Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms
ANDAs的质量源于设计：速释制剂的实例
Introduction to the Example实例简介
This is an example pharmaceutical development report illustrating how ANDA applicants can move toward implementation of Quality by Design (QbD). The purpose of the example is to illustrate the types of pharmaceutical development studies ANDA applicants may use as they implement QbD in their generic product development and to promote discussion on how OGD would use this information in review.
这是一个有关药物开发报告的实例，用以说明ANDA申请人如何实施质量源于设计(QbD)。该实例的目的是说明ANDA申请人在其仿制药开发过程中实施QbD时，可使用的药物开发研究的类型，同时促进探讨OGD在审评中如何使用该信息。
Although we have tried to make this example as realistic as possible, the development of a real product may differ from this example. The example is for illustrative purposes and, depending on applicants’ experience and knowledge, the degree of experimentation for a particular product may vary. The impact
of experience and knowledge should be thoroughly explained in the submission. The risk assessment process is one avenue for this explanation. At many places in this example, alternative pharmaceutical development approaches would also be appropriate.
虽然我们已试图让实例尽可能切合实际，但真实产品的开发可能与该实例不同。该实例是用于说明的目的，并取决于申请人的经验和知识，个别产品的实验程度可能会有所不同。在提交时应充分说明经验和知识的作用。风险评估过程是该解释的一个途径。该实例的许多地方，也可适用其他药物开发方法。
Notes to the reader are included in italics throughout the text. Questions and comments may be sent to GenericDrugs@v
整篇文章的斜体内容为致读者的内容。如有任何问题和意见，请发送至GenericDrugs@v。
Pharmaceutical Development Report Example QbD for IR Generic Drugs
IR仿制药的药物开发报告的QbD实例
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Table of Contents 目录表
1.1 Executive Summary 概述
1.2 Analysis of the Reference Listed Drug Product 分析参考列表药品
1.2.1 Clinical 临床
1.2.2 Pharmacokinetics 药动学
1.2.3 Drug Release 药物释放
1.2.4 Physicochemical Characterization 理化性质
1.2.5 Composition 成分
1.3 Quality Target Product Profile for the ANDA Product ANDA药品的目标药品质量概述1.4 Dissolution Method Development and Pilot Bioequivalence Studies
溶出方法开发和中试生物等效性研究
1.4.1 Dissolution Method Development 溶出方法开发
1.4.2 Pilot Bioequivalence Study 中试生物等效性研究
2.1 Components of Drug Product 制剂成分
2.1.1 Drug Substance 原料药
2.1.1.1 Physical Properties 物理性质
2.1.1.2 Chemical Properties化学性质
2.1.1.3 Biological Properties 生物学性质
2.1.2 Excipients 辅料
2.1.2.1 Excipient Compatibility Studies辅料相容性研究
2.1.2.2 Excipient Grade Selection辅料级别选择
2.2 Drug Product 制剂
2.2.1 Formulation Development 处方开发
2.2.1.1 Initial Risk Assessment of the Formulation Variables 处方变量的初始风险评估
2.2.1.2 Drug Substance Particle Size Selection for Product Development
制剂开发中的原料药粒径选择
2.2.1.3 Process Selection工艺选择
2.2.1.4 Formulation Development Study #1 处方开发研究#1
2.2.1.5 Formulation Development Study #2 处方开发研究#2
2.2.1.6 Formulation Development Conclusions 处方开发结论
2.2.1.7 Updated Risk Assessment of the Formulation Variables 更新的处方变量风险评估2.2.2 Overages 过量投料
2.2.3 Physicochemical and Biological Properties 理化和生物学性质
2.3 Manufacturing Process Development 生产工艺开发
2.3.1 Initial Risk Assessment of the Drug Product Manufacturing Process
制剂生产工艺的初始风险评估
2.3.2 Pre-Roller Compaction Blending and Lubrication Process Development
预碾压混合和润滑工艺开发
2.3.3 Roller Compaction and Integrated Milling Process Development
碾压和集成粉碎工艺开发
2.3.4 Final Blending and Lubrication Process Development 最终混合和润滑工艺开发
2.3.5 Tablet Compression Process Development 压片工艺开发
2.3.6 Scale-Up from Lab to Pilot Scale and Commercial Scale
从实验室规模放大至中试规模和工业规模
2.3.6.1 Scale-Up of the Pre-Roller Compaction Blending and Lubrication Process
预碾压混合和润滑工艺的放大
