Transcript QbD在制剂开发中怎么体现？

开发报批美国FDA的仿制药
与相关问题探讨
上海复星普适医药科技有限公司
何平
内容提要
• 开发仿制药的重要性和机遇
• 开发仿制药的挑战
• 申报仿制药的分类
• 仿制药研发团队
• 仿制药的研发过程
• QbD在制剂开发中怎么体现
• 研发(高难)仿制药的一些体会：案例研究
开发仿制药的重要性
• 新药与仿制药-NDA and ANDA
• 开发仿制药与我国药物研发的海外战略
药物制剂
JAPEN 10% CHINA 4%
目标主流市场
US 40%
EUROPE 38%
开发仿制药的挑战性
开发仿制药更具挑战性
– 药物制剂
– 专利
– 仿制药的竞争
• 仿制药厂之间的竞争
• 由品牌药转成仿制药
仿制药竞争的方式
HOW TO COMPETE
• Cost-IR Product
– Raw Materials
– Process
– Finished Product
• Technology-Modified Release
Products
申报(仿制)新药的分类
规范市场(FDA)
中国市场（sFDA）
1。P-I
2。P-II
3。P-III
4。P-IV (1st to file)
1类
2类
3类
4类
5类
6类
仿制药研发团队
CONCEPT-1 BUILD UP A TEAM
INFORMATION
BIOPHARMACEUTICAL
PRODUCT
PROJECT
FORMULATION
REGULATORY
LEGEL
ANALYTICAL
缓控释给药的技术平台和给药系统
CONCEPT-2 BUILD UP A SYSTEM
• DRUG DELIVERY SYSTEMS FOR ORAL
SOLID FORMULATIONS-MR
– MATRIX SYSTEMS
– RESERVIOR SYSTEMS
– OSMOTICAL PUMP SYSTEMS
– COMBO-SYSTEMS
Product Development Roadmap
仿制药的研发过程
What is QbD (Quality by Design )?
QbD在制剂开发中怎么体现？
• Quality
– Acceptably low risk of failing to achieve the desired
clinical attributes
• Pharmaceutical Quality
= f {drug substance, excipients, manufacturing..}
• QbD
– ‘Product and process performance characteristics
scientifically designed to meet specific objectives, not
merely empirically derived from performance of test
batches’
What is QbD?
QbD在制剂开发中怎么体现？
• Pharmaceutical Quality by Design (QbD)
– QbD means designing and developing
formulations and manufacturing processes to
ensure predefined product quality
• Understanding and controlling formulation and
manufacturing process variables affecting the
quality of a drug product
What is QbD?
QbD在制剂开发中怎么体现？
Essential elements of QbD
􀂃 Definition of the quality target product profile
High level quality aspects of the product: purity, drug release
(dissolution/disintegration time), pharmacokinetic profile, etc.
􀂃 Critical quality attributes (CQAs) for drug product
• Characteristics of DP which have impact on desired profile
• Conscious attempt to study and control
􀂃 Critical Process Parameters (CPPs)
• Identification of material properties and process parameters which have
effect on product CQAs
􀂃 Design Space: The multidimensional combination and interaction of
input variables and process parameters that have been demonstrated to
provide assurance of quality
􀂃 Identification of a control strategy for critical process parameters
What is QbD?
QbD在制剂开发中怎么体现？
How Did We Work in the Past
Variable Inputs x
Raw Materials
Equipment
Environment
Operators
“Locked” Process =
Variable Quality
What is QbD?
QbD在制剂开发中怎么体现？
How Can We Work in the Future
Understood
Variable
Inputs
x
Understood and
Controlled
Process
Raw Materials
Equipment
Environment
Operators
Flexible Process
Design Space
=
Predefined Quality
What is QbD?
QbD在制剂开发中怎么体现？
Raw
Materials
Wet
Granulation
Fluid Bed
Drying
Blending
Compression
Product
What is QbD?
QbD在制剂开发中怎么体现？
Raw
Materials
Drug
Substance
Excipients
Wet
Granulation
Fluid Bed
Drying
Source
Assay
Impurities
……
LOD
PS … …
Blending
Compression
What is QbD?
QbD在制剂开发中怎么体现？
Raw
Materials
Wet
Granulation
Water
Binder
Temp
Spray Rate
Speed
Time
P.S
Fluid Bed
Drying
Blending
Compression
What is QbD?
QbD在制剂开发中怎么体现？
Raw
Materials
Wet
Granulation
Fluid Bed
Drying
Air Flow
Temp
RH
Shock Cycle
P.S.
Blending
Compression
What is QbD?
QbD在制剂开发中怎么体现？
Raw
Materials
Wet
Granulation
Fluid Bed
Drying
Blending
Fill Volume
Rotation Speed
End Point (Time)
Blend Uniformity
Densities
Angle of Repose
Compression
What is QbD?
QbD在制剂开发中怎么体现？
Raw
Materials
Wet
Granulation
Fluid Bed
Drying
Blending
Compression
Feed Frame
Tooling
Punch Penetration
Depth
Compression
Force
Press Speed
Feeder Speed
……
Quality Assessment under QbR
• Question-based Review (QbR) is a general
•
framework for a science and risk-based
assessment of product quality
QbR contains the important scientific and
regulatory review questions to
– Comprehensively assess critical formulation and
manufacturing process variables
– Set regulatory specifications relevant to quality
– Determine the level of risk associated with the
manufacture and design of the product
Examples of QbD questions under QbR
• Control of Drug Substance
– What is the drug substance specification?
