focus on the housekeeping procedures implemented. All cleanroom surfaces will be cleaned frequently by wipedown, washing with wet mops, or spraying, in many cases, with chemicals that could be considered aggressive cleaning agents.
Frequent movement of equipment, such as portable tanks and skids, to support the process will require strong, impact-resistant materials with durable wall and corner guards to prevent damage from the errant, runaway vessel.
Artchitectural details of the pharmaceutical cleanroom must focus on eliminating areas of contamination ingress/egress and areas promoting stagnation or particle buildup, while minimizing to the greatest extent possible surfaces that will attract and/or collect particles. It is, therefore, important to provide seamless construction in door and window frames by requiring welded jambs and sealable hardware cutouts. Require the use of electric boxes without knockout plugs, and be sure that for custom-built construction, walls are sealed above the ceiling to prevent the propagation of dust and debris between walls. Also, be sure that fixtures within the cleanroom are provided with gasketed seals.
Qualification
GMPs require validation of cleanroom design from both a construction and operational standpoint. Validation involves three levels of qualification: installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ).
Installation Qualification: Documentation that the HVAC system is installed in accordance with approved design drawings and specifications, regulatory codes, and that the manufacturer`s installation recommendations have been taken into consideration. Specific acceptance criteria would include:
1. Verification of cleaning all supply and return ducts.
2. Confirmation of system component conformance (including all filters) to design specifications and construction drawings.
3. Review of air system test documentation for room pressurization, damper adjustments, balancing, supply and return air velocities, air distribution, air changes per hour, and differential pressures.
4. Duct leak test documentation for supply and return ducts.
5. HEPA filter integrity testing (DOP or equivalent challenge material).
6. Completion of initial room sanitization per Standard Operating Procedure (SOP).
Operational Qualification: Documentation that the equipment (system) can operate as designed and is capable of repeatable operation over the entire operating range of process variables. Examples of specific acceptance criteria would include:
1. Conformance to design for air changes per hour, pressure differentials between rooms or areas, air flow patterns, air velocities, system pressures, temperature and humidity.
2. Performance of airborne particulate testing under static conditions. Static conditions are defined as “no equipment in operation, no components present and minimal personnel for environmental monitoring.” “Tested conditions shall not be more than 10 percent of the applicable 290E particulate requirement for each controlled environment. Monitoring shall be performed daily for ten days.”
3. Microbial testing under static conditions “shall demonstrate an average microbial content not more than 25 percent of the proposed microbial levels for each environment. Monitoring shall be performed daily for ten days.”
Performance Qualification: Documentation that the systems operate consistently and reliably. Examples of specific acceptance criteria would include:
1. Air flow patterns, pressure differentials between rooms or areas, and temperature and humidity conform to design criteria under load conditions.
2. Performance of airborne particulate testing under routine operation conditions. Routine operation requires equipment in operation, components present, and full staffing of personnel. Tested conditions “shall not exceed 25 percent of applicable 209E particulate requirement for each controlled environment. Data shall be collected over a 90-day period before the start of operations.”
3. Microbial testing under routine operating conditions “shall demonstrate average microbial content not more than 75 percent of proposed levels. Data shall be collected over a 90 day period before the start of operations.”
Summary
The cleanroom project designed and constructed for the production of sterile drug products involves many regulatory and operational issues that differ greatly from the cleanroom projects of other manufacturing industries. Cleanliness issues related not to total particle count, but to the types of particles and their viability, are the concern. Federal regulations mandate proof of compliance to recognized design, construction and operational standards that provide a foundation for the safety of the drug products used by every citizen. n
References
1. CFR 21, Part 211.42, item 10, sub-items 2, 3, 4.
2. CFR 21, Part 211.46, item a.
3. CFR 21, Part 211.42, item 10, sub-item 1.
4. CFR 21, Part 211.46, item b.
Jeffery N. Odum is the Director of Technical Services for Gilbane Process in Raleigh, NC, a division of Gilbane Building Company. His responsibilities involve GMP compliance and Program Management for numerous pharmaceutical and biotech projects in the United States. He is the author of “Sterile Product Facility Design and Project Management,” a reference book on design and construction issues related to sterile facility development for the pharmaceutical and biotech industries.
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Significant product and regulatory issues must be addressed when developing the design of a cleanroom for a pharmaceutical or biotech facility that will produce sterile drug products through aseptic manufacturing.
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Cleanrooms designed and constructed for the production of sterile drug products involve cleanliness issues related not to total particle count, but to the types of particles and their viability.
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Modular cleanrooms offer a cost-effective, viable alternative to custom-built cleanrooms used in the pharmaceutical and biotech industries. Photo courtesy of MSS Cleanrooms.