stability studies
in pharmaceutical
development
Kathy Waddle, MS
Wei Pan, Ph.D. RAC
Catalent Pharma Solutions
Agenda
Overview of stability studies during drug product Lifecycle
•
Stability considerations during early development
•
Review ICH and WHO stability guidelines
•
Stability requirements to support registration
•
Post approval stability
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1
Importance of Product Stability
Definition of Product Quality
•
Free of contamination and reproducibly delivers the
therapeutic benefit promised in the label to the consumer
Definition of Stability
•
Consistent product quality and therapeutic benefit over the
product shelf-life under various environment conditions
Consumer Expect Stability!
-
Gary Buehler, Director, OGD, FDA, AAPS SFG Stability Workshop, Sept 2007
Catalent Pharma Solutions
2
Stability Quality by Design
Pharmaceutical product stability is a function of:
Drug
Drug
Substance
Substance
Excipients
Excipients
Product
Understanding
Container
Container
Closure
Closure
Manufacturing
Manufacturing
Process
Process
Catalent Pharma Solutions
3
Stability Studies During Pharmaceutical Product
Lifecycle
File
IND
Drug
Drug
Discovery
Discovery
PrePreclinical
clinical
File
NDA
Phase
Phase II
Phase
Phase IIII
Stability studies to support
formulation development
and clinical studies
Phase
Phase III
III
Approval
Final
Final
Labeling
Labeling
Discussions
Discussions
Stability studies to
support marketing
application
Catalent Pharma Solutions
Phase
Phase IV
IV
PLCM
PLCM
Rx
Rx to
to OTC
OTC
Stability studies to
monitor product quality
and support post
approval changes
4
Stability Considerations During Early Development
•
Limited regulatory requirement
—
•
conduct stability studies to demonstrate clinical trial materials meet
specifications during the course of trial
Stability studies are done to gain understanding of the
compounds/formulation in development
—
Chemical and physical property of API
—
Excipient compatibility
—
Manufacturing process
—
Interaction with packaging materials
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5
Stability Considerations During Early Development
API
+
Manufacturing
Process
Packaging
Selection
DRUG PRODUCT
PACKAGED
PRODUCT
EXCIPIENTS
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6
API Mechanisms of Instability - Chemical
•
Identify functional groups and labile centers
—2º
and 3º Amines --> N-oxide, hydroxylamine by oxidation
—Aldehyde
--> Acid by oxidation
—Esters/Lactones
•
Consider external contributing factors
—pH,
•
-->Acid/Alcohol by hydrolysis
temperature, humidity, light
Perform forced degradation studies
—Acid/base
—Heat
—Oxidation
—Photolysis
Understand mechanisms of degradation of drug substance
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7
API Mechanisms of Instability - Physical
•
Polymorphs
—
Polymorphic transition
—
Hydrate/solvate formation
—
Dehydration/desolvation
—
Crystallization of amorphous materials
•
Particle size/surface area
•
Other quality attributes
—
Resuspendibility
—
Aggregation
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8
Excipient Compatibility
•
ICH Q8 guidance recommends evaluating drug-excipient
interactions as part of the design of a stable formulation.
•
For solutions and suspensions, the solution studies indicate
which buffer to use and the optimum pH.
•
For solids, the compatibility studies are more extensive with
the objective to establish which excipients can be used with
the intended drug.
- Binary excipients compatibility studies
- Trial formulations (DOE)
- Q8(R2): Pharmaceutical Development, Nov 2005
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9
Case Study 1
An compound with a carboxyl functional group is the candidate for a HFA MDI
formulation development. Due to poor aqueous solubility, ethanol was chosen
as co-solvent and the experimental formulation was put on accelerated
stability. A degradant peak was observed and it reached >3% at 3 month time
point.
The sample was send to the LC-MS lab for peak ID.
Question: What is the structure of the degradant?
Answer: it’s the ethyl ester of the API.
Hint: Know your chemistry.
