The in-process monitoring applications for headspace inspection are headspace oxygen monitoring control of purging systems on liquid and powder filling lines, headspace vacuum and oxygen monitoring for leak detection and moisture monitoring for inspection of freeze dried product.
Oxidative chemical degradation of active ingredients and excipients in pharmaceutical formulation is well-documented and leads to a range of safety, quality and efficacy issues including toxicity, reduced product shelf-life, product discoloration, precipitation, and lowering of drug potency.
Molecular oxygen is involved in the propagation step of autoxidation reactions and is integral to the catalytic cycle responsible for the generation of oxidative degradation of drug substances in pharmaceutical formulations. (Templeton et al., 2002)
Many sterile liquids are oxygen sensitive and maintaining product stability requires packaging the formulation under an inert atmosphere. Vials and ampoules are filled and then purged with nitrogen or argon to reduce oxygen levels remain below specified limits. In-process purge control historically involves periodic sampling of products using destructive measurement methods (e.g., electrochemical analyzers and gas chromatography). In these methods (Wang et al., 1997) a sealed container is broken open and the headspace gases are transferred to the measuring instrument. There are many obvious disadvantages to destructive process monitoring methods. For containers with small volume headspaces (e.g., a 2 mL ampoule with a liquid fill may only leave 0.5 mL headspace volume of gas needed for measurement. The technique yields an average oxygen measurement over all the sampled containers. Second, measurement speed is limited by the time it takes to break open containers and feed samples into an instrument. Reliability and accuracy depend on not introducing any room air during the process of breaking open containers and transferrin gases to the electrochemical cell. Third, the destructive nature of the testing methodology reduces production yield. Measurement times on the order of minutes and the necessity of destroying sample containers during the measurement preclude the possibility of doing real-time, automated process control.
In principle, analytical methods should operate at speeds comparable with the filling line and perform measurements nondestructively. Sterile liquid pharmaceutical products are compounded and filled into vials and ampoules at rates of 10,000 containers per hour or higher. This high speed presents a challenge to personnel responsible for assuring quality of sterile products. At-line or off-line product quality testing currently occurs only at periodic intervals, typically 3-30 containers per hour, which can lead to significant production losses and potential liability if process upsets occur between tests. The rationale for testing only 0.03% of manufactured product is that a validated process that runs continuously should have consistent performance. Work flow is, however, periodically interrupted due to jams, line speed variations, and operator error. When these situations occur, the probability increases for manufacturing significant amounts of out-of-specification product. The ability to nondestructively test large numbers of product at or near line speeds would provide better control over purging processes.
Increasing testing rates to better match production rates enables continuous process monitoring. This allows manufacturers to identify process upsets quickly, before thousands of out of specification containers are filled. Using a non-destructive measurement method also reduces the number of destroyed containers due to scheduled testing or due to a process upset. This reduces operating costs as well as the environment impact due to waste disposal.