The guidance document finalizes the 2005 draft guidance "Guidance for Industry: Manufacturing Biological Drug Substances, Intermediates, or Products Using Spore-Forming Microorganisms".
The document aims to provide recommendations following the modified regulatory requirements in 2004, which were introduced to allow greater manufacturing flexibility for companies that produced biologics using organisms that were capable of spore production, such as bacteria.
Bacteria produce spores when they meet adverse environmental conditions.
The spores are resistant to high temperatures, freezing, dryness, antibacterial agents, radiation and toxic chemicals, thereby posing a challenge to drug manufacturers to ensure stringent controls are in place.
The former regulations required all work with spore-bearing/spore-forming microorganisms be conducted in separate buildings or in a completely walled-off portion of a multi-product building with several stipulated measures to prevent cross-contamination, including equipment reserved exclusively for use with the spore-former.
Under the revised regulations, permanently dedicated buildings and exclusively used equipment are no longer required as long as certain controls and precautions are applied.
"We recognize that advances in facility, system, equipment design, testing, and sterilization technologies have increased the ability of manufacturers to control and analyze the manufacture of biological products," the FDA reported in the document.
The guidance said manufacturers that used a separate building must have properly sealed walls, and separate heating, ventilation, air conditioning, water drops, and sewer line and an independent entrance, with the recommendation that "all surfaces be solid, hard, non-porous, and cleanable, including ceilings and walls".
The FDA recommended that personnel shower and complete a "clean" clothing change prior to entering other areas of the building, meanwhile any material transferred out of the manufacturing area must be decontaminated via a decontamination chamber or a series of airlocks with a decontamination agent.
The FDA recommended a similar approach for waste disposal involving biohazard bags via multiple airlocks.
"We recommend that you incorporate a worst-case approach," the report said.
The report also gave recommendations for manufacturers using a multi-product manufacturing facility.
"We recommend that the manufacturing areas used for spore-forming microorganisms have double serial entry, exit, and material airlocks to minimize the potential for cross-contamination via personnel, materials, and air turbulence."
The security recommendations for facilities where a number of products were manufactured were similar to those noted for separate manufacturing buildings.
The FDA listed a number of steps recommended for campaign changeovers and the introduction of a new product to the area and equipment, including rigorous decontamination of all removable and stay-in-place equipment and room fixtures.
The FDA also recommended environmental monitoring specific for the spore-formers and a quality control unit.
The report added: "We recommend that procedures be in place to address emergency responses for all spills involving spore-forming microorganisms regardless of location.
These procedures should include validated processes for containing the spill, and cleaning and decontaminating the area and equipment affected by the spill."
The FDA also gave recommendations for the maintenance and decommissioning of the activities.
While the FDA acknowledged the likely need to use spore-formers in the immediate future, the agency also "encouraged" manufacturers to find alternatives such as sporulation deficient strains, or recombinant proteins expressed in non-spore forming microorganisms.