• 한국임상약학회지
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• 제28권2호
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• pp.146-153
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• 2018

Objective: Multi-regional clinical trials have been widely used for accelerating global drug development by multinational pharmaceutical companies. In this study, we aimed to review and analyze the international trends in regulations and guidelines on multi-regional clinical trials by regulatory authorities and international organizations, such as International Conference on Harmonisation, for referring to policies, including development of domestic guidelines for multi-regional clinical trials. Methods: The policies, regulations, and guidelines published by the US Food and Drug Administration, European Medicines Agency, Pharmaceuticals and Medical Devices Agency (Japan), and China Food and Drug Administration were searched, and the International Conference on Harmonisation E17 draft guideline was reviewed. Results: The regulatory authorities in developed countries have developed and implemented regulations and guidelines on multi-regional clinical trials to promote simultaneous global drug development and evaluate the regional differences in drug safety and efficacy. International Conference on Harmonisation developed the draft guideline for planning/designing of multi-regional clinical trials in 2016, which recommends the general principles for strategy-related issues and design of multi-regional clinical trials, and for protocol-related issues, such as consideration of regional variability, subject selection, dose selection, endpoints, comparators, overall sample size, allocation to regions, collecting information on efficacy and safety, and statistical analysis. Conclusion: It is important to understand the international regulatory requirements for designing and planning of multi-regional clinical trials for global drug development. Moreover, it is necessary to prepare multi-regional clinical trial guidelines in accordance with the Korean regulation for clinical trials and drug administration.

• 약학회지
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• 제47권2호
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• pp.104-109
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• 2003

The present paper reviews the notion and comparison of the Korea Food and Drug Administration(KFDA) general pharmacology and the International Conference on Harmonisation (ICH) safety pharmacology. General pharmacology or safety pharmacology is termed the study to determine the potential of a compound to induce adverse pharmacological effects. KFDA general pharmacology studies have been considered an important component in drug safety assessment and these were originally referred to those designed to examine effects other than the primary therapeutics effect of a drug candidate. The KFDA notified the Guideline for General Pharmacology in 1997. Safety pharmacology studies were focused on identifying adverse effects on physiological functions. In the ICH came into place S7A Safety Pharmacology Studies for Human Pharmaceuticals in 2001. A new chemical entity should be assessed for its side effects, initially in those physiological systems which are generally agreed to be the key systems that are essential for life; these "core system" include the central nervous system, cardiovascular system and respiratory system in safety pharmacology studies. These studies should be performed in compliance with Good Laboratory Practice (GLP).

• 분석과학
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• 제35권3호
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• pp.93-115
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• 2022

의약품의 제조, 유통, 보관 과정에서 발생할 수 있는 잠재적 불순물은 의약품의 품질과 안전에 영향을 미치며 반응성이 높은 불순물의 경우 인체에 대한 발암성(변이원성)을 나타내기도 한다. 이를 위해 국제의약품규제조화위원회(International Conference on Harmonisation, ICH)에서는 "잠재적 발암 위해를 제한하기 위한 의약품 중 DNA 반응성(변이원성) 불순물의 평가 및 관리"에 대한 내용을 담은 M7(R1) 가이드라인을 제공하여 채택을 권고하였다. 하지만 가이드라인에서도 잠재적 불순물에 대한 분류, 섭취 허용량, 관리방안 등과 대표적인 불순물 14 종에 대한 가이드라인 적용을 소개하는데 그치고 있어 제약회사와 규제 당국에서 실제 관리를 위한 의약품 중 잠재적 불순물의 분석에 어려움을 겪고 있다. 이에 따라 본 총설에서는 비의도적 변이원성 불순물의 정의와 ICH M7(R1) 가이드라인에 소개된 내용을 간략하게 살펴보는 한편 현재까지 보고된 주요 잠재적 불순물의 분석 동향을 살펴보고자 한다. 이를 통해 식약처를 비롯한 감독 기관과 제약회사 등에서 의약품 중 잠재적 불순물 관리에 조금이나마 도움이 되고자 한다.