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10
Case Study 2
Trace level of Aldehydes in common excipients
•
Cause of gelatin cross-linking
•
Reactive with primary and secondary amine
•
Present as trace level impurities or formed by excipient
degradation (e.g. PEG or Tween)
-Leonardo Allain and W. Peter Wuelfling, Merck Research Labs, AAPS Stability Workshop, 2009
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11
Case Study 2
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12
Case Study 2
•
Compendial: PVP and Ethylcellulose in USP
•
Wet chemistry techniques (one is enzymatic and the other is
colorimetric)
•
100 ppm limit test
•
100 ppm formaldehyde ~ 10% API (mol/mol) (assuming
0.5 g formulated drug with 2-5% drug load)
•
LOD of Merck GC derivatization method: 0.1 ppm
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13
Case Study 2
Excipients
Formaldehyde (ppm)
Avicel
1.1
HPMC
12.3
PEG 400
65.0
PEG 4000
0.5
Tween 80
1.5 -20
Triglycerides
0.2
Polyoxyl 35
1.4
Opadry white
4.7
Kollicoat
13.7
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14
Manufacturing Process
•
Choose manufacturing conditions to improve stability
- Exposure to solvents
•
Exposure to temperature
- Drying time and temperature
•
Stability of in-process materials
•
Drug Product may be tested to identify critical process
parameters
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15
Container Closure Systems
•
Linked to mechanisms of instability
—
Does it need to be protected from light or moisture?
•
Potential drug absorption or adsorption to container closure
•
Effect of container orientation
•
Potential for leachables
—
container, closure, glue and ink
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16
Case Study - Stability of Sterile Product M in Glass
and Plastic Packages
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17
Stability Studies During Pharmaceutical Product
Lifecycle
File
IND
Drug
Drug
Discovery
Discovery
PrePreclinical
clinical
File
NDA
Phase
Phase II
Phase
Phase IIII
Stability studies to support
formulation development
and clinical studies
Phase
Phase III
III
Approval
Final
Final
Labeling
Labeling
Discussions
Discussions
Stability studies to
support marketing
application
Catalent Pharma Solutions
Phase
Phase IV
IV
PLCM
PLCM
Rx
Rx to
to OTC
OTC
Stability studies to
monitor product quality
and support post
approval changes
18
Stability Studies for Registration
“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 environmental factors
such as temperature, humidity and light, and to establish a
retest period for the drug substance or a shelf-life for the
drug product and recommended storage conditions”
-ICH Q1A(R2): Stability testing of new drug substance and product (2003)
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19
Stability Guidelines
•
ICH (US, Japan, EU)
•
WHO
•
Regional
—
US: FDA (1998 draft and 1987 guidance withdrawn, June 1 2006)
—
EU: EMEA (European Medicines Agency), CPMP
—
Japan: MHLW (Ministry of Health, Labor and Welfare: Drug Approval
and Licensing Procedures in Japan, 2008)
—
ASEAN (Association of Southeast Asia Nations)
—
Brazil (Resolucao-Re No 1, July 29, 2005)
—
China (Chinese Pharmacopeia 2005)
—
SADC (Southern African Development Community), Medicines Control
Council: Stability January 2005
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20
FDA Stability Guidelines
FDA withdraws stability and CMC information related guidance
documents on June 1, 2006:
•
Not because following them will lead to problem with drug
registration
•
But because these documents are overly prescriptive, which is not
consistent with the FDA’s current thinking of providing broad
guidance
•
In the meantime…refer to the following ICH documents…as
alternative resources
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21
Stability Studies to Support Global Registration
“In order to be able to reduce the amount of stability testing
required, the number of different long-term testing conditions
must be reduced to a sufficient extent. This approach was
proposed by Paul Schumacher in 1972 (1) and by Wolfgang
Grimm in 1986 (2), and in 1998 (3) when they defined four
different long-term testing conditions, which match with the
climatic conditions of the target markets categorized in just
four different climatic zones.”
