The role of mass spectrometry and related techniques in the analysis of extractable and leachable chemicals.

In addition to degradation products, impurities, and exogenous contaminants, industries such as pharmaceutical, food, and others must concern themselves with leachables. These chemicals can derive from containers and closures or migrate from labels or secondary containers and packaging to make their way into products. Identification and quantification of extractables (potential leachables) and leachables, typically trace level analytes, is a regulatory expectation intended to ensure consumer safety and product fidelity. Mass spectrometry and related techniques have played a significant role in the analysis of extractables and leachables (E&L). This review provides an overview of how mass spectrometry is used for E&L studies, primarily in the context of the pharmaceutical industry. This review includes work flows, examples of how identification and quantification is done, and the importance of orthogonal data from several different detectors. E&L analyses are driven by the need for consumer safety. These studies are expected to expand in existing areas (e.g., food, textiles, toys, etc.) and into new, currently unregulated product areas. Thus, this topic is of interest to audiences beyond just the pharmaceutical and health care industries. Finally, the potential of universal detector approaches used in other areas is suggested as an opportunity to drive E&L research progress in this arguably understudied, under-published realm.

Bacterial contamination of lightproof covers for high-calorie infusion solutions in wards.

Deterioration of drugs due to light exposure is one of the major concerns, especially regarding protection of high-calorie infusion solutions, lightproof covers are used in hospitals. In the absence of any set standards regarding their usage, they are often reused. This study aimed to investigate bacterial contamination of lightproof covers used in hospital wards. For this, lightproof covers which had been used or stored in wards were collected and bacterial cultures were carried out from them. Examination of the cultures revealed that bacteria were present in the used lightproof covers. The bacterial species detected in the used lightproof covers were Bacillus species Coagulase-negative Staphylococci (CNS) and Methicillin-resistant Staphylococcus aureus (MRSA). Bacillus species and CNS were also detected in lightproof covers stored in wards, whereas MRSA was not detected. Intestinal bacteria were detected in only one lightproof cover. However, no bacteria were detected from either inside or outside of the unused lightproof covers that were stored in the drugs department. After allowing the unused lightproof covers stored in the drugs department to stand for 24 h, Bacillus species and CNS were detected in only one of the covers, whereas no bacteria was detected in other covers. These results indicate that there is a risk of bacterial contamination in the reuse of lightproof covers and that they should either be disposed off properly after usage or hand, finger disinfectants should be used while handling them to prevent any possible contamination.

Evaluation of Different Quality-Relevant Aspects of Closed System Transfer Devices (CSTDs).

PURPOSE: Health care professionals can be exposed to hazardous drugs such as cytostatics during preparation of drugs for administration. Closed sytem transfer devices (CSTDs) were introduced to provide protection for healthcare professional against unintended exposure to hazardous drugs. The interest in CSTDs has significantly increased after USP <800> monograph was issued. The majority of the studies published so far on CSTDs have focused on their "containment" function. However, other important attributes for CSTDs with potential importance for product quality impact are not yet fully evaluated. METHODS: In the current study, we evaluated four sytems from different suppliers, in combination with different container closure systems (CCS), using solutions of different viscosity and surface tension. The different CSTD / CCS combinations were tested for (a) containment (integrity) using a highly sensitive helium leak test, (b) the force required for mounting the vial adaptor, (c) contribution to visible and subvisible particles as well as (d) the hold-up volume. RESULTS: Results show that the majority of CSTDs may have leaks varying in size, and that some of them generated visible particles due to stopper coring and subvisible particles, both due to silicon oil and particulate contaminations of the Devices. Finally, the holdup volume was up to 1 mL depending on the CSTD type, vial size and solution viscosity. CONCLUSION: These results show that there is a need to evaluate the compatibility of CSTD systems to select the best system for the intended use and that CSTDs may adversely impact product quality and delivered dose.

Light transmission properties of pharmaceutical liquid bottles and evaluation of their photoprotective efficacy.

