Acute Megakaryoblastic Leukemia

BASKING RIDGE, N.J.--(BUSINESS WIRE)-- Daiichi Sankyo (TSE: 4568) today announced that VANFLYTA® (quizartinib) is now available by prescription in the U.S. VANFLYTA is the first and only FLT3 inhibitor to be approved by the U.S. Food and Drug Administration (FDA) specifically for FLT3-ITD positive acute myeloid leukemia (AML) and across the three phases of treatment – induction, consolidation and maintenance in patients without transplant – for newly diagnosed AML. VANFLYTA was approved by the FDA on July 20, 2023 in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed AML that is FLT3-ITD positive as detected by an FDA-approved test. VANFLYTA is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with VANFLYTA in this setting has not been demonstrated. “With VANFLYTA now available by prescription in the U.S., physicians and patients have a new treatment option for the aggressive FLT3-ITD subtype of acute myeloid leukemia,” said Dan Switzer, Head of U.S. Oncology Business, Daiichi Sankyo, Inc. “VANFLTYA is the first FLT3 inhibitor to be developed and approved specifically for FLT3-ITD positive AML and has demonstrated potential to change the way the disease is treated.” In the QuANTUM-First trial, VANFLYTA combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation, and continued as maintenance monotherapy following consolidation, resulted in a 22% reduction in the risk of death compared to standard chemotherapy alone (HR = 0.78 [95% CI: 0.62-0.98; 2-sided p=.0324]) in patients with newly diagnosed FLT3-ITD positive AML. While complete remission (CR) rates were similar between both arms of the trial, the median duration of CR was more than three times longer at 38.6 months (95% CI: 21.9, NE) for patients receiving VANFLYTA compared to 12.4 months for those receiving placebo plus standard chemotherapy alone (95% CI: 8.8-22.7). The results of QuANTUM-First were published in The Lancet.1 The safety of VANFLYTA was evaluated in 265 patients with newly diagnosed FLT3-ITD positive AML who received VANFLYTA once daily (35.4 mg with chemotherapy, 26.5 to 53 mg as maintenance) in the QuANTUM-First trial. VANFLYTA is approved with a Boxed WARNING for QT prolongation, torsades de pointes and cardiac arrest. Treatment emergent QT interval prolongation events of any grade were reported in 14% of patients who received VANFLYTA, including 3.0% who experienced a grade 3 or 4 event. Of the 265 patients treated with VANFLYTA and standard chemotherapy, QTcF >500 ms occurred in 2.3% of patients based on central ECG review and 10% of patients had an increase from baseline QTcF greater than 60 ms. The most common adverse reactions (frequency ≥10% all grades with a difference between arms of ≥2%), including laboratory abnormalities, in patients receiving VANFLYTA included lymphopenia (60%), hypokalemia (59%), hypoalbuminemia (53%), hypophosphatemia (52%), alkaline phosphatase increased (51%), hypomagnesemia (44%), febrile neutropenia (44%), diarrhea (42%), mucositis (38%), nausea (34%), hypocalcemia (33%), abdominal pain (30%), sepsis (30%), neutropenia (29%), headache (28%), creatine phosphokinase increased (26%), vomiting (25%), upper respiratory tract infection (21%), hypertransaminasemia (19%), thrombocytopenia (18%), decreased appetite (17%), fungal infections (16%), epistaxis (15%), hyperkalemia (15%), herpes virus infection (14%), insomnia (14%), electrocardiogram QT prolonged (14%), hypermagnesemia (14%), hypernatremia (13%), dyspepsia (11%), anemia (11%) and eye irritation (11%). Because of the serious risk of QT prolongation, torsades de pointes, and cardiac arrest, VANFLYTA is available only through a restricted program called the VANFLYTA Risk Evaluation