Impurity Control Research Articles

On the compatibility of liquid sodium as heat transfer fluid for advanced concentrated solar thermal energy systems

The use of liquid sodium as a heat transfer fluid has shown great promise and application in nuclear power generation and it is now being utilized in concentrated solar thermal power (CSP) applications, owing to its favorable thermodynamic properties. Its implementation, however, comes with a unique array of technical issues in CSP applications, primarily the incompatibility of structural materials with liquid sodium in these operational environments. In this review, major damage mechanisms will be discussed, with a focus on their relevance to advanced CSP plants. Such mechanisms include corrosion, liquid metal embrittlement, carburization/de-carburization, erosion, creep, and thermal fatigue. The degradation factors such as impurities in the sodium (e.g. oxygen) and the dissolution of the structural material's alloying elements (Cr, Mn, Ni and Si, etc.) are also discussed. This review presents a holistic overview of these inter-connected mechanisms, and most importantly explores potential solutions to mitigate these issues, including better structural material candidates, robust plant operational parameters/design, better service life predictions, and improved purification and monitoring methods for stringent control of impurities. The future directions of research are also discussed to ensure the successful use of liquid sodium in the next generation of CSP technology.

Leveraging light chain binding avidity for control of mispaired byproducts during production of asymmetric bispecific antibodies

Many biotherapeutic formats leverage antibody light chain affinity chromatography to enable robust manufacturing processes and to streamline process development. These include multi-specific antibody and antibody fragment platforms which are often designed for specific capture purification methods that can provide efficient removal of commonly expressed product-related impurities. Recently, several accounts of product-related impurity separation by leveraging binding avidity during affinity chromatography have been described in the literature. However, a more comprehensive evaluation of avidity-based separations, particularly for light chain affinity media with specificity for constant regions of antibody light chains, is valuable for development of emerging multi-specific and fragment antibody formats. Results in this work demonstrate the capability of camelid antibody-based light chain affinity media to separate asymmetric bispecific antibody heterodimers from impurities possessing more than one light chain of the same class that the media binds to, including mispaired variants, aggregates, and fragment impurities. Largest resolution for respective mispaired species were provided by CaptureSelect KappaXP and LambdaXP chromatography media. The addition of elution modifiers provided increased impurity separation, with CaptureSelect KappaXP requiring up to 500 mM concentrations of elution modifiers to produce substantial improvements to resolution, and LambdaXP showing much higher sensitivity. Isocratic elution methods developed for lambda light chain affinity chromatography media provided near complete removal of mispaired variants, and substantial removal of aggregates and fragment impurities. Addition of just 20 mM of elution modifiers such as NaCl are shown to drive increased binding strength and separation of heterodimer species from impurities on CaptureSelect LambdaXP. These results provide scalable and transferable methods for product-related impurity control for various biotherapeutic modalities by lambda light chain affinity chromatography.

Mathematical Modeling and Optimization to Inform Impurity Control in an Industrial Active Pharmaceutical Ingredient Manufacturing Process

Mathematical Modeling and Optimization to Inform Impurity Control in an Industrial Active Pharmaceutical Ingredient Manufacturing Process

Collaborative reliance in medicine safety and quality regulation: Investigation of experiences in handling N-nitrosamine impurities among ZaZiBoNa participating countries.

