M A N O S T A X X
How we can best design an OSD facility to protect our drug products from physical, chemical, and biological contamination during manufacturing?
Product protection, against contamination and/or mix-up, is one of the most important manufacturing considerations in the pharmaceutical industry and also one of the major regulatory items that often results in an FDA warning letter noting that an inspector found a violation. Therefore, pharmaceutical manufacturers have typically implemented a wide range of procedures, strategies, technologies, and equipment for ensuring adequate and reliable product protection.
Some of the implemented design strategies include: 1) HVAC designs that incorporate pressurization schemes, 2) air filtration, 3) once-through airflow, and 4) airlocks for material and/or personnel. Some equipment and technology strategies that can provide engineering control for manufacturers include: 1) integrated systems, i.e., an integrated granulation train or gravity-fed compression system; 2) containment at all make/break connections, such as split butterfly valves and isolators, 3) local exhaust; and 4) wash-in-place or clean-in-place systems and use of intermediate bulk containers for handling and transferring materials. Additionally, the facility’s layout and the process flow have a large impact on risks related to product protection.
In an attempt to allow manufacturers a bit more freedom in their design and operational approaches, modern guidance’s—such as the International Society for Pharmaceutical Engineering’s OSD Baseline Guide, third edition, released in November of 2016—use a protection scheme based on risk assessment and mitigation of risks . Furthermore, it defines a matrix used for cGMP spaces that identifies three levels of protection centering on in-process materials being open, partially open, or closed to the environment and the operation.
Level 1 (L1)—general area or low risk. These include “the areas of the facility or process where there is no potential for product or product contact surface exposure, and the environment and/or activities in these areas have no direct or indirect impacton the product” . In an L1 area, the contamination risk is low. The containers or other packaging for ingredients and raw materials typically remain closed in the area. L1 areas may include warehousing, shipping, and receiving and GMP support spaces. Pharmaceutical manufacturers often refer to this level as a black zone or tertiary control area of the facility. L1 areas normally provide environmental control of temperature and humidity. Gowning for personnel may include facility uniforms and access control.
Level 2 (L2)—protected area or medium risk. These include “the areas of the facility or process where there is no potential for product or product contact surface exposure; however, the environment and/or activities in these areas may have direct or indirect impact on the product” . In an L2 area, the contamination risk is medium. In these spaces, materials may be in process, but their containers typically remain closed; however, exposure can happen. L2 areas may include manufacturing areas where the product is generally in a closed environment, such as during in-bin blending or secondary packaging. Pharmaceutical manufacturers often refer to this level as a gray zone or secondary control area of the facility. L2 areas normally provide environmental control of temperature, humidity, and filtration. Gowning for personnel may include overgowning and access control.
Level 3 (L3)—controlled area or high risk. These include “the areas of the facility or process where open processing occurs and there is potential for product or product contact surface exposure, and the environment or activities have direct or indirect impact on the product . In an L3 area, materials are in process, and the contamination risk is at its highest. L3 areas typically include the direct manufacturing areas where the product is in open containers, such as during sampling, dispensing, formulation, granulation and drying, milling and sifting, compression and encapsulation, and coating. Pharmaceutical manufacturers often refer to this level as a white zone or primary control area of the facility. L3 areas normally provide environmental control of temperature, humidity, and filtration. Dust collection is also prevalent in these areas. L3 areas also use engineering controls and equipment for improving overall containment and minimizing dust. L3 areas are the costliest in a cGMP facility in terms of construction and operation.
In addition to the three levels above, the levels in the protection matrix also account for spaces outside the manufacturing areas. Pharmaceutical manufacturers typically separate these spaces from the cGMP spaces. They are normally the areas where the support functions of an OSD facility are, such as offices, laboratories, and break rooms.
In designing a modern OSD facility, your engineers and architects, in coordination with regulatory and quality groups, should carefully categorize the various areas of the facility into the levels of protection described above and apply the appropriate operational strategies, engineering controls, and equipment. For example, in L3 areas, engineering controls should increase, and HVAC design should be tighter. Meeting requirements related to ISO classifications—nominally ISO 8, i.e., controlled, not classified—require examination of such items as air changes, filtration quality, and other items with greater controls than those of L2 or L1. When feasible, you should also minimize the square footage of the L3 space. Keeping these areas compact, without sacrificing the operation’s requirements, offers advantages.
In assessing the risks for product protection, your engineers should typically look at the degree of risk to a drug product’s quality, as it relates to the following categories:
- The level of exposure to contamination of materials and drug products, i.e., how often and how long is the process open?
- The potential for cross contamination, i.e., what else is prevalent in the area that could contaminate?
- Material and product hazards, i.e., how fine or dusty is the product?
- Single versus multi-product manufacture, i.e., will different products be manufactured concurrently?
From the standpoint of the facility’s design and layout, you can mitigate risk in areas at each level of protection:
- Provide for and design an appropriate, adequate working space that is available as needed for a given unit operation. Provide enough room but not an overabundance.
- Provide for and design a logical and efficient flow of material, product, equipment, and personnel throughout the operation and facility. Strive to link unit operations and minimize travel distances.
- Provide for and design appropriate segregation.
- Provide for and design with appropriate materials of construction and cleanable finishes, both from an architectural standpoint and from the standpoint of process and equipment.
In summary, product protection in an OSD manufacturing facility is a primary consideration in process and facility design. Safe products are the focus of regulatory agencies worldwide, and the manufacturer of drug products is responsible for ensuring safety. The ISPE OSD Baseline Guide is an internationally accepted guidance document for your OSD facility designs, and its level-of-protection matrix provides a tool for you to address the issue adequately.
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