美国ANDA片剂(IR)开发模板-1(中英文对照)

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@https://www.360docs.net/doc/563324082.html,

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@https://www.360docs.net/doc/563324082.html,。

Pharmaceutical Development Report Example QbD for IR Generic Drugs

IR仿制药的药物开发报告的QbD实例

___________________________________________________________________________

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 Process

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治疗等效的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标签和预定患者人群。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 DOE. 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。

工业规模下，拟定了已确认的CPPs操作范围，在常规工艺生产中将进行限定并持续验证。Finally, we proposed a control strategy that includes the material attributes and process parameters identified as potentially high risk variables during the initial risk assessments. Our control strategy also includes in-process controls and finished product specifications. The process will be monitored during the lifecycle of the product and additional knowledge gained will be utilized to make adjustments to the control strategy as appropriate.

最后，我们提出了控制策略，包括初始风险评估中确认为潜在高风险变量的物质属性和工艺参数。将在产品的生命周期中监测工艺并且获得的额外知识将用于对控制策略的适当调整。The development time line for Generic Acetriptan Tablets, 20 mg, is presented in Table 1.

仿制药20 mg Acetriptan片的开发时间线列于表1。

Table 1. Development of Generic Acetriptan Tablets, 20 mg, presented in chronological order

表1 仿制药20 mg Acetriptan片的开发，以时间顺序排序

Study 研究Scale 规模Page

页码Analysis of the Reference Listed Drug product 分析参考列表药品N/A 6 Evaluation of the drug substance properties 评估原料药性质N/A 18 Excipient compatibility 辅料相容性N/A 25

In silico simulation to select acetriptan PSD for product development

计算机模拟选择用于制剂开发的acetriptan PSD

N/A 30

Attempted direct compression of RLD formulation 尝试直压RLD处方Lab (1.0 kg)

小试(1.0 kg)

32

Lab scale roller compaction process feasibility study 实验室规模碾压工艺可行性研究Lab (1.0 kg)

小试(1.0 kg)

65

Formulation Development Study #1: Effect of acetriptan PSD,

MCC/Lactose ratio and CCS level

处方开发研究#1：acetriptan PSD，MCC/乳糖比和CCS浓度的影响Lab (1.0 kg)

小试(1.0 kg)

33

Dissolution testing using FDA-recommended method

使用FDA推荐的方法进行溶出度检查

N/A 36 In-house dissolution method development 内部溶出方法开发N/A 13

Formulation Development Study #2: Effect of extragranular magnesium stearate and talc level

处方开发研究#2：外加硬脂酸镁和滑石粉浓度的影响Lab (1.0 kg)

小试(1.0 kg)

44

Formulations with different acetriptan PSD for pilot BE study 不同acetriptan PSD的处方用于中试BE研究Lab (1.0 kg)

小试(1.0 kg)

14

Dissolution testing of formulations for pilot BE study

处方的溶出检查用于中试BE研究

N/A 16 Pilot BE Study #1001 中试BE研究#1001 N/A 14

Pre-roller compaction blending and lubrication process development: effect of acetriptan PSD and number of revolutions

预碾压混合和润滑工艺开发：acetriptan PSD和转数的影响Lab (5.0 kg)

小试(5.0 kg)

56

Development of in-line NIR method for blending endpoint determination 开发在线NIR法用于混合终点判断Lab (5.0 kg)

小试(5.0 kg)

59

Roller compaction and integrated milling process development: effect of roller pressure, roller gap, mill speed and mill screen orifice size 碾压和集Lab (5.0 kg)

小试(5.0 kg)

65

成粉碎工艺开发：轧辊压力，轧辊间隙，轧制速度和细筛孔径的影响

Final blending and lubrication process development: effect of magnesium stearate specific surface area and number of revolutions

最终混合和润滑工艺开发：硬脂酸镁比表面积和转数的影响Lab (5.0 kg)

小试(5.0 kg)

79

Tablet compression process development: effect of main compression force, press speed, and ribbon relative density

压片工艺开发：主压缩力，压制速度和带状物相对密度的影响Lab (5.0 kg)

小试(5.0 kg)

83

Scale-up strategy from lab to pilot and commercial scale

从实验室规模至中试和工业规模的放大策略

N/A 90

Exhibit batch for pivotal BE study 申报批用于关键BE研究Pilot (50.0 kg)

中试(50.0 kg)

95

1.2 Analysis of the Reference Listed Drug Product 分析参考列表药品

1.2.1 Clinical 临床

The Reference Listed Drug (RLD) is Brand Acetriptan Tablets, 20 mg, and was approved in the United States in 2000 (NDA 211168) for therapeutic relief of moderate to severe symptoms. The RLD is an unscored immediate release (IR) tablet with no cosmetic coating. The tablet needs to be swallowed “as is” without any intervention. Thus, the proposed generic product will also be an unscored IR tablet with no cosmetic coating. The maximum daily dose in the label is 40 mg (i.e., one tablet twice per day). A single tablet is taken per dose with or without food. Brand Acetriptan Tablets, 20 mg, should be swallowed whole with a glass of water.