IntroductionThe presence of N-nitrosamine impurities in medicines raised concerns globally as they are genotoxic and probable human carcinogens. A review of N-nitrosamine impurities in medicines provides an opportunity for National Regulatory Authorities (NRAs) to ensure that corrective and preventive actions are applied so that safe and good quality medicines are made available to the public. This study aimed to investigate the experiences on reviews conducted by NRAs from various Southern African Development Community countries which participate in the regional work-sharing forum, ZaZiBoNa, on the quality and safety data due to the presence of N-nitrosamine impurities in medicines.MethodsA comparative, descriptive study using mixed methods was conducted. Purposive sampling was applied in selecting research participants based on their participation status in the ZaZiBoNa initiative. A standardized questionnaire structured into five parts was completed by ZaZiBoNa focal persons/nominated individuals to determine the experience of each NRA in addressing the safety and quality issues related to the presence of N-nitrosamine impurities in the affected medicines. Profiled medicines included sartans, ranitidine, metformin, rifampicin, and rifapentine.ResultsSartan medicines had been reviewed by all countries participating in the ZaZiBoNa initiative. Although most NRAs have yet to conduct reviews on other profiled medicines, evaluations have been implemented to ensure access to safe and good quality medicines within the region. Most countries experienced challenges in communicating with applicants or marketing authorization holders (MAHs) on reviewing N-nitrosamine impurities in their medicines. The majority of NRAs agree that there is a need for further collaboration efforts to review N-nitrosamine impurities in medicines.ConclusionThe review of N-nitrosamine impurities in the profiled medicines by NRAs within the region has demonstrated the importance of enhanced regulatory oversight to safeguard against the risks associated with medicines. Collaborative reliance on the review of the safety and quality of medicine, continuous monitoring, implementation and review of processes, testing methods, and regular engagements with stakeholders could be essential in ensuring adequate control of N-nitrosamine impurities in medicines.

Application of ICH Guidelines for the Assessment and Control of Elemental Impurities in Parecoxib Sodium by Graphite-Digestion and ICP-MS.

Parecoxib sodium is a widely used parenteral cyclooxygenase 2 selective inhibitor to relieve acute postoperative pain following gynecologic laparotomy surgery. To ensure the quality of the drug, a detailed quality specification is indispensable. Nevertheless, it is unavoidable to introduce inorganic impurities during the drug preparation process and how to assess and control them matters. This study proposed an analytical procedure for the determination of elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Li, Sb, and Cu) in parecoxib sodium, where an easier and safer digestion protocol, graphite digestion, combined with an inductively coupled plasma-mass spectrometer (ICP-MS) was adopted when compared with microwave digestion. Moreover, the study also discussed whether should they be listed in specification to comply with ICH Q3D guidelines after test of process validation batches. Limit of quantitation (LOQ) of the above elemental impurities reached to 0.05, 0.125, 0.375, 0.075, 0.125, 0.25, 0.5, 6.25, 2.25 and 7.5 ppm, respectively, and recovery in accuracy item ranged from 90.2% to 129.9%, reflecting a sensitive and accurate method.

Control of Organic Impurities in Semisynthetic Antibiotics

In 2012, the European Medicines Agency (EMA) adopted a guideline, which divided all antibiotics into groups according to the manufacturing process and established acceptance criteria for organic impurities for each of the groups.The aim of the study was to justify the requirements and methodological approaches to setting the limits for organic impurities in semisynthetic antibiotics.Materials and methods: the authors analysed the requirements established by the leading world pharmacopoeias and the State Pharmacopoeia of the Russian Federation regarding the control of organic impurities in semisynthetic antibiotics, using the example of four semisynthetic antibiotics: doxycyline hyclate, clarithromycin, meropenem, and ceftriaxone. The study used the methods of comparative analysis and content analysis. Results: the study demonstrated that the organic impurity profiles of the analysed active substances and the corresponding finished medicinal products often differ significantly across the leading pharmacopoeias, either qualitatively or quantitatively. The Russian, European, and United States pharmacopoeias provide for the use of impurity reference standards in the test procedures for the determination of impurities in active substances of the semisynthetic antibiotics in question, whereas the Japanese Pharmacopoeia allows the use of non-compendial reference substances in the assessment of the chromatographic system separation power.Conclusions: the ability of a pharmacopoeial text to cover a variety of medicinal products coming to the Russian market from different countries has become a vital issue. This includes covering the impurity determination procedures, reference standards, and limits used, because general-purpose methods and limits do not always allow for correct assessment of impurity profiles in substances produced by different manufacturing processes. The current USP practice is to include various impurity control procedures in monographs on medicinal products, and the limits may also vary. This approach may be applied in the State Pharmacopoeia of the Russian Federation as well.