• 대한약침학회지
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• 제17권4호
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• pp.36-49
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• 2014

Objectives: Quercetin and curcuminoids are important bioactive compounds found in many herbs. Previously reported high performance liquid chromatography ultraviolet (HPLC-UV) methods for the detection of quercetin and curcuminoids have several disadvantages, including unsatisfactory separation times and lack of validation according the standard guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Methods: A rapid, specific, reversed phase, HPLC-UV method with an isocratic elution of acetonitrile and 2% v/v acetic acid (40% : 60% v/v) (pH 2.6) at a flow rate of 1.3 mL/minutes, a column temperature of $35^{\circ}C$, and ultraviolet (UV) detection at 370 nm was developed. The method was validated and applied to the quantification of different types of market available Chinese medicine extracts, pills and tablets. Results: The method allowed simultaneous determination of quercetin, bisdemethoxycurcumin, demethoxycurcumin and curcumin in the concentration ranges of $0.00488-200{\mu}g/mL$, $0.625-320{\mu}g/mL$, $0.07813-320{\mu}g/mL$ and $0.03906-320{\mu}g/mL$, respectively. The limits of detection and quantification, respectively, were 0.00488 and $0.03906{\mu}g/mL$ for quercetin, 0.62500 and $2.50000{\mu}g/mL$ for bisdemethoxycurcumin, 0.07813 and $0.31250{\mu}g/mL$ for demethoxycurcumin, and 0.03906 and $0.07813{\mu}g/mL$ for curcumin. The percent relative intra day standard deviation (% RSD) values were $0.432-0.806{\mu}g/mL$, $0.576-0.723{\mu}g/mL$, $0.635-0.752{\mu}g/mL$ and $0.655-0.732{\mu}g/mL$ for quercetin, bisdemethoxycurcumin, demethoxycurcumin and curcumin, respectively, and those for intra day precision were $0.323-0.968{\mu}g/mL$, $0.805-0.854{\mu}g/mL$, $0.078-0.844{\mu}g/mL$ and $0.275-0.829{\mu}g/mL$, respectively. The intra day accuracies were 99.589%-100.821%, 98.588%-101.084%, 9.289%-100.88%, and 98.292%-101.022% for quercetin, bisdemethoxycurcumin, demethoxycurcumin and curcumin, respectively, and the inter day accuracy were 99.665%-103.06%, 97.669%-103.513%, 99.569%-103.617%, and 97.929%-103.606%, respectively. Conclusion: The method was found to be simple, accurate and precise and is recommended for routine quality control analysis of commercial Chinese medicine products containing the flour flavonoids as their principle components in the extracts.

• Bulletin of the Korean Chemical Society
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• 제34권9호
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• pp.2663-2670
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• 2013

The purpose of stability testing is to provide evidence about how the quality of a drug varies with time under the influence of a variety of environmental factors. In this study, erythropoietin (EPO) was analyzed under different pH (pH 3 and pH 9) and temperature ($25^{\circ}C$ and $40^{\circ}C$) conditions according to current Good Manufacturing Practice (cGMP) and International Conference on Harmonisation (ICH) guidelines. The molecular weight difference between intact EPO and deglycosylated EPO was determined by SDS-PAGE, and aggregated forms of EPO under thermal stress and high-pH conditions were investigated by size exclusion chromatography. High pH and high temperature induced increases in dimer and high molecular weight aggregate forms of EPO. UPLC-ESI-TOF-MS was applied to analyze the changed modification sites on EPO. Further, normal-phase high-performance liquid chromatography was performed to identify proposed glycan structures and high pH anion exchange chromatography was carried out to investigate any change in carbohydrate composition. The results demonstrated that there were no changes in modification sites or the glycan structure under severe conditions; however, the number of dimers and aggregates increased at $40^{\circ}C$ and pH 9, respectively.

• 한국임상약학회지
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• 제22권1호
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• pp.21-29
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• 2012

Modern biologics are biotechnology-derived therapeutics, including recombinant therapeutic proteins like monoclonal antibodies, cytokines and tissue growth factors. Although the pharmacokinetics of therapeutic biologics should be evaluated based on the same general principles as small molecules, careful considerations should be given to bioanalytics and pharmacokinetics when designing pharmacokinetic studies of biologics during their drug development, due to their different physicochemical properties compared with small molecules. The aim of this study was to develop a draft guidance on pharmacokinetic studies of therapeutic biologics in clinical studies. All the elements outlined in the current Food and Drug Administration (FDA), European Medicinal Agency (EMEA), and International Conference on Harmonisation (ICH) guidelines and regulations, and the related literatures previously published were searched and evaluated. In this draft guidance, the specific problems related to the pharmacokinetics of therapeutic biologics that need special consideration during drug development process were addressed, and differences in pharmacokinetic characteristics between biologics and small molecules affecting the content of the development programme were presented.

