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Photostability chambers must pass the drug test: to ensurecompliance and product quality, photostability chambers must overcome lamp selection, light control and other chamber design issues.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industries of Europe, Japan and the U.S. to discuss scientific and technical aspects of drug registration--seeking to ensure that safe, effective and high-quality medicines are developed and registered in the most resource-efficient manner.

ICH Q1B guideline is the harmonized effort to standardize photostability testing on new pharmaceutical drug substances and drug products. Forcompanies developing or manufacturing pharmaceutical drugs, a robust photostability testing process is essential to ensure product quality and regulatorycompliance. Inadequate or substandard testing equipment can result in costly delays and lost revenue. The first step in choosing a photostability chamber is to select the proper light source. ICH allows either single lamps (Option I: fluorescent D65, metal halide or xenon) or two lamps (Option II: fluorescent near-UV and cool white) to be used. Option I uses single lamps emitting both UVA and visual irradiance, thus the UVA to visual irradiance ratio is fixed.

This fixed ratio varies according to lamp type. At the minimum confirmatory testing requirement, UVA overexposure is around 540 W hr/[m.sup.2] for xenon and 2500 W hr/[m.sup.2] for metal halide. This corresponds to 270 and 1250% overexposure respectfully. Because of fluorescent D65 lamps' lower UVA irradiance, they overexpose in the visual region. Ideally, the illuminance and UVA irradiance would be controlled independently. This problem is only alleviated by using two different fluorescent lamps, as in Option II.

In addition to overexposure, xenon and metal halide lamps produce significant amounts of heat. At elevated temperatures, dark controls are needed to segregate photochemical degradation from thermal degradation. Large internal cooling fans are necessary to dissipate this heat and can pose presentation problems by blowing samples around. Sample color changes because of high temperatures cannot be easilycompensated for.

Problems with xenon and metal halide are not limited ro overexposure and excessive heat generation. Xenon and metal halide lamps have a short life span and need replacement every 750 to 1500 hr. They require light filters to eliminate radiation below 320 mn. Over time, the filters become solarized and the wavelength of the UV cutoff increases. They also have a relativeiy small illumination area.

While chemical actinometers can be used to measure sample dose, selecting a suitable chemical actinometer involves trade-offs. Each chemical actinometer used must be calibrated for the light source used. Absorption spectra of the testcompound and actinometer should be similar. ICH describes the use of quinine hydrochloride dehydrate as an example of a chemical actinometer. Quinine has a "dark reaction" where the reaction continues after it is used. Not only is quinine wavelength dependent, it is affected by temperature and pH variations. Because of these characteristics, quinine has been shown to be inaccurate with lamps that produce significant amounts of heat, such as xenon lamps.

Control problems

Selecting the proper physical actinometer, such as a radiometer, to measure light is not trivial either. Irradiance measurements with instrumental radiometers have high margins of uncertainty; 10% is not uncommon. Unless using a spectral radiometer, two radiometers configured specifically for each wavelength region (UVA and visual) are required. The radiometer should have a wide bandwidth and be cosine-corrected. Radiometers need to be calibrated or certified before use. Spectral radiometers are cumbersome to use and awkward to integrate with photostability chamber lamp controls.

Chemical actinometers are inherently limited with respect to a photostability chamber. They do not provide a mechanism to automatically turn the lamps off or alert the operator when the desired exposure level is reached, "What if confirmatory testingcompletes while the chamber is unattended? Chemical actinometers cannot record irradiance levels throughout the test.

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Performing photostability studies based on time creates dose level uncertainty. As lamps age, their intensity decreases. This causes irradiance levels of full-power light sources to fluctuate over time. Because timed tests are unable tocompensate for irradiance level changes, a timed test based on initial light intensity would terminate prematurelycompared to the desired dose. This is particularly troublesome for confirmatory studies.

Using a proper light source does not guarantee product samples will receive the correct light spectrum radiation as required by ICH guidelines. Interior chamber materials that reflect light onto samples should reflect/absorb radiation uniformly across the UVA and photopic spectrums. If not, samples will be subjected to light having a spectral power distribution different than that specified by ICH. This is especially truecomparing reflective properties of UVA verses visual irradiance. Chamber interior materials, such as mirrored stainless steel and white paint, distort reflected light by absorbing different amounts of irradiance over the relevant spectrum.

While not required by ICH for confirmatory studies, the state of hydration also affects the photostability of some samples. This means identical drug substances subjected to identical irradiance and temperature conditions can have very different results if exposed to different humidity levels. When product presentation is such that samples are exposed to ambient (chamber) air, the effects of humidity must be considered. Uncontrolled, humidity can alter photostability testing results and cloud their interpretation. Using steam or vapor generators to raise the humidity level adds more heat into the chamber and requires long warm-up times. Ideally, humidification equipment would quickly reach equilibrium by dispersing fine droplets without introducing heat.