(Invited) Metallic Impurity Control in Silicon Processing

In this paper we review the performances of a few techniques for the analysis of metal contamination in silicon. A few case studies are discussed to compare the ability of these techniques in detecting contaminants with different properties as silicon impurities. Common contaminants and elements recently introduced in the fabrication process are considered.TXRF (Total reflection X Ray Fluorescence), recombination lifetime measurement techniques, DLTS (Deep Level Transient Spectroscopy) and micro-photoluminescence analyses are compared. The results reported in this paper show that it is not possible to define a unique recipe that can be applied in all cases. Different approaches are required depending, on one hand, on the contaminant diffusivity and solubility, and, on the other hand, on the process step to be monitored.The techniques for monitoring metal contamination can schematically be divided into two main groups, one consisting of the techniques that measure the chemical concentration at the silicon surface and the other of the techniques that measure the electrical activity of the contaminant in the silicon volume.Mostly in case of metal contamination detection during wafer manufacturing, techniques which intentionally deposit thin films of polysilicon or thermal oxide and then perform chemical etching of them associated to ICP-MS analysis are also used, mostly addressed to detect fast diffusers like Cu and Ni [1], not always associated to clear electrical response. Indeed, these elements retain significant diffusivity even near room temperature, where the solid solubility is negligibly low, so they mostly segregate at the silicon surface or in getter sites, and for this reason they are hardly revealed in the silicon volume. However, these elements can be revealed by the recovery from deep depletion of MOS capacitors, because the segregated metals significantly increase the surface generation velocity.Some medium-fast diffusers like iron diffuse through several hundred microns during an ordinary thermal treatment, and mostly remain in the solid solution in silicon [1]. A comparison was carried out between TXRF and carrier recombination lifetime measurement for their ability to reveal iron contamination after a cleaning process. To prepare the samples for carrier lifetime measurements, the samples had to be thermally treated by RTP (Rapid Thermal Process). This study showed that TXRF and recombination lifetime measurements have essentially the same sensitivity to iron contamination. Vice versa, the detection of slow diffusers is found to be critical, because a very low concentration per unit area (≈107cm-2) may result in a non-negligible volume concentration in the device region (≈1010cm-3). As a consequence, the sensitivity per unit area required for these elements is difficult to reach with surface techniques such as TXRF. Molybdenum and tungsten [1] are examples of this sort. These elements do not diffuse deep enough to be efficiently revealed by recombination lifetime measurements, but they are easily revealed in the silicon volume by DLTS, which is probably the best approach for these elements, though it requires a considerable sample preparation. On the other hand, these elements are very common contaminants in ion implantation or epitaxial processes, and are very harmful for devices sensitive to carrier recombination, such as image sensors. Therefore, a technique able to detect near-surface contamination with no or limited sample preparation would be needed. Band-to-band micro-photoluminescence proved to be a good candidate, though DLTS still has the best sensitivity.Silicon contamination may also happen in the final part of the device process flow when the wafer frontside is protected by several dielectric layers and low-temperature thermal treatments only are allowed. In that case, contamination may come from the wafer backside only, but fast diffusers are still able to reach the wafer frontside and damage the device. In a study of palladium contamination from a contaminated chuck, TXRF proved not to be sensitive enough to palladium contamination. Palladium is best revealed by recombination lifetime measurements, such as the SPV (Surface PhotoVoltage) technique, but a high temperature treatment is required to activate it, so also in this case some sample preparation is required.Finally, we recall that the device itself can be a very sensitive monitor of metal contamination [2], though of course methods that prevent the impact of contamination of the device are generally preferred. The analysis of the dark current in image sensors not only reveals the presence of metal contamination (see the enclosed figure), but also provides some hints about the contaminant element.

