Health Sciences Authority Research Articles

Regulatory requirements for the approval of anti-cancer drugs as per CDSCO in India comparison with Singapore

This study examines the regulatory requirements for anticancer medications in Singapore and India are compared in this abstract. It draws attention to the frameworks set up by Singapore's Health Sciences Authority (HSA) and India's Central Drugs Standard Control Organization (CDSCO). The procedures for clinical studies, approval schedules, and post-marketing surveillance are among the main distinctions. Singapore places a strong emphasis on strict safety and efficacy criteria, whereas India stresses a quicker clearance process to address pressing healthcare needs. The investigation highlights how various regulatory methods affect patient access, innovation, and medicine supply in both nations. Recent decades have seen extraordinary improvements in the discovery of anticancer medications, transforming both cancer treatment and patient outcomes. With an emphasis on the main areas of anticancer therapeutics—chemotherapy, targeted therapy, immunotherapy, and hormone therapy—this study offers a thorough summary of the state of the field. We examine each drug class's methods of action, effectiveness, and difficulties while showcasing more recent developments like immune checkpoint inhibitors and CAR-T cell therapy. We also go over side effects, drug resistance, and how tailored medicine might improve the effectiveness of treatment. A look is also given to new developments in drug research, such as the application of nanotechnology and AI-driven drug discovery. The review attempts to shed light on the changing tactics used to fight cancer and the potential paths for anticancer medication development.

Anaphylaxis post-COVID-19 vaccinations in Singapore.

Anaphylaxis was the first serious adverse event (AE) of special interest surfaced in Singapore following coronavirus disease 2019 (COVID-19) vaccination. Individuals who developed physician-diagnosed severe allergic reactions to the mRNA vaccines would be medically ineligible for mRNA vaccines and offered non-mRNA alternatives. This paper describes anaphylaxis reports received by the Health Sciences Authority (HSA) and presents a review of individuals who received heterologous COVID-19 vaccination. Reports of anaphylaxis associated with the COVID-19 vaccines received till 31 July 2022 were reviewed and adjudicated using the Brighton Collaboration case definition criteria by an HSA-appointed expert panel. Additional review was conducted for cases with heterologous vaccination for any subsequent reactions until administration of third dose of COVID-19 vaccines. Among 112 adjudicated anaphylaxis cases, majority occurred in females, adults and persons with allergy histories, which were consistent with global observations. Most cases (71%) occurred within 30 minutes of vaccination. The reporting incidence rates (IRs) of 0.67 and 0.55 per 100,000 administered doses for Comirnaty and Spikevax vaccines, respectively, were comparable with IRs reported overseas, whereas the IRs for non-mRNA vaccines (Sinovac-CoronaVac and Nuvaxovid) were much higher at 4.14 and 29.82 per 100,000 administered doses, respectively, likely due to selection bias. Review of the 20 cases following heterologous vaccination found varying reactions to subsequent vaccinations. Anaphylaxis is a rare but serious AE in which outcomes can be mitigated with timely medical intervention. The case review helped to guide vaccination strategies and added to the cumulative knowledge of safety with heterologous vaccination.

Index of application status transparency and availability of public information for Project Orbis agencies

The purpose of this paper is to provide a guideline for understanding and comparing the regulatory framework of Project Orbis Partners (POPs) and Project Orbis observers, with a focus on their approaches to drug approvals, rejections, and withdrawals. While each agency has its own regulatory framework and guidance, there are some similarities and differences between the language used to describe drug approvals, rejections, withdrawals, and the public availability of these decisions. Project Orbis is an international partnership of regulatory agency, led by the U.S. Food and Drug Administration (FDA), aimed at streamlining the submission and review processes to expedite the global availability of oncology medications for patients. Since its inception, Australia’s Therapeutic Goods Administration (TGA), Brazil’s National Health Surveillance Agency (ANVISA), Canada’s Health Canada (HC), Israel’s Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, Singapore’s Health Sciences Authority (HSA), Switzerland’s Swissmedic (SMC), and United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) have joined and become POPs. Other international agencies such as, the European Medicines Agency (EMA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) are currently observing Project Orbis, as of late 2023. They are not full Project Orbis partners but work closely with the FDA to facilitate oncology drug approval through international collaboration. Running Title: An Index of the FDA and international regulators involved in Project Orbis looking at the similarities and differences between approval, rejection, and withdrawal characteristics of applications and public transparency of actions.