-WHO Technical Report Series, No. 953, 2009: Stability testing of active pharmaceutical ingredients and finished
pharmaceutical products
Catalent Pharma Solutions
22
ICH Guidelines
•
Founded 1990
•
ICH region – European Union, Japan and US
•
Regulators and pharmaceutical industry representatives
•
Stability was one of the first issues discussed and
harmonized
Step1
Step1
Step2
Step2
Consensus
building
by EWG
Consensus
Agreed
six parties
Step3
Step3
Regulatory
Consultation
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Step4
Step4
Adopt
Step5
Step5
Implement
23
ICH Stability Guidelines
ICH Stability Guideline Q1A(R2): Stability Testing of New
Drug Substances and Products (Second Revision) Reached
implementation step (step 5) in the ICH Tripartitate Region
EU : Adopted by CPMP, March 2003, issued as CPMP/ICH/2736/99
MHLW : Adopted June 3, 2003, PFSB/ELD Notification No. 0603001
FDA : Published in the Federal Register, Vol, 68, No. 225, Friday,
November 21, 2003; pages 65717-18
Also adopted by some non-ICH countries including Canada, Australia
Switzerland
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ICH Stability Guidelines
The Four Climate Zones:
Zone I
Temperate
21ºC±2ºC /45%RH ±5%RH
Zone II
Subtropical &
Mediterranean
25ºC±2ºC/60%RH ±5%RH
Zone III*
Hot & Dry
30ºC±2ºC/35%RH ±5%RH
Zone IV*
Hot & Humid
30ºC±2ºC/65%RH ±5%RH
*
Q1F: Stability Data Package for Registration Applications in Climatic Zones III
and IV was withdrawn June 2006 and decided to leave definition of storage
conditions in Climatic Zones III and IV to the respective regions and WHO.
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World View of Climatic Zone Determinations by Country
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ICH Stability Guidelines
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ICH Stability Guidelines
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WHO Stability Guideline
•
193 Member States
•
Split Climate Zone IV (hot and humid) to two zones
- Climate Zone IVA (hot & humid) 30ºC/65%RH
- Climate Zone IVB (hot & very Humid) 30ºC/75%RH
•
Evaluation of climate condition by each Member State results
in the recommendation of long term storage conditions
•
More severe conditions are acceptable
-WHO Technical Report Series, No. 953, 2009: Stability testing of active pharmaceutical ingredients and finished
pharmaceutical products
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29
WHO Stability Guidelines at a Glance
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WHO Stability Guideline
Additional Guidance Provided in WHO Document:
•
Testing parameter recommendations
•
Storage statement and labeling guidance
•
Covers new drug and marketed product
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WHO Stability Guideline
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Stability Studies During Pharmaceutical Product
Lifecycle
File
IND
Drug
Drug
Discovery
Discovery
PrePreclinical
clinical
File
NDA
Phase
Phase II
Phase
Phase IIII
Stability studies to support
formulation development
and clinical studies
Phase
Phase III
III
Approval
Final
Final
Labeling
Labeling
Discussions
Discussions
Stability studies to
support marketing
application
Catalent Pharma Solutions
Phase
Phase IV
IV
PLCM
PLCM
Rx
Rx to
to OTC
OTC
Stability studies to
monitor product quality
and support post
approval changes
33
Key Elements of a Stability Protocol
21CFR 211.166 (a)
There shall be a written testing program designed to assess the stability
characteristics of drug products. The results of such stability testing shall be used in
determining appropriate storage conditions and expiration dates. The written program
shall be followed and shall include:
•
Sample size and test intervals
•
Storage condition
•
Reliable, meaningful and specific test methods
•
Store the drug product in the proposed container for
marketing
•
Testing of drug product for reconstitution at time of dispensing
as well post reconstitution
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34