Divertor detachment operation in helium plasmas with ITER-like tungsten divertor in EAST

Detachment in helium (He) discharges has been achieved in the EAST superconducting tokamak equipped with an ITER-like tungsten divertor. This paper presents the experimental observations of divertor detachment achieved by increasing the plasma density in He discharges. During density ramp-up, the particle flux shows a clear rollover, while the electron temperature around the outer strike point is decreasing simultaneously. The divertor detachment also exhibits a significant difference from that observed in comparable deuterium (D) discharges. The density threshold of detachment in the He plasma is higher than that in the D plasma for the same heating power, and increases with the heating power. Moreover, detachment assisted with neon (Ne) seeding was also performed in L- and H-mode plasmas, pointing to the direction for reducing the density threshold of detachment in He operation. However, excessive Ne seeding causes confinement degradation during the divertor detachment phase. The precise feedback control of impurity seeding will be performed in EAST to improve the compatibility of core plasma performance with divertor detachment for future high heating power operations.

Real-time wall conditioning and recycling modification utilizing boron and boron nitride powder injections into the Large Helical Device

Controlled particulate injections from the PPPL impurity powder dropper (IPD) into the Large Helical Device have demonstrated positive effects on the wall conditions on both an intra and inter-shot basis. Injections over a range of densities, input powers, pulse lengths, heating schemes, injection quantities and main ion species show conclusive evidence of improvement to plasma wall conditions. Successful injections are confirmed by both spectroscopic measurements as well as real-time visible camera signals. In 7 s long plasmas the responses include a reduction in wall recycling as well as a reduction in native impurity content as observed over the course of several discharges. For plasmas longer than 40 s, improvements to the recycling rate and increased impurity control are observed in real time as a consequence of the extended particulate injections. These experiments demonstrate the extended applicability of this solid particulate conditioning technique to the control and maintenance of the plasma wall conditions. In addition they are an important initial step in the development of the real-time boronization technique as a supplement to standard conditioning scenarios.

Speciation study of the aqueous Fe-Cu-As-Sb-Bi-H2SO4 system and prediction of redox potential in copper electrorefining from 25 °C to 70 °C

• A thermodynamic model for solutions in copper electrorefining was developed. • Species of Fe, Cu, As, Sb and Bi were identified and thermodynamic data was collected and assessed. • Distribution of each species was obtained and discussed up to 70 °C. • The model was validated by reliable and accurate prediction of measured ORPs. • Fe 3+ /Fe 2+ couple dominates in ORPs with presence of Fe(II, III), As(III, V) and Sb(III, V). The control of impurities is crucial for production of high-purity cathode copper by electrorefining, especially due to its surging demand stimulated by the promotion of electric vehicles. In the present study, a thermodynamic model has been developed to reliably simulate the distribution of impurity species such as Fe(II, III), As(III, V), Sb(III, V) and Bi(III) in industrial copper electrorefining solutions up to 70 °C. Through extensive literature review, relevant aqueous species were identified and thermodynamic data were collected and critically assessed, including free Fe 2+ , FeHSO 4 + , FeSO 4 °, free Fe 3+ , FeSO 4 + , FeHSO 4 2+ , Fe(SO 4 ) 2 - , Cu 2+ , CuSO 4 °, CuHSO 4 + , H 3 AsO 3 o , AsO + , H 2 AsO 4 - , H 3 AsO 4 o , SbO + , H 3 SbO 3 o , Sb(OH) 6 - , HSb(OH) 6 o , BiO + and Bi 3+ . The previously developed model of Fe(II, III)-Cu(II)-H 2 SO 4 -H 2 O system was firstly evaluated. Then, additional impurities including As(III, V), Sb(III, V) and Bi(III) were gradually added for model simulation. The distribution of each species was obtained and discussed in terms of solution composition and temperature. Species concentrations were thus quantified and used for analysis of oxidation and reduction potentials (ORPs). The reliable and accurate prediction of measured ORPs confirms that the proposed model was quantitatively validated. Analysis of measured and model-calculated ORPs strongly support that the redox couple of free Fe 3+ /Fe 2+ from Fe(III)/Fe(II) plays a predominant role in ORPs determination, even after addition of As(III, V) and Sb(III, V). The expression developed previously to predict ORPs can still be applied in this work. The pH and ionic strength were also obtained and discussed. These findings can provide a deeper understanding on speciation in copper electrorefining solutions.