参考列表药品(RLD)为商品名20 mg Acetriptan片，于2000年在美国批准(NDA 211168)用于治疗缓解中度至重度症状。RLD为无刻痕非包衣的速释(IR)片。需“依现状”吞下片剂而无任何干预。因此，拟定仿制药也是为无刻痕非包衣IR片。标签中的最大日剂量为40 mg (即一日

两次，每次一片)。单位剂量的单片可与食物或不与食物服用。商品名20 mg Acetriptan片，应用一杯水整片吞服。

1.2.2 Pharmacokinetics 药动学

Acetriptan is well absorbed after oral administration. The median Tmax is 2.5 hours (h) in patients. The mean absolute bioavailability of acetriptan is approximately 40%. The AUC and Cmax of acetriptan are increased by approximately 8% to 12% following oral dosing with a high fat meal. The terminal elimination half-life of acetriptan is approximately 4 hours.

Acetriptan口服后吸收良好。患者的平均Tmax为2.5小时。Acetriptan的平均绝对生物利用度约40%。与高脂肪饮食一起服用后，acetriptan的AUC和Cmax增加了约8%～12%。Acetriptan的末端消除半衰期约4小时。

1.2.3 Drug Release 药物释放

Drug release is usually the rate limiting process for absorption of a Biopharmaceutics Classification System (BCS) Class II compound like acetriptan due to its low solubility. Therefore, the dissolution of the RLD tablets was thoroughly evaluated. Initially, the dissolution method recommended in the FDA dissolution methods database for this product was utilized (900 mL of 0.1 N HCl with 2.0% w/v sodium lauryl sulfate (SLS) using USP apparatus 2 (paddle) at 75 rpm). The temperature of the dissolution medium was maintained at 37 ± 0.5 °C and the drug concentration was determined using UV spectroscopy at a wavelength of 282 nm. The drug release of RLD tablets was also obtained at different medium pH (pH 4.5 acetate buffer and pH 6.8 phosphate buffer) with 2.0% w/v SLS. As shown in Figure 1, RLD tablets exhibited a very

rapid dissolution using the FDA-recommended method without any sensitivity to medium pH.

对于像acetriptan的生物药学分类系统(BCS) II类化合物的吸收，由于其低溶解度，药物释放通常是速率限制过程。因此，应彻底评估RLD片剂的溶出。开始，使用该产品在FDA溶出方法数据库中推荐的溶出方法(用USP装置2(桨法)，转速为75 rpm，900 mL含2.0% w/v 十二烷基硫酸钠(SLS) 的0.1 N HCl溶出介质)。溶出介质的温度维持在37 ± 0.5 °C，用UV 分光光度法在282 nm波长处测定药物浓度。也得到了在含2.0% w/v SLS的不同pH值 (pH 4.5 醋酸缓冲液和pH 6.8磷酸缓冲液)溶出介质的RLD片剂的药物释放。如图1所示，使用FDA 推荐的方法，RLD片剂显示出快速溶出，对介质pH值不敏感。

Figure 1. RLD dissolution profile in 900 mL of medium (pH as shown) with 2.0% w/v SLS using USP

apparatus 2 at 75 rpm

图1 使用USP装置2，75 rpm转速的900 mL 含2.0% w/v SLS的介质(pH值如图所示)中，

RLD的溶出曲线

1.2.4 Physicochemical Characterization 理化性质

The physicochemical characterization of the RLD tablet is summarized in Table 2. Characterization included determination of the level of ACE12345, a known degradant, in near expiry product.