Key Elements of a Stability Protocol
•
Purpose (R&D, NDA, ANDA, Commercial, etc)
•
Regulatory compliance/intended Market (US, EU, Global, etc)
•
Name of the product and dosage strengths
•
Container closures (and orientations, if applicable)
•
Test methods and specification
•
Storage condition and test intervals
•
Sampling plan
•
Bracketing and/or matrixing rational (if utilized)
•
Data reporting and statistical analysis (proposed)
•
Signature and change control
•
Proposed expiration dating period
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Container Closure Systems
Solid Orals – US
•
HDPE bottles
•
PVC, PVC/PVDC, or ACLAR blisters
•
Bulk Storage/bulk sales
- Double PE bags
- PET/PE/Aluminum Foil/PE Barrier bags
Solid Orals – Europe
•
Primarily PVC, PVC/PVDC blisters
•
Often opaque rather than clear blisters
- color: white, blue or green
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Container Closure Systems
Climate Zone 4 –Solid Orals
•
Glass or HDPE Bottles
•
Blister
- Cold-formed aluminum foil-foil blister
- PVC, PVC/PVDC or ACLAR blister
- Only for moisture insensitive, stable dosage forms
Regional – Solid Oral
•
Simple blister with Al/PE film over wrap
•
Glass bottle
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Test Methods/Specifications
•
Q6 : Specifications for New Drug Substances and Products
- Q6A: Specifications: Chemical Substances,
Oct 1999
- Q6B: Specifications: Biotechnological/Biological
Products, March 1999
•
Q2(R1): Validation of Analytical Procedures: Text and
Methodology, Oct 1994
•
Q3A(R2): Impurities in New Drug Substances (Revised
Guideline) Oct 2006
•
Q3B(R2): Impurities in New Drug Products (Revised
Guideline) June 2006
•
Q1E : Evaluation of Stability Data, February 2003
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Example 1 – A Really Simple Stability Protocol
Tablets in 30-count HDPE bottle for US market
Condition
25ºC/60%RH
30ºC/65%RH
40ºC/75%RH
Initial
3M
6M
9M
12M
18M
24M
36M
Total
Stored
[2]
[2]
[2]
[2]
[2]
[2]
[2]
[2]
24
X
X
X
X
X
X
X
X
-
[2]
[2]
[2]
[2]
-
-
-
12
(X)
(X)
(X)
(X)
[2]
[2]
-
-
-
-
-
6
X
X
-
X = Appearance (n=1), Assay/RS (n=2),Dissolution (n=6), Water Content (n=2)
[ ] = number of bottles pulled
( ) = Optional testing only when significant changes occurs under accelerated conditions
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Definitions of Significant Change
1. A 5% change in assay from its initial value; or failure to meet the
acceptance criteria for potency when using biological or
immunological procedures.
2. Any degradation product’s exceeding its acceptance criterion.
3. Failure to meet the acceptance criteria for appearance, physical
attributes, and functionality test.
4. Failure to meet the acceptance criterion for pH; or
5. Failure to meet the acceptance criteria for dissolution for 12 dosage
units.
-ICH Q1A(R2)
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Example 2 – a Simple Stability Protocol
Tablets in 30-count HDPE Bottle for Global Registration
Condition
25ºC/60%RH
30ºC/65%RH
40ºC/75%RH
Initial
3M
6M
9M
12M
18M
24M
36M
Total Stored
[2]
[2]
[2]
[2]
[2]
[2]
[2]
[2]
24
X
X
X
X
X
X
X
X
-
[2]
[2]
[2]
[2]
[2]
[2]
[2]
X
X
X
X
X
X
X
[2]
[2]
-
-
-
-
-
X
X
-
22
6
X = Appearance (n=1), Assay/RS (n=2),Dissolution (n=6), Water Content (n=2)
[ ] = number of bottles pulled
Note: There is no intermediate condition for Zone III/IV
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Example 3 - a Complicated Stability Protocol
Sterile product in glass vials for US market (store inverted)
Condition
25ºC/60%RH
30ºC/65%RH
40ºC/75%RH
Initial
3M
6M
9M
12M
18M
24M
36M
Total
Stored
[4]
[4]
[4]
[4]
[50]
[4]
[50]
[50]
200
X
X
X
X
XPSL
X
XPSL
XPSL
-
[4]
[4]
[4]
[50]
-
-
-
90
(X)
(X)
(X)
(XPSL)
[4]
[14]
-
-
-
-
-
36
X
XPL
-
X = Appearance including color and clarity, Assay/RS, Preservative content, pH
P = Particulate matter by HIAC
S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure integrity
L = Leachables
[ ] = number of bottles pulled