Does it include all the critical
drug substance attributes that affect the manufacturing and quality of the
drug product? (2 pages)
• Drug Product
– What attributes should the drug product possess? (1.5 pages)
– How were the excipients and their grades selected?
– How was the final formulation optimized?
• Manufacturing Process
– How are the manufacturing steps (unit operations) related to the drug
product quality?
– How were the critical process parameters identified, monitored, and/or
controlled?
• Pharmaceutical Development
• Manufacture
• Container Closure System
QbD小结-SUMMARY
Aspects
Traditional
QbD
Empirical; univariate
experiments
Systematic; multivariate
experiments
Fixed; validation on 3 initial
full-scale batches;
focus on reproducibility
Adjustable within design space;
continuous verification;
focus on control strategy
In-process testing for
go/nogo; offline analysis
w/slow response
PAT utilized for feedback &
feed forward, real time
Product
specification
Primary means of quality
control; based on batch data
Part of the overall quality
control strategy; based on
desired product performance
Control
strategy
Lifecycle
management
Mainly by intermediate and
end product testing
Risk-based; controls shifted
upstream; real-time release
Reactive to problems &
OOS; post-approval
Continuous improvement
enabled within design space
Pharmaceutical
development
Manufacturing
process
Process control
研发(高难)仿制药的一些体会
案例研究-1
CASE STUDY 1-IR Tablets
• Very Low Water Solubility (低水溶性)
• Very Low Potency (低剂量)
• Micronized API used (微粉化原料药)
• Wet Granulation Process (湿法制粒)
Dissolution Profile-体外溶出曲线
Dissolution of Product G in pH 7.8 Buffer
120
100
% Released
80
60
40
Brand-pH7.8
20
Tested-pH7.8
0
0
10
20
30
Time (min)
40
50
60
生物等效(BE)结果
Summary of in vivo study results of Test Formulation vs. RLD
AUC0-t
AUC0-inf
Cmax
Fast
Ratio
90% Geometric
C.I.
108.01%
103.49% to
112.73%
108.12%
103.64% to
112.79%
86.26%
75.28% to
98.84%
Fed
Ratio
90% Geometric
C.I.
111.21%
104.40% to
118.47%
112.48%
105.78% to
119.60%
85.24%
73.47% to
98.90%
原因调查
Dissolution of Product G in Different Media
120
100
% Released
80
60
40
Brand-pH7.5
Tested-pH7.5
Brand-pH6.8
Tested-pH6.8
20
0
0
10
20
30
Time (min)
40
50
60
案例研究-2
CASE STUDY 2-ER CAPSULES
• No Patent (无专利)
• Coated Pellets (包衣微丸)
• 1st Bio Study Failed
– Fast: Close
– Fed(Compared with Fast):
• Brand: BA Reduced
• Tested: BA Increased
TEAM WORK
• More Information Collected
• Analytical Support
– Identify the Process Used
– Provide the Info for Functional Coating
• One more Pilot and One Full Bio---Passed
案例研究-3
CASE STUDY 3 - ER CAPSULES
• Brand Product
– Micro-Tablets in Capsules
– 95% of API existed in Finished Product
– System and Process Patented
UNIQUE SYSTEM-CREATIVE DESIGN
• Compressed Granules in Capsules
– Requirement
• Same Dissolution Behavior
• Uniform
• Yield Acceptable
SYSTEM COMPARISON
PILOT BIO-STUDY
PRODUCT P DATA (Log Transformed Data, Fast, n-12)
Ratio of
Geometric
Means x 100
90% CI of Log
Transformed
Data
CV (%)
Test A vs Reference
AUC
106
90.4; 123
22.0
Cmax
104
80.1; 134
36.4
Test B vs Reference
AUC
133
114; 155
22.0
Cmax
129
100; 167
36.4
PILOT BIO-STUDY
PRODUCT P DATA (Log Transformed Data, FED, n-11)
Ratio of
Geometric
Means x 100
90% CI of Log
Transformed
Data
CV (%)
Test A vs Reference
AUC
96.1
75.4; 123
32.7
Cmax
109
83.5; 141
35.3
Test B vs Reference
AUC
92.4
72.5; 118
32.7
Cmax
109
83.7; 141
35.3
PIVOTAL BIO-STUDY
PRODUCT P DATA (Log Transformed Data)
Ratio of
Geometric
Means x 100
90% CI of Log
Transformed
Data
CV (%)
AUC
102
93; 111
33,9
Cmax
105
94.5; 116
38.8
AUC
98.8
91.6; 107
26.4
Cmax
99.6
89.2; 111
38.4
FAST
FED
案例研究-4
CASE STUDY 4 - ER CAPSULES
Dissolution Profile for xxxx ER Formulation,
USP Apparatus II, Water, 50 RPM
100
80
Amount dissolved (%)
API is Water Soluble.
Prototype formulation
was proposed based on
in vitro dissolution (OGD
method).
60
40
Ref
20
T-1
T-2
0
0
4
8
12
Time (Hrs)
16
20
24
PILOT BIO-STUDY
PRODUCT DATA (Log Transformed Data)
AUC0-t
AUC0-inf
Cmax
T-1
Ratio
90% Geometric
C.I.
111.21%
104.40% to
118.47%
112.48%
105.78% to
119.60%
140%
133.7% to
147.0%
T-2
Ratio
90% Geometric
C.I.
117.5%
113.2% to
122.2%
117.2%
112.4% to
122.1%
135.9%
129.5% to
142.4%
Further Investigation
Simulated Dissolution for xxxx ER Formulation,
120
Amount dissolved (%)
100
80
60
40
Ref
20
T-2
0
0
4
8
12
Time (Hrs)
16
20
24
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