Quality by Design for ANDAs:
An Example for
Immediate-Release Dosage Forms
Introduction to the Example
This is an example pharmaceutical development report illustrating how ANDA sponsors can move toward implementation of quality by design (QbD). The example builds on acetriptan tablets (ACE) case study by treating that product as the reference product for the development of a generic product.
The purpose of the example is to illustrate the types of pharmaceutical development studies ANDA sponsor may use as they implement QbD in their development process and promote discussion on how OGD would use this information in review.
Although we have tried to make the 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 a firms experience and prior knowledge the degree of experiments for a particular product may vary. The impact of experience and prior knowledge should be 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. This example illustrates one of many possible approaches.
Notes to the reader are included in italics at the beginning of many sections and throughout the text.
Pharmaceutical Development Report
Example QbD for IR Generic Drugs
Draft April 26, 2011
Table of Contents
1.1 Overview (4)
1.2 Analysis of the Reference Listed Drug (RLD) Product (5)
1.2.1 RLD Composition (6)
1.2.2 Physicochemical Characterization (6)
1.2.3 RLD Dissolution and Selection of Product Development Dissolution Method (7)
1.2.4 Clinical (8)
1.2.5 Pharmacokinetics (8)
1.3 QTPP for ANDA Product (9)
2.1 Components of Drug Product (12)
2.1.1 Drug Substance (12)
2.1.1.1 Physicochemical and Biological Properties of Drug Substance (12)
2.1.1.2 Risk Assessment of Potential Impact of API Attributes on Drug Product CQAs (16)
2.1.2 Excipients (16)
2.2 Drug Product (17)
2.2.1 Formulation Development (17)
2.2.1.1 Effect of Particle Size on Dissolution (17)
2.2.1.2 Development PK Study 1001 (19)
2.2.1.3 Effect of Particle Size on Material Properties (21)
2.2.1.4 Excipient Compatibility Studies (22)
2.2.1.5 Excipient Grade Selection (23)
2.2.1.6 Formulation Risk Assessment (25)
2.2.1.7 Formulation Development Study #1 (27)
2.2.1.8 Formulation Development Study #2 (31)
2.2.2 Conclusions of Formulation Development (31)
2.3 Process Development (33)
2.3.1 Identification of Critical Process Parameters (35)
2.3.1.1 Pre-Granulation Blending (36)
2.3.1.2 Roller Compaction and Milling (42)
2.3.1.3 Granule Lubrication (51)
2.3.1.4 Tablet Compression (52)
2.3.2 Scale Up (58)
2.3.2.1 Scale Up of the Blending Process (58)
2.3.2.2 Scale Up of the Roller Compaction Process (59)
2.3.2.3 Scale Up of Lubrication Process (61)
2.3.2.4 Scale Up of Tableting Process (62)
2.3.2.5 Manufacture of Exhibit Batch (62)
2.3.3 Control Strategy (63)
2.3.3.1 Control Strategy for Blending (66)
2.3.3.2 Control Strategy for Roller Compaction and Milling (66)
2.3.3.3 Control Strategy for Lubrication (67)
2.3.3.4 Control Strategy for Tablet Compression (67)
2.3.3.5 Reduced Release Testing (67)
3.1 Development Conclusions (67)
1.1 Overview
This pharmaceutical development report summarizes the development of acetriptan tablets, 20 mg, a generic version of Brand (20 mg) tablet (listed as RLD). The product was developed as immediate release (IR) tablets manufactured using the roller compaction (RC) process. The drug product development is outlined below:
•Analysis of the reference listed drug (RLD) product
•Defining Quality Target Product Profile (QTPP)
•Identification of Critical Quality Attributes (CQAs) for the drug product (DP)
•Identification and prioritization of potential risks for each unit operation (Risk assessment)
•Screening and optimization of formulation (DOE for high risk components) including a development PK study
tablet驱动下载•Development of a robust process (DOE for high risk parameters)
o Blending
o Roller compaction
o Lubrication
o Compression
•Scale up and manufacture of the exhibit batch
•Establishment of control strategies
o Input material
o Unit operations
Blending
Roller compaction and milling
Lubrication
Tablet compression
o Finished product specifications
The timeline along with the scales for the development process of acetriptan tablets (20 mg) are listed in Table 1.
Table 1 Development presented in chronological order
Time Study Scale
Section Q1 200x Evaluation of RLD    1.2
Q1 200x Evaluate DS properties    2.1.1
Q1 200x Selection of formulation for pilot PK study    2.2.1
Q1 200x  In vitro dissolution method development using DS with
different particle size
2.2.1.1
Q2 200x PK Study 1001: Pilot formulation with variation of DS particle size Lab
(1.0 kg)
2.2.1.2
Q2 200x Dissolution study on drug product formulation used in PK study Lab
(1.0 kg)
2.2.1.2
Q1 200x Attempted direct compression of RLD formulation Lab
(1.0 kg)
2.1.1.3 Q1 200x DS/Excipient compatibility    2.2.1.4
Q2 200x Formulation Dev-1: Variation of Lactose/MCC/CCS and particle size Lab
(1.0 kg)
2.2.1.7
Q2 200x Formulation Dev-2:
Attempted removal of magnesium stearate Lab
(1.0 kg)
2.2.1.8
Q1 200x Selection of roller compaction    2.3
Q2 200x Development of laboratory scale roller compaction process Lab
(1.0 kg)
2.3
Q2 200x ProcDev-1: Critical process parameters for blending Pilot
(5.0 kg)
2.3.1.1.2
Q3 200x ProcDev-2: Critical process parameters for roller compaction Pilot
(5.0 kg)
2.3.1.2.2
Q3 200x Critical process parameters for lubrication Pilot
(5.0 kg)
2.3.1.3
Q3 200x ProcDev-3: Tablet compression parameters Pilot
(5.0 kg)
2.3.1.4.2
Q3 200x ProcDev-4: Effect of material variation on compression Pilot
(5.0 kg)
2.3.1.4.3
Q3 200x Scale up to exhibit batch size    2.3.2
Q3 200x BioStudy Exhibit
(50 kg)
1.2 Analysis of the Reference Listed Drug (RLD) Product
The RLD drug product is an IR tablet with no cosmetic coating and no scoring. The tablet needs to be swallowed “as is” without any intervention. Thus the proposed product will also be an IR tablet with no cosmetic coat and no scoring.
Characterization included determination of the RLD composition and characterization of the impurity level for ACE12345 (a known degradation product).

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