A multi-centre randomised controlled trial comparing megestrol acetate to levonorgestrel-intrauterine system in fertility sparing treatment of atypical endometrial hyperplasia.

The objective of the trial was to compare the regression rate of atypical endometrial hyperplasia (AEH) in patients treated with megestrol acetate (MA) vs. levonorgestrel-intrauterine device (LNG-IUS). We also aimed to assess the fertility and pregnancy outcomes in these patients. The study was a phase II multi-centre randomised controlled trial on the use of MA compared to LNG-IUS in the treatment of AEH conducted from January 2020 to January 2024 in Singapore. Women who were diagnosed with AEH and between 21 and 40years old were included. The patients were randomised to receive either MA (160mg orally daily) or LNG-IUS. The primary outcomes assessed were the regression rates at 3months, 6months and 9months of treatment. The secondary outcomes assessed were the side effects, patient acceptability and fertility outcomes. Thirty-six patients completed the trial. The overall regression rate was 88.9% by 9months. There was no statistically significant difference in the 9-month complete regression rate between MA vs. LNG-IUS. There was also no significant difference in side effects and weight change between both arms. Nineteen patients were actively pursuing fertility after complete regression. There were 8 pregnancies achieved, with resultant 4 live births and 4 miscarriages. Our study confirms a high regression rate of AH with medical treatment. LNG-IUS is a non-inferior treatment compared to megestrol acetate. Successful pregnancy outcomes can be achieved after regression of AEH. Long-term studies of sufficient sample-size are needed to assess for fertility and pregnancy outcomes, risk of recurrence and long-term risk of malignancy. The study was registered with the Health Science Authority (HSA) (License No.: CTA1900087) on September 5, 2019: https://eservice.hsa.gov.sg/prism/ct_r/enquiry.do?action=loadSpecificDetail . The trial was registered retrospectively on ClinicalTrials.gov (ID: NCT05492487) on April 7, 2022: https://clinicaltrials.gov/study/NCT05492487 .

A consensus survey of neurologists and clinical geneticists on spinal muscular atrophy treatment in Singapore

Just a decade ago, spinal muscular atrophy (SMA) was considered a debilitating, progressive neuromuscular disease that inevitably led to chronic disability and a shortened lifespan. Now, it is treatable with nusinersen, onasemnogene abeparvovec (OAV) and risdiplam—the 3 disease-modifying drugs approved by the US Food and Drug Administration, the European Medicines Agency and most recently, the Health Science Authority in Singapore.1 Clinical trials and real-world data have consistently shown improvement in motor milestones for all 3 drugs, especially if introduced early in the disease course.2-4 More significantly, presymptomatic treatment has enabled age-appropriate development of motor milestones, leading to improved respiratory, orthopaedic and nutritional outcomes.

The Problems with Online Health Product Sales: How can Regulations be Improved?

With the rapid proliferation of online businesses, national authorities are facing challenges managing the online supply of illegal health products due to the anonymity of the internet, increasing number of global syndicates, new technologies, and inability to enforce against overseas sellers. This paper describes these challenges and the Health Sciences Authority's regulatory approaches to tackle the online sales of illegal health products. These include partnering with platform administrators to remove illegal online postings, leveraging technological tools and relevant legislation, empowering consumers to make informed decisions, and fostering closer collaborations across different jurisdictions to combat online pharmaceutical crimes.

An updated analysis on myocarditis and pericarditis cases reported following mRNA SARS-CoV-2 vaccination in Singapore.

Messenger ribonucleic acid (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been associated with myocarditis/pericarditis, especially in young males. We evaluated the risk of myocarditis/pericarditis following mRNA vaccines by brand, age, sex and dose number in Singapore. Adverse event reports of myocarditis/pericarditis following mRNA vaccines received by the Health Sciences Authority from 30 December 2020 to 25 July 2022 were included, with a data lock on 30 September 2022. Case adjudication was done by an independent panel of cardiologists using the US Centers for Disease Control and Prevention case definition. Reporting rates were compared with expected rates using historical data from 2018 to 2020. Of the 152 adjudicated cases, males comprised 75.0%. The median age was 30 years. Most cases occurred after Dose 2 (49.3%). The median time to onset was 2 days. Reporting rates were highest in males aged 12-17 years for both primary series (11.5 [95% confidence interval [CI] 6.7-18.4] per 100,000 doses, post-Dose 2) and following booster doses (7.1 [95% CI 3.0-13.9] per 100,000 doses). In children aged 5-11 years, myocarditis remained very rare (0.2 per 100,000 doses). The reporting rates for Booster 1 were generally similar or lower than those for Dose 2. The risk of myocarditis/pericarditis with mRNA vaccines was highest in adolescent males following Dose 2, and this was higher than historically observed background rates. Most cases were clinically mild. The risk of myocarditis should be weighed against the benefits of receiving an mRNA vaccine, keeping in mind that SARS-CoV-2 infections carry substantial risks of myocarditis/pericarditis, as well as the evolving landscape of the disease.

