2013-09-18 USP Stability 1 Regulations
2013-09-18 USP Stability 1 Regulations
2013-09-18 USP Stability 1 Regulations
Ph ti l P d t Pharmaceuticals Products
September 2013 p
Presented for US Pharmacopeia
Copyright 2013 The United States Pharmacopeial Convention (USP)
12601 Twinbrook Parkway, Rockville, MD 20852
All rights reserved.
Critical Stability Systems
Regulations Procedures Regulations
(I)
Procedures
(II)
Stability Systems
Operations
(III)
Investigations
(IV)
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Agenda Day One
I. Understanding cGMPs of Stability Testing
Requirements
C iti l l f D St bilit Critical role of Drug Stability
Impact of Chinese GMPs on Stability
Impact of 21 CRF 211 on Stability Impact of 21 CRF 211 on Stability
ICH process and Q1AR2
Stability protocol for global submission
II. Developing Stability Indicating Test Methods
ICH Q2 A/B on Validation ICH Q2 A/B on Validation
USP <1225> Validation
Method verification based on USP<1226>
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Stability-indicating test methods
4
Agenda Day Two
III. Critical Stability Operations
Critical steps of Stability Process
Reduce testing with bracketing and matrixing
Benefits and drawbacks of bracketing and matrixing
St bilit D t E l ti Stability Data Evaluation
IV Conduct Out-of-Spec investigation for Stability IV. Conduct Out-of-Spec investigation for Stability
Results
FDA draft guidance on OOS and FDA Guides to
inspection
Analysts and supervisors roles in OOS investigation
O t f T d f St bilit D t
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Out-of-Trend for Stability Data
Determine Corrective Actions/Preventive Actions
5
I Understanding cGMPs of I. Understanding cGMPs of
Stability Testing Requirements
Critical Stability Systems
Regulations Procedures Regulations
(I)
Procedures
(II)
Stability Systems
Operations
(III)
Investigations
(IV)
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Types of Medications
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Product Development
cGMPs
Regional
GMPs
Product
manufactured
in 1 Country
Brazil
ICH
WHO
ASEAN
Latin
America
Product
marketed
in 150+
Brazil
INDIA
WHO
ASEAN
in 150+
Countries
Regulations
Interpretations
Cultural differences
9
Recent inspection data (2012)
Inadequate Lab Controls
Others
21%
Inadequate Lab Controls
15%
Lack of/Inadequate SOPs
Inadequate Process
Validation
4%
Lack of/Inadequate SOPs
10%
Stability Program
4%
QA Systems
9%
Process Validation
4%
Raw Materials
4%
Deficiencies in
Records/Reports
7%
Metrology Program
7%
Production/Process
Controls
System Qualification
5%
Test Methods
4%
4%
10
7%
6%
Price of Medicines
On average 5 out of 5000 new drug candidates are
tested in human and only one (1) is approved.
Average cost of bringing one medicine on the market is
800M to 1.2 Billions
It t k 10 12 t di d d l It takes 10-12 years to discover and develop a new
medicine
Cost of research increase significantly Cost of research increase significantly
Cost of law suits and litigations
Cost of marketing and advertising
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Stability Goals
ACTIVE PHARMACEUTICAL INGREDIENT (API)
To establish a retest date for API
Data to support submission of drug product Data to support submission of drug product
DRUG PRODUCT
To establish a shelf life for the commercial product
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Drug Product Stability
Stability characteristics of API or Drug Product is a
critical quality attribute of pharmaceutical product
St bilit St di d t t th d l t f Stability Studies are used to support the development of
necessary medical supplies
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Critical Role of Drug Stability
Safety and efficacy of drug product are established
during development via clinical studies
Q lit i t bli h d f id tif t th lit d Quality is established for identify, strength, quality and
purity (CFR 211.137)
If drug product stability changes beyond established If drug product stability changes beyond established
acceptance criteria, established safety and efficacy are
no longer applicable.