and Mitigation Strategy (REMS). VANFLYTA may only be prescribed and dispensed by healthcare providers and pharmacies who become certified in the VANFLYTA REMS. More information is available at or by calling 1-855-212-6670. Daiichi Sankyo is committed to ensuring that patients in the U.S. who are prescribed VANFLYTA can access the medication and receive appropriate financial support. Provider and patient support and information regarding distribution, access, and reimbursement are now available through Daiichi Sankyo Access Central by visiting or calling 1-866-4-DSI-NOW (1-866-437-4669). Please see for full Prescribing Information including Boxed WARNING and Medication Guide. About FLT3-ITD Positive Acute Myeloid Leukemia More than 474,500 new cases of leukemia were reported globally in 2020 with more than 311,500 deaths.2 AML accounts for 23.1% of total leukemia cases worldwide and is most common in adults.3,4 In the U.S., an estimated 20,380 new cases of AML will be diagnosed in 2023 with the five-year survival rate reported at 31.7%.5,6 A number of gene mutations have been identified in AML, and FLT3 (FMS-like tyrosine kinase 3) mutations are the most common.7 Up to 37% of newly diagnosed cases of AML have a FLT3 gene mutation and approximately 80% of these have FLT3-ITD mutations, which drive cancer growth and contribute to particularly unfavorable prognosis including increased risk of relapse and shorter overall survival.7,8 The five-year survival rate for patients with FLT3-ITD AML has been reported at approximately 20%.9 About VANFLYTA VANFLYTA® (quizartinib) is an oral, highly potent, type II FLT3 inhibitor that selectively targets FLT3-ITD mutations and has been specifically developed for patients with FLT3-ITD positive AML.7 VANFLYTA is approved in the U.S. in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed AML that is FLT3-ITD positive as detected by an FDA-approved test. VANFLYTA is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with VANFLYTA in this setting has not been demonstrated. The FDA had granted Priority Review to the application. VANFLYTA also is approved in Japan for the treatment of AML that is FLT3-ITD mutation positive, including for use in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy and as maintenance monotherapy for adult patients with newly diagnosed FLT3-ITD positive AML, and as a monotherapy for relapsed/refractory AML that is FLT3-ITD positive as detected by an approved test. VANFLYTA is an investigational medicine in all countries outside of Japan and the U.S. About the VANFLYTA Clinical Development Program The VANFLYTA clinical development program includes a phase 1/2 trial in pediatric and young adult patients with relapsed/refractory FLT3-ITD positive AML in Europe and North America, and several phase 1/2 combination studies as part of a strategic research collaboration with The University of Texas MD Anderson Cancer Center. A regulatory application for VANFLYTA in newly diagnosed FLT3-ITD positive AML is currently under review in the EU based on the results of the QuANTUM-First trial. Important Safety Information WARNING: QT PROLONGATION, TORSADES DE POINTES, and CARDIAC ARREST VANFLYTA® (quizartinib) prolongs the QT interval in a dose- and concentration-related manner. Prior to VANFLYTA administration and periodically, monitor for hypokalemia or hypomagnesemia, and correct deficiencies. Perform electrocardiograms (ECGs) to monitor the QTc at baseline, weekly during induction and consolidation therapy, weekly for at least the first month of maintenance, and periodically thereafter. Torsades de pointes and cardiac arrest have occurred in patients receiving VANFLYTA. Do not administer VANFLYTA to patients with severe hypokalemia, severe hypomagnesemia, or long QT syndrome. Do not initiate treatment with VANFLYTA or escalate the VANFLYTA dose if the QT interval corrected by Fridericia’s formula (QTcF) is greater than 450 ms. Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required. Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure. Because of the risk of QT prolongation, VANFLYTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the VANFLYTA REMS. Indication VANFLYTA is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)–positive as detected by an FDA-approved test. Limitations of Use: VANFLYTA is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with VANFLYTA in this setting has not been demonstrated. Contraindications VANFLYTA is contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes. Warnings and Precautions QT Prolongation, Torsades de Pointes, and Cardiac Arrest (See BOXED WARNING) VANFLYTA prolongs the QT interval in a dose- and concentration-dependent manner. The mechanism of QTc interval prolongation is via inhibition of the slow delayed rectifier potassium current, IKs, as compared to all other medications that prolong the QTc interval, which is via the rapid delayed rectifier potassium current, IKr. Therefore, the level of QTc prolongation with VANFLYTA that predicts the risk of cardiac arrhythmias is unclear. Inhibition of IKs and IKr may leave patients with limited reserve, leading to a higher risk of QT prolongation and serious cardiac arrhythmias, including fatal outcomes. Torsades de pointes, ventricular fibrillation, cardiac arrest, and sudden death have occurred in patients treated with VANFLYTA. Of the 1,081 patients with AML treated with VANFLYTA in clinical trials, torsades de pointes occurred in approximately 0.2% of patients, cardiac arrest occurred in 0.6% of patients, including 0.4% with a fatal outcome, and 0.1% of patients experienced ventricular fibrillation. These severe cardiac arrhythmias occurred predominantly during the induction phase. Of the 265 patients with newly diagnosed FLT3-ITD–positive AML treated with VANFLYTA in combination with chemotherapy in the clinical trial, 2.3% were found to have a QTcF greater than 500 ms and 10% of patients had an increase from baseline QTcF greater than 60 ms. The clinical trial excluded patients with a QTcF ≥450 ms or other factors that increased the risk of QT prolongation or arrhythmic events (eg, NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome). Therefore, avoid use in patients who are at significant risk of developing torsades de pointes, including uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, tachyarrhythmias, uncontrolled hypertension, high-degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Do not initiate treatment with VANFLYTA if the QTcF interval is greater than 450 ms. Do not use VANFLYTA in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes. Perform an ECG and correct electrolyte abnormalities prior to initiation of treatment with VANFLYTA. During induction and consolidation, perform an ECG prior to initiation and then once weekly during VANFLYTA treatment or more frequently as clinically indicated. During maintenance, perform ECGs prior to initiation, once weekly for at least the first month following dose initiation and escalation, and as clinically indicated thereafter. Do not escalate the dose if QTcF is greater than 450 ms. Perform ECG monitoring of the QT interval more frequently in patients who are at significant risk of developing QT interval prolongation and torsades de pointes, or following dose escalation. Monitor and correct hypokalemia and hypomagnesemia prior to and during treatment with VANFLYTA. Maintain electrolytes in the normal range. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea or vomiting. Monitor patients more frequently with ECGs if coadministration of VANFLYTA with drugs known to prolong the QT interval is required. Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure. Reduce VANFLYTA if QTc increases to greater than 480 ms and less than 500 ms. Interrupt and reduce VANFLYTA if QTc increases to greater than 500 ms. Permanently discontinue VANFLYTA in patients who develop recurrent QTc greater than 500 ms or QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. VANFLYTA is available only through a restricted program under a REMS. VANFLYTA REMS VANFLYTA is available only through a restricted distribution program under a REMS called the VANFLYTA REMS because of the serious risk of QT prolongation, torsades de pointes, and cardiac arrest. Notable requirements of the VANFLYTA REMS include the following: Prescribers must be certified in the VANFLYTA REMS by enrolling and completing training. Prescribers must counsel patients receiving VANFLYTA about the risk of QT prolongation, torsades de pointes, and cardiac arrest, and provide patients with a Patient Wallet Card. Pharmacies that dispense VANFLYTA must be certified with the VANFLYTA REMS and must verify prescribers are certified through the VANFLYTA REMS. Further information about the VANFLYTA REMS is available at or by telephone at 1-855-212-6670. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VANFLYTA and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with VANFLYTA and for 4 months after the last dose. Adverse Reactions The safety of VANFLYTA (35.4 mg orally once daily with chemotherapy, 26.5 mg to 53 mg orally once daily as maintenance) in adult patients with newly diagnosed FLT3-ITD positive AML is based on QuANTUM-First. Serious adverse reactions in ≥5% of patients who received VANFLYTA plus chemotherapy were: febrile neutropenia (11%). Fatal adverse reactions occurred in 10% of patients who received VANFLYTA plus chemotherapy, including sepsis (5%), fungal infections (0.8%), brain edema (0.8%), and one case each of febrile neutropenia, pneumonia, cerebral infarction, acute respiratory distress syndrome, pulmonary embolism, ventricular dysfunction, and cardiac arrest. Permanent discontinuation due to an adverse reaction in patients in the VANFLYTA plus chemotherapy arm occurred in 20% of patients. The most frequent (≥2%) adverse reaction which resulted in permanent discontinuation in the VANFLYTA arm was sepsis (5%). Dosage interruptions of VANFLYTA due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in ≥2% of patients in the VANFLYTA arm included neutropenia (11%), thrombocytopenia (5%), and myelosuppression (3%). Dose reductions of VANFLYTA due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dosage reductions in ≥2% of patients in the VANFLYTA arm were neutropenia (9%), thrombocytopenia (5%), and electrocardiogram QT prolonged (4%). The most common adverse reactions (≥10% with a difference between arms of ≥2% compared to placebo), including laboratory abnormalities, were decreased lymphocytes, decreased potassium, decreased albumin, decreased phosphorus, increased alkaline phosphatase, decreased magnesium, febrile neutropenia, diarrhea, mucositis, nausea, decreased calcium, abdominal pain, sepsis, neutropenia, headache, increased creatine phosphokinase, vomiting, upper respiratory tract infections, hypertransaminasemia, thrombocytopenia, decreased appetite, fungal infections, epistaxis, increased potassium, herpesvirus infections, insomnia, QT prolongation, increased magnesium, increased sodium, dyspepsia, anemia, and eye irritation. Drug Interactions Strong CYP3A Inhibitors VANFLYTA is a CYP3A substrate. Concomitant use of