Taiwan Food And Drug Administration Research Articles

Occurrence and risk assessment of glycidyl and 3-monochloropropanediol esters in infant formulas marketed in Taiwan

Glycidyl esters (GEs) and 3-monochloropropanediol esters (3-MCPDEs) are process contaminants commonly found in refined edible oils which are often added to infant formulas. The Taiwan Food and Drug Administration (TFDA) launched regulations for GEs in infant formulas that went into effect on 1 July 2021. To investigate levels of GEs and 3-MCPDEs in infant formula powder, 45 products were sampled and analysed during 2020–2021. The contents of GEs and 3-MCPDEs in formulas of different brands significantly varied, but their concentrations in all of the formulas complied with European Union (EU) regulations. Infant formulas containing palm oil had significantly higher 3-MCPDE levels in both extracted oils and milk powder than those without palm oil. Concentrations of GEs and 3-MCPDEs in infant formula powder and extracted oils were significantly lower in products from Europe than those from Australia and New Zealand. Infants aged 0–1 years in Taiwan who consumed only infant formula showed a margin of exposure (MoE) exceeding 25,000. Mean consumer exposures to 3-MCPDEs stayed below the tolerable daily intake (TDI), while high exposures at the 95th percentile (P95) exceeded the TDI by 1.7-fold. Herein, we present the changing trends in the risk assessment results of infant formula across various countries in the decade. Implementation of regulations and mitigation strategy effectively reduced the risk of infants being exposed to GEs and 3-MCPDEs through infant formula.

Update on Regulation of Regenerative Medicine in Taiwan.

Due to rapid development of biotechnology in recent years, the field of regenerative medicine has attracted considerable attention. Regenerative medicine-related regulations have been established in several countries to ensure the quality, safety, and efficacy of innovative treatments. Considering the diversity of regenerative medicine, the regulatory framework in Taiwan has been adjusted in response to global trend and local demand. Before 2010, cell and gene therapies were regarded as "new medical practice" under the "Medical Care Act." Along with the establishment of Taiwan Food and Drug Administration (TFDA) in 2010, regenerative medicine was regulated as "medicinal products" under the "Pharmaceutical Affairs Act." Then, the Ministry of Health and Welfare (MOHW) established a new dual-track regulatory pathway for regenerative medicine in 2016. The dual-track pathway divided regenerative medicine into medical practices and medicinal products, aiming to improve the accessibility of new treatments to patients and maintain the flexibility for clinical operations. In order to refine the regulation, the MOHW proposed two draft Acts for regenerative medicine in 2022. The two draft Acts are currently under legislative process. It is expected that the research and development of regenerative medicine can be further accelerated, thus providing early access to innovative therapies for patients in the future.

Determination of perfluoroalkyl substances in food packaging in Taiwan using ultrasonic extraction and ultra-performance liquid chromatography/tandem mass spectrometry.

Perfluoroalkyl substances (PFASs), as coating materials, possess oil-resistant and waterproof properties. However, their persistency and toxicity have caused concerns. This study developed a method for determining five types of 20 PFASs with ultra-performance liquid chromatography/tandem mass spectrometry, and measured seven categories of 32 commercial samples of oil-resistant food packaging in Taiwan. The assay was validated according to the specification of Taiwan Food and Drug Administration (TFDA). Samples of 100 cm2 were cut into pieces and were ultra-sonicated in 20-mL methanol at 50 °C for 45 minutes. The extracts were concentrated to 1 mL for instrumental analysis. Most matrix effect factors and extraction efficiencies of the analytes were 50%-80% and 52%-99%, respectively. Most limits of detection and limits of quantification were between 0.07-11.3 ng/dm2 and 0.17-18.3 ng/dm2, respectively. Most recoveries ranged from 70% to 117% at three tested levels, and the precisions (%RSD) were lower than 19%. Microwave popcorn paper contained more types and higher levels of PFASs than other packaging, with perfluoroalkyl acids at 8.3-1960 ng/dm2 and fluorotelomer alcohols (FTOHs) at 9.7-7188 ng/dm2. High concentrations of FTOHs were also observed in one oil-proof paper bag at 454-2595 ng/dm2 and in one French fries paper bag at 22.4-167 ng/dm2.