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Drug Product Stability
Stability Data are used to:
Establish how product changes over time under
iti l i t l f t (t t h idit critical environmental factors (temperature, humidity
and light)
Determine appropriate product specifications Determine appropriate product specifications
Select marketing container closure system
Determine appropriate storage conditions pp p g
Justification of expiry of commercial product
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Change of Drug Stability
Change of Drug Stability would risk patient safety
Quality of finished products decrease
Potential sub-potent or over-dose products
Potential toxic unknown impurities
U t ll d d t i ti ti d t Uncontrolled process product investigation product
recalls
cGMP violations consent decree criminal cGMP violations consent decree criminal
prosecution
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Factors affecting Drug Stability
API related:
Stability of the API from storage
Interaction between the API and excipient FD
Effect of storage (temperature, humidity and light)
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Factors affecting Drug Stability
Process related:
Selection of different dosage form
Manufacturing process of drug product (DP)
Selection of marketing image
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Factors affecting Drug Stability
Packaging related:
Selection of container closure packaging system
Handling of DP
Distribution of DP
M k ti i Marketing regions
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DRUG DEVELOPMENT PROCESS
Excipients
DRUG
Drug Product Stability
Excipient compatibility
Formulation interaction
DRUG
PRODUCT
API
FORMULATION
DEVELOPMENT
PACKAGING
SELECTION
DEVELOPMENT
FINAL
PACKAGED
API Stability
Process impurity
PRODUCT
Packaging interaction
Storage conditions
Storage configuration
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Purpose of Stability Testing
The purpose of stability testing is to provide evidence
on how the quality of a drug substance or drug product
varies with time under the influence of a variety of varies with time under the influence of a variety of
environmental factors such as temperature, humidity
and light.
Stability testing permits the establishment of
recommended storage conditions retest periods and recommended storage conditions, retest periods, and
shelf-lives.
ICH harmonized Tripartite Guideline for Stability Testing of New Drug Substances
and Products [ICH Q1AR2]
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GMP 21 CFR 211 GMP - 21 CFR 211
PART 211--cGMP Practices for Finished Pharmaceuticals
Sec. 211.1 SCOPE (a) The regulations in this part
contain the minimum current GMP practice for
preparation of drug products for administration to p p g p
humans or animals.
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PART 211--cGMP Practices for Finished Pharmaceuticals
Sec. 211.137 EXPIRATION DATING
(a) To assure that a drug product meets applicable
standards of identity strength quality and purity at the standards of identity, strength, quality, and purity at the
time of use, it shall bear an expiration date determined
by appropriate stability testing described in Sec.
211.166. 211.166.
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21 CFR 211.166 - Stability Testing
Stability program must be written and followed:
(a) used in determining appropriate storage
conditions and expiration date.
Written program must include: Sample size and test
intervals Storage conditions for samples intervals, Storage conditions for samples,
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21 CFR 211.166 - Stability Testing
Stability program must be written and followed (contd):
Reliable, meaningful, and specific test methods,
Testing of drug product in marketed container,
Testing of drug product for reconstitution at
dispensing time and reconstituted time dispensing time and reconstituted time.
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211.166 Stability Testing
(b) An adequate number of batches must be tested
to determine an appropriate expiration date. A
d f h d t t b i t i d record of such data must be maintained.
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211.166 Stability Testing
Accelerated studies, combined with basic stability
information on the components, drug products, and
container closure system may be used to support container-closure system, may be used to support
tentative expiration dates.
Full shelf-life studies if not available are being Full shelf life studies, if not available, are being
conducted.
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USP General Information Chapters
Three critical components of Documentary Standards
1. Monographs
2. General Chapters
3. General Notices
USP General Information Chapters
C i f h 1000 d d Consist of chapter <1000> and upwards
Chapters provide information they contain no
standards tests assays nor other mandatory standards, tests, assays, nor other mandatory
specifications, with respect to any Pharmacopeial
articles
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<1150> Pharmaceutical Stability - Obsolete
Apply to drug dosage form
Chemical, physical & micro integrity of the unit
Shelf life = initial preparation to expiration
Specifications (identity, strength, quality and purity) p ( y, g , q y p y)
throughout shelf life
Influenced by environmental conditions (temperature,
light, air, and humidity)
REMOVED from USP34.
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Controlled Room Temperature
Labeled controlled room temperature or upto 25
o