RLD片的理化性质概述在表2中。性质包括了测定ACE12345，一种已知降解物，在临失效产品中的浓度。

Table 2. Physicochemical characterization of Brand Acetriptan Tablets, 20 mg

表2 商品名20 mg Acetriptan片的理化性质

Description 性状White round tablet debossed with ACE

带ACE凹陷的白色圆形片

Batch No. 批号A6970R

2011

2011年11月

Expiry date 失效期 November

Strength (mg) 规格(mg)20

Average weight (mg) 平均重量(mg)201.2

无

Score 刻痕 No

未包衣

Coating 包衣 Uncoated

Diameter (mm) 直径(mm)8.02-8.05

Thickness (mm) 厚度(mm) 2.95-3.08

Volume (mm3) 体积(mm3)150.02 average measured using image analysis

采用图像分析法测量。平均值为150.02 Hardness (kP) 硬度(kP)7.4-10.1

Disintegration time (min)

崩解时间(min)

1.4-1.6

Disintegration observation 崩解观察Rapidly disintegrates into fine powder 快速崩解为细小粉末

Assay (% w/w of label claim)

含量(% w/w标示量)

99.7-100.2

Related Compound 1 (RC1) (%)

有关物质1(RC1) (%)

ND

Related Compound 2 (RC2) identified as

ACE12345 (%)

确认为ACE12345的有关物质2(RC2) (%)

0.41-0.44

Related Compound 3 (RC3) (%)

有关物质3(RC3) (%)

ND

Related Compound 4 (RC4) (%)

有关物质4(RC4) (%)

ND

Highest individual unknown (%)

最高单个未知物(%)

0.07-0.09

1.2.5 Composition 组分

Based on the RLD labeling, patent literature and reverse engineering, Table 3 lists the composition of Brand Acetriptan Tablets, 20 mg. The level provided for each excipient is consistent with previous experience and is below the level listed in the inactive ingredient database (IID) for FDA-approved oral solid dosage forms.

基于RLD标签，专利文献和倒序工程，表3列出了商品名20 mg Acetriptan片的组分。每个辅料提供的浓度与之前的经验一致，低于FDA批准的口服固体制剂非活性成分数据库(IID)所列出的浓度。

Table 3. Composition of Brand Acetriptan Tablets, 20 mg 表3 商品名20 mg Acetriptan片的组分

Component 组分Function 作用Unit 单位

(mg per tablet)

(mg /片) Unit 单位(% w/w)

Acetriptan, USP Active 活性成分20.0 10 Lactose Monohydrate, NF

一水乳糖, NF

Filler 填充剂64-86 32-43 Microcrystalline Cellulose (MCC), NF

微晶纤维素(MCC) , NF

Filler 填充剂72-92 36-46

Croscarmellose Sodium (CCS), NF 羧甲基淀粉钠(SSG) , NF Disintegrant

崩解剂

2-10 1-5

Magnesium Stearate, NF* 硬脂酸镁, NF* Lubricant

润滑剂

2-6 1-3

Talc, NF

滑石粉, NF Glidant/Lubricant

助流剂/润滑剂

1-10 0.5-5

Total tablet weight 总片重200 100

*Magnesium stearate level estimated by EDTA titration of magnesium. 硬脂酸镁浓度通过EDTA滴定镁估计。

1.3 Quality Target Product Profile for the ANDA Product

ANDA药品的目标药品的质量概况

Note to Reader: The quality target product profile (QTPP) is “a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.” 1 The QTPP is an essential element of a QbD approach and forms the basis of design of the generic product. For ANDAs, the target should be defined early in development based on the properties of the drug substance (DS), characterization of the RLD product and consideration of the RLD label and intended patient population. The QTPP includes all product attributes that are needed to ensure equivalent safety and efficacy to the RLD. This example is for a simple IR tablet; other products would include additional attributes in the QTPP. By beginning with the end in mind, the result of development is a robust formulation and manufacturing process with a control strategy that ensures the performance of the drug product.

致读者：目标药品的质量概况(QTPP)是“从理论上达到对药品质量特性的前瞻性总结，确保预期的质量，同时兼顾药品的安全性和有效性“。1 QTPP是QbD方法的基本要素并形成仿制药设计的基础。对于ANDAs，应在开发的早期，基于药物(DS)性质，RLD药品的特征并兼顾RLD标签和预期的患者人口确定目标。QTPP包括需要保证与RLD安全性和有效性等效的所有产品属性。该实例适用于单一IR片；其他产品将包括QTPP中的额外属性。通过以终为始，开发的结果是处方稳定，生产工艺的控制策略可确保药品的性能。

A critical quality attribute (CQA) is “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.”1 The identification of a CQA from the QTPP is based on the severity of harm to a patient should the product fall outside the acceptable range for that attribute.

关键质量属性(CQA)是“物理，化学，生物学，或微生物学性质或特点，应在适宜的限度内，

范围内，或分布内以保证预期的药品质量”。1 QTPP中确认CQA是基于该属性在可接受范围外的药品对患者伤害的严重程度。

All quality attributes are target elements of the drug product and should be achieved through a good quality management system as well as appropriate formulation and process design and development. From the perspective of pharmaceutical development, we only investigate the subset of CQAs of the drug product that also have a high potential to be impacted by the formulation and/or process variables. Our investigation culminates in an appropriate control strategy.