Microfluidic colorimetric system for nitrite detection in foods

A microfluidic colorimetric system comprising of a colorimetric paper-chip device and a microanalysis cassette is presented for detecting the nitrite concentration in foods. In the proposed system, 1 μl of nitrite sample is dropped into the reaction region of the colorimetric paper-chip device, where its reacts with embedded Griess reagent to produce a pink complex. A color image of the reaction complex is caught using an embedded camera and transmitted to a cell phone within the microanalysis cassette via a WiFi connection. Finally, the images were analyzed by self-written RGB (Red, Green, and Blue) software to evaluate the nitrite concentration. The results acquired for 11 known nitrite solutions ranging from 1 to 100 ppm show that the measured R + G + B intensity is related to the nitrite concentration, and the determination coefficient (R2) are 0.9908 and 0.9948 in the two concentration ranges of 1–50 ppm and 50–100 ppm, respectively. The practical feasibility of the current microfluidic system is indicated by analysis the nitrite concentrations of 24 actual samples. Therefore, the difference between the concentration analysis obtained with the current system differ from those obtained using a conventional TFDA (Taiwan Food and Drug Administration) standard method by no more than 7.3%. Furthermore, the detection limit is just 1 ppm.

Comparison and establishment of appropriate methods to determine EU priority PAHs in charcoal-grilled chicken drumsticks with different treatments and their dietary risk assessments

Three major polycyclic aromatic hydrocarbons (PAHs) analytical methods, gas chromatography-mass spectrometer (GC-MS), high performance liquid chromatography-photodiode-array detector (HPLC-PDA) and HPLC-fluorescence detector (FLD) were compared to analyze the European Union (EU) priority PAHs. In addition to the highest sensitivity, HPLC-FLD could be developed to rapidly determine the PAHs. A QuEChERS method was also established to rapidly extract the PAHs from chicken drumsticks. The method detection limits (0.004–0.25 ng/g), method quantification limits (0.01–0.75 ng/g), recoveries (67–114%), and coefficients of variations for intra- (1–15%) and inter- (1–21%) assays for the determination of the PAHs were in compliance with the EU and Taiwan Food and Drug Administration (TFDA) requirements. The PAHs contents in charcoal-grilled chicken drumsticks (without skin, with skin, and skin removal after processing) at different processing times were also determined by the developed methods. Although the risk assessment results for all samples showed a low level of concern, the presence of skin and long-term grilling had a greater impact on PAHs levels and dietary risks. Therefore, excessive processing should be avoided, and the skin of chicken drumsticks should be removed before and after charcoal-grilling to reduce the risk of PAHs intake.

