Applying Quality by Design to Sterile Manufacturing Processes - Pharmaceutical Technology

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Applying Quality by Design to Sterile Manufacturing Processes
The author reviews the draft guidance on process validation, its QbD applications, and its potential impact on sterile manufacturing operations.


Pharmaceutical Technology


Technology transfer

Assuming that the manufacturing process design space has been properly developed and CQAs and DOEs have been verified, technology transfer, as well as scale-up, should go smoothly. As with most typical API-manufacturing operations, process design and controls ensure a state of control. When these approaches and technologies are applied to a batch-based system, they may, in the future, lead to more continuous sterile processing due to the increased level of control.

The following sterile-process technologies are well defined in the literature: sterile filtration (F), autoclaves (A), steam cycles, dry-heat (DH) ovens and tunnels, gas sterilization (ETO), chlorine dioxide (ClO2), ionization radiation (ebeam, gamma), and terminal sterilization (steam, gamma radiation). These technologies must be validated with the specific component, drug product, or commodity.

Sterilization technology review. Sterile filtration. Filter validation is normally done by filter manufacturers or outside laboratories but the responsibility remains with the drug manufacturer (5).

Steam sterilization. Steam sterilization (i.e., autoclaves, sterilize-in-place [SIP]), is the method of choice whenever possible due to data available and capability to assure sterility. This method is used for transfers into the aseptic area, process sterilization, SIP of the product delivery system, and product contact-component sterilization. Steam sterilization is limited by its temperature and pressure impact. Many plastic items, therefore, require other methods of sterilization. Control is typically ≥121.1 C. Product contact components must have had prior pyrogen removal steps to ensure expectation of a minimum 3-log reduction.

Dry-heat sterilization. The DH approach is mainly used for glass components because of the temperature during processing (a dry-heat oven is typically controlled ≥200–250 F and dry-heat tunnels are typically controlled at 275–350 F). Dry-heat sterilization can also be validated for a 3-log or greater pyrogen reduction.

ETO. Gas sterilization or ETO, is used for product contact plastics and commodity transfers. The method is not used in processes and operations due to safety issues. Product contact components require ETO degassing after the cycle is completed. ETO is a toxic and hazardous chemical. Cycle control includes ETO concentration, humidity, and pressure and similar to steam sterilization, requires prior pyrogen removal steps.

Ebeam. Ebeam is easy to define and makes it easy to control sterilization of the surface and, to some extent, the depth of exposure and microbial kill. Recently, the ebeam method has been used to sterilize the lids of syringe bulk containers before filling. Because ebeam is not currently used for product contact components, pyrogens are not an issue. The sterilization dose for radiation processes (i.e., ebeam and gamma) are 25 kGy (2.5 Mrad).

Vaporized hydrogen peroxide (VHP). VHP is currently the method of choice for isolator decontamination. Sterility is sometimes claimed. Because VHP is not a true gas, it can be affected by cold spots. VHP also can be used to sanitize transfer items into aseptic-filling operations, but cannot be used to sterilize or depyrogenate components. Cycle requires control of concentration of H2O2, relative humidity, and temperature. Circulation fans within an isolator are often used to help provide constant conditions within the isolator (5).

Chlorine Dioxide (CD). CD is currently the least used method throughout industry for sterilization, but provides significant opportunities because it is a true gas and can be validated for sterility. Areas of opportunity include isolators, transfers to the aseptic area, and processing equipment. CD is widely used in the food industry for sanitization and disinfection. Concentration can be monitored and controlled. Aeration is repeatable. Passivation of stainless steel may be required. Controls consists of concentration, humidity, temperature, and pressure.

Other sterilization technologies include gamma radiation, which is used for product terminal sterilization and component sterilization by contract manufacturing organizations (CMOs). Gamma-radiated presterilized syringes are a common usage of this technology in the industry. Transfer of these types of presterilized components to aseptic-filling areas can be troublesome, however, without a defined transfer sterilization method. Recently, some equipment suppliers have included ebeam sterilization to improve this transfer. Ozone (O3) technology has potential as a sterilization method as well, but is not currently commercially available. Peracetic acid as a sterilization technology may still be used by a few companies, but most have switched to VHP. Other forms of sterilization or environmental control have limited support data and therefore represent an increased risk requiring in-house technical knowledge (e.g., high-intensity light, ultraviolet light).


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