The light sensitive pharmaceutical dosage forms are well protected from light by packing in light protective bottles especially the colored glass and plastic bottles. In the present study the transmission characteristics of transparent glass bottle, amber glass bottle, polyvinyl chloride amber plastic bottle (PVC) and low density polyethylene semi-opaque plastic bottles (LDPE) (empty and drug filled) have been evaluated and the data compared for compliance with Pharmacopoeial limits of percentage transmission. The variations in thickness affect the amount of light transmitted through the bottles. For an average thickness, the transmission of bottles was not uniform indicated the effect of manufacturing variables on the transmission of light. The drug filled bottles showed an increase in light transmission probably as a result of interaction between drug and bottle components. The leaching of any coloring agents from glass bottles or the pigments from plastic bottles into the solution during storage appeared to increase the transmission of light which could be detrimental to photosensitive drugs in a formulation. The light protective efficacy of bottles was in the order: Semi-opaque plastic (LDPE) > amber plastic (PVC) > amber glass. The photoprotection of aqueous solution of riboflavin as a model compound in these bottles has been studied and its shelf-lives and stability ratio were determined.

Systematic Review of Drug Packaging Methods in Body Packing and Pushing: A Need for a New Classification.

A systematic review of the literature regarding drug packaging methods in body packing and materials used is presented, with the aim (a) to summarize data regarding the packaging methods adopted by drug trafficking organizations, (b) to support forensic pathologists and police forces to classify and describe drug packages, (c) to propose a new classification for drug packaging techniques, and (d) to better clarify the impact of packaging methods on radiological detectability.Packaging methods have been described in 2981 cases, permitting us to summarize the different materials used and to propose a new classification for packaging method based on the materials used. Information concerning the affiliation of body packers and pushers with major (or not) drug trafficking organizations and techniques used to reduce the radiological detectability of the concealed drugs have also been collected.Besides the packaging methods described over the years, our study suggests a standardized approach for the description of drug packages based on the use of different materials and packaging procedures, which provide a possible insight to the type of drug trafficking organization involved.

Large-Scale Assessment of Extractables and Leachables in Single-Use Bags for Biomanufacturing.

Single-use technologies (SUTs) are widely used during biopharmaceutical manufacture as disposable bioreactors or media and buffer storage bags. Despite their advantages, the risk of release of extractable and leachable (E&Ls) substances is considered an important drawback in adopting disposables in the biomanufacturing process. E&Ls may detrimentally affect cell viability or productivity or may persist during purification and present a risk to the patient if remaining in the final drug product. In this study, 34 plastic films from single-use bags (SUBs) for cell cultivation were extracted with selected solvents that represent reasonable worst-case conditions for most typical biomanufacturing applications. SUBs were incubated at small-scale under accelerated-aging conditions that represented standard operational conditions of use. Leachables analysis was performed following dispersive liquid-liquid microextraction (DLLME) for analyte preconcentration and removal of matrix interference. Resulting extracts were characterized by GC-headspace for volatiles, high resolution GC-Orbitrap-MS/MS for semivolatiles, high resolution LC-Orbitrap-MS/MS for nonvolatiles, and ICP-MS for trace elemental analysis. Multivariate statistical analysis of the analytical data revealed significant correlations between the type and concentration of compounds and bags features including brand, manufacturing date and polymer type. The analytical data demonstrates that, over recent years, the nature of E&Ls has been altered due to the implementation of manufacturing changes and new types of polymers and may change further with the future advent of regulations that will limit or ban the use of certain raw materials and additives. The broad E&L database generated herein facilitates toxicological assessments from a biomanufacturing standpoint and provides practical guidelines for confident determination of E&Ls to enable screening and elimination of nonsatisfactory films for single use bioprocessing.

Assessment of the permeability properties of cryopreservation outer bags used in NHSBT.

This study was carried out to investigate leakage/transport across the bag material of six outer cryopreservation bags in common use within NHS Blood and Transplant. In order to do this two different leak testing procedures; coloured dye and hydrogen tracer gas, were used. The data obtained show that a coloured dye cannot permeate through the materials both at room temperature and following storage at liquid nitrogen temperature (- 196 °C). In addition, when filled with the smallest elemental molecule, hydrogen, in the form of a tracer gas, all of the bags only allowed trace amounts of hydrogen to escape, either through the seal or the bag material. The data indicated that each of the bag materials tested would be capable of preventing bacterial or viral cross-contamination as long as the material remained intact.

Microbiological Investigations of ReNu Plastic Bottles and the 2004 to 2006 ReNu With MoistureLoc-Related Worldwide Fusarium Keratitis Event.