2.3.6.2 Scale-Up of the Roller Compaction and Integrated Milling Processprofile中文
碾压和集成粉碎工艺的放大
2.3.6.3 Scale-Up of the Final Blending and Lubrication Process
最终混合和润滑工艺的放大
2.3.6.4 Scale-Up of the Tablet Compression Process压片工艺的放大
2.3.7 Exhibit Batch 申报批
2.3.8 Updated Risk Assessment of the Drug Product Manufacturing Process
更新的制剂生产工艺风险评估
2.4 Container Closure System 容器密封系统
2.5 Microbiological Attributes 微生物属性
2.6 Compatibility 相容性
2.7 Control Strategy 控制策略
2.7.1 Control Strategy for Raw Material Attributes 原材料属性的控制策略
2.7.2 Control Strategy for Pre-Roller Compaction Blending and Lubrication
预碾压混合和润滑的控制策略
2.7.3 Control Strategy for Roller Compaction and Integrated Milling
碾压和集成粉碎的控制策略
2.7.4 Control Strategy for Final Blending and Lubrication 最终混合和润滑的控制策略2.7.5 Control Strategy for Tablet Compression 压片的控制策略
2.7.6 Product Lifecycle Management and Continual Improvement
产品生命周期管理和持续改进
List of Abbreviations 缩略语表
1.1 Executive Summary 概述
The following pharmaceutical development report summarizes the development of Generic Acetriptan Tablets, 20 mg, a generic version of the reference listed drug (RLD), Brand Acetriptan Tablets, 20 mg. The RLD is an immediate release (IR) tablet indicated for the relief of moderate to severe physiological symptoms. We used Quality by Design (QbD) to develop generic acetriptan IR tablets that are therapeutically equivalent to the RLD.
总结了如下药物开发报告，开发20 mg Acetriptan片的仿制药，一种商品名20 mg Acetriptan 片的参考目录药物(RLD)的仿制药。RLD为速释(IR)片，用于缓解中度至重度生理症状。我们使用质量源于设计(QbD)法用以开发与RLD等效的acetriptan IR片的仿制药。Initially, the quality target product profile (QTPP) was defined based on the properties of the drug substance, characterization of the RLD product, and consideration of the RLD label and intended patient population. Identification of critical quality attributes (CQAs) was based on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute of the drug product. Our investigation during pharmaceutical development focused on those CQAs that could be impacted by a realistic change to the drug product formulation or manufacturing process. For generic acetriptan tablets, these CQAs included assay, content uniformity, dissolution and degradation products.
最初，明确目标药品的质量概况(QTPP)是根据原料药的性质，RLD产品的特性，并考虑到RLD标签和预
定患者人。关键质量属性(CQAs)的确定是基于由于不符合药品的质量属性而对患者造成的伤害严重性(安全性和有效性)。我们在药物开发中的研究集中在那些可能受制剂处方或生产工艺的实际变动而受到影响的CQAs。对acetriptan片的仿制药，这些CQAs 包括含量，含量均匀度，溶出和降解物。
Acetriptan is a poorly soluble, highly permeable Biopharmaceutics Classification System (BCS) Class II compound. As such, initial efforts focused on developing a dissolution method that would be able to predict in vivo performance. The developed in-house dissolution method uses 900 mL of 0.1 N HCl with 1.0% w/v sodium lauryl sulfate (SLS) in USP apparatus 2 stirred at 75 rpm. This method is capable of differentiating between formulations manufactured using different acetriptan particle size distributions (PSD) and predicting their in vivo performance in the pilot bioequivalence (BE) study.
Acetriptan为难溶，高渗透生物药剂分类系统(BCS)II类化合物。因此，初始工作集中于开发一种可预测体内性能的溶出方法。开发的内部溶出方法为，在75 rpm转速的USP装置2中，使用900 mL含1.0% w/v十二烷基硫酸钠(SLS)的0.1 N HCl溶液。该方法能辨别使用不同acetriptan粒度分布(PSD)生产的处方并预测其在中试生物等效性(BE)研究中的体内性能。Risk assessment was used throughout development to identify potentially high risk formulation and process variables and to determine which studies were necessary to achieve product and process understanding in order to develop a control strategy. Each risk assessment was then updated after development to capture the reduced level of risk based on our
improved product and process understanding.
