Introduction
What steps can be taken to prevent and control of fungal contamination in tablets?
The presence of water is the key element in the growth of fungal contamination. This document discusses the prevention and control of fungal contamination in tablets production to include: raw material and API testing, manufacturing processes, environmental monitoring, and final product testing.
Recommendations & Rationale for Recommendations
- Steps of the manufacturing process of the tablet where water is present (e.g., wet granulation, coating solutions).
- Contaminated raw materials, excipients or active pharmaceutical ingredients (API).
- The lack of good manufacturing practices (e.g., water quality, processing equipment sanitization).
- Inappropriate storage, handling, and transport conditions where humidity may be problematic.
The primary concern of fungal contamination in a tablet is generally not the direct medical hazard it may cause the patient, but the possible spoilage of the product itself and non-compliance with contemporary regulatory expectations (cGMP) regarding microbiological quality of non-sterile dosage forms. It should also be noted that fungi are ubiquitous in nature and that their mere presence does not necessarily indicate that microbial control has been lost in the manufacturing process. The topics discussed below will provide more detailed information on the prevention and control of fungal contamination in tablets.
Raw Materials and Active Pharmaceutical Ingredient (API) Quality and Testing:
The microbial quality of the raw materials and APIs directly impact the microbial quality of the final tablet product. Fungal populations that may be found in these raw materials can contaminate the final tablet product. This is because the manufacturing of most tablets does not include processing steps that can eliminate the indigenous bioburden found originally in the raw material. Based on the materials contribution to the final drug product and their ability to be validated for their microbial attributes, it may be necessary to test RMs and API on a routine or periodic basis.
Therefore, it is recommended that raw materials and API’s used in the manufacturing of the tablet be evaluated for their contribution to Total Yeast and Molds in tablets. This includes the testing of APIs that are manufactured and/or milled at one site (internal or external) and then transferred to the tablet-manufacturing site. Testing can be waived for those materials or excipients that are known to be microbiocidal by nature (e.g., strong acids and bases, preservatives, organic solvents) or where the manufacturing process for the material has been shown to be under control with regards to microbial quality. Close attention should be paid to those raw materials of natural origin (e.g., starch), as these materials can possess higher fungal populations than synthetic materials. Finally, microbial quality considerations (i.e., microbiological process control) should be taken into account during the external audits of raw material suppliers and API manufacturers.
The Total Yeast and Mold Count tests for raw materials and APIs in the tablet formulation are validated and tested according to compendial methods and/or internal requirements. Specific limits for fungal levels in raw materials and APIs are used to ensure that the microbial quality of the final dosage form will not be adversely affected.
A laboratory investigation should be conducted on any material that does not meet those limits.
Manufacturing Process Considerations
During the manufacturing of a tablet, fungal contaminants may be introduced into the tablet via the water introduced into the process. In addition, the presence of water found in the manufacturing process may also facilitate the growth of an existing fungal population introduced from one or more of the raw materials.
Wet granulation
The wet granulation process involves moistening the powder blends and then drying the wet mass at temperatures that are not typically cidal to fungi. Therefore, Purified Water, (not potable water), should be used in the manufacturing process. The holding times of the wet powder should also be validated with microbial/fungal considerations in mind. The validation of a holding time should be based on both time and temperature parameters. The longer the wet powder is stored, the greater the possibility the microbial quality of the tablet will be adversely affected.
Tablet coating
The coating of tablets is another potential source of contamination and/or proliferation of fungi in the final product tablet. Holding times of the coating solutions should be validated with microbial considerations in mind. Aqueous coating solutions can serve as a substrate for fungal growth. The holding time validation should be based on both time and temperature parameters. The equipment design of the coating solution holding tanks and the spraying apparatuses should also be evaluated. Poor equipment design that allows for the coating solution to be trapped (e.g., piping dead legs, spray heads) may also affect the microbial quality of the final product.
Compaction
Although the bioburden of a tablet can be reduced during the tablet compression process, this should not be relied upon as a kill step in tablet manufacturing (Baird and Bloomfield).