• 한국임상약학회지
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• 제29권4호
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• pp.267-277
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• 2019

Backgrounds: With the globalization of drug development, multi-regional clinical trials (MRCTs) have emerged to facilitate rapid availability of medicines to patients worldwide. The present study aimed to has explored attitudes and perceptions towards adopting the Korean MRCT guideline. Methods: An online survey, consisting of 16 questions, classified into two subjects, was administered to stakeholders in Korea. Most quantitative components were measured using the Likert scales. A content analysis of the qualitative components was carried out to identify the keywords in open-ended responses. Results: A total of 94 survey responses were analyzed: 51 participants from pharmaceutical companies, 11 from clinical research organizations, and 21 from clinical trial centers. The content of the guideline was rated as appropriate for clarity, acceptability, and applicability (96.8, 96.8, and 93.6%, respectively). The local environmental impact of the systemic/political, academic/technical, and industrial/economical aspects of the guideline was rated as appropriate at 95.7, 97.9, and 91.5%, respectively. The suggested adoption period was 1~2 years (40, 42.6%). The concept and individuals' domestic circumstances were the key problems affecting the clarity, applicability, and local environmental impact of the guideline. Conclusion: The Korean MRCT guideline was well-developed. Their overall impact on the local environmental impact of MRCTs in Korea was expected to be beneficial, but methods are needed to minimize the negative impacts. The findings of this study can inform the priorities for the future adoption of the guideline in Korea.

• Toxicological Research
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• 제22권2호
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• pp.109-116
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• 2006

Safety pharmacology studies are conducted to investigated the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. In the International Conference on Harmonisation (ICH), the guideline 'S7A: Safety Pharmacology Studies for Human Pharmaceuticals' has been developed and reached Step 5 of the ICH process in 2001. Now the Korea Food and Drug Administration (KFDA) are going to transfer 'The Guideline for General Pharmacology' into 'The Guideline for Safety Pharmacology'. Safety pharmacology studies should be performed in compliance with Good Laboratory Practice (GLP). Thus, the present paper reviews the Japanese GLP guidelines for pharmaceuticals to help the conduct and inspection of safety pharmacology studies in compliance with GLP. We also reviewed the ICH guidelines 'S7B revised : The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals' and 'E14 : The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs' to apply our drug approval systems.

• 대한화장품학회지
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• 제33권4호
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• pp.263-267
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• 2007