PURPOSES: The purposes of this study were to determine whether the contact lens solution RevitaLens Ocutec (containing the antimicrobial agents alexidine and polyquaternium-1) would inhibit Fusarium organisms when heated in ReNu plastic bottles; whether alexidine would inhibit Fusarium organisms when heated in non-ReNu plastic bottles; and whether an alexidine-neutralizing compound leaches from heated ReNu bottles. METHODS: RevitaLens and an alexidine solution (0.00045%), previously stored in ReNu bottles at room temperature (RT) and 56°C, were incubated with 7 different Fusarium organisms. The alexidine solution was similarly stored in seven non-ReNu plastic bottles and incubated with these same organisms. To determine if an alexidine-neutralizing compound might be leaching from heated ReNu bottles, phosphate-buffered saline (PBS) was incubated at RT and 56°C in ReNu bottles, combined with alexidine, and then tested for anti-Fusarium capability. RESULTS: After being heated in ReNu bottles, RevitaLens retained its anti-Fusarium capability, whereas the alexidine solution did not. The alexidine solution heated in seven non-ReNu plastic bottles retained its anti-Fusarium capability. The alexidine solution retained its anti-Fusarium capability when incubated with a PBS solution that had been heated in ReNu bottles, indicating, microbiologically, that an alexidine-neutralizing compound did not leach from the heated ReNu bottle. CONCLUSIONS: Alexidine uniquely fails to inhibit Fusarium organisms when heated in a plastic ReNu bottle, but not in seven other plastic bottles, whereas the anti-Fusarium capability of RevitaLens (containing the antimicrobial agents alexidine and polyquaternium-1) is unaffected by heating in a ReNu bottle. There does not seem to be an alexidine-neutralizing compound leaching from heated ReNu bottles. An interaction between alexidine and its heated ReNu bottle may have been a critical factor in the worldwide ReNu with MoistureLoc-related Fusarium keratitis event of 2004 to 2006.

Does electronic monitoring influence adherence to medication? Randomized controlled trial of measurement reactivity.

BACKGROUND: Electronic monitoring is recommended for accurate measurement of medication adherence but a possible limitation is that it may influence adherence. PURPOSE: To test the reactive effect of electronic monitoring in a randomized controlled trial. METHODS: A total of 226 adults with type 2 diabetes and HbA1c ≥58 mmol/mol were randomized to receiving their main oral glucose lowering medication in electronic containers or standard packaging. The primary outcomes were self-reported adherence measured with the MARS (Medication Adherence Report Scale; range 5-25) and HbA1c at 8 weeks. RESULTS: Non-significantly higher adherence and lower HbA1c were observed in the electronic container group (differences in means, adjusting for baseline value: MARS, 0.4 [95 % CI -0.1 to 0.8, p = 0.11]; HbA1c (mmol/mol), -1.02 [-2.73 to 0.71, p = 0.25]). CONCLUSIONS: Electronic containers may lead to a small increase in adherence but this potential limitation is outweighed by their advantages. Our findings support electronic monitoring as the method of choice in research on medication adherence. (Trial registration Current Controlled Trials ISRCT N30522359).

Perforation of the gastrointestinal tract caused by inadvertent ingestion of blister pill packs: report of two cases diagnosed by MDCT with emphasis on maximal intensity and volume rendering reformations.

We report two cases of elderly patients presenting with life-threatening complications due to inadvertent accidental ingestion of blister pill packs (BPPs). The first patient presented with obstruction followed by anemia and finally perforation of the small bowel. The second presented with rapidly lethal mediastinitis due to a large perforation of the lower esophagus. The responsible BPPs were identified by multidetector computed tomography and the best result in their characterization was obtained through maximal intensity projections and volume rendering reformations.

Source strength assay of iodine-125 seeds sealed within sterile packaging.

Early-stage prostate cancer is widely treated by iodine-125 (I-125) seed implantation. While quality assurance methods are in place to assure consistency in I-125 seed source strength, current methods involve the breaking of the sterilization package, raising issues concerning sterility and time limitations. The purpose of this study was to develop a method of characterizing the total source strength of I-125 seeds within a cartridge that has been sealed within a sterilization package and to evaluate the probability of detecting an out-of-calibration seed (aberrant seed). We defined a protocol to determine the ability of a well-type ionization chamber to detect aberrant I-125 seeds within a cartridge sealed in the sterilization package. A novel jig for a well-type ionization chamber was designed to accommodate the sterilization package. One seed was chosen randomly from two cartridges containing five or 15 seeds (0.544 U source strength) and was exchanged with aberrant seeds of six different source strengths. The source strength was measured at each position within the cartridge. The results indicated that the response of the well chamber was sensitive to changes in the aberrant seed position within the cartridge and the source strength of the aberrant seed. The correlation coefficient between single seed and batch assay results was high (0.998). A novel jig and a measurement method using a well ionization chamber were developed, which allowed for a batch assay characterization of the total source strength of I-125 seeds within a cartridge sealed within sterilization package. This method is simple, time-saving, and offers greater practical application.

