Cleaning Verification: Method Development and Validation Using Ion Mobility Spectrometry1

The cleanliness of manufacturing and packaging equipment in the pharmaceutical industry is critical to ensure product efficacy, personal safety, and the absence of unwanted active pharmaceutical ingredient (API) before the introduction of a different compound. Upon completion of processing a drug substance or tablet formulation, a detergent cleans each part of the pharmaceutical equipment. The cleaning verification process in the pharmaceutical industry involves several steps. First, the clinical supply or manufacturing unit of a company submits samples for analysis following the equipment cleaning process. The sample analysis is completed by an analytical department or quality control (QC) personnel. The results are reported back to the clinical supply unit, and the process is repeated until all samples have met the acceptable residual limit (ARL). The subject exposure limit (SEL) (in units of mg/subject/day) for a given compound is provided by a drug-safety evaluation group and is an industry-wide practice. The ARL of the API in each swab sample is a set at one-tenth of the SEL.
These types of samples have been analyzed by high-performance liquid chromatography (HPLC). In an effort to significantly reduce sample turnaround time, which can take as long as several days, ion mobility spectrometry (IMS) has been evaluated as an alternative method for analysis (1–4). The time taken for analysis is important because the faster that cleaning can be confirmed, the faster the plant can return to operation. This article discusses the theory of IMS, the benefit of IMS over HPLC analysis, and experimental considerations for method development and validation.
Theory

Figure 1: The IonScan-LS ion mobility spectometer with the Cobra autosampler.(FIGURES COURTESY OF THE AUTHORS)

IMS is a type of separation technique, similar to time-of-flight mass spectrometry, that distinguishes ions of a given compound based on their velocities through a drift tube under the influence of a weak electric field. The technique characterizes chemical substances based on their gas-phase ion mobilities and provides detection and quantitation of trace analytes (1). There are several IMS instrument vendors. Figure 1 shows the IonScan-LS ion mobility spectrometer with the Cobra autosampler (Smiths Detection, Warren, NJ), which was used in the studies described in this article.

Figure 2: Cross-sectional view of the ion mobility spectrometer sample inlet, ionization chamber, drift tube, and detector.

To perform the IMS analysis, a sample solution containing a compound of interest is injected by the autosampler onto a PTFE substrate and allowed to dry. Figure 2 shows the sample inlet, ionization chamber, drift tube, and detector (5). Sample is introduced by heating the substrate to ~290 °C, which results in desorption or vaporization of the sample into an inlet tube. Primary ion formation occurs through atmospheric pressure chemical ionization (APCI) using nickel-63 as the radioactive source. Following many collisions, product ions are formed and gated into the drift tube. These ions-based on size, shape, and charge-travel through the drift tube toward the detector at different velocities. In contrast to mass spectrometers, separation of ions is based on a size–charge relationship rather than the mass–charge ratio (6).