所有的质量属性都是药品的目标元素，应通过良好质量管理系统，适宜的处方和工艺设计及开发来实现。从药物开发的角度来看，我们仅研究也有高度可能受处方和/或工艺变量影响的药品CQAs的一部分。我们的研究以适宜的控制策略告终。

Based on the clinical and pharmacokinetic (PK) characteristics as well as the in vitro dissolution and physicochemical characteristics of the RLD, a quality target product profile (QTPP) was defined for Generic Acetriptan Tablets, 20 mg (see Table 4).

基于RLD的临床和药动学(PK)特征及体外溶出和理化性质，确定了仿制药20 mg Acetriptan 片的目标药品的质量概况(QTPP)(见表4)。

__________________________________________________

1 ICH Harmonised Tripartite Guideline: Q8(R2) Pharmaceutical Development. August 2009.

1 ICH三方协调指南：Q8(R2)药物开发，2009年8月。

Table 4. Quality Target Product Profile (QTPP) for Generic Acetriptan Tablets, 20 mg

表4 仿制药20 mg Acetriptan 片的目标药品的质量概况(QTPP)

QTPP Elements QTPP 元素

Target 目标

Justification 合理性说明 Dosage form 剂型 Tablet 片剂

Pharmaceutical equivalence requirement: same dosage form 药学等效要求：相同剂型

Dosage design 剂型设计

Immediate release tablet without a score or coating 无刻痕或包衣的速释片

Immediate release design needed to meet label claims

速释设计需要符合标签诉求 Route of administration 给药途径 Oral 口服

Pharmaceutical equivalence requirement: same route of administration

药学等效要求：相同给药途径

Dosage strength 剂型规格

20 mg

Pharmaceutical equivalence requirement: same strength 药学等效要求：相同规格

Pharmacokinetics 药动学

Immediate release enabling Tmax in 2.5 hours or less;

Bioequivalent to RLD 速释的Tmax 应在或低于2.5小时内达到；生物等效于RLD

Bioequivalence requirement Needed to ensure rapid onset and efficacy

生物等效性要求需要确保迅速开始并有效

Stability 稳定性

At least 24-month shelf-life at room temperature 室温下至少24个月货架期

Equivalent to or better than RLD shelf-life 等于或优于RLD 货架期 Physical Attributes 物理属性

Identification

鉴别 Assay 含量 Content Uniformity 含量均匀度 Dissolution 溶出 Degradation Products 降解物

Residual Solvents 残留溶剂

Drug product quality attributes 药品质量属性

Water Content

Pharmaceutical equivalence requirement: Must meet the same compendial or other applicable (quality) standards (i.e., identity, assay, purity, and quality).

药学等效要求：必须符合相同药典或其他适用的(质量)标准(即特性，含量，纯度，和质量)。

水分

Container closure system 容器密封系统Container closure system

qualified as suitable for

this drug product

容器密封系统具备适用

于该制剂的合格条件。

Needed to achieve the target shelf-life

and to ensure tablet integrity during

shipping

需要达到目标货架期，并保证运输期

间片剂的完整性。

Administration/Concurrence with labeling 标签中的给药/合并给药Similar food effect as

RLD

与RLD相似的食物影响

RLD labeling indicates that a high fat

meal increases the AUC and Cmax by

8-12%. The product can be taken

without regard to food.

RLD标签标明高脂肪饮食使AUC和

Cmax增加了8%～12%。服用药品可

不考虑食物。

Alternative methods of administration 给药的替代方法None 无None are listed in the RLD label.

RLD标签中未列出。

Table 5 summarizes the quality attributes of generic acetriptan tablets and indicates which attributes were classified as drug product critical quality attributes (CQAs). For this product, assay, content uniformity (CU), dissolution and degradation products are identified as the subset of CQAs that have the potential to be impacted by the formulation and/or process variables and, therefore, will be investigated and discussed in detail in subsequent formulation and process development studies.

表5概述了仿制药acetriptan片的质量属性，并指出了那些属性被列为药品关键质量属性(CQAs)。对于该产品，确定含量，含量均匀度(CU)，溶出和降解物为可能受处分和/或工艺变量影响的CQAs的一部分，并因此，将在随后的处方和工艺开发研究中详细研究并讨论。On the other hand, CQAs including identity, residual solvents and microbial limits which are unlikely to be impacted by formulation and/or process variables will not be discussed in detail in the pharmaceutical development report. However, these CQAs are still target elements of the QTPP and are ensured through a good pharmaceutical quality system and the control strategy.