Sanitization
It is important to sanitize the direct product contact surfaces of processing equipment. Typically, hot water alone (usually around 80oC.) is considered sufficient. Purified Water should be used for the final rinse with equipment sanitization procedures. Tablet manufacturing equipment (e.g. coating solution tanks, spray lines, spraying
apparatus) that is sanitized with hot water should be dried after cleaning. Water should not be allowed to stagnate in tanks or piping as this may also lead to the proliferation of fungal contamination. Periodic inspections of equipment and processing lines can also assist in detecting potential problems before they arise.
Utilities
The processing, packaging and storage areas should be equipped with ventilation systems to adequately control humidity and temperatures. Purified Water should be used in tablet manufacturing processes. Compressed air and other gases used in tablet processing steps should have the same microbiological requirements as the surrounding room air. Environmental Monitoring of Non-Sterile Manufacturing
Environmental monitoring of the manufacturing areas for tablets should be performed on a periodic basis to assure an adequate level of microbiological control over the facility. Environmental monitoring for this type of manufacturing is not performed on a frequent basis, as it is primarily used to establish an historical database to determine if adverse trends in the environment are occurring. Preservation and Water Activity
Considerations in Tablet Formulation
Preservatives are not typically used in tablet formulations because of the low water activity. Water activity (Aw) is defined as the amount of bound versus available water
that can be utilized for microbial/fungal growth. The lower water activity, the less likely microbial growth will occur. Fungi typically can grow at low water activity levels (approximately 0.6 Aw), which are much lower than available water requirements for bacteria or non-osmophilic yeasts. These types of microorganisms require water activity levels above 0.85 for growth to occur. Dry, uncoated tablets typically have lower water activities than those tablets that utilize water in the tabletting process. It should be noted that a low water activity may prevent the proliferation of fungi, but unlike a preservative, it does not kill those microorganisms that may be present in the tablet. Typically, fungi and fungal spores can survive at extremely low water activity levels.
Water activity measurements of the final product tablets can assist in determining the quality of the tablet and potential processing problems that may be conducive for possible fungal growth.
Packaging and Storage
Packaging:
It is important to perform microbial testing on packaging components that may contribute to the contamination of the packaged tablet. Components that may require testing include those of natural origin such as cotton or sealing adhesives. It is generally not necessary to perform microbial testing on bottles, caps or other packaging components.
Blister Packs:
Fungal growth has been noted on tablets in blister packs after packaging. This is due the introduction of water from condensation produced during the blister packaging process, therefore, it is important to a.) Control the humidity and temperature in the packaging area and b.) Ensure that the fungal bioburden of the tablet be kept at a minimum, so that if some condensation occurs, there will be no subsequent fungal growth.
Storage, Handling and Transport:
It is recommended that the humidity and temperature of the environment are controlled during the storage, handling and transport of the final product tablet. This is because dry tablets (especially uncoated) may be hygroscopic and can potentially take up moisture quickly if the humidity is high in the surrounding environment. This can easily lead to the rapid growth of fungi on the stored tablets.
Final Product Testing
Tablets should be tested for Total Yeast and Mold. Skip-lot testing is appropriate for solid oral dosage forms when the lot history of the tablet demonstrates consistently low microbial counts. Typically the first 10 batches/lots of a new drug product should be tested before skip lot testing is considered. If all test results for the first 10 batches/lots are acceptable, reduced testing can be performed on every 10th lot. The decision for skip lot testing should be not solely based upon lot product history. All at risk raw materials and APIs in the drug product should be tested as well.
If the final tablet test does not meet the prescribed fungal limits, an “Out of Specification” investigation should be conducted of the laboratory and the manufacturing environment to determine the source of the microbial contamination.
The Total Yeast and Mold Count tests for the final product tablets should be validated and assayed according to compendial methods and/or internal requirements. Specific limits for fungal levels in non-sterile drug products are used to ensure high microbial quality of the final dosage form.