VANFLYTA with a strong CYP3A inhibitor increases quizartinib systemic exposure, which may increase the risk of VANFLYTA adverse reactions. Reduce the dosage of VANFLYTA. Strong or Moderate CYP3A Inducers Concomitant use of VANFLYTA with strong or moderate CYP3A inducers decreases quizartinib systemic exposure, which may reduce VANFLYTA efficacy. Avoid concomitant use of VANFLYTA with strong or moderate CYP3A inducers. QT Interval–Prolonging Drugs VANFLYTA prolongs the QT/QTc interval. Coadministration of VANFLYTA with other drugs that prolong the QT interval may further increase the incidence of QT prolongation. Monitor patients more frequently with ECG if coadministration of VANFLYTA with drugs known to prolong the QT interval is required. Use in Specific Populations Pregnancy VANFLYTA can cause embryo-fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Lactation Advise women not to breastfeed during treatment with VANFLYTA and for one month after the last dose. Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential within 7 days before starting treatment with VANFLYTA. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with VANFLYTA and for 7 months after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VANFLYTA and for 4 months after the last dose. Infertility Females Based on findings from animal studies, VANFLYTA may impair female fertility. These effects on fertility were reversible. Males Based on findings from animal studies, VANFLYTA may impair male fertility. These effects on fertility were reversible. Pediatric Use Safety and effectiveness of VANFLYTA have not been established in pediatric patients. Geriatric Use No overall differences in safety or efficacy were observed between patients 65 years of age and older and younger adult patients. Renal Impairment No dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min). VANFLYTA has not been studied in patients with severe renal impairment (CLcr <30 mL/min). Hepatic Impairment No dosage adjustment is recommended in patients with mild hepatic impairment or moderate hepatic impairment. VANFLYTA has not been studied in patients with severe hepatic impairment. To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc, at 1-877-437- 7763 or the FDA at 1-800-FDA-1088 or fda.gov/medwatch. Please see Full Prescribing Information, including Boxed WARNINGS, and Medication Guide. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit . VANFLYTA is a registered trademark of Daiichi Sankyo Company, Limited. Access Central™ is a trademark of Daiichi Sankyo, Inc. Trademarks not owned by Daiichi Sankyo are the property of their respective owners. © 2023 Daiichi Sankyo, Inc. PP-US-VN-0262 08/23 References ____________________________ 1 Erba H et al. The Lancet. April 25, 2023;Online First. S0140-6736(23)00464-6 2 Global Cancer Observatory. Population Fact Sheet: World. Updated March 2021 3 American Cancer Society: Key Statistics for Acute Myeloid Leukemia. Updated January 2023 4 Dong Y et al. Exp Hematol Oncol. 2020;9:14 5 American Cancer Society: Key Statistics for Acute Myeloid Leukemia. Updated January 2023 6 National Cancer Institute SEER Program. Cancer Stat Facts: Acute Myeloid Leukemia. 7 Daver N et al. Leukemia. (2019) 33:299-312 8 Patel JP et al N Engl J Med 2012 Mar 22;366(12):1079-89 9 Frohling et al. Blood (2002) 100 (13): 4372-4380