另一方面，药物开发报告中不详细讨论不可能受处分和/或工艺变量影响的CQAs包括特性，残留溶剂和微生物限度。但是，这些CQAs仍然是QTPP的目标元素，并通过良好药品质量系统和控制策略得到保证。

Table 5. Critical Quality Attributes (CQAs) of Generic Acetriptan Tablets, 20 mg 表5 仿制药20 mg Acetriptan片的关键质量属性(CQAs)

Quality Attributes of the Drug Product 制剂的质量属性Target 目标Is this a CQA?

是CQA？

Justification 依据

Appearance 外观Color and shape acceptable

to the patient. No visual

tablet defects observed.

患者接受的颜色和形状。无

肉眼观察到的片剂缺陷。

No 否Color, shape and appearance are not directly linked to safety and efficacy.Therefore, they are

not critical. The target is set to ensure patient acceptability.

颜色，形状和外观与安全性和有效性无直接关系。因此，它们不是关键。设定目标以确

保患者可接受。

Odor 气味No unpleasant odor

无难闻气味No 否In general, a noticeable odor is not directly linked to safety and efficacy, but odor can affect patient acceptability. For this product, neither the drug substance nor the excipients have an

unpleasant odor. No organic solvents will be used in the drug product manufacturing process.

一般来说，可觉察的气味与安全性和有效性无直接关系，但气味可影响患者可接受性。

该产品，药物和辅料都无难闻气味。在药品生产工艺中未使用有机溶剂。

Size 大小Similar to RLD

与RLD类似No 否For comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the target for tablet dimensions is set similar to the RLD.

为比较容易吞咽和患者接受及遵守治疗方案，设定片剂大小的目标与RLD类似。

Score configuration 刻痕结构Unscored 无刻痕 No

否The RLD is an unscored tablet; therefore, the generic tablet will be unscored. Score

configuration is not critical for the acetriptan tablet.

RLD为无刻痕片；因此，仿制药将为无刻痕片。刻痕结构不是acetriptan片的关键。

Physical

Attributes

物理属性

Friability 脆碎度NMT 1.0% w/w No 否Friability is a routine test per compendial requirements for tablets. A target of NMT 1.0%

w/w of mean weight loss assures a low impact on patient safety and efficacy and minimizes

customer complaints. 按照药典对片剂的要求，脆碎度是常规检查。平均重量损失目标不

高于1.0% w/w保证了对患者安全性和有效性的影响低并最大限度降低客户的投诉。

Identification 鉴别Positive for acetriptan

acetriptan正反应Yes*

是*

Though identification is critical for safety and efficacy, this CQA can be effectively

controlled by the quality management system and will be monitored at drug product release.

2012年4月14

Formulation and process variables do not impact identity. Therefore, this CQA will not be discussed during formulation and process development. 虽然鉴别是安全性和有效性的关键，但该CQA可通过质量管理体系得到有效控制，并在药品放行时进行监测。处方和工艺变量不影响特性。因此，该CQA在处方和关于开发中将不讨论。

Assay 含量100% w/w of label claim

100% w/w标示量Yes 是Assay variability will affect safety and efficacy. Process variables may affect the assay of the drug product. Thus, assay will be evaluated throughout product and process development. 含

量差异将影响安全性和有效性。工艺变量可影响药品的含量。因此，含量将在整个产品

和工艺开发中进行评估。

Content Uniformity (CU) 含量均匀度(CU) Conforms to USP <905>

Uniformity of Dosage Units

符合USP <905>含量均匀度

Yes 是Variability in content uniformity will affect safety and efficacy. Both formulation and process

variables impact content uniformity, so this CQA will be evaluated throughout product and

process development. 含量均匀度差异将影响安全性和有效性。处方和工艺变量都影响含

量均匀度，因此该CQA将在整个产品和工艺开发中进行评估。

Dissolution 溶出NLT 80% at 30 minutes in

900 mL of 0.1 N HCl with

1.0% w/v SLS using USP

apparatus 2 at 75 rpm

使用USP装置2，在转速为

75 rpm的900 mL含1.0%

w/v SLS 的0.1 N HCl 溶出

介质中，30分钟内的溶出度

不低于80% Yes 是Failure to meet the dissolution specification can impact bioavailability. Both formulation and process variables affect the dissolution profile. This CQA will be investigated throughout

formulation and process development.

