In sterile fill–finish operations, the monitoring of critical quality parameters, such as oxygen content, moisture content, and container-closure integrity, has been accomplished off-line using multiple destructive technologies, including electrochemical analyzers and gas chromatography for oxygen analysis and Karl Fischer titration for moisture analysis, or in-line methods, such as spark testing and vacuum decay that suffer from limited dynamic range and/or high false reject rates. Laser headspace analysis, which involves measurement of the gas phase using light, provides several advantages over these conventional techniques, according to James Veale, president of Lighthouse Instruments, a provider of headspace inspection systems.
Lighting the way
In laser headspace analysis, the light from a tunable diode laser is shined through the headspace of a sterile product container (above the product and below the stopper). The wavelength of light is tuned to match the unique absorption wavelength of a headspace gas molecule (e.g., oxygen or moisture). Measuring both the amount of laser light absorbed at a specific wavelength and the range of wavelengths absorbed provides information about the gas concentration and gas pressure. Specifically, the amount of light absorbed at a specific wavelength provides quantitative information about the gas density while the range of wavelengths absorbed provides quantitative information about the gas pressure.
“Analytical instruments incorporating laser headspace technology are available commercially and are proven, fully validated, and approved by regulatory agencies for oxygen, moisture, and leak detection applications,” Veale states. He adds that these commercial systems are configured either as laboratory instruments useful for development and quality-control laboratory implementation or as fully automated inspection systems useful in manufacturing for 100% inspection of batches.
The ability to measure headspace gas composition and pressure rapidly and nondestructively allows sterile product manufacturers to simultaneously monitor a number of important quality parameters, including oxygen content, moisture content, and container-closure integrity.
“For example,” says Veale, “oxygen-sensitive, sterile liquid pharmaceutical products are compounded and filled into vials and ampuls at rates of 10,000 containers per hour. This high speed presents a challenge to personnel responsible for assuring product quality.” In fact, off-line process monitoring of headspace oxygen occurs only at periodic intervals, typically 3–10 containers per hour, which can lead to significant production losses and potential customer complaints if process upsets occur between tests. The rationale for testing only 0.03–0.1% of manufactured product, according to Veale, is that a validated process that runs continuously should have consistent performance. “Workflow is, however, periodically interrupted due to jams, line-speed variations, and operator error. Such process upsets increase the probability for manufacturing significant amounts of out-of-specification product.”
Moisture monitoring of freeze-dried products using Karl Fisher analysis also suffers from limitations. Typically less than 1% of manufactured product (20–200 samples from batches of 20,000) are destructively analyzed for residual moisture content, again under the assumption that a validated process should produce uniform product within specifications, according to Veale. “We have found, however, that [when] using nondestructive analysis of entire batches, even after extensive lyophilization cycle development, a significant number of vials in a batch can be out of specification for moisture content due to process defects and variability from, for example, stopper seating and shelf positioning.”
Finally, Veale points out that the vast majority of lyophilized product manufactured today are not tested in-process for container-closure integrity. “The reasons are an historic lack of available in-process analytical methods and a generally held belief that once a package is developed and has shown container closure integrity (CCI) in laboratory tests, in-process testing is no longer necessary.” The increasing number of product recalls in recent years that have been related to package integrity defects, however, indicates that package defects often occur in-process and there is a need for new test and measurement technologies for the inspection of 100% of a batch in order to understand where and why defects occur and enable the removal of defective packages from fill and finish lines.
“In general, laser headspace analysis can provide more detailed knowledge of sterile fill and finish processes and will help to locate where quality defects are occurring,” Veale asserts. “This ability will in turn allow improvements to be made that minimize the amount of rework, reduce customer complaints, and reduce the risk of recall.”
Case study one: deep cold storage of sterile products
Many products are candidates for transport on dry ice, which keeps product vials at -80 °C. A recent article described customer complaints coming from the field concerning vials of liquid product that had not only lost vacuum, but also developed an overpressure (1). When a syringe was inserted into the vials to remove product for injection, the overpressure caused product to spray out of the needle holes.
“The vials were specified to have a certain headspace gas composition and air pressure of 1 atmosphere after filling. Laser headspace analysis of the vials revealed that they were filled with a carbon dioxide (CO2)/air mixture and the pressure was 1.5 atmospheres,” notes Veale. Further studies showed that when the stoppered vials were cooled to below the glass transition temperature of the stoppers, the stoppers lost elasticity and leaks developed. In a dry ice (CO2) environment at -80 °C, the vials then filled with dense cold (CO2) gas to a total pressure of 1 atmosphere. Subsequently, when the vials were warmed the stoppers regained elasticity and the seals reformed. As the temperature continued to rise, the headspace gases expanded and increased the headspace pressure to 1.5 atmospheres.
“Careful attention must be paid during package and process development regarding stopper materials and capping forces in order to avoid container-closure failures at low storage temperatures. The use of headspace analysis can help ensure that the types of issues described above are avoided,” Veale concludes.
Case study two: in-process leak detection
Specifications for an oxygen-sensitive sterile product were established at < 1% headspace oxygen and < 0.2 atmospheres of pressure in the vial headspace because exposure to oxygen resulted in degradation and discoloration of the product. Despite these specifications, customer complaints regarding the quality of the product led to an investigation and subsequent recall and quarantine of several batches. After headspace analysis of these batches, the source of the problem was identified, the problem was addressed, and production was allowed to resume. “From this experience, the manufacturer came to recognize the value of in-line headspace analysis and as a result installed an automated laser headspace analysis system capable of simultaneously measuring for container-closure integrity and oxygen content at production speeds,” Veale notes.
1. B. Zuleger et al., PDA J. Pharm. Sci. Technol. 66 (5) 453-465 (2012).