前言杂质研究，是贯穿于药品生命周期的重点药学研究内容之一，工作量占比非常大。从早年间行业对杂质的浅层理解，到阶段性杂质研究的如痴如醉，杂质研究工作在技术不断强化的过程中，正在向更为科学、合理的方向发展。如何运用好全球化可接受的指导原则，同时兼顾我国国情下的药品研发特点，即满足监管要求，又不浪费研发资源，这就需要对研发过程中杂质研究阶段性的深入理解，以及研究程度上的精准把控。基于此，总结全文如下。1 、ICH指导原则框架内的杂质研究自2017年我国加入ICH后，国内药品研发工作按照其相关指导原则，已经和国际接轨。对于杂质研究，主要参照的ICH指导原则为Q3A、Q3B和Q6A。1.1 ICH-Q3A新原料药中的杂质应分两个方面阐述：1）化学方面，包括对杂质的分类和鉴定、检测报告的形成、在质量标准中列出杂质以及对分析方法的简要讨论；2）安全性方面，对用于安全性研究和临床研究的新原料药批次中不存在或含量很低的那些杂质的界定提供专门的指导。表1-1 药学研究工作中的杂质分类➣ 有机杂质 M 上述杂质分类中，有机杂质的研究内容和复杂程度相对最高。基于Q3A内容：1）申请人应对新原料药在合成、精制和储存过程中那些实际存在的和最可能产生的潜在杂质进行综述。该综述应建立在对合成所涉及的化学反应、由起始物料引入的杂质及可能的降解产物进行合理的、科学的评估基础之上。可以局限于根据化学反应以及相关条件下可能会产生的杂质进行讨论。2）申请人还应对新原料药中杂质检测的实验室研究工作进行综述。其内容包括对采用研制工艺的和拟上市工艺生产的所有批次产品的试验结果，以及为鉴定在储存期间可能产生的潜在杂质而进行的强制降解试验结果。同时应对那些拟上市的原料药批次和研制开发过程的原料药批次中的杂质谱进行比较，并就任何不同之处进行讨论。➣ 质量标准中的杂质检查项目在新原料药的质量标准中应包括杂质检查项目。稳定性研究、化学方面的开发研究以及日常批次分析检验的结果有助于预测在上市产品中可能出现的杂质。在新原料药质量标准中收载的杂质应根据在采用拟上市工艺生产的批次中所发现的杂质来加以取舍。这里再重点介绍下特特定杂质。所谓特定杂质，是指列入新原料药质量标准中、具有特定限度要求的各个杂质。申报资料应对质量标准中纳入哪些杂质提供合理的依据。该依据应包括对用于安全性和临床研究中批次中所发现的杂质谱进行讨论，同时也要考虑采用拟上市工艺生产的原料药中的杂质谱情况。➣ 杂质限度建立的杂质合理限度不能高于经安全性资料界定合理的水平，并且必须与生产工艺和分析能力所能达到的水平一致。如果没有安全性方面的问题，杂质限度应根据采用拟上市工艺生产的新原料药批次测定的数据来建立，并应为常规生产和分析上的正常变异及药物的稳定性特性留有足够的余地。尽管常规生产中的变化是可以预料的，然而批与批之间杂质水平的显著变化可能预示着新原料药的生产工艺尚未得到充分的控制和验证。图1-1 ICH-Q3A/杂质限度内容➣ 杂质的界定杂质的界定是获得和评价某些数据的过程，这些数据可用于确保单个杂质或在特定的含量下的一系列杂质的生物安全性。申请人应对所确定的杂质限度提供包括安全性研究在内的理由。对于一个通过充分的安全性研究和临床研究的新原料药，其中任何一个杂质的水平应被认为是已经通过合理界定的。对于是动物和/或人体中的重要代谢物的杂质，通常也视为已通过界定。杂质的界定限量（水平）如果高于药物实际所含的杂质量，则同样可以根据对已完成的安全性研究中使用药物中的实际杂质量来判断其合理性。如果可获得的数据不能界定某一杂质拟定的限度，而且当该限度超过了指导原则所列的界定限度时，则必须做进一步研究，以获得必要的数据来支持该限度的合理性。图1-2 ICH-Q3A/杂质鉴定界定决策树1.2 ICH-Q3B一般情况下，存在于新原料药中的杂质在新药制剂中不需要监控，除非它们也属于降解产物。ICH-Q3B的重点内容即为降解产物相关的研究要求。➣ 降解产物报告和控制的合理性申请人应对新药制剂的生产和/或稳定性考察中所发现的降解产物进行综述。该综述应包括对制剂中可能的降解途径和因与赋形剂和/或包装容器反应所产生杂质的科学评价。另外，申请人还要对新药制剂降解产物检测的所有实验室研究工作进行总结，也包括研发过程中生产的批次和采用拟上市工艺生产的批次的试验结果。 图1-3 ICH-Q3B/降解产物限度申报资料中应提交用于临床、安全性研究、稳定性试验的所有相关批次以及采用拟上市工艺生产的有代表性批次的制剂的分析结果。申报资料中应提供每一批次新药制剂的详细信息，具体内容如下：批号、规格和批量；生产日期；生产地点；生产工艺；直接接触的包装容器；单个降解产物和降解产物总量；批次的用途（如：临床研究、稳定性研究）；所涉及的分析方法的说明；用于该制剂的原料的批号；稳定性研究的放置条件。如果没有安全性问题，降解产物的限度应建立在来自拟上市工艺生产的新药制剂各批次获取的数据基础上，并允许留有足够的余地以适应常规的生产、分析方法和稳定性方面的正常变异。图1-4 ICH-Q3B/降解产物鉴定界定决策树1.3 ICH-Q6AICH-Q6A研究工作内容为化学药物相关的新原料药和新药制剂的检测方法和可接受标准。所谓质量标准由一系列的检测项目、相应的分析方法和合理的可接受标准组成，可接受标准以限度值、范围或其他描述来表示。原料药和制剂的质量是由设计、开发、生产过程控制、GMP控制、工艺验证以及开发和生产中执行的质量标准所决定的。在申报时，由于仅有有限的数据，所以会影响可接受标准的制订。因此，在原料药或制剂的生产中获得新的经验时，有必要提出修订可接受标准（如某一特定杂质的限度）。申报时可接受标准必须在基于安全性和有效性的基础上制订。当申报时只获得有限的数据时，有必要随着更多资料的获得，对最初获批的检测项目和可接受标准重新审核，必要时可以降低或提高可接受标准。首次提出质量标准时，应对每一个检测方法和每一个可接受标准进行论证。论证包括有关的研究开发数据、药典标准、用于毒理和临床研究的原料药及制剂的检测数据、加速试验和长期稳定性研究的结果；另外，还应考虑分析方法和生产可能波动的合理范围。制订和论证质量标准时，应考虑稳定性批次和生产规模放大/验证批次的检测结果，特别是申报稳定性批次的结果。如果计划有多个生产场所，在建立最初的检测项目和可接受标准时，应充分考虑所有这些场所获得的数据，尤其是在任一场所所得到的原料药和制剂的生产经验有限时。如果根据一个有代表性的场所的数据来制订检测项目和可接受标准，那么各个其他生产场所生产出来的产品均应符合该标准。 图1-5 新原料药中特定杂质可接受标准的制订2. 杂质研究限度制订具体示例在上述ICH指导原则中，与杂质息息相关的一个概念，就是其对应的限度。我国药审中心黄晓龙老师曾对创新药的杂质研究进行过总结发刊，围绕杂质限度制订的依据以实例进行说明，具体关联杂质限度制订的3个关键依据，即“杂质的安全性”、“工艺的可行性”和“稳定性”。➣ 示例1：杂质的安全性某批原料药中杂质A的含量为0.12％，该批原料药曾分别用于犬及大鼠6个月的长期毒性试验，剂量分别为5、10、40mg/kg d，10、40、200mg/kg d。另一批杂质A含量为0.0409%的原料药用于小鼠5个月的致癌试验剂量为50、100、200mg/kg d。另外以最大耐受剂量采用杂质A的含量为0.004％～0.01％的各批样品进行大鼠的24个月的试验。结果均未发现与杂质有关的毒性。而本品的临床剂量为160mg/d，以患者的体重为60kg计则人的给药剂量为2.67mg/kg，与犬的给药剂量比较则该杂质的安全限度应为（40/2.67）×0.12%＝1.8%。也就是说如果仅从安全性考虑，现有的安全性试验支持杂质A的限度设定为1.8％。而实际上由于现工艺生产的批次样品中杂质A的含量均低于其定量限度（0.05%）且稳定性研究结果证明该杂质在放置过程中无增加，所以考虑到工艺与杂质分析方法的正常波动，将质量标准中该杂质的限度定为0.1%。➣ 示例2：工艺的可行性某原料药中存在1个已知的工艺杂质，前期的强制降解试验与定性研究表明该杂质并非降解产物。从生产的可行性考虑，15批一定规模样品中杂质A的平均含量为0.29％，标准偏差为0.16％平均值＋3×标准偏差为0.77％。而另一方面毒性试验用样品的杂质含量为：长毒试验用样品中杂质A的含量为0.3％，大鼠长毒试验中杂质A的给药量为0.120mg/kg/月，狗长毒试验中杂质A的给药量为0.090、0.120mg/kg/月，质量标准中杂质A的限度0.8％，拟定限度下人体接受杂质A的最大剂量为0.029mg/kg/月。故该杂质的安全窗至少为0.120/0.029＝4.1。综上，从杂质的安全性与制备工艺的可行性考虑该杂质的限度可定为0.8％。➣ 示例3：稳定性某制剂质量标准中总杂质限度的确定考虑了以下因素：样品的实测值、长期留样的结果。批号分别为9701、9702、9703、9704、9901、9902、9903的7批样品中总杂质的实测值（括号中的数字是指非特定杂质的个数）分别为0.15％（0）、0.30％（0）、0.40％（0）、0.34％（0）、0.76％（2）、0.52％（1）、0.33％（0），平均值为0.40％标准偏差为0.19％平均值＋3×标准偏差为0.97％。在25℃ 60％RH条件下长期留样24个月时3批样品（批号分别为9702、9703、9704）中总杂质的含量分别为：0.31％（0）、1.03％（6）、0.93％（7）。综合考虑以上研究结果本品质量标准中总杂质的限度确定为1.0％。3. 药品各临床阶段杂质研究开发侧重点杂质研究工作，对于小分子化学创新药物来说，不同临床阶段对应着不同的研究要求，除ICH指导原则大背景的指导基础外，国内可重点关注《新药I期临床试验申请技术指南》、《创新药（化学药）III期临床试验药学研究信息指南》、《已上市化学药品药学变更研究技术指导原则（试行）》。