Thermodynamics Analysis and Pilot Study of Reusing Medium and High Alloy Steel Scrap Using Induction Melting and Electroslag Remelting Process

The annual cumulative quantity of high and medium alloy steel scrap has exceeded 10 million tons. Using the traditional smelting process involving electric arc refining in a smelting furnace for these scraps causes high percentages of alloy losses, which decreases the value of the alloy steel scrap and poses environmental threats. Existing studies have rarely focused on separate smelting of the scrap and oxidation behaviors of the alloying elements. Therefore, this study proposes an induction melting and electroslag remelting scheme to process the scrap. Based on this scheme, the effects of the temperature, oxygen content, and element contents on the recovery percentages of the alloying elements were investigated using pilot experiment and thermodynamic analysis. The experimental results showed that the alloying elements (tungsten, chromium, nickel, molybdenum, and vanadium) exhibited recovery percentages of 97.36%, 94.62%, 97.63%, 95.09%, and 89.49%, respectively; furthermore, the impurity content did not increase during smelting. The thermodynamic analysis indicated that an increase in carbon content improved the oxidation resistance of the alloying elements except for nickel, whereas the increases in the contents of oxygen and alloying elements increase their oxidation. Steam partial pressure and air suction dramatically increase the concentrations of nitrogen, hydrogen and oxygen. This scheme is an alternative for smelting medium and high alloy steel scrap, and the thermodynamic analysis provides a theoretical understanding of the oxidation behaviors of the alloying elements in the steel scrap and the control of impurity.

Argon pumpout by ICRF waves in C-Mod L- and I-mode plasmas

Pumpout of argon ions by ICRF waves has been observed in C-Mod deuterium L- and I-mode plasmas that had a substantial hydrogen fraction. The effect is manifested by a reduction of core argon x-ray brightness up to a factor of 90% on time scales of tens of milliseconds following injection of ICRF power. For Ar16+, the pumpout is strongest for hydrogen minority concentrations between 0.25 and 0.4, when the ICRF waves are not expected to result in minority heating. Modeling with the TORIC code suggests that the pumpout process occurs when the H/D mode conversion layer overlaps with the 2nd harmonic impurity resonance layer. The magnitude of the argon pumpout is independent of ICRF power above an apparent threshold of ∼500 kW, independent of electron density and appears to decrease as the plasma current is increased. Potential application as a heavy impurity control tool in reactors is discussed.

Determination of amoxicillin trihydrate impurities 4-hydroxyphenylglycine (4-HPG) and 6-Aminopenicylanic acid (6-APA) by means of ultraviolet spectroscopy

Amoxicillin is one of the broad-spectrum β-lactam antibiotics widely used in the treatment of many diseases. It is inevitable that 4-hydroxyphenylglycine (4-HPG) and 6-Aminopenicylanic acid (6-APA), which are used during the production of this antibiotic, are incorporated into the molecular lattice of the product as impurities. Today, many expensive methods and chemical devices are used for the purification of Amoxicillin by determining 6-APA and 4-HPG, which are defined as impurities. In this study, it was aimed to develop a fast, simple, and specific UV-spectrophotometric method for the determination of 4-HPG and 6-APA. Another aim of this article is to cause as little harm as possible to the environment and human health by using as few chemicals as possible throughout the study. In this study, all attempts to determine 6-APA and 4-HPG, which are impurities in the production of amoxicillin, were carried out with the help of a UV/VIS spectrophotometer. Also, Four different concentrations of NaOH were used as a solvent for each impurity. UV spectra of 4-HPG and 6-APA concentrations between 210 and 400 nm were measured. In the literature, the UV spectrum of 4-HPG has been revealed for the first time in this study and examined in detail. The UV spectrum of 4-HPG was characterized in 3 regions. Again, the response of 6-APA to different NaOH concentrations was demonstrated for the first time in this study. It was determined that the peaks of 6-APA dissolved in NaOH shifted from 222 nm to 227 nm depending on the concentration amount. In addition, it is an ideal green procedure that makes a difference in the literature, as the study is carried out for the control and determination of impurities without the use of any organic solvents or chemicals harmful to the environment.