在整个开发中使用风险评估以确认潜在的高风险处方和工艺变量，并确定哪些研究是必须的以达到对产品和工艺的理解以便开发一种控制策略。然后基于我们对产品和工艺改进的理解，在开发后更新每个风险评估以获得降低的风险水平。
For formulation development, an in silico simulation was conducted to evaluate the potential effect of acetriptan PSD on in vivo performance and a d90 of 30 μm or less was selected. Roller compaction (RC) was selected as the granulation method due to the potential for thermal
degradation of acetriptan during the drying step of a wet granulation process. The same types of excipients as the RLD product were chosen. Excipient grade selection was based on experience with previously approved ANDA 123456 and ANDA 456123 which both used roller compaction. Initial excipient binary mixture compatibility studies identified a potential interaction between acetriptan and magnesium stearate. However, at levels representative of the final formulation, the interaction was found to be negligible. Furthermore, the potential interaction between acetriptan and magnesium stearate is limited by only including extragranular magnesium stearate.
对于处方开发，进行计算机模拟以评估acetriptan PSD对体内性能的潜在影响，选择了d90为30 μm或低
于30 μm。选择碾压(RC)作为制粒方法由于acetriptan在湿法制粒工艺的干燥步骤中可能发生热降解。选择与RLD产品相同类型的辅料。辅料级别的选择是基于先前批准的ANDA 123456和ANDA 456123都使用碾压的经验。初始辅料二元混合物相容性研究确认acetriptan和硬脂酸镁间有潜在相互作用。但是，在表示最终处方的浓度下，发现该相互作用可忽略不计。此外，acetriptan和硬脂酸镁间的潜在相互作用受仅包括外加硬脂酸镁的限制。Two formulation development design of experiments (DOE) were conducted. The first DOE investigated the impact of acetriptan PSD and levels of intragranular lactose, microcrystalline cellulose and croscarmellose sodium on drug product CQAs. The second DOE studied the levels of extragranular talc and magnesium stearate on drug product CQAs. The formulation composition was finalized based on the knowledge gained from these two DOE studies.
进行了两个处方开发实验设计(DOE)。第一个DOE研究了acetriptan PSD和外加乳糖，微晶纤维素和交联羧甲基纤维素钠的浓度对制剂CQAs的影响。第二个DOE研究了外加滑石粉和硬脂酸镁的浓度对制剂CQAs的影响。基于这两个DOE研究所得的知识，确定了处方成分。An in-line near infrared (NIR) spectrophotometric method was validated and implemented to monitor blend uniformity and to reduce the risk associated with the pre-roller compaction blending and lubrication step. Roller pressure, roller gap and mill screen orifice size were identified as critical process parameters (CPPs) for the roller compaction and integrated milling process step and acceptable ranges were identified through the DO
E. Within the ranges studied during development of the final blending and lubrication step, magnesium stearate specific surface area (5.8-10.4 m2/g) and number of revolutions (60-100) did not impact the final product CQAs. During tablet compression, an acceptable range for compression force was identified and force adjustments should be made to accommodate the ribbon relative density (0.68-0.81) variations between batches in order to achieve optimal hardness and dissolution.
验证了在线近红外(NIR)分光光度法并用于监测混合均匀度和降低与预碾压混合和润滑步骤相关的风险。轧辊压力，轧辊间隙和细筛孔径确定为碾压和集成粉碎工艺步骤的关键工艺参数(CPPs)并通过DOE确定了可接受范围。在开发最终混合和润滑步骤中的研究范围内，硬脂酸镁比表面积(5.8～10.4 m2/g)和转数(60～100)不影响最终产品CQAs。在压片中，确定了可接受范围的压缩力并应调整压缩力以容纳批次间带状物相对密度(0.68～0.81)的变化以便达到硬度和溶出的最优化。
Scale-up principles and plans were discussed for scaling up from lab (5.0 kg) to pilot scale (50.0 kg) and then proposed for commercial scale (150.0 kg). A 50.0 kg cGMP exhibit batch was manufactured at pilot scale and demonstrated bioequivalence in the pivotal BE study. The operating ranges for identified CPPs at commercial scale were proposed and will be qualified and continually verified during routine commercial manufacture.
讨论了从实验室规模(5.0 kg)放大至中试规模(50.0 kg)的放大原则和计划，然后拟定了工业规模(150.0 kg)。在中试规模下生产了50.0 kg cGMP申报批并在关键BE研究中显示生物等效。