Portable analytical systems for quality control and monitoring in pharmaceutical manufacturing facilities

Currently, the miniaturized portable analytical devices that have succeeded in providing a substantial impact in their field of application are mainly based on electrochemistry and spectroscopy. They are simple, automated and do not require significant sample preparation. However, electrochemical methods suffer from the adsorption of matrix constituents and loss of electrode sensitivity and point-and-shoot handheld devices based on spectral analysis like IR and FTIR have low sensitivity due to the low field of view for surface analysis and suffer from interferences. Separation-based portable analytical devices can provide better selectivity and sensitivity. Apart from using the few available portable ion mobility spectroscopy and gas chromatography instruments, samples collected in the field are either sent to the laboratory to be extracted and analysed or manually extracted and then analysed using a portable device on-site. They still require extensive intervention from a professional analyst for sampling, sample preparation and analysis. Miniaturized liquid chromatography is still barely past the prototype stage. It takes a longer time when compared with other separation techniques. CE is a potentially cheaper and faster separation-based portable analytical device inherently simpler for miniaturization. It requires a very low volume of reagents and samples (nL to ˜í¬¿L). Most of the portable CE instruments are still prototypes or still require sample preparation before analysis. However, the GreyScan¬¨vÜ ETD-100 is a new portable analytical device that integrates a sample swab extraction system into CE coupled with capacitively coupled contactless conductivity detection (C4D). Within 40 s from inserting a swab, inorganic explosives residues on swabs are automatically extracted and analysed. The system is small and portable and provides a convenient way of field sampling and analysis. This work aims to evaluate the potential of using swab-based sampling and portable CE in different fields related to pharmaceutical analysis and repurpose the GreyScan¬¨vÜ ETD-100 in applications other than explosive detection. Chapter 1 presents the benefits and drawbacks of portable analytical devices with a brief history of the evolution of portable analytical devices. Moreover, some selected portable devices are described according to their field of application. Chapter 2 provides an insight into the fundamentals of CE with a detailed review of the development of portable CE instrumentation since the first portable CE was described in the literature 25 years ago until now. In chapter 3, the feasibility of using GreyScan¬¨vÜ ETD-100 in cleaning verification in industrial facilities was evaluated. Lidocaine was chosen as a model compound. A sensitive and selective method was developed and validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Moreover, different types of swabs were tested and evaluated. Then, the sensitivity and selectivity of the device to detect lidocaine was demonstrated and compared with the official limits set by the regulatory authority. The recovery of lidocaine from a stainless-steel coupon was 81.3%, with a limit of detection (LOD) of 0.13 ˜í¬¿g/swab, which was comparable with those obtained from other LC and CE methods. In chapter 4, a novel approach for the mass production of polymeric permanently coated capillaries was demonstrated where the inner surface of fused-silica capillaries was coated via gas-phase chemical reactions using chemical vapour deposition (CVD) for electroosmotic flow (EOF) control. Fused-silica capillaries with a 25 ˜í¬¿m ID were coated with (3-glycidyloxypropyl) trimethoxysilane (GPTMS) by both CVD and liquid phase deposition (LPD) approaches, and the EOF was measured from pH 3-9. The CVD coating showed a more significant reduction in EOF at all pH values than LPD approach. Capillaries were also modified with the weak base (3-aminopropyl) trimethoxysilane (APTMS) to provide a pH-dependent positive surface charge, the weak acid 3-mercaptopropyltrimethoxysilane (MPTMS) was used to provide a pH-dependent negative surface charge and trichloro(1H,1H,2H,2H-perfluorooctyl) silane (PFOCTS) was used to provide a neutral hydrophobic coating. APTMS showed a reduction of the EOF at pH 9, with EOF reversal observed below pH 6. MPTMS provided a slightly lower EOF than an unmodified capillary at high pH, and a slightly higher EOF at lower pH. PFOCTS provided the most consistent EOF as a function of pH. CVD was also used for in situ molecular layer deposition (MLD) of poly(p-phenylene terephthalamide) (PPTA) using the self-limiting sequential reaction between terephthalaldehyde (TA) and p-phenylenediamine (PD). The deposition of successive layers resulted in increased surface coverage of the polymer and a greater reduction in EOF at pH higher than 5. The stability of the coated capillaries was tested at pH 8.8 for the separation of inorganic anions. Over 1.5 months of continuous operation (‚Äöv¢v†4130 runs), the reproducibility of the apparent mobilities for chloride, nitrite, nitrate and sulfate were 2.43%, 2.56%, 2.63% and 3.05%, respectively. In chapter 5, the manual setup developed in chapter 4 was modified to develop an automated system for coating capillaries using the proposed CVD technique. The system design was automated using Labview. After the coating conditions were optimized, the system was used to develop a permanent polymeric coating made of 50 layers of PPTA inside a 25 ˜í¬¿m capillary to eliminate the EOF. Finally, the inner surface of the coated capillaries was characterized using scanning electron microscopy (SEM) In chapter 6, GreyScan¬¨vÜ ETD-100 was examined in a more challenging application. A sensitive and robust method was developed and tested to detect methamphetamine and its precursor in clandestine drug laboratories and non-invasively collected biological fluids. Unlike the ideal cleaned pharmaceutical manufacturing units, swabbing walls, floors and carpets in clandestine laboratories provided a more complex sample matrix with high salt deposits. Moreover, an enhanced sensitivity was achieved using transient isotachophoresis (tITP) on the novel polymeric capillary coating developed in Chapter 4 and 5. The ETD-100 showed LOD and LOQ ‚ÄövÑv¨ acceptable with the guidelines for analysis of methamphetamine (MA) in clandestine labs ‚ÄövÑv¨ of 0.02 and 0.05 ˜í¬¿g/swab with an enhancement factor of 118 and 328 for MA and pseudoephedrine (PSE), respectively, with a recovery above 60 % for all swabs used. In chapter 7, some problems were identified while using the Greyscan¬¨vÜ ETD-100 and CVD; potential solutions were tested to address these problems and future plans and recommendations were offered to the manufacturer to enhance the system performance.