Comparative Expedited Regulatory Programs of U.S Food & Drug Administration and Project Orbis Partners.

Project Orbis was initiated in May 2019 by the Oncology Center of Excellence to facilitate faster patient access to innovative cancer therapies by providing a framework for concurrent submissions and review of oncology products among international partners. Since its inception, Australia's Therapeutic Goods Administration (TGA), Canada's Health Canada (HC), Singapore's Health Sciences Authority (HSA), Switzerland's Swissmedic (SMC), Brazil's National Health Surveillance Agency (ANVISA), United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA), and most recently Israel's Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, have joined Project Orbis. While each country has its own expedited review pathways to bring promising therapies to patients, there are some similarities and differences in pathways and timelines.FDA's fast-track designation and MHRA's marketing authorization under exceptional circumstances (MAEC) allow non-clinical and limited clinical evidence to support approval under these programs. HC's Extraordinary Use New Drug (EUND) pathway allows granting exceptional use authorization with limited clinical evidence. ANVISA, HSA, MTIIR, and TGA do not have standard pathways that allow non-clinical evidence and limited clinical evidence. While there is no definite regulatory pathway for HSA, the current framework for approval does allow flexibility in the type of data (non-clinical or clinical) required to demonstrate the benefit-risk profile of a product. HSA may register a product if the agency is satisfied that the overall benefit outweighs the risk. All Project Orbis Partner (POP) countries have similar programs to the FDA accelerated approval program except ANVISA. Although HSA and MTIIR do not have defined pathways for accelerated approval programs, there are opportunities to request accelerated approval per these agencies. All POP countries have pathways like the FDA priority review except MHRA. Priority review timelines for new drugs range from 120 to 264 calendar days (cd). Standard review timelines for new drugs range from 180 to 365cd.

Evaluation of low-density lipoprotein cholesterol equations by cross-platform assessment of accuracy-based EQA data against SI-traceable reference value.

Low-density lipoprotein cholesterol (LDLC) is the primary cholesterol target for the diagnosis and treatment of cardiovascular disease (CVD). Although beta-quantitation (BQ) is the gold standard to determine LDLC levels accurately, many clinical laboratories apply the Friedewald equation to calculate LDLC. As LDLC is an important risk factor for CVD, we evaluated the accuracy of Friedewald and alternative equations (Martin/Hopkins and Sampson) for LDLC. We calculated LDLC based on three equations (Friedewald, Martin/Hopkins and Sampson) using the total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDLC) in commutable serum samples measured by clinical laboratories participating in the Health Sciences Authority (HSA) external quality assessment (EQA) programme over a 5years period (number of datasets, n=345). LDLC calculated from the equations were comparatively evaluated against the reference values, determined from BQ-isotope dilution mass spectrometry (IDMS) with traceability to the International System of Units (SI). Among the three equations, Martin/Hopkins equation derived LDLC had the best linearity against direct measured (y=1.141x-14.403; R2=0.8626) and traceable LDLC (y=1.1692x-22.137; R2=0.9638). Martin/Hopkins equation (R2=0.9638) had the strongest R2 in association with traceable LDLC compared with the Friedewald (R2=0.9262) and Sampson (R2=0.9447) equation. The discordance with traceable LDLC was the lowest in Martin/Hopkins (median=-0.725%, IQR=6.914%) as compared to Friedewald (median=-4.094%, IQR=10.305%) and Sampson equation (median=-1.389%, IQR=9.972%). Martin/Hopkins was found to result in the lowest number of misclassifications, whereas Friedewald had the most numbers of misclassification. Samples with high TG, low HDLC and high LDLC had no misclassification by Martin/Hopkins equation, but Friedewald equation resulted in ∼50% misclassification in these samples. The Martin/Hopkins equation was found to achieve better agreement with the LDLC reference values as compared to Friedewald and Sampson equations, especially in samples with high TG and low HDLC. Martin/Hopkins derived LDLC also enabled a more accurate classification of LDLC levels.