(Invited) Metallic Impurity Control in Silicon Processing

The performances of a few techniques for the analysis of metal contamination in silicon are reviewed. The chemical dissolution of a polysilicon gettering layer associated to ICP-MS (Inductively Coupled Plasma - Mass Spectroscopy) analysis, TXRF (Total Reflection X-Ray Fliuorescence) Recombination lifetime measurement techniques, DLTS (Deep Level Transient Spectroscopy) and micro-photoluminescence analyses are compared. A few case studies are discussed to test the ability of these techniques in detecting contaminants with different properties as silicon impurities. The results reported in this paper show that it is not possible to define a unique recipe that can be applied in all cases. Different approaches are required depending, on one hand, on the contaminant diffusivity and solubility, and, on the other hand, on the process step to be monitored. Finally, we show that the device itself can be a sensitive monitor of metal contamination.

Analysis of the polymerized impurities in cefmetazole sodium based on novel separation principle by liquid chromatography tandem ion trap/time-of-flight mass spectrometry

To effectively control the polymerized impurities in cefmetazole sodium, novel high performance gel filtration chromatography (HPSEC) with TSK-gel G2000SWxl column and RP-HPLC method with C18 column were used in replace of classical gel filtration chromatography with Sephadex G-10 gel. By studying the chromatographic behavior of polymerized impurities in both chromatographic systems with different chromatographic separation principles, the polymerized impurities in cefmetazole sodium were separated and detected effectively. The two-dimensional liquid chromatography tandem ion trap/time-of-flight mass spectrometry (2D LC-IT-TOF MS) was applied to characterize the structures of polymerized impurities eluted from HPSEC method, and liquid chromatography tandem ion trap/time-of-flight mass spectrometry was applied to characterize the structures of polymerized impurities and other unknown impurities eluted from RP-HPLC method. The structures of fourteen unknown impurities in cefmetazole sodium were deduced based on the MS n data, nine of which were polymerized impurities. The corresponding relationship between impurities in the HPSEC method and RP-HPLC method was established, and the specificity of the two methods was evaluated. The RP-HPLC method for analysis of the polymerized impurities has higher column efficiency and specificity than the HPSEC method. The RP-HPLC method is suitable for quality control of the polymerized impurities in cefmetazole sodium. The forming mechanisms of degradation impurities in cefmetazole sodium were also studied.

Identification of Process-Related Impurities and Corresponding Control Strategy in Biocatalytic Production of 2-O-α-d-Glucopyranosyl-l-ascorbic Acid Using Sucrose Phosphorylase.