Motor Vehicle Accident Risk after Methadone Use: A Population-Based Study

Background: Opioid dependence, a major global public health concern, can be alleviated through methadone maintenance treatment (MMT). However, MMT possibly increases motor vehicle accident risk. The aim of this study was to determine motor vehicle accident risk in MMT users. Methods: We performed preliminary estimation of motor vehicle accident incidence rates in Taiwan. In this population-based retrospective cohort study with frequency-matched controls, adult opiate users receiving MMT and not receiving MMT (control) were identified at a 1:2 ratio by linking data from several nationwide administrative registry databases. All individuals were followed for motor vehicle accident events. Data were adjusted for potential covariates and assessed using Kaplan–Meier and Cox proportional hazard model analyses. Findings: From 2009 to 2016, the crude incidence rate of motor vehicle accidents was the lowest in the general adult population, followed by that in adult opiate users, and it was the highest in adults receiving MMT. Among opiate users, motor vehicle accident incidence rates were significantly higher in those receiving MMT than in those not receiving MMT (adjusted hazard ratio [aHR] 2.75, 95% CI 1.87–4.04; p<0.001). Kaplan–Meier curves of the incidence of motor vehicle accidents differed significantly between groups (log-rank test p<0.001), with a significant decline during the first 90 days of follow-up. Rural area residents had a higher motor vehicle accident risk than did urban area residents (aHR 1.56, 95% CI 1.05–2.32; p=0.029). Interpretation: Drivers receiving MMT have an increased motor vehicle accident risk, particularly during the first 90 days of MMT. These findings should be considered for motor vehicle accident prevention in opiate users receiving MMT. Funding Taiwan Food and Drug Administration. Funding Statement: This study was supported by 2 grants from the Taiwan Food and Drug Administration (TFDA) (MOHW106-FDA-D-114-000671 and MOHW107-FDA-D-114-000636). Declaration of Interests: Authors have no potential conflicts of interest to disclose. Ethics Approval Statement: The study was approved by the Institutional Review Boards (TSMH IRB No.: 17-010-B1 and 18-049-B); the need for written informed consent was waived because we used deidentified information from the databases.

Real‐world efficacy and safety of vedolizumab among patients with inflammatory bowel disease: A single tertiary medical center experience in Central Taiwan

AbstractThe incidence of IBD is increasing in Eastern countries. The anti‐TNF‐α biological agents are available in patients with severely active IBD. Recently, the vedolizumab was approved by Taiwan Food and Drug Administration (TFDA). The efficacy and safety of vedolizumab in real‐world practice for Asia regions is uncertain. Our primary endpoint is to evaluate the efficacy of vedolizumab for TNF‐α exposure and naive patients during induction phase. The secondary endpoints are adverse events, infection, and emergent surgery during induction. We conducted a retrospective observational cohort study from November 2017 to April 2019 in our hospital. We enrolled patients receiving vedolizumab with or without previous anti‐TNF‐α agent exposure. The study results of continuous and categorical variables are presented as median (interquartile range [IQR]), with the IQR presented as 25th percentile to 75th percentile, and number (percentage), respectively. Categorical variables were compared with Fisher's exact test or Pearson's chi‐square test, and continuous variables were compared with a Mann‐Whitney U test. Twenty‐four patients received vedolizumab from November 2017 to April 2019. Sixteen patients had finished the postinduction phase of the clinical evaluation. None of the patients discontinued vedolizumab due to an adverse drug reaction. The study group all fulfilled the criteria for clinical response and two of them achieved clinical remission. 50% of the patients could successfully discontinue systemic and topical steroid treatment. Three patients from CD group had endoscopic remission. Compare CD to UC patients, the efficacy of vedolizumab is comparable to both groups, but endoscopic response is slightly better in CD group. One patient developed systemic infection (urinary tract infection). None of tuberculosis complex infection or hepatitis B flare up observed during follow‐up period. In this study, we offer our real‐world experience of vedolizumab and suggest that the use of vedolizumanb is safe and effective. Moreover, 50% of steroid‐dependent patients can discontinue steroid after vedolizumab induction. This can be addressed in the future study.

Analysis of Pollution of Phthalates in Pork and Chicken in Taiwan Using Liquid Chromatography-Tandem Mass Spectrometry and Assessment of Health Risk.