重点关注：杂质谱。➣ 《新药I期临床试验申请技术指南》杂质要求内容如下：1）重点关注对计划研究的受试者安全性相关的药学研究信息（如基于现有知识对杂质谱的解析，有关物质检查专属性、灵敏度的方法学验证，潜在遗传毒性杂质分析和控制，生物新药的免疫原性和免疫毒性等）。2）应提供初步的杂质谱分析结果、潜在遗传毒性杂质控制策略和分析信息。可参照ICH M7指南研究并提交报告。3）杂质报告方式可参照ICH Q3A和Q3B。 图3-1 I期临床杂质谱分析表格➣ 《创新药（化学药）III期临床试验药学研究信息指南》杂质要求内容如下：1）对于由所用物料引入终产品的杂质，包括异构体（如适用）、毒性有机溶剂/催化剂、潜在遗传毒性杂质和生物外源性物质（如适用）等，需进行控制或结合后续步骤的转化、清除情况进行说明。2）列表说明杂质分析情况，包括杂质名称和/或代号、结构、来源、是否订入标准、安全性支持限度等。对于结构尚未阐明的超过鉴定限度的杂质，也需提供相对保留时间、是否在标准中作为特定杂质控制、安全性支持限度等信息。对于工艺中用到的溶剂/催化剂但未进行常规控制的，需进行分析说明。对于潜在的遗传毒性杂质，需提供相关研究信息（如来源、结构、控制策略等）。3）说明质量标准中的项目设定以及关键项目（如杂质、可能影响制剂性能的质量特性）限度设定依据。如涉及杂质分析方法的重大变更，需提供支持变更的研究信息，评估方法变更的合理性。必要时，采用变更前、后方法对安全性研究批次重新测定，评估杂质限度的合理性。➣ 《已上市化学药品药学变更研究技术指导原则（试行）》杂质要求内容主要为当对比研究结果符合以下条件时，则可认为杂质谱一致：1）新增杂质未高于《化学药物杂质研究的技术指导原则》及ICH Q3A等规定的鉴定限度；2）已有杂质（包含立体异构体）及杂质总量均在质量标准规定的限度内，如标准中无规定，应在原工艺生产的多批产品测定范围内；3）新使用的溶剂残留量符合《化学药物有机溶剂残留量研究的技术指导原则》及ICH Q3C等的有关规定；4）新的无机杂质符合《化学药物杂质研究的技术指导原则》及ICH Q3D等的有关要求；5）应参考ICH M7对致突变杂质进行考察，必要时进行控制。4. 国内杂质研究的共性问题虽然，ICH指导原则和国内相关指导原则对临床不同阶段药物开发杂质研究的内容和程度进行了科学的指引，但在具体实施过程中，申报资料也是集中暴露了很多问题，可通过以下共性问题的汇总进行说明。➣ 《化学药品创新药I期临床试验申请药学共性问题相关技术要求》杂质共性问题如下：1）未进行杂质谱分析或者分析过于简单，缺少对生产过程中用到的有毒有害试剂、金属催化剂等残留杂质的汇总分析。样品中的杂质记录不够详细，提供的检验信息中仅简单说明合格、未提供具体检测数据。未分析说明杂质限度拟定的初步依据。2）未进行致突变杂质分析，或者对于潜在的致突变杂质仅凭经验简单分析和界定为不具有致突变性。仅说明致突变杂质含量符合要求，未提供具体的分析方法以及必要的方法学验证信息、检测数据等。 图4-1 CDE关于I期临床药学共性问题的信息发布➣ 《化学药品创新药Ⅲ期临床试验前会议药学共性问题及相关技术要求（试行）》工艺杂质和降解产物杂质，共性问题如下：1）原料药潜在杂质分析不充分；杂质检查方法的检出能力不足。重点建议如下：1）申请人应提供有关物质方法学研究阶段性总结资料，根据研究需要重点说明采用不同分析方法的对比研究考察结果。2）建议根据研究进展及时开展杂质在原料药工艺中的转化与清除研究，制定起始原料、中间体与原料药的杂质控制策略。如原料药生产工艺发生变更，需分析可能产生的新杂质，必要时应优化有关物质检查方法。致突变杂质，共性问题如下：1）致突变杂质的研究与控制不充分。重点建议如下：1）对于ICH M7中1类、2类及关注队列杂质，通常应建立专属灵敏的检测方法，参照ICH M7及问答文件中此类杂质临床试验期间相关要求进行研究，制定合理的控制策略。2）对于原料药生产工艺发生变更的，应参照ICH M7及问答文件等开展新杂质的致突变性研究。建议申请人基于已有的致突变杂质研究结果拟定后续研究方案与控制策略，并与药品审评机构共同讨论。 图4-2 CDE关于Ⅲ期临床药学共性问题的信息发布5. 阶段小结以上，即为在ICH指导原则大背景下，同时兼顾我国国内药品研发各阶段过程中，杂质研究的特点。对于是否要“抠杂质”，一直以来都存在着不同的声音。监管方出台的政策，大都要求科学合理的对杂质进行研究，确定那些最有可能在新药的合成、纯化和贮存期间出现的实际和潜在杂质。基于此，不同研究者基于不同的风险背景，就有不同的理解，以及不同的研究产出。但，如果只从科研的角度来看待杂质研究问题，根据不同阶段药学数据的支撑能力，就很容易的配备研发资源。笔者认为，药学研究过程中的杂质研究，还是非常客观且需要合理的进行研究夯实的，切不可因过多的其他因素而有意为之的放大风险系数。

在接近生产过程结束时使用过滤器对药物产品 (DP) 进行除菌，然后再将其灌装到注射器中。进行可溶出物和可析出物 (E&L) 风险评估，过滤器被评为是导致可析出物最终进入 DP 的潜在高风险，因为接触表面积大，并且在将 DP 用于患者之前没有进一步降低的途径。一般而言，需要冲洗过滤器以去除可析出物，预计最高水平的可析出物会在冲洗的前几毫升内从过滤器中析出。需要建立适当体积的 DP 以在灌装过程开始之前通过过滤器冲洗并在保持期后重新启动灌装过程，但也需要对其进行优化，以确保患者安全和废物最小化。为了了解注射器中的可析出物分布和可析出物水平，进行了过滤器冲洗研究，取等分试样并通过总有机碳 (TOC) 和气相色谱质谱 (GC-MS) 进行分析。TOC 分析提供了可以析出的碳化合物数量的指示，通过 GC-MS 筛选挥发性和半挥发性物质，提供单个物质的身份和水平。虽然来自非特定 TOC 分析的潜在可析出物水平在所有保持后大于累积分数的计算安全阈值，但通过 GC-MS 测量的单个物质的水平不大于该阈值。因此，过滤器中可析出物的潜在安全风险与生产过程中的过滤器冲洗方案相结合被证明是低的，并且确定了过滤器冲洗的最小体积，以确保工艺优化。简介监管机构要求进行可溶出物和可析出物 (E&L) 风险评估，以评估最终药品中可析出物对患者的安全风险。E&L 风险评估包括生产过程中使用的材料、医疗器械和容器密闭系统的风险识别、风险分析和风险评估。风险可以按严重性（危害的可能后果的衡量标准）和概率（已识别风险发生的可能性）进行评分。失效模式效应分析可用于描述与药品接触的工艺步骤和材料。了解风险发生的方式和地点可用于对产品生产过程、存储和配料中每个步骤的严重性和可能性进行评分。此外，材料的生物相容性和来自供应商的可溶出物信息可用于支持材料评分。可影响可析出物的数量和水平的因素包括接触时间、流体成分、产品接触表面积比、温度、材料的相容性和可析出物的减少潜力。当材料被评为高风险时，需要进一步开展工作，例如，进行可溶出物和可析出物研究，以了解产品质量和安全的风险。过滤器通常用于生物制药行业的上游和下游工艺，以去除或控制生物负荷。当在生产过程结束时用于过滤药品时，过滤器往往被认为是最终药品中可析出物的潜在高风险。这主要是由于它们与药物产品接触的表面积大，并且在工艺后期减少可析出物的可能性较低。通常，过滤器在使用前需要冲洗，以调节和去除潜在的可析出物。供应商可能会提供有关调节和冲洗过滤器的可溶出物信息和建议，但这些研究倾向于使用不适用于实际生产过程的苛刻或加速条件，因此可能高估了潜在的可析出物和冲洗量。生产过程是特定于产品的，包括预处理步骤，这些步骤未包含在供应商提供的可溶出物信息中。来自伽马辐照过滤器装置的典型可析出物由膜亲水剂（如果使用）、有机酸和一些可通过冲洗过滤器轻松去除的挥发物组成。过滤器的可溶出物是来自膜或过滤器外壳的分解产物、添加剂或来自初始聚合的起始材料。总有机碳 (TOC) 分析可用于估计溶出材料的总量并提供可溶出物的概况。可溶出物的表征通常通过分别使用顶空 GC-MS、直接进样 GC-MS 和液相色谱质谱 (LC-MS) 筛选挥发性、半挥发性和非挥发性物质的材料溶出物来完成。TOC 是量化筛选方法中未检测到的可溶出物的有效工具。样品的 TOC 分析显示对于从过滤器中获取可溶出物的准确概况非常有用，并且可用于计算最小冲洗量。使用 TOC 的过滤冲洗研究建议执行初始冲洗并丢弃初始冲洗，以最大程度地减少可析出物。在本案例研究中，使用过滤器对药品进行除菌，然后再将其灌装到最终容器（1 mL 注射器）中，最终过滤器下游没有产品合并。由于过滤器的表面积大并且没有减少可析出物的可能性，因此过滤器被评为高故障模式。因此，对过滤器的可溶出性研究旨在模拟生产过程，并提供对最终药品中潜在可析出物风险的理解。用水冲洗过滤器并收集累积馏分，以获得 TOC 溶出曲线，表明潜在可析出物的总量。此外，使用顶空 GC-MS 分析收集的馏分，以筛选挥发性物质，并使用直接进样 GC-MS 筛选半挥发性物质。