2-O-α-d-Glucopyranosyl-l-ascorbic acid (AA-2G) is an ideal substitute for l-ascorbic acid because of its remarkable stability and improved biological activity, which can be easily applied in cosmetic, food, and medicine fields. However, impurity identification and control are significant procedures during the manufacturing of AA-2G. This study assessed a manufacturing routine of AA-2G synthesized by sucrose phosphorylase (SPase). First, three unknown process-related impurities were observed, which were further identified as 3-O-α-d-glucopyranosyl- l-ascorbic acid (impurity I), 2-O-α-d-glucopyranosyl-l-dehydroascorbic acid (impurity II), and 13-O-α-d-glucopyranosyl-2-O-α-d-glucopyranosyl-l-ascorbic acid (impurity III), respectively. Second, a comprehensive formation pathway of impurities was elucidated, and specific strategies corresponding to controlling each impurity were also proposed. Specifically, the content of impurity I can be reduced by 50% by fine tuning reaction conditions. The impurity II-free purification process was also achieved by applying a low concentration of alkali. Finally, a semi-rational design was introduced, and a single mutant L343F was obtained by site-directed mutagenesis, which reduced impurities I and III by 63.9 and 100%, respectively, without affecting the transglycosylation activity. It is expected that the reported impurity identification and control strategies during the AA-2G production will facilitate its industrial production.

Development of a derivatization RP-HPLC method for determination of sulfuryl chloride in chlorosulfonic acid for gefapixant citrate manufacture

Control of process impurities during manufacturing of drug substance is critical to ensure quality and process robustness. During commercial process development for the gefapixant citrate drug substance, several process impurities were found to derive from sulfuryl chloride, an impurity in the raw material, chlorosulfonic acid (CSA). This made controlling the CSA quality essential for commercial production of this drug substance. Various direct analysis methods were evaluated and found unsuitable because of the highly reactive nature and structural similarity of sulfuryl chloride and CSA. Therefore, a robust derivatization reversed-phase high performance liquid chromatography (RP-HPLC) method was developed and validated to accurately quantify sulfuryl chloride in CSA. The derivatization method was utilized to evaluate many CSA batches from different commercial suppliers and to establish a correlation between sulfuryl chloride levels in CSA and the levels of process impurities in downstream materials. The methodology described herein informed the development of setting the specification on sulfuryl chloride for CSA to ensure a robust process for manufacturing high-quality gefapixant citrate drug substance. The derivatization method was successfully validated and transferred to the commercial commodity supplier for release testing of CSA as a raw material for gefapixant citrate commercial campaigns.

Role of carbon and hydrogen in limiting n -type doping of monoclinic (AlxGa1−x)2O3

We use hybrid density functional calculations to assess $n$-type doping in monoclinic $({\mathrm{Al}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}{)}_{2}{\mathrm{O}}_{3}$ alloys. We focus on silicon, the most promising donor dopant, and study the structural properties, formation energies, and charge-state transition levels of its various configurations. We also explore the impact of carbon and hydrogen, which are common impurities in metal-organic chemical vapor deposition (MOCVD). In ${\mathrm{Ga}}_{2}{\mathrm{O}}_{3}, {\mathrm{Si}}_{\mathrm{Ga}}$ is an effective shallow donor, but in ${\mathrm{Al}}_{2}{\mathrm{O}}_{3}\phantom{\rule{4pt}{0ex}}{\mathrm{Si}}_{\mathrm{Al}}$ acts as a $\mathit{DX}$ center with a ($+/\ensuremath{-}$) transition level in the band gap. Interstitial hydrogen acts as a shallow donor in ${\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ but behaves as a compensating acceptor in $n$-type ${\mathrm{Al}}_{2}{\mathrm{O}}_{3}$. Interpolation indicates that Si is an effective donor in $({\mathrm{Al}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}{)}_{2}{\mathrm{O}}_{3}$ up to 70% Al, but it can be compensated by hydrogen already at 1% Al. We also assess the diffusivity of hydrogen and study complex formation. ${\mathrm{Si}}_{\mathrm{cation}}\text{\ensuremath{-}}\mathrm{H}$ complexes have relatively low binding energies. Substitutional carbon on a cation site acts as a shallow donor in ${\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$, but can be stable in a negative charge state in $({\mathrm{Al}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}{)}_{2}{\mathrm{O}}_{3}$ when $x>5%$. Substitutional carbon on an oxygen site (${\mathrm{C}}_{\mathrm{O}}$) always acts as an acceptor in $n$-type $({\mathrm{Al}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}{)}_{2}{\mathrm{O}}_{3}$, but will incorporate only under relatively oxygen-poor conditions. ${\mathrm{C}}_{\mathrm{O}}\text{\ensuremath{-}}\mathrm{H}$ complexes can actually incorporate more easily, explaining observations of carbon-related compensation in ${\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ grown by MOCVD. We also investigate ${\mathrm{C}}_{\mathrm{cation}}\text{\ensuremath{-}}\mathrm{H}$ complexes, finding they have high binding energies and act as compensating acceptors when $x>56%$; otherwise the hydrogen just passivates the unintentional carbon donors. C-H complex formation explains why MOCVD-grown ${\mathrm{Ga}}_{2}{\mathrm{O}}_{3}$ can exhibit record-low free-carrier concentrations, in spite of the unavoidable incorporation of carbon. Our study highlights that, while Si is in principle a suitable shallow donor in $({\mathrm{Al}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}{)}_{2}{\mathrm{O}}_{3}$ alloys up to high Al compositions, control of unintentional impurities is essential to avoid compensation.