Regulatory Oversight of Cell, Tissue, and Gene Therapy Products in Singapore.

The Health Sciences Authority of Singapore has implemented a fit-for-purpose regulatory framework for Cell, Tissue, and Gene Therapy Products (CTGTPs) on 1 March 2021. A total of 11 pieces of subsidiary legislation for CTGTP are gazetted under the Health Products Act as Health Products (CTGTP) Regulations 2021. The CTGTPs are stratified into lower-risk Class 1 CTGTP or moderate- to higher-risk Class 2 CTGTP based on their degree of manipulation, intended use, and if they are combined or used with therapeutic products or medical devices. The regulatory controls are calibrated to the different risk profiles of the products. This risk-based regulatory approach aims to facilitate successful product development and registration in Singapore for innovative CTGTP with a least burdensome regulatory framework while ensuring reasonable safeguards on the safety, quality, and efficacy of the products. This chapter describes the regulatory oversight of CTGTP in Singapore.

Fast and accurate isotope dilution mass spectrometry method for the assignment of trihalomethanes in water in an uncommon accuracy-based proficiency testing programme in Singapore

ABSTRACT In the light of the instability of trihalomethanes (THMs) in water, a fast and high accuracy method based on headspace gas chromatography-isotope dilution mass spectrometry (HS-GC-IDMS) technique was developed. The optimised method was validated using fortified water samples. Recoveries between 96.1% and 108.8% with an intermediate precision between 3.9% and 5.7% were achieved. The method was applied in the value assignment of THMs in water in an accuracy-based proficiency testing (PT) programme organised by the Health Sciences Authority (HSA) Singapore. The assigned values obtained for chloroform, bromodichloromethane, dibromochloromethane and bromoform were 73.6 ± 9.3 µg/L, 49.1 ± 5.2 µg/L, 47.7 ± 4.4 µg/L and 70.8 ± 6.8 µg/L, respectively. The PT programme was especially valuable and uncommon as it allowed local water testing laboratories to have access to traceable reference values for the benchmarking of their technical competencies. The procedure undertaken by the Laboratory to prepare a batch of PT sample comprising the unstable analytes, conduct homogeneity and stability testing, as well as value assignment, are presented. The between-samples relative standard deviations (RSDs) obtained in a feasibility batch of THMs concentrate in methanol were improved by four to six times compared to those from the first feasibility batch of THMs in water. Based on z-scores, evaluated using the assigned reference value determined by HS-GC-IDMS, 85% of the participating laboratories in the PT programme achieved satisfactory results. The provision of metrological assigned values heightened the testing laboratories’ awareness on the importance of accuracy-based PT programmes for evaluation of true method biases, which is particularly valuable for analytes with regulated limits.

First-in-Human Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Rapidly Developed SARS-CoV-2 Therapeutic Antibody, AOD01, in Healthy Adults.

IntroductionAOD01 is a novel, fully human immunoglobulin (Ig) G1 neutralizing monoclonal antibody that was developed as a therapeutic against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AOD01 in healthy volunteers.MethodsIntravenous doses of AOD01 were evaluated in escalating cohorts [four single-dose cohorts (2, 5, 10, and 20 mg/kg) and one two-dose cohort (two doses of 20 mg/kg, 24 h apart)].ResultsTwenty-three subjects were randomized to receive AOD01 or a placebo in blinded fashion. A total of 34 treatment-emergent adverse events (TEAEs) were reported; all were mild in severity. Related events (headache and diarrhea) were reported in one subject each. No event of infusion reactions, serious adverse event (SAE), or discontinuation due to AE were reported. The changes in laboratory parameters, vital signs, and electrocardiograms were minimal. Dose-related exposure was seen from doses 2 to 20 mg/kg as confirmed by Cmax and AUC0–tlast. The median Tmax was 1.5–3 h. Clearance was dose independent. Study results revealed long half-lives (163–465 h). Antidrug antibodies (ADA) to AOD01 were not detected among subjects, except in one subject of the two-dose cohort on day 92. Sustained ex vivo neutralization of SARS-CoV-2 was recorded until day 29 with single doses from 2 to 20 mg/kg and until day 43 with two doses of 20 mg/kg.ConclusionsAOD01 was safe and well tolerated, demonstrated dose-related PK, non-immunogenic status, and sustained ex vivo neutralization of SARS-CoV-2 after single intravenous dose ranging from 2 to 20 mg/kg and two doses of 20 mg/kg and show good potential for treatment of SARS-CoV-2 infection.(Health Sciences Authority identifier number CTA2000119).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00681-1.

