Controlling the Microbiological Quality of Solid Oral Dosage Forms
Introduction
To control the microbial quality of a non-sterile Solid Oral Dosage (SOD) form, it is recommended to perform a risk assessment of the manufacturing process to identify
potential sources of microbial contamination. The intention of this document is to provide guidance to determine and control these sources of microbial contamination.
A documented risk assessment should consider the facility, equipment, materials, and personnel as related to the potential contribution of microbial contamination to the final SOD (Solid Oral Dosage) product. The level of risk determined from this assessment will assist in formulating the microbiological control program.
Recommendations
The lack of well defined regulatory standards or guidelines for the microbiological monitoring of a non-sterile SOD manufacturing environment can lead to the development of a program that parallels the monitoring practices of an aseptic manufacturing environment.
The monitoring program performed in an aseptic manufacturing operation is not designed for the control of microbial contamination sources in a non-sterile production setting.
The microbial quality of a solid oral dosage form can be managed by identifying and controlling the microbial contamination sources relevant to the non-sterile manufacturing process. This can be achieved through a documented risk assessment that incorporates an evaluation of the steps in the manufacturing operation and an evaluation of the materials present in the formulation. From these evaluations, potential microbial hazards at relevant process steps can be identified. A microbial hazard is defined as any circumstance in the process that allows a microbial contamination event to occur.
After the microbial hazards are identified, the existing measures in the process, if any, are evaluated to determine if they are effectively controlling the identified microbial hazards.
If adequate controls are not present, controls are put in place to prevent or minimize the introduction of microbial contamination. These controls may be physical (e.g., temperature, holding times), chemical (e.g., pH), procedural (e.g., cleanliness, dryness), or microbiological (e.g., raw material acceptability, microbial reduction steps).
A program can be established that will monitor (by observation or by measurement -physical or microbiological) these controls to assess the manufacturing process as operating properly and subsequently reducing the risk of microbial contamination.
There are specific circumstances or situations within the manufacturing process that may allow for a microbial hazard to occur. An assessment of the manufacturing process would include a review of the following:
- Raw materials (API and excipients)
- Manufacturing equipment
- Facility designs
- Cleaning & sanitization methods
- Water / utilities
- Processing conditions
- Pre/post manufacturing storage & transport conditions
- Personnel behaviors
The most common microbial hazards that can jeopardize product quality of solid oral dosage forms can often be attributed to contaminated raw materials. Microbial hazards may be introduced into a manufacturing process due to the improper sanitary design of the manufacturing equipment; especially equipment used for aqueous processing steps (i.e., wet granulation or tablet coating). For example, microbial contamination can arise from entrapped water or product residues that remain hidden from procedural cleaning processes due to threaded pipe fittings, non-sanitary valves, piping dead legs, non-sloping pipes, equipment crevices, recessed access ports, bottom discharge valves, and pocket flow meters. Inadequate equipment maintenance may also serve as a potential microbial hazard. For example, misaligned, damaged, or over torqued gaskets between piping connections may harbour a reservoir of trapped microorganisms.
Microbial hazards may also originate from improper facility design. Such hazards could include deficient control of humidity and temperature within the manufacturing area, improper air ventilation systems, or poor room construction design (e.g., porous walls, drop down ceilings, uncovered floor drains).
Inadequate cleaning and sanitization of the equipment and manufacturing areas can potentially serve as a major cause of microbial hazards. Other examples of potential microbial hazards could include the following:
- Cleaned equipment that is not properly dried after cleaning and stored water wet.
- Cleaned equipment that is not properly stored.
- Manufacturing areas that are not adequately or routinely cleaned before use (e.g., standing pools of water, construction materials, cardboard or other debris).
- Cleaning utensils such as mops, buckets, and brushes that are not stored dry or clean.
- For continuous manufacturing with no cleaning between batches, campaign lengths, with consideration of microbial growth, are not established.
Water, a major component in many non-sterile dosage forms, is a potential source of microbial contamination if the incorrect purity standard is utilized during production.
A solid oral dosage form requires the use of at least Purified Water (PW) for production use and as a final rinse during equipment cleaning.15
Microbial hazards can arise if key processing conditions employed during the manufacturing of an SOD are not properly established or controlled. For example, if maximum holding times for in-process materials with appreciable water content (e.g., wet granulations, coating suspensions, & binder solutions) are not properly validated, microbial proliferation could readily occur. Other process condition hazards include the improper validation of a microbial reduction step (e.g., pasteurization) or the inability to control excess condensation during blister packaging.
Inappropriately maintained and controlled warehouse and storage areas maybe potential microbial hazards. For example, uncoated tablets are very hygroscopic, therefore it is imperative that the humidity of the storage areas are controlled or microbial proliferation could occur.
Although personnel do not present a significant microbial risk to Solid Oral Dosage forms, microbial hazards may occur due to the lack of proper gowning (e.g., lack of gloves, lack of hair covers, lack of shoe covers or the use of dedicated work shoes, unclean smocks and uniforms) or inadequate hygiene practices.18
The surrounding environment, such as ambient air, floors, walls or other non-product contact surfaces, may pose a risk to product quality in a sterile manufacturing environment.
However, if adequate controls are in place, the impact from these same sources is typically negligible when manufacturing non-sterile SODs.
A risk assessment of the non-sterile manufacturing process is a recommended means to determining potential microbial hazards. Once such an assessment is completed, the product quality of an SOD can then be managed by ensuring these identified microbial hazards are under control.