没有研究水溶出物的非挥发性物质，因为众所周知，水溶出物仅显示可忽略不计的非挥发性可溶出物。在本案例研究的生产过程中，最初用 DP 冲洗过滤器，以去除潜在的可析出物，并在将 DP 灌装到最终容器之前丢弃初始体积。本研究的目的是确定通过过滤器的最小冲洗体积，以去除潜在的可析出物，并确保质量和产品安全。材料与方法实验设计进行了四次过滤器实验，从保持 20 分钟开始，并以特定流速初始冲洗 380 mL，以代表生产过程中的灌装步骤。初次冲洗后，对两个过滤器应用 1 小时保持，对另外两个过滤器应用 16 小时保持。在过滤器之后和收集馏分之前，连接一根管子以模拟在生产过程中过滤和最终灌装注射器之间的管子体积。如表 1 中所述，收集馏分用于 TOC 分析和 GC-MS 分析。分析评估阈值ICH M7 指南评估和控制药物中的 DNA 反应性（诱变）杂质以限制潜在致癌风险中概述的原则被用作定义报告阈值的方法。考虑到药品的不同剂量和给药方式，已定义了与 ICH M7 中的毒理学关注阈值 (TTC) 概念一致的报告阈值，即 10 mcg/day，给药持续时间为 1 至 10 年。基于每天 3 个注射器的最大剂量，TTC 相当于 3.3 mcg/注射器的最大可析出水平。从这些注射器中输送的标称体积为 1 mL。因此，这相当于 3.3 mcg/mL 作为生产过程的输出，并且是为 TOC 分析设置的报告阈值。由于受控可提取物研究使用去离子水而不是实际药物产品，并且由于 GC-MS 的响应因子变化，因此对使用 GC-MS 检测的可溶出物应用不确定因子。1.6 mcg/mL 的分析评估阈值 (AET 50%) 用于 GC-MS 检测的可溶出物。设备和样品制备总有机碳 (TOC)在配备 GE 自动进样器的 Sievers M9 TOC 仪器上对收集的水馏分进行 TOC 测量。氧化剂是 15% 的过硫酸铵水溶液，酸化剂是 6 摩尔磷酸水溶液。Sievers 认证的 TOC 40 mL 样品瓶用于收集 40 mL 及以下的馏分。将较大的馏分收集在选定尺寸的Durans玻璃中以减少顶部空间，用 10% v/v 硝酸溶液和纯净水进行预冲洗。这些在使用前进行了预测试。使用前确保所有玻璃器皿的浓度低于 0.05 mg/L。制备浓度均为 500 ppb 的 1,4-苯醌和蔗糖溶液，并使用样品溶液进行分析，以确保测量的准确性。在过滤器冲洗前，用于 TOC 的水的测量值小于 0.05 mg/L。顶空气相色谱质谱法 (HS GC-MS)使用装有能够进行顶空分析的 Gerstel MPS 的 Agilent 8890 气相色谱仪和质谱仪分析水馏分的等分试样的挥发性物质。使用分流模式（比例 5:1）。载气为恒定流速为 1 mL/分钟的氦气。使用 DB624，60 m x 0.25 mm x 1.4 µm 膜厚分析柱，温度梯度为 35 °C 至 240 °C，历时 45 分钟。质谱仪在扫描模式下使用 m/z 30–500 范围和 5 分钟的溶剂延迟运行。在 80 °C 下以 500 rpm 的搅拌速度孵育 60 分钟。单个挥发性物质的半定量基于内标添加，在本例中为甲苯-d8（99.6%，Sigma-Aldrich）。对于每个样品制备，将 1 g ± 0.1 g 氯化钠（≥ 99%，Sigma-Aldrich）放入 10 mL 顶空钳口瓶中，然后加入 1.0 mL 去离子水和 20 mcL 浓度为 80 mcg/mL的内标。使用 1000 mcL 的注射体积。气相色谱质谱法 (GC-MS)使用配备 Gerstel MPS 的 Agilent 7890 气相色谱仪和质谱仪分析等份的水馏分的半挥发性物质。脉冲不分流，初始进样脉冲压力为 15 psi，持续 1 分钟，1 分钟后吹扫至分流口的流量为 50 mL/min。前入口温度设置为 300 °C。载气为氦气，流速恒定为 1 mL/min。使用 HP1，50 m x 0.32mm x 1.05 µm 膜厚分析柱，温度梯度为 60 °C 至 300 °C，历时 24 分钟。质谱仪在扫描模式下运行，使用 m/z 30–500 范围和 6.5 分钟的溶剂延迟。单个半挥发性物质的半定量基于内标添加，在本例中为芴-d10（≥ 99%，Sigma-Aldrich）。对于每个样品制备，将 1.0 mL 去离子水和 20 mcL 80 mcg/mL 内标置于玻璃离心管中。然后使用氯仿（99.9%，ACROS Organics）作为萃取溶剂对所有制剂进行分散液-液微萃取（DLLME）。使用 1 mcL 的注射体积。结果和讨论TOC与通过过滤器后的水样中所见的水平相比，管路中的 TOC 水平最低 (0.06 mcg/mL)。来自过滤器的样品中的 TOC 水平未针对来自管路的 TOC 水平进行校正，并且被认为是最坏的情况。图 1 显示了获得的数据。图 1 中过滤器冲洗曲线上的数据点代表样本收集点。额外的累积馏分 800 mL、840 mL、880 mL、920 mL 和 960 mL 仅通过过滤器收集并保留 16 小时，并显示 TOC 水平进一步降低。过滤器之间存在一些差异，但是所有四个过滤器都遵循相同的趋势。保持 20 分钟并开始冲洗后，TOC 水平在前 100 mL 中增加。在模拟管路体积的 140 mL 冲洗后，TOC 水平达到最大值，之后水平再次下降。在用 380 mL 冲洗后和保持之前，所有过滤器的 TOC 水平不超过 3.3 mcg/mL 的 AET。在保持并再次冲洗过滤器后，TOC 水平再次增加到大于 3.3 mcg/mL，随后 TOC 水平下降。保持 1 小时后过滤器冲洗中的最大 TOC 水平低于保持 16 小时后过滤器冲洗中的最大 TOC 水平。这些数据证实了在之前的研究中已经观察到的情况，其中显示大约两倍的过滤器死体积已经包含过滤器释放的 TOC 的 50-70%。此外，与 16 小时保持相比，1 小时保持将 TOC 水平降低至不大于 3.3 mcg/mL 所需的冲洗量更少。第一次保持后，在 140 mL、160 mL 或 180 mL 冲洗馏分中检测到最高 TOC 水平，表明可析出物积聚在过滤器上，而不是过滤器后的 140 mL 管路中。当生产过程继续进行时，可析出物会在过滤器中积聚并被冲出过滤器。还表明，过滤器的 TOC 水平是多种可析出物的总和，这些可析出物在过滤器冲洗过程中缓慢释放成累积馏分。TOC 分析检测所有含碳化合物，并指示可析出物的总量。TOC 可以在这里应用，作为一种快速筛选工具，并且使用比通常静态的可溶出物研究更温和的条件。挥发性和半挥发性物质在 TOC 分析完成后，对单个挥发性和半挥发性物质进行了筛选。使用相同样品的不同等分试样。选择具有最高 TOC 水平的选定馏分作为最坏情况进行分析。图 2、图 3、图 4 和图 5 显示了初始保持 20 分钟、1 小时和 16 小时后从过滤器收集的馏分的叠加色谱图。上图显示了叠加色谱图和内标，所有峰均不超过 1.6 mcg/mL。下图显示了灰色方块的扩展色谱图，并表明相同的峰出现在多个累积馏分中，表明物质分布在多个 1 mL 注射器中。挥发性和半挥发性物质的筛选表明，在初始保持 20 分钟、1 小时和 16 小时后，挥发性和半挥发性物质的水平不超过 1.6 mcg/mL AET。色谱图中存在多个峰表明多个潜在的可析出物可以从过滤器中析出，并且在几个累积馏分中检测到的峰表明物质不会最终出现在单个 1 mL 注射器中，而是分布在多个注射器中。总结在这项研究中，TOC 已被证明是一种有价值的筛选和分析可析出物的工具。尽管在最初的 20 分钟、1 小时和 16 小时保持后的累积馏分中 TOC 水平大于 3.3 mcg/mL，但单个物质的水平不超过 1.6 mcg/mL 的 AET，强大的冲洗策略实现了最终过滤器下游没有产品合并的工艺。在目前的生产过程中，在最初的 20 分钟保持后，至少有 380 mL 的药品被丢弃，这降低了患者暴露于大于 3.3 mcg/mL 的可析出物的风险，其中大部分可析出物被丢弃。这表明过滤器在用于生产过程之前始终进行冲洗是多么重要，因为在过滤器冲洗过程中存在的化合物水平会降低。如果没有这项过滤器冲洗研究，则必须按照供应商的建议使用超过 1 L的默认冲洗量。设置的 380 mL 体积超过推荐体积的一半。过滤器中可析出物的潜在安全风险与生产过程中的过滤器冲洗方案相结合被证明是低的，并且确定了过滤器冲洗的最小体积，以确保工艺优化。原文：J. Marques, P. Booij, R. Collier, flush studies to review the leachable safety risk of a filter in the drug product manufacturing process. Biopharm Asia, 2022.