Assessment of heavy metal content in herbal raw materials traded in India

Presence of heavy metals in herbal raw materials exceeding the safety limit have potential security risks and has proven adverse effects and its prolonged consumption may causes serious health problems. The present study was carried out to quantify the heavy metals, content in some of the herbal raw materials traded in Indian market. A total 183 samples belongings to 74 different herbal raw materials and 69 species were sampled and analyzed for the presence of Arsenic (As), Cadmium (Cd), Mercury (Hg), and Lead (Pb). As per the permissible limit of Ayurvedic Pharmacopoeia of India (API), 5.46% samples were failed due to Cd accumulation followed by Hg (3.82%), Pb (1.09%), and As (0.55%). Higher accumulation of Cd was main reason behind higher percent of failed samples as per different safety standards such as 13.11% for World Health Organistion (WHO), 5.46% for United States Food and Drug Administration (USFDA) and 72.13% for Health Science Authority Singapore (HSA). Hg contributed higher percent of failed sample (18.03%) as per the safety standards of Pharmacopoeia of People's Republic of China (CP). The results showed that due to higher accumulation of Cd, Pb, As, and Hg, 9.58 - 12.33%, 0.00 to 10.96%, 1.37 to 2.74%, and 8.22 to 30.14% samples were failed respectively in safety standards of different pharmacopoeias. Bacopa monnieri (L.) Wettst., Caesalpinia bonduc (L.) Roxb., Cedrus deodara (Roxb. ex D. Don) G. Don, Cinnamomum zeylanicum Blume, Croton tiglium L., Curcuma longa L., Mucuna pruriens (L.) DC., Nardostachys jatamansi (D. Don) DC., Piper longum L., Pistacia chinensis Bunge, Senna alexandrina Mill., Tamarindus indica L., Teramnus labialis (L.f.) Spreng. and Valeriana wallichi DC. were among the species which failed in minimum of two or more than two pharmacopoeias due to higher concentration of one or more heavy metals. The quality of the herbal raw materials can be enhanced and the wastage of herbal raw material due to accumulation of heavy metals can be reduced by implementing WHO guidelines on Good Agricultural Practices, Good Field Collection Practice and Good Post-Harvest Processing Practices.

Post COVID-19 vaccine deaths - Singapore’s early experience

Singapore has been using mRNA vaccines developed by Pfizer-BioNTech and Moderna as part of the nation’s COVID vaccination program since 30 December 2020. From 1 February 2021–30 June 2021, a total of 34 deaths that occurred within 72 h of the deceased receiving their COVID-19 vaccination were referred to the Forensic Medicine Division of the Health Sciences Authority of Singapore. Autopsies, histological sampling and ancillary investigations consisting of total tryptase level, Immunoglobulin E (IgE), and C-reactive Protein (CRP), were performed on 29 of these cases. Our study has shown no definite causative relationship between the mRNA vaccination and deaths of individuals who died within 72 h after receiving the vaccination, in particular with regards to anaphylactic reactions, myocarditis and pericarditis, and thrombotic complications. Further studies may consider increasing the incident time frame from 72 h to seven days post-vaccination or longer to include any potential delayed presentation of adverse effects.