Pan-antimicrobial failure of alexidine as a contact lens disinfectant when heated in Bausch & Lomb plastic containers: implications for the worldwide Fusarium keratitis epidemic of 2004 to 2006.

OBJECTIVE: ReNu with MoistureLoc (ReNuML), containing the antimicrobial agent alexidine 0.00045%, was associated with the Fusarium keratitis epidemic of 2004 to 2006. Although a single-point source contamination was ruled out, only Fusarium organisms were reported during the outbreak. This study investigated whether the reported loss of antimicrobial effectiveness toward Fusarium of ReNuML after exposure to heat in high-density polyethylene (HDPE) plastic containers could also be demonstrated with other common fungal and bacterial agents of keratitis. METHODS: A buffered solution of alexidine 0.00045% was incubated in glass and ReNu HDPE plastic containers at room temperature (RT) and 56°C for 4 weeks, serially diluted, and tested for its ability to inhibit the growth of 20 bacterial isolates, 12 non-Fusarium fungal isolates, and 7 Fusarium isolates originally involved in the keratitis epidemic. RESULTS: A statistically significant loss of antimicrobial capability was seen with all fungi, all gram-positive bacteria, and all isolates of Klebsiella when alexidine 0.00045% was incubated at 56°C in ReNu HDPE containers compared with RT or glass incubation (P≤0.0001). CONCLUSIONS: Heating of an alexidine solution in ReNu HDPE plastic (but not glass) containers results in the same loss of anti-Fusarium activity as reported when testing the original ReNuML solution. This loss of inhibitory activity is not specific to Fusarium and occurs with other fungi and bacteria that cause keratitis. The reasons for the lack of reports of bacterial and/or non-Fusarium fungal keratitis during the original Fusarium keratitis epidemic remain unclear at this time.

[The development of multifunction intravenous infusion quantitative packaging device].

Aimed at tackling the compatibility issues arising from the drug reaction in intravenous infusion tube, we developed a simple, suitable and multi-function intravenous infusion tube for the special use for rescuing critical patients, the elderly, children etc. Each drug in a transfusion process can be filtered to realize quantitative packet and packet delivery. Thus, the drugs in the infusion tube are prevented from meeting with each other. No overlap, no particle pollution occurred. Stable performance and accurate dosage are maintained. As a result safety is ensured during drug delivery.

Process optimization and transfer of freeze-drying in nested vial systems.

Scale-up and transfer of freeze-drying processes is a crucial challenge in biopharma industry. With the success of small batch processing lines utilizing rack vial holding systems, further detailed knowledge about freeze-drying cycles and their scale-up for vials in a rack is required. Therefore, product temperature (TP) profiles as well as Kv values of vials nested in a Polyetheretherketon (PEEK) rack were compared to those of vials placed in a commonly used stainless steel tray. Additionally, both setups were challenged with varying fill volume and partially versus fully loaded rack. Additionally, a process developed for rack was compared to a tray freeze-drying cycle. Freeze-drying in vials placed in the rack is markedly faster for center vials and more homogeneous compared to vials in bulk tray setting, as indicated by TP and Kv values. Due to the more homogeneous drying the rack is more flexible regarding variation of the fill volume. The key point for the transfer of a freeze-drying cycle from rack to tray is to consider the higher sublimation rates in the rack by adapting chamber pressure or shelf temperature for the tray. Furthermore, transfer from one rack per shelf in a laboratory freeze-dryer to pilot scale with four racks per shelf was successful. Thus, understanding of the process in rack and tray setup was enhanced to ensure efficient scale-up and transfer of freeze-drying processes.

Fabrication and evaluation of nanocontainers for lipophilic anticancer drug delivery in 3D in vitro model.