Phthalates are widely used plasticizers that can cause endocrine disruption, mutagenicity, and carcinogenic effects and can contaminate food through various pathways. Investigations are scanty on phthalate pollution of livestock and poultry meat and their dietary exposure to humans. The present study assessed residual levels of phthalates in unpackaged pork (30 samples) and unpackaged chicken (30 samples) and their relevance to meat consumption and health risks in the Taiwanese population. Phthalate quantity was assessed by liquid chromatography–tandem mass spectrometry; the materials included diisononyl phthalate, diisodecyl phthalate, benzyl butyl phthalate, di-2-ethylhexyl phthalate (DEHP), and di-n-butyl phthalate. The Taiwan Food and Drug Administration (TFDA) has established values of tolerable daily intake (TDI) for the five phthalates. The major compound detected was DEHP, which ranged from 0.62 to 0.80 mg/kg in two pork samples, and 0.42–0.45 mg/kg in three chicken samples. Collectively, 8.33% of the phthalate-residue-containing samples tested positive for DEHP. The concentrations of DEHP were lower than the screening value of 1.0 mg/kg, as defined by the TFDA. Health risk was calculated as the estimated daily intake (DI) for any likely adverse effects; the DI of DEHP residues was <1% of the TDI value. The estimated risk was insignificant and considered to be safe, indicating that there is no risk to the health of Taiwanese population due to meat consumption. However, it is suggested that a phthalate monitoring program in meat should be instituted for any possible effects in future on human health.

Probabilistic health risk assessment for dietary exposure to aflatoxin in peanut and peanut products in Taiwan

Aflatoxins are secondary metabolites naturally occurring in many foods such as peanuts, spices, rice, tree nuts, and maize. Aflatoxins are both genotoxic and carcinogenic substances and can cause severe adverse health effects. The purpose of this study is to estimate the probabilistic risk of consuming aflatoxin-contaminated peanuts and peanut products. Concentration data (1.84 ± 4.03 ppb) were gathered from the Taiwan Food and Drug Administration (TFDA) between 2005 and 2015, along with consumption rate data (from Nutrition and Health Survey in Taiwan) for five age groups, namely 1-2 years (babies), 3-9 years (toddlers), 10-17 years (teenagers), 18-65 years (adults), and above 65 (elderly), in two sub-populations (whole group and consumer only). These data are essential material for exposure analysis. According to the benchmark dose lower confidence limit 10% (BMDL10) (170 ng/kg bw/day) suggested by the European Food Safety Authority (EFSA), the calculated margin of exposure (MOE) value cannot reach 10,000. Cancer potency data from Joint FAO/WHO Expert Committee on Food Additives (JECFA) indicates that the estimated population risk ranges from 0.0007 to 0.2713 cancers/100,000 population/year. Although aflatoxin contamination does not seem to largely account for the occurrence of liver cancer in Taiwan, MOE calculations point out that it may cause potential health concerns.

Analysis of veterinary drug residue monitoring results for commercial livestock products in Taiwan between 2011 and 2015

Antibiotics have been widely used in the treatment of livestock diseases. However, the emergence of issues related to drug resistance prompted governments to enact a series of laws regulating the use of antibiotics in livestock. Following control of the problem of drug resistant bacteria, public attention has shifted to the recurring incidence of human health and safety issues caused by residual veterinary drugs in livestock products. To guarantee the safety and hygiene of meat, milk, and eggs from food-producing animals, governments and relevant agencies established laws and regulations for the use of veterinary drugs. It is, therefore, necessary to monitor the content of residual drugs in livestock products at regular intervals to assess whether the regulations have resulted in the effective management of food product safety, and to prevent and manage sudden problems related to this issue. A 2011–2015 livestock product post-marketing monitoring program launched by the Taiwan Food and Drug Administration (TFDA) inspected 1487 livestock products. Over the past 5 years, there were 34 samples identified that did not conform to the regulations; these samples included residue drugs such as β-agonists, chloramphenicols, β-lactam antibiotics, sulfa drugs, enrofloxacin, and lincomycin. Inspections of commercial livestock products with the consistent cooperation of agricultural authorities did not detect the drugs that were banned by the government, whereas the detection of other drugs decreased annually with an increase in the post-market monitoring sample size. In the future, the TFDA will continue to monitor the status of residual veterinary drugs in commercial livestock products, adjust the sampling of food products annually according to monitoring results, and closely cooperate with agricultural authorities on source management.