Key comparison study on peptide purity - hexapeptide of HbA0

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a key comparison, CCQM-K115.2018, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Ten Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of the hexapeptide of HbA0 (VE) present as the main component in the comparison sample for CCQM-K115.2018. The comparison samples were prepared by HSA/BIPM from synthetic VE purchased from a commercial supplier and used as provided without further treatment or purification.VE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and without modification. It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) with a correction for structurally-related peptide impurities approach as the amount of material that had been provided to each participant (25 mg) was insufficient to perform a full mass balance based characterization of the material by a participating laboratory. The coordinators, the BIPM, the HSA and the NIM, were the laboratories to use the mass balance approach as they had more material available.It was decided to propose KCRVs for both the VE mass fraction and the mass fraction of the peptide related impurities as indispensable contributor regardless of the use of PICAA, mass balance or any other approach to determine the VE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the VE mass fraction. In particular, it allowed participants to demonstrate the efficacy of their implementation of peptide related impurity identification and quantification.More detailed studies on the identification/quantification of peptide related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the VE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that only the most consistent set of results is taken for the calculation of the KCRVPepImp. The sum of the combined cis/trans VE depsipeptide impurities (only identified/quantified by NRC and confirmed by BIPM and HSA) and mass fractions of peptide related impurities that have been identified by at least two participants have been used to establish the KCRVPepImp. The KCRVPepImp of 53.0 mg/g is associated with a corresponding expanded uncertainty of 17.3 mg/g (k = 2) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide related impurity profile indicates that in all cases the major related peptide impurity, VE depsipeptide, has not been identified. The VE depsipeptide impurity was initially and uniquely identified and quantified by the NRC by the use of 1H-NMR. The related peptide impurity mass fraction results of only four participants (NRC, LGC, LNE and HSA) are in agreement with the KCRVPepImp. The NRC has identified and quantified the VE depsipeptide whereas the LGC, LNE and HSA have not identified the VE depsipeptide but accounted for that contribution.The approach selected to obtain a KCRVVE for the mass fraction of VE is based on a mass balance calculation that takes into account the most consistent set of results for the peptide related impurities KCRVPepImp, TFA mass fraction and the water mass fraction. The KCRVVE for CCQM-K115.2018 is 613 mg/g with a corresponding expanded uncertainty of the KCRVVE of 20 mg/g (k = 2).To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Pilot study on peptide purity - hexapeptide of HbA0

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a pilot study, CCQM-P55.2.2018, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Three Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of hexapeptide of HbA0 (VE) present as the main component in the comparison sample for CCQM-P55.2.2018. The comparison samples were prepared by HSA/BIPM from synthetic VE purchased from a commercial supplier and used as provided without further treatment or purification.VE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and without modification. It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) or quantitative nuclear magnetic resonance (PICqNMR) spectroscopy with a correction for structurally related peptide impurities. It was decided to assign reference values (RVs) based on the KCRVs of CCQM-K115.2018 for both the VE mass fraction and the mass fraction of the peptide-related impurities as indispensable contributor regardless of the use of PICAA, mass balance or any other approach to determine the VE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the VE mass fraction. In particular, it allows participants to demonstrate the efficacy of their implementation of peptide-related impurity identification and quantification.More detailed studies on the identification/quantification of peptide related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the VE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that only the most consistent set of results is taken for the calculation of the RVPepImp. The sum of the combined cis/trans VE depsipeptide impurities (only identified/quantified by NRC and confirmed by BIPM and HSA) and mass fractions of peptide-related impurities that have been identified by at least two participants have been used to establish the RVPepImp. The RVPepImp of 53.0 mg/g is associated with a corresponding expanded uncertainty of 17.3 mg/g (k = 2) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide-related impurity profile indicates that in all cases the major related peptide impurity, VE depsipeptide, has not been identified. The VE depsipeptide impurity was initially and uniquely identified and quantified by the NRC by the use of 1H-NMR in the parallel CCQM-K115.2018. The related peptide impurity mass fraction results of only four participants (NRC, LGC, LNE and HSA) are in agreement with the RVPepImp. The NRC has identified and quantified the VE depsipeptide whereas the LGC, LNE and HSA have not identified the VE depsipeptide but accounted for that contribution.The approach selected to obtain a RVVE for the mass fraction of VE is based on a mass balance calculation that takes into account the most consistent set of results for the peptide-related impurities RVPepImp, TFA mass fraction and the water mass fraction. The RVVE based on CCQM-K115.2018 is 613 mg/g with a corresponding expanded uncertainty of the RVVE of 20 mg/g (k = 2). Inspection of the degree of equivalence plots for the mass fraction of VE shows that all results obtained by PICAA agree with the RVVE while the result obtained by the BIPM with PICqNMR disagrees with the RVVE.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Key comparison study on peptide purity - glycated hexapeptide of HbA1c