Chamber solutions

A skillfully designed photostability chamber will address the challenges of photostability testing in accordance with ICH guidelines. The advantages of cool white and near-UV fluorescent lighting (Option II of ICH guidelines) outshine other options. Independent control of illuminance and UVA irradiance eliminates overexposure for confirmatory tests and provides flexibility for forced degradation and research studies. Fluorescent lamps generate minimal heat and eliminate the need for expensive light filters and dark controls. Small internal fans can be employed to subtly maintain proper air temperature without disturbing sample presentation. Fluorescent lamps typically last more than 10,000 hr, have low replacement costs and provide a large illumination area.

Accurate illuminance and UVA irradiance measurements can be achieved with a built-in radiometer. Photopic detectors have a wide bandwidth and spectral response that closely follows the CIE photopic action spectrum. Near-UV irradiance is then measured by an independent UVA light detector. Detectors utilizing a Teflon hemisphere may result in an exceptionally good cosine response. Detectors should be both cosine-corrected and calibrated to NIST or other traceable standards.

An integrating radiometercombined with chamber controls should be used to ensure precise dose levels at testcompletion. Lamps can then be programmed to automatically shut-off based on an exposure level (dose). Advanced systems are capable of running based on exposure level or timed tests. Whether operating at full power or dimmed condition, the programmable exposure level should automatically adjust testing time tocompensate for influencing factors like lamp aging, as well as pause testing for sample evaluation. During both exposure level and time-based testing, the radiometer should show irradiance, test time remaining and accumulated dose levels.

Ihe lamp's spectral power distribution is best preserved by using specular aluminum on interior reflective surfaces. Specular aluminum uniformly reflects light across both UVA and photopic spectrums. It is available with a 95% total reflection (DIN 5036-3) and only 0.01% diffuseness at 15 [degrees]. Specular aluminum's superior reflective properties outshine mirrored stainless steel and white-painted surfaces for not only illuminance reflection, but also UVA irradiance.

Precise humidity control can be achieved by using state-of-the-art ultrasonic nebulizers. Nebulizers vaporize water droplets so small that they only have a 3 micron mean diameter. This small particle size enhances uniform humidity distribution throughout the chamber without injecting additional unwanted heat--especially beneficial in acompact chamber. Employing solid state controls enables nearly instantaneous response, further facilitating tight humidity control. Dehumidification is often accomplished through mechanical refrigeration.

Numerous photostability chamber features are available that enhance the end-user experience. Chambers should keep track of accumulated lamp hours and alert the operator when to replace the lamps. High and low process alarms should signal out-of-tolerance testing conditions. Validation is simple with pre-written IQ/OQ/ PQ validation protocols and professional on-site validation services. Chart recorders assist in demonstrating regulatorycompliance by permanently recording illuminance, UVA irradiance, temperature and humidity testing conditions.

Global response

As pharmaceuticalcompanies and government regulations throughout the world adopt ICH guidelines, it becomes increasingly important that photostability chambers accommodate the worldwide customer by tailoring each photostability chamber to regional utilities. Electrical power and water hook ups should coincide with local standard facilities' resources and connections. Replacement parts, such as lamps and ballasts, should be available on the open market and from local suppliers. Lamps should not be of proprietary nature so as to not limit the purchaser to the chamber manufacturer. Controls should be icon-based and available in multiple languages.

The Caron 6540 series chambers overcome the previously discussed challenges of photostability testing. They prudently utilize cool white and near-UV lamps and an integral radiometer accurately measures and controls lighting. Specular aluminum surfaces line the chamber interior, maintaining proper spectral power distribution. Ultrasonic nebulizers are used for tight humidity control and all controls are programmed through an eye-level icon-based multi-language color touchscreen interface that tracks lamp usage. Off-the-shelfcomponents allow users to replace consumables locally.

By integrating technical requirements with practical solutions, these photostability chambers enhance the testing process to ensure quality and regulatorycompliance.

CONTACT

For more information, contact: Caron Products & Services at 740-373-6809, or visit www.caronproducts.com

AT A GLANCE

* ICH guidelines seek to standardize drug substances.

* A robust photostability testing process is essential to ensure regulatorycompliance.

* Xenon and metal halide lamps produce too much heat.

* Both hydrogen and humidity affect the photostability of samples.

by Bob Dotter, Applications Engineer, Caron Products & Services, Inc., Marietta, Ohio
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Title Annotation:Feature
Author:Dotter, Bob
Publication:Laboratory Equipment
Date:Dec 1, 2011
Words:1600
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