미생물의 오염을 통해 화장품이 변질되거나 분해되는 것을 방지하여 소비자를 보호하기 위해 화장품에 보존제가 사용된다. 파라벤류는 제형화하기 쉽고, 활성 범위가 넓으며, pH에 화학적으로 안정하면서 저렴하여 거의 모든 종류의 화장품에 널리 사용된다. 페녹시에탄올과 클로페네신 역시 화장품에 일반적으로 사용되는 보존제로 보통 파라벤과 함께 사용된다. 파라벤의 독성은 일반적으로 낮지만, 손상된 피부에는 자극을 유발할 수 있으며, estrogenic 잠재성, 마취 효과 및 생식 독성의 가능성에 대한 논란이 있어 왔다. 따라서 파라벤은 배합한도 원료로 지정 관리되고 있으며, 페녹시에탄올과 클로페네신도 마찬가지로 최대 허용량이 지정되어 있다. 그러므로 제품 중 보존제의 함량을 관리하는 것은 중요하다. 그러나 일반적으로 사용되는 역상 액체크로마토그래프법으로는 이성질체를 포함한 6종의 파라벤과 페녹시에탄올 및 클로페네신을 동시에 분리 분석하기 어려웠다. 용출 시간이 길어져, 피크 모양이 나쁘고 분리능이 좋지 않아 정확한 정량이 불가능하였다. 본 연구에서는 ultra performance liquid $chromatography^{TM}\;(UPLC^{TM}$)를 이용하여 8종의 보존제를 10 min 이내에 동시분석을 시도하였다. 또한, International conference on harmonisation (ICH) 가이드라인의 밸리데이션 방법에 근거하여 본 시험법의 적합성을 검증하고, 로션, 팩트, 파운데이션 및 립글로스 등 다양한 제형에 적용이 가능함을 보였다. 본 시험법은 파라벤류를 포함한 다양한 보존제를 함유한 화장품 중 보존제의 함량을 단시간에 간편하고 정확하게 정량하는데 활용될 수 있을 것이다.360 nm)에서 3개의 피이크로 분리되었다. 분리된 3가지 성분은 luteolin, quercetin 및 kaempferol이었으며, 그들의 성분비는 각각 18.24 %, 58.79 %, 22.97 %로 quercetin의 함량이 가장 큰 것으로 나타났다. 루이보스 추출물의 ethylacetate 분획의 TLC 크로마토그램은 7개의 띠로 분리되었고, HPLE 크로마토그램은 9개의 피이크를 보여주었다. TLC와 HPLC의 띠와 피이크를 확인한 결과, HPLC의 9개의 피이크는 용리순서로 peak 1 (조성비 14.71 %)은 isoorientin, peak 2 (28.84 %)는 orientin peak 3 (5.63 %)은 vitexin, peak 4 (12.73 %)는 rutin과 isovitexin, peak 5 (9.24 %)는 hyperoside, peak 6 (5.40%)은 isoquercitrin, peak 7 (1.48 %)은 luteolin, peak 8 (17.61 %)은 quercetin 및 peak 9 (4.59 %)는 kaempferol로 확인되었다. Aglycone 분획은 elastase 저해활성($IC_{50}$)이 $9.08\;{\mu}g/mL$로 매우 큰 활성을 나타내었다. 이상의 결과들은 루이보스 추출물이 $^1O_2$ 혹은 다른 ROS를 소광시키거나 소거함으로써 그리고 ROS에 대항하여 세포막을 보호함으로써 생체계, 특히 태양 자외선에 노출된 피부에서 항산화제로서 작용할 수 있음을 가리키며, 루이보스 성분에 대한 분석과 ethylacetate 분획의 당 제거 실험 후 얻어진 aglycone 분획의 큰 elastase 저해활성으로부터

• Journal of the Korean Wood Science and Technology
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• 제44권3호
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• pp.337-349
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• 2016

본 연구는 꾸지뽕나무 열매에서 분리 및 정제한 isoflavonoid 성분에 대하여 Ultra Performance Liquid Chromatography(UPLC)을 이용하여 분석법을 개발하고 검증하고자 하였다. 꾸지뽕나무 열매를 methanol로 추출하여 n-hexane, ethyl acetate, 물 순으로 분액 후, ethyl acetate 추출물을 silica gel 컬럼과 sephadex LH-20 컬럼을 사용하여 4종의 isoflavonoid들을 분리하였다. 분리한 4종의 isoflavonoid들은 기기분석(UV-Vis spectroscopy, ESI-MS, $^1H\;NMR$, $^{13}C\;NMR$)을 통하여 alpinumisoflavone, 6,8-diprenyl orobol, 6,8-diprenyl genistein, 4'-O-methylalpinumisoflavone으로 확인 및 동정하였다. 이 성분들을 2% acetic acid 용액(용매 A)과 2% acetic acid가 함유된 MeOH 용액(용매 B)을 기울기 이동상으로 하여 $C_{18}$ 컬럼이 장착된 UPLC로 분석하였다. 분석 조건은 ICH (International Conference on Harmonisation) 가이드라인에 기술된 선택성, 직선성, 정량한계, 검출한계, 정확성 및 정밀성을 측정하여 분석법의 타당성을 검증하였다. 또한 검증한 분석방법을 이용하여 꾸지뽕나무 열매의 채취시기별 함량을 조사하였다. 그 결과, 미숙과는 7월과 8월에 각 성분의 함량이 증가하였다가 9월에는 감소하였고, 성숙과의 경우 9월 미숙과 보다 각 성분들이 전반적으로 많이 함유되어 있었다.