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a key comparison, CCQM-K115.c, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Nine Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of the glycated hexapeptide of HbA1c (GE) present as the main component in the comparison sample for CCQM-K115.c. The comparison samples were prepared by HSA/BIPM from synthetic GE purchased from a commercial supplier and used as provided without further treatment or purification.GE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and modification (mono-glycation). It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) or quantitative nuclear magnetic resonance (PICqNMR) spectroscopy with a correction for structurally-related peptide impurities approach as the amount of material that has been provided to each participant (25 mg) is insufficient to perform a full mass balance based characterization of the material by a participating laboratory. The coordinators, the BIPM, the HSA and the NIM, were the laboratories to use the mass balance approach as they had more material available.It was decided to propose KCRVs for both the GE mass fraction and the mass fraction of the peptide-related impurities as indispensable contributor regardless of the use of PICAA, PICqNMR or mass balance to determine the GE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the GE mass fraction. In particular, it allows participants to demonstrate the efficacy of their implementation of peptide-related impurity identification and quantification.More detailed studies on the identification/quantification of peptide-related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the GE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that that all results are directly taken for the calculation of the KCRVPepImp by use of random-effects meta-analysis (DerSimonian-Laird (DSL) variance-weighted mean). The KCRVPepImp of 45.4 mg/g is associated with a corresponding expanded uncertainty of 9.5 mg/g (k =2.26) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide-related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide-related impurity profile indicates that in most cases the major related peptide impurities have been identified and quantified.The approach selected to obtain a KCRVGE for the mass fraction of GE is based on the DerSimonian-Laird (DSL) variance-weighted mean. The DSL mean takes into account the uncertainties of the results while introducing sufficient excess variance to allow for their observed dispersion resulting in a larger expanded uncertainty U(KCRVGE). The KCRVGE for CCQM-K115.c is 628 mg/g with a corresponding expanded uncertainty of the KCRVGE of 27 mg/g (k =2.26). All GE mass fraction results are in agreement with the KCRVGE.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Human leukocyte antigen allele and haplotype frequencies in Singapore bone marrow donors and cord blood units.

We describe the allele and haplotype frequencies seen in a volunteer unrelated bone marrow donor registry, a public cord blood bank, and donor/recipient samples processed by the Health Sciences Authority (HSA) in Singapore. Historical human leukocyte antigen (HLA) typing reports were anonymized and combined. They were checked for HLA typing nomenclature discrepancies or ambiguities using the HLA-net UNIFORMATE tool, and for analysis, the validated data were subsequently separated into Chinese, Malay, Indian, and "Others," according to the race classification system used in Singapore. Individual ethnic allele and haplotype frequencies were calculated with the HLA-net GENE[RATE] pipeline using basic statistics. The Basic Statistics Tool of HLA-net was used to estimate haplotype frequency using an expectation maximization algorithm, given a set of multi-allelic data pairs for a given HLA locus. The outputs downloaded from the site comprised plain text files with haplotype frequency estimates, results of a global linkage disequilibrium test, and standardized residuals (stdres) corresponding to deviations from expected frequencies. HLA typing results from 59,186 individuals met the inclusion criteria, yielding 118,372 analyzable alleles. In our study population, the haplotype A*33:03-B*58:01-C*03:02-DRB1*03:01～DQB1*02:01:01G with a frequency of 4.91% was the most common. This haplotype was also the most common among Singaporean Chinese donors. Consistent with the predominant Chinese population, haplotypes with a frequency greater than 1% were also the most frequently observed haplotypes in the Singaporean population. In the Malay donor population, the most common haplotype was A*33:03～B*44:03～C*07:01:01G～ DRB1*07:01-DQB1*02:01:01G, with a frequency of 3.41%, whereas within the Indian donor population, the most common haplotype was A*01:01-B*57:01-C*06:02～DRB1*07:01-DQB1*03:03, with a frequency of 3.42%. Haplotype diversity and composition statistics within donor pools provide HLA background data required for the targeted recruitment of donors to support the hematopoietic stem cell donor requirements of the country. These data may be used in the future to devise donor recruitment strategies for optimizing the donor pool through targeted publicity and accruals.