不符合溶出质量标准可影响生物利用度。处方和工艺变量都影响溶出曲线。该CQA将在

整个处方和工艺开发中进行研究。

Degradation Products 降解物ACE12345: NMT 0.5%,

ACE12345：不高于0.5%，

Any unknown impurity:

NMT 0.2%,

任何未知杂质：不高于Yes 是Degradation products can impact safety and must be controlled based on compendial/ICH requirements or RLD characterization to limit patient exposure. ACE12345 is a common

degradant of acetriptan and its target is based on the level found in near expiry RLD product.

The limit for total impurities is also based on RLD analysis. The target for any unknown

impurity is set according to the ICH identification threshold for this drug product.

2012年4月15

0.2%，

Total impurities: NMT 1.0%总杂质：不高于1.0% Formulation and process variables can impact degradation products. Therefore, degradation products will be assessed during product and process development.

降解物可影响安全性，必须基于药典/ICH要求或RLD特性来控制以限制患者暴露量。ACE12345为acetriptan的常见降解物，其目标是基于临失效RLD产品中发现的浓度。总杂质的限度也是基于RLD的分析。任何位置杂质的目标设定是根据该药品的ICH鉴定阈值。处方和工艺变量可影响降解物。因此，将在产品和工艺开发中评估降解物。

Residual Solvents 残留溶剂USP <467> option 1

USP <467>选项1 Yes* 是* Residual solvents can impact safety. However, no solvent is used in the drug product manufacturing process and the drug product complies with USP <467> Option 1. Therefore,

formulation and process variables are unlikely to impact this CQA.

残留溶剂可影响安全性。但是，在药品生产工艺中未使用溶剂，并且药品符合USP <467>

选项1。因此，处方和工艺变量不太可能影响该CQA。

Water Content 水分NMT 4.0% w/w No 否Generally, water content may affect degradation and microbial growth of the drug product

and can be a potential CQA. However, in this case, acetriptan is not sensitive to hydrolysis

and moisture will not impact stability. 一般来说，水分可影响药品的降解和微生物生长，

可能是潜在的CQA。但是，在该情况中，acetriptan对水解不敏感，水分将不影响稳定性。

Microbial Limits 微生物限度Meets relevant

pharmacopoeia criteria

符合相关的药典标准Yes* 是* Non-compliance with microbial limits will impact patient safety. However, in this case, the risk of microbial growth is very low because roller compaction (dry granulation) is utilized

for this product. Therefore, this CQA will not be discussed in detail during formulation and

process development. 不符合微生物限度将影响患者的安全性。但是，在该情况中，微生

物生长的风险非常低，因为该产品使用碾压(干法制粒)，因此，该CQA在处方和工艺开

发中将不详细进行研究。

*Formulation and process variables are unlikely to impact the CQA. Therefore, the CQA will not be investigated and discussed in detail in subsequent risk assessment and pharmaceutical development. However, the CQA remains a target element of the drug product profile and should be addressed accordingly.

*处方和工艺变量不可能影响CQA。因此，随后的风险评估和药物开发中将不详细研究和讨论CQA。但是，CQA仍然是药品概况的目标元素，应相应的进行讨论。

2012年4月16

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

Note to Reader: A pharmaceutical development report should document the selection of the dissolution method used in pharmaceutical development. This method (or methods) may differ from the FDA-recommended dissolution method and the quality control method used for release testing.

致读者：药物开发报告应记录药物开发中使用的溶出方法的选择。该方法(或这些方法)可不同于FDA推荐的溶出方法和用于释放检查的质量控制方法。

1.4.1 Dissolution Method Development 溶出方法开发

Acetriptan is a BCS Class II compound displaying poor aqueous solubility (less than 0.015 mg/mL) across the physiological pH range. As such, development of a dissolution method that can act as the best available predictor of equivalent pharmacokinetics to the RLD was pursued to allow assessment of acetriptan tablets manufactured during development.

Acetriptan在整个生理pH值范围内显示出水溶性差(低于0.015 mg/mL)，为BCS II类化合物。因此，进行一种在预测与RLD药动学等效方面起最佳作用的溶出方法的开发，以允许评估开发期间acetriptan片的生产。

The target is an immediate release product, so dissolution in the stomach and absorption in the upper small intestine is expected suggesting the use of dissolution medium with low pH. Development began with the quality control dissolution method recommended for this product by the FDA: 900 mL of 0.1 N HCl with 2.0% w/v SLS using USP apparatus 2 at 75 rpm. Initial development formulations (Batches 1-11) exhibited rapid dissolution (NLT 90% dissolved in 30 minutes (min)) and were comparable to the RLD. It became a challenge for the team to select the formulations which might perform similarly to the RLD in vivo. The solubility of acetriptan in various media was determined (Table 6) and suggests that the solubility of acetriptan in 0.1 N HCl with 1.0% w/v SLS is similar to its solubility in biorelevant media.