Determination of Purge Factors for Use in Oligonucleotide Control Strategies

The understanding, control, and removal of nonoligonucleotide process-related impurities (PRI) are of key importance for the manufacturing of therapeutic oligonucleotides as their presence in the final product is both a quality and safety concern. Regulatory agencies require manufacturers to demonstrate that PRI are under control or adequately purged during the manufacturing process. Purging depends on the physicochemical properties of the impurities and the unit operations of the manufacturing process but should be independent of oligonucleotide size or type. The purging power of unit operations relevant to oligonucleotide manufacturing (synthesis, cleavage and deprotection, chromatography, ultrafiltration/diafiltration) was measured using representative solvents and other small molecules typical for oligonucleotide synthesis. The results show that each unit operation has significant purging capability (synthesis >1000; cleavage and deprotection >100 (reactivity, when applicable); chromatography >1000; ultrafiltration/diafiltration >10) and that large overall purge factors can be obtained (≥1 × 107). Experimentally determined purge values are aligned with theoretical purge values; thus, the use of purge arguments in oligonucleotide control strategies is a sound scientific approach. Guidance on reasonable purge values for oligonucleotide unit operations is presented. Additionally, the data demonstrate that solvents and reagents typically used in oligonucleotide synthesis are robustly cleared by the process and should not require testing in the final product.

Characterization of false positive, contaminant-driven mutagenicity in impurities associated with the sotorasib drug substance

Sotorasib (Lumakras™) is a first-in-class, non-genotoxic, small molecule inhibitor of KRAS G12C developed as an anticancer therapeutic for treatment of patients that have a high unmet medical need. Anticancer therapeutics are considered out of scope of ICH M7 guidance for control of mutagenic impurities; however, based on ICH S9 Q&A, mutagenicity assessments are needed for impurities that exceed the qualification threshold, consistent with ICH Q3A/B, and non-mutagenic drugs. Here, we carried out hybrid-based mutagenicity assessment of sotorasib drug substance (DS) impurities using in silico quantitative structure-activity relationship (QSAR) modelling and Ames tests (for in silico positive mutagens). We encountered contradictive mutagenicity results for 2 impurities (Beta-Chloride and PAC). PAC was negative initially by QSAR but positive in a GLP full plate Ames test and Beta-Chloride was positive by QSAR, negative in a non-GLP micro-Ames but positive in a GLP full plate Ames assay. Root cause analyses identified and characterized mutagenic contaminants, 3-chloropropionic acid in batches of Beta-Chloride and 3-chloropropionic acid and Chloro-PAC in batches of PAC, used in initial GLP full-plate Ames tests. Significant reduction of these contaminants in re-purified batches resulted in no induction of mutagenicity in follow-up GLP micro-Ames tests. In summary, root-cause analyses led to accurate mutagenicity assessment for sotorasib DS-associated impurities.