Elements in lipstick material

Main textCosmetics and personal care products are widely used globally. Although toxic elements are banned as intentional ingredients, they may exist as impurities either as contaminants in the raw ingredients, or as by-products of the manufacturing process. These toxic elements can accumulate in the body over time and cause adverse health effects. Different regions around the world have established relevant guidelines and regulations to safeguard the safety of consumers. Therefore, there is a need for metrology institutes to strengthen their measurement capabilities in this area.The supplementary comparison APMP.QM-S17: Elements in Lipstick Material was coordinated by the Health Sciences Authority, Singapore. Four measurands (arsenic, cadmium, mercury and lead) with maximum limits stated under the Association of Southeast Asian Nations (ASEAN) Guidelines on Limits of Contaminants for Cosmetics were chosen. Only one key comparison in the area of cosmetics (CCQM-K106: Lead, Arsenic and Mercury in Cosmetic Cream) was organised by the National Institute of Metrology (NIM) China in 2013. Hence, it was timely to organise another comparison in this area that covered cosmetics but in a different matrix. The study sample (lipstick) offered different analytical challenges as compared to the cream material used in the previous comparison. Moreover, it enabled National Metrology Institutes/Designated Institutes (NMIs/DIs) that did not participate in CCQM-K106 to demonstrate their measurement competencies.Seven institutes participated in the comparison for arsenic, nine for cadmium and lead, and eight for mercury. All participating NMIs/DIs employed microwave-assisted acid digestion for sample dissolution. Inductively coupled plasma mass spectrometry (ICP-MS) and sector field ICP-MS (SF-ICP-MS) were the two most commonly used instrumental techniques. Results of all participating NMIs/DIs were evaluated against the supplementary comparison reference value (SCRV). The SCRV and associated uncertainty were determined from results of NMIs/DIs that participated in the supplementary comparison using methods with demonstrated metrological traceability. For cadmium, mercury and lead, the median was used as estimator of the SCRVs. For arsenic, the arithmetic mean was used as estimator of the SCRV. The SCRVs (± expanded uncertainty) for arsenic, cadmium, mercury and lead (in mg/kg) were 4.188 (± 0.237), 2.0670 (± 0.0171), 2.732 (± 0.147) and 10.406 (± 0.080), respectively. The degree of equivalence and its associated uncertainty were calculated for each submitted result. Most participating institutes were able to demonstrate their capabilities in the determination of elements in lipstick material.Participating NMIs/DIs that have successfully participated in APMP.QM-S17 have demonstrated measurement capabilities in determining mass fraction of transition elements and metalloids/semi-metals, in mass fraction range from 0.1 mg/kg to 25 mg/kg in cosmetic matrices with high organic contents, such as lipstick.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Pilot study on peptide purity - glycated hexapeptide of HbA1c

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a pilot study, CCQM-P55.2.c, was coordinated by the Bureau International des Poids et Mesures (BIPM), the Health Sciences Authority (HSA) of Singapore and the Chinese National Institute of Metrology (NIM). Three Metrology Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of glycated hexapeptide of HbA1c (GE) present as the main component in the comparison sample for CCQM-P55.2.c. The comparison samples were prepared by HSA/BIPM from synthetic GE purchased from a commercial supplier and used as provided without further treatment or purification.GE was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of chemically synthesized peptides of known sequence, without cross-links, up to 5 kDa and modification (mono-glycation). It was anticipated to provide an analytical measurement challenge representative for the value-assignment of compounds of broadly similar structural characteristics.The majority of participants used amino acid analysis (PICAA) or quantitative nuclear magnetic resonance (PICqNMR) spectroscopy with a correction for structurally-related peptide impurities. It was decided to assign reference values (RVs) based on the KCRVs of CCQM-K115.c for both the GE mass fraction and the mass fraction of the peptide related impurities as indispensable contributor regardless of the use of PICAA, mass balance or any other approach to determine the GE purity. This allowed participants to demonstrate the efficacy of their implementation of the approaches used to determine the GE mass fraction. In particular, it allows participants to demonstrate the efficacy of their implementation of peptide related impurity identification and quantification.More detailed studies on the identification/quantification of peptide related impurities revealed that the integrity of the impurity profile of the related peptide impurities obtained by the participant is crucial for the impact on accuracy of the GE mass fraction assignment.The assessment of the mass fraction of peptide impurities is based on the assumption that all results are directly taken for the calculation of the RVPepImp by use of random-effects meta-analysis (DerSimonian-Laird (DSL) variance-weighted mean). The RVPepImp of 45.4 mg/g is associated with a corresponding expanded uncertainty of 9.5 mg/g (k =2.26) providing a more realistic basis of evaluation for the capabilities of the participants to identify/quantify peptide related impurities. Inspection of the degree of equivalence plots for the mass fraction of peptide impurities and additional information obtained from the peptide related impurity profile indicates that in all cases the major related peptide impurities have been identified and quantified.The approach selected to obtain a RVGE for the mass fraction of GE is based on the DerSimonian-Laird (DSL) variance-weighted mean. The DSL mean takes into account the uncertainties of the results while introducing sufficient excess variance to allow for their observed dispersion resulting in a larger expanded uncertainty U(RVGE). The RVGE based on CCQM-K115.c is 628 mg/g with a corresponding expanded uncertainty of the RVGE of 27 mg/g (k =2.26). All GE mass fraction results are in agreement with the RVGE.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).