目标为速释产品，因此预期在胃内的溶出和在小肠上部内的吸收，建议使用具有低pH值的溶出介质。该产品的开发以FDA推荐的质量控制溶出方法开始：900 mL0.1 N HCl和2.0% w/v SLS的溶出介质，用USP装置2，75 rpm转速。初始开发的处方(批次1～11)显示出快速溶出(30分钟(min)内溶出度不低于NLT 90%)，与RLD类似。对于团队来说，选择体内行为与RLD类似的制剂成为一种挑战。测定了acetriptan在各种介质中的溶解度(表6)，显示acetriptan在0.1 N HCl和1.0% w/v SLS的介质中的溶解度与其在生物相关性介质中的溶解度类似。

Table 6. Acetriptan solubility in different media

表6 Acetriptan在各种介质中的溶解度

Media 介质Solubility 溶解度

-- (mg/mL)

Biorelevant FaSSGF2生物相关性FaSSGF20.12

Biorelevant FaSSIF-V22生物相关性FaSSIF-V220.18

0.1 N HCl with 0.5% SLS 0.1 N HCl和0.5% SLS 0.075

0.1 N HCl with 1.0% SLS 0.1 N HCl和1.0% SLS 0.15

0.1 N HCl with 2.0% SLS 0.1 N HCl和2.0% SLS 0.3

____________________________________

2 Jantratid E, Janssen N, Reppas C, and Dressman JB. Dissolution Media Simulating Conditions in the Proximal Human Gastrointestinal Tract: An Update. Pharm Res 25:1663-1676, 2008.

Figure 2 presents the dissolution of the RLD in 0.1 N HCl with different SLS concentrations.

图2呈现了在0.1 N HCl和不同SLS浓度中的RLD溶出。

Figure 2. RLD dissolution profile in 900 mL of 0.1 N HCl with various SLS concentrations using USP

apparatus 2 at 75 rpm

图2使用USP装置2，75 rpm转速的900 mL 含SLS不同浓度的0.1 N HCl介质中，RLD的溶出曲线

The dissolution method selected for product development uses 900 mL of 0.1 N HCl with 1.0%

w/v SLS in a dissolution apparatus equipped with paddles (speed 75 rpm) and maintained at a temperature of 37°C, followed by UV spectroscopy at a wavelength of 282 nm. Dissolution in 1.0% w/v SLS is not sensitive to medium pH (similar in 0.1 N HCl, pH 4.5 buffer and pH 6.8 buffer) (data not shown). Additionally, this method is capable of detecting dissolution changes in the drug product caused by deliberately varying the drug substance (DS) particle size distribution (PSD) (see Section 1.4.2).

产品开发选择的溶出方法使用了900 mL0.1 N HCl和1.0% w/v SLS的装备桨(转速75 rpm)的溶出装置，温度维持在37°C，然后是波长为282 nm的UV分光光度仪。在1.0% w/v SLS中的溶出对介质pH值(类似于在0.1 N HCl, pH 4.5缓冲液和pH 6.8缓冲液中)不敏感(数据未显示)。此外，该方法能检测出通过故意改变药物(DS)粒度分布(PSD)而引起的药品的溶出变化(见1.4.2节)。

1.4.2 Pilot Bioequivalence Study 中试生物等效性研究

Note to Reader: For low solubility drugs, pilot bioequivalence (BE) studies are invaluable to demonstrate that the in vitro dissolution used is appropriate. When pilot bioequivalence studies are conducted, the following is an example of how they should be described in the development report to support controls on critical attributes such as particle size and to understand the relationship between in vitro dissolution and in vivo performance. Inclusion of formulations that perform differently will help to determine if there is a useful in vivo in vitro relationship.

致读者：对于低溶解度药物，证明使用的体外溶出是适宜的中试生物等效性(BE)研究是极其宝贵的。当进行中试生物等效性研究时，以下为示范说明它们应怎样在开发报告中描述以支持对关键属性如粒径的控制和理解体外溶出和体内性能间的相关性。包括不同行为的处方将有助于判断是否对体内外相关性有用。

The formulation development studies identified drug substance particle size distribution as the most significant factor that impacts drug product dissolution (see Section 2.2.1.4). In order to understand the potential clinical relevance of drug substance particle size distribution on in vivo

performance, a pilot bioequivalence (BE) study (Study # 1001) was performed in 6 healthy subjects (four-way crossover: three prototypes and the RLD at a dose of 20 mg).