Current Status and Prospectives of CEUS in Taiwan

The clinical experiences of Levovist (Schering AG, Germany) in Taiwan (1996) were promising in the characterization of focal liver tumors. Although effective in the application in various organs, Levovist has certain shortcomings, e.g., shorter longevity of the echo-enhancing effect and incapability of being satisfactorily with harmonic imaging techniques with these limitations. Levovist was withdrew from Taiwan market in 2003. Since there was a general consensus that contrast-enhanced US (CEUS) may facilitate an accurate US diagnosis and can overcome the limitation of conventional US imaging, it was believed CEUS should be introduced to Taiwan. SonoVue, Definity, and Sonazoid are three of the more successful contrast agents in the past 10-15 years. SonoVue have been widely used in Europe and parts of Asia and Sonazoid is now in the process to obtain approval to be used in Asian countries out of Japan, Korea, and Taiwan, as well as America. Definity is now in the process to get approval in Taiwan. Other echopharmaceuticals are now designed to change the attenuation or impedance of sound for enhancing the differentiation of signals of a target organ from that of the surrounding tissue. During the past 9 years, a lot of efforts have been made to introduce USCA into the Taiwan healthcare community. In order to conduct a pilot study to convince Taiwan Food and Drug Administration (TFDA) for the possible approval of USCA to be used in Taiwan, three manufacturers (SonoVue, Sonazoid, and Definity) were invited to survey the Taiwan market. Finally, GE Healthcare got the first chance to convince the subcommittee of USCA (under the umbrella of Commission of Research and Development of Medical Ultrasound, Chinese Taipei Society of Ultrasound in Medicine, CTSUM). And Sonazoid was the priority agent accepted by CTSUM. We expect with the wide applications of USCA in Taiwan, more experience can be accumulated. The subcommittee of USCA with its 40 committee members subspecialized in different fields (e.g., gastroenterology, gynecology, cardiovascular, small parts, neurology, pediatric, etc.) will conduct more studies to find out other utilities of CEUS to benefit patients.

Regulation of New Drug Approval in Taiwan.

Taiwan Food and Drug Administration (TFDA) was established in 2010 as the nation's principal consumer product protection agency of food, drugs, medical devices, and cosmetics. By integrating 4 agencies (the Bureau of Food Safety, Bureau of Pharmaceutical Affairs, Bureau of Food and Drug Analysis, and Bureau of Controlled Drugs), TFDA holds the mission of protecting and promoting the public health through regulation modernization to enhance the availability of safe medical products and foods. To address the unmet medical needs and public health, TFDA has utilized regulatory science to evaluate review principles and risk management to properly oversee the overall life cycle of medicinal products. A lot of measures have been accomplished to build an efficient, transparent, and internationally harmonized regulatory system. With the first-in-the-world new drug afatinib approved in Taiwan, TFDA has successfully built up capacity and capability in the review and approval of new drugs. This article summarizes the efforts TFDA has been making in the domain of medicinal product management, highlighting policies and strategies for the future.

Similarities and Differences of International Practices and Procedures for the Regulation for Active Substance Master Files/Drug Master Files of Human Use: Moving Toward Regulatory Convergence