Presently, most of anticancer drugs are high toxic for normal cells and, and as a result, they have severe side effects. Moreover, most of the formulations are lipophilic and have poor selectivity. To overcome these limitations, various drug delivery systems could be proposed. The aim of the current study was to fabricate novel polysaccharide nanocontainers (NC) by one-step ultrasonication technique and to evaluate their accumulation efficacy and cytotoxicity in 2D (monolayer culture) and 3D (tumor spheroids) in vitro models. NC with mean sizes in a range of 340-420 nm with the core-shell structure are synthetized and characterized. The NC shell is composed from diethylaminoethyl dextran/xanthan gum polyelectrolyte complex, while the hydrophobic core was loaded with the lipophilic anticancer drug thymoquinone. To enhance NC accumulation in human breast adenocarcinoma MCF-7 cells, the NC surface was modified with poly-L-lysine (PLL) or polyethylene glycol. Cell uptake of the NC loaded with Nile Red into the tumor cells was investigated by laser scanning confocal microscopy, fluorescent flow cytometry and fluorimetry. Modification of the NC with PLL allowed to obtain the optimal drug delivery system with maximal cytotoxicity, which was tested by MTT-test. The developed NC are promising for lipophilic anticancer drug delivery.

Evaluation of medication adherence methods in the treatment of malaria in Rwandan infants.

OBJECTIVES: To compare three methods for evaluating treatment adherence in a 7-day controlled treatment period for malaria in children in Rwanda. METHODS: Fifty-six children (< 5 years) with malaria were recruited at the University Hospital of Butare, Rwanda. Patients were treated with quinine sulfate, taste-masked, pellets during seven days: three days in hospital (in-patient) followed by a four-day out-patient period. Three methods to evaluate medication adherence among patients were compared: manual pill count of returned tablets, patient self-report and electronic pill-box monitoring. These pill-boxes were equipped with a microchip registering date and time of every opening. Medication adherence was defined as the proportion of prescribed doses taken. The inter-dose intervals were analysed as well. RESULTS: Medication adherence data were available for 54 of the 56 patients. Manual pill count and patient self-report yielded a medication adherence of 100% for the in- and out-patient treatment periods. Based on electronic pill-box monitoring, medication adherence during the seven-day treatment period was 90.5 +/- 8.3%. Based on electronic pill-box monitoring inpatient medication adherence (99.3 +/- 2.7%) was markedly higher (p < 0.03) than out-patient adherence (82.7 +/- 14.7%), showing a clear difference between health workers' and consumers' medication adherence. CONCLUSION: Health workers' medication adherence was good. However, a significant lower medication adherence was observed for consumers' adherence in the outpatient setting. This was only detected by electronic pill-box monitoring. Therefore, this latter method is more accurate than the two other methods used in this study.

Application of laser ablation multicollector inductively coupled plasma mass spectrometry for the measurement of calcium and lead isotope ratios in packaging for discriminatory purposes.

The potential of high-precision calcium and lead isotope ratio measurements using laser ablation coupled to multicollector inductively coupled plasma mass spectrometry (LA-MC-ICP-MS) to aid distinction between four genuine and five counterfeit pharmaceutical packaging samples and further classification of counterfeit packaging samples has been evaluated. We highlight the lack of reference materials for LA-MC-ICP-MS isotope ratio measurements in solids. In this case the problem is minimised by using National Institute of Standards and Technology Standard Reference Material (NIST SRM) 915a calcium carbonate (as solid pellets) and NIST SRM610 glass disc for sample bracketing external standardisation. In addition, a new reference material, NIST SRM915b calcium carbonate, has been characterised in-house for Ca isotope ratios and is used as a reference sample. Significant differences have been found between genuine and counterfeit samples; the method allows detection of counterfeits and aids further classification of packaging samples. Typical expanded uncertainties for measured-corrected Ca isotope ratio values ((43)Ca/(44)Ca and (42)Ca/(44)Ca) were found to be below 0.06% (k = 2, 95% confidence) and below 0.2% for measured-corrected Pb isotope ratios ((207)Pb/(206)Pb and (208)Pb/(206)Pb). This is the first time that Ca isotope ratios have been measured in packaging materials using LA coupled to a multicollector (MC)-ICP-MS instrument. The use of LA-MC-ICP-MS for direct measurement of Ca and Pb isotopic variations in cardboard/ink in packaging has definitive potential to aid counterfeit detection and classification.