处方开发研究确定药物粒度分布是影响药品溶出的最重要因素(见2.2.1.4节)。为理解因为粒度分布对体内性能的潜在临床意义，在6个健康受试者内进行了一项中试生物等效性(BE)研究(Study # 1001) (四交叉：剂量为20 mg 的3个原型和1个RLD)。

The formulation used to produce the three prototypes and the composition is shown in Table 7. The only difference between each prototype was the drug substance particle size distribution. Drug substance Lot #2, #3 and #4 with a d90 of 20 μm, 30 μm and 45 μm was used for prototype Batch 18, 19, and 20, respectively. Characterization of the drug substance lots is provided in Section 2.2.1.2, Table 19.

处方用于生产3个原型，组分如表7所示。各个原型间的唯一差异是药物粒度分布。用于原型批18，19和20的药物批分别是#2，#3和#4，d90分别是20 μm，30 μm和45 μm。药物批的特征见2.2.1.2节，表19。

Table 7. Formulation of Generic Acetriptan Tablets, 20 mg, used in Pilot BE Study #1001

表7 用于中试BE Study #1001的仿制药20 mg Acetriptan片的处方

Ingredient 成分Function 作用Composition 组分

(mg per tablet)

(mg/片)

(% w/w) Acetriptan Active 活性成分20.0 10.0

Intragranular Excipients 内加辅料

Lactose Monohydrate, NF

一水乳糖, NF

Filler 填充剂79.0 39.5 Microcrystalline Cellulose (MCC), NF

微晶纤维素(MCC), NF

Filler 填充剂79.0 39.5

Croscarmellose Sodium (CCS), NF 交联羧甲基纤维素钠(CCS), NF Disintegrant

崩解剂

10.0 5.0

Talc, NF 滑石粉, NF Glidant/lubricant

助流剂/润滑剂

5.0 2.5

Extragranular Excipients 外加辅料

Magnesium Stearate, NF 硬脂酸镁, NF Lubricant

润滑剂

1.2 0.6

Talc, NF 滑石粉, NF Glidant/lubricant

助流剂/润滑剂

5.8 2.9

Total Weight 总重200.0 100

The pharmacokinetic results are presented in Figure 3 and Table 8.

药动学结果见图3和表8。

Figure 3. Mean PK profiles obtained from Pilot BE Study #1001

图3 中试BE研究#1001所得的平均PK曲线

Table 8. Pharmacokinetic parameters (geometric mean) from Pilot BE Study #1001 表8 中试BE Study #1001的药动学参数(几何均数)

Pharmacokinetic Parameters 药动学参数

Lot #2

批#2

(d90 20 μm)

Lot #3

批#3

(d90 30 μm)

Lot #4

批#4

(d90 45 μm)

N/A

(RLD)

Drug Product Batch No.

药品批号

18 19 20 A6971R

AUC∞(ng/ml h) 2154.0 2070.7 1814.6 2095.3

AUC0-t (ng/ml h) 1992.8 1910.6 1668.0 1934.5

Cmax (ng/ml) 208.55 191.07 158.69 195.89

Tmax (h) 2.0 2.5 3.0 2.5

t1/2(h) 6.0 6.0 6.0 6.0

Test/Reference AUC∞ Ratio

受试/参比AUC∞比

1.028 0.988 0.866 --

Test/Reference AUC0-t Ratio

受试/参比AUC0-t比

1.030 0.988 0.862 --

Test/Reference Cmax Ratio

受试/参比Cmax比

1.065 0.975 0.810 --

According to the literature3, when the mean Cmax and AUC responses of 2 drug products differ by more than 12-13%, they are unlikely to meet the bioequivalence limits of 80-125%. Therefore, the predefined selection criterion was a mean particle size that yielded both a Cmax ratio and an AUC ratio for test to reference between 0.9 and 1.11. The results of the PK study indicated that a drug substance particle size distribution with a d90 of 30 μm or less showed similar in vivo performance based on test to reference ratio calculations for AUC and Cmax. A drug substance particle size distribution with a d90 of 45 μm did not meet the predefined criterion of a test to reference ratio for Cmax and AUC between 0.9 and 1.11. The results confirmed the in silico simulation data obtained during preformulation work (see Section 2.2.1.2).

根据文献3，当2种药品的平均Cmax和AUC响应相差在12～13%以上时，它们不可能符合生