Purpose. A gap analysis survey of international practices for Active Substance Master Files (ASMFs)/Drug Master Files (DMFs) of human use was conducted as a project of the ASMF/DMF working group of the International Generic Drug Regulators Pilot (IGDRP) to identify similarities and differences among ASMF/DMF procedures of 10 IGDRP members and 2 observers. Methods. We conducted a questionnaire survey and compared the following aspects: overall ASMF/DMF procedures, submission requirements for ASMFs/DMFs, assessment processes for ASMFs/DMFs, the technical requirements for active pharmaceutical ingredients (APIs), generation of assessment reports for ASMFs/DMFs, procedures for changing ASMF/DMF details, and Good Manufacturing Practice (GMP) inspection/certification of API manufacturers. Twelve organizations participated in this project: the Brazilian Health Surveillance Agency (Anvisa), the European Union (EU), Health Canada (HC), the Singapore Health Sciences Authority (HSA), the South African Medicines Control Council (MCC), the South Korean Ministry of Food and Drug Safety (MFDS), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Swiss Agency for Therapeutic Products (Swissmedic), the Taiwan Food and Drug Administration (TFDA), the Australian Therapeutic Goods Administration (TGA), the European Directorate for the Quality of Medicines &amp; HealthCare (EDQM) (Observer) and the Prequalification Team (PQT) of the World Health Organization (WHO), which includes the PQT–Medicines (Observer). Results. Although there were many similarities among the participating agencies surveyed, there were also differences that should be discussed such as assessment processes of ASMFs/DMFs and Technical requirements for APIs. Conclusions. These differences revealed by this survey will be key considerations in order to facilitate the filing of ASMFs/DMFs globally and to establish a framework for sharing and utilizing information related to ASMFs/DMFs among IGDRP members in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

APEC Workshop Report of Good Review Practices on Medical Products.

As part of the implementation of the 2020 Good Review Practices (GRevP) Roadmap championed by Chinese Taipei in the Asia-Pacific Economic Cooperation (APEC) Regulatory Harmonization Steering Committee (RHSC), the Taiwan Food and Drug Administration (TFDA) organized 2 workshops. The purpose of these workshops was to address the fundamental elements of a well-designed regulatory review system, to provide complementary modules for GRevP and approaches to the exchange and the use of product assessment reports between regulatory authorities, and to further promote regulatory efficiencies and best practices. The workshops brought together 81 regulatory representatives from 15 economies for the basic workshop and 133 from 20 economies for the advanced workshop. Participants forged a common understanding of GRevP and highlighted its importance. While the adoption of GRevP is key to building trust between agencies, each economy should address its needs and adopt its own best practices based on its resources and environment. The outcomes of these workshops could be used as a framework for the development of a GRevP best-practice document or could serve as material for further training in each economy.

Regulation of Cell and Gene Therapy Medicinal Products in Taiwan.

Owing to the rapid and mature development of emerging biotechnology in the fields of cell culture, cell preservation, and recombinant DNA technology, more and more cell or gene medicinal therapy products have been approved for marketing, to treat serious diseases which have been challenging to treat with current medical practice or medicine. This chapter will briefly introduce the Taiwan Food and Drug Administration (TFDA) and elaborate regulation of cell and gene therapy medicinal products in Taiwan, including regulatory history evolution, current regulatory framework, application and review procedures, and relevant jurisdictional issues. Under the promise of quality, safety, and efficacy of medicinal products, it is expected the regulation and environment will be more flexible, streamlining the process of the marketing approval of new emerging cell or gene therapy medicinal products and providing diverse treatment options for physicians and patients.

Crisis management turns Taiwan's plasticizer nightmare into progressive policy

The world’s largest emergency food safety effort began in April 2011, when a Taiwan Food and Drug Administration (TFDA) scientist testing a probiotics product noticed irregular results. After weeks of intensive investigation, it was discovered that a widely used emulsifier known as clouding agent had been adulterated with a high concentration (113,402 ppm) of di(2-ethylhexyl) phthalate (DEHP), an industrial plasticizer whose use is prohibited in food due to toxicity and possible endocrine-disrupting effects. Investigators uncovered a profit motive for the contamination: DEHP was used by Yu-Shen Chemical Company, New Taipei City, Taiwan instead of palm oil to reduce the cost of production. One week later, the investigation also revealed another illegal use of plasticizers: the Pin Han Perfumery Company, New Taipei City, Taiwan had used di-isononyl phthalate (DINP) to adulterate its clouding agent. The disclosure that clouding agents with DEHP and DINP had been used in many foods and beverages caused great concern in Taiwan. The government met the crisis with a whirlwind program of inspections. Officials collected and