( ) = Optional testing only when significant changes are observed under accelerated conditions
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Example 4–an Even More Complicated Stability
Protocol
Sterile Product in a Semi - permeable Containers for Us Market
Condition
25ºC/40%RH
30ºC/65%RH
40ºC/20%RH
Initial
3M
6M
9M
12M
18M
24M
36M
Total Stored
[4]
[4]
[4]
[4]
[50]
[4]
[50]
[50]
200
X
X
X
X
XPSL
X
XPSL
XPSL
-
[4]
[4]
[4]
[50]
-
-
-
90
(X)
(X)
(X)
(XPSL)
[4]
[14]
-
-
-
-
-
40
X
XPL
-
X = Appearance including color and clarity, Assay/RS, Preservative content, pH
P = Particulate matter HIAC
S = Sterility, Bacterial Endotoxin, Antimicrobial effectiveness, Container Closure Integrity
L = Leachable,
[ ] = number of bottles pulled
( ) = Optional testing only when significant changes are observed under accelerated conditions
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Example 4–an Even More Complicated Stability
Protocol
Sterile Product in Semi -permeable Containers for US Market
Condition
Initial
3M
6M
9M
12M
18M
24M
36M
Total
Stored
25ºC/40%RH
[10]
W
[10]
W
[10]
W
[10]
W
[10]
W
[10]
W
[10]
W
[10]
W
10
30ºC/65%RH
-
[10]
(W)
[10]
(W)
[10]
(W)
[10]
(W)
-
-
-
10
40ºC/20%RH
-
[10]
W
[10]
W
-
-
-
-
-
10
W = Weight Loss (n=10)
Note1 : The same 10 units are used for weight loss test as in-and-out of the chamber stability
samples. The stability coordinator and lab analyst need to coordinate testing to minimize the
time the samples are out of the chamber.
Note 2: A 5% loss in water from its initial value is considered a significant change for a
product packaged in a semi-permeable container after an equivalent of 3 months’ storage at
40°C/NMT 25% RH.
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Batch Selections
Stability studies should be performed on each individual strength
and container size of the drug product unless bracketing or
matrixing is applied.
•
At least three primary batches
•
•
•
•
•
•
•
Final formulation
Manufacturing process simulating production batch
Product with same quality and meeting same specification
In container closure system as proposed for marketing
At least two of the three are pilot scale*
The third batch can be smaller, if justified
Using different batches of API (if possible)
* For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale
or 100,000 tablets or capsules, whichever is the larger.
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Stability Data at Submission
For NDAs:
•
Three primary batches
•
12 months long term
•
6 months accelerated
•
6 months intermediate if significant changes @ accelerated
•
May statistically project expiry up to 6 months past real time data
For ANDAs
•
One batch
•
3 months accelerated
•
3 months satisfactory accelerated data may permit 24 month expiry
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Other Stability Studies
•
•
•
In-use stability
—
Minimum of two batches
—
At beginning and toward end of shelf-life
Photostability
—
One batch
—
In the proposed container and closure systems
—
ICH Q1B option 1 or option 2
Thermocycling or excursion study
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Stability Data at Submission
Based on the data and product understanding, a sponsor should
provide:
•
Proposed expiration dating period and justification
•
Proposed label storage condition and justification
•
Proposed in-use label storage condition and in-use time
period and justification, if applicable
Product
Product
Understanding
Understanding
Stability
Stability
Data
Data
Product
Product shelf-life
shelf-life
and
and
Storage
Storage Conditions
Conditions
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Stability Commitment
When available long term stability data on primary batches
do not cover the proposed shelf life granted at the time of
approval, a commitment should be made to continue the
stability studies post approval in order to firmly establish the
shelf life.
•
Submission data from 3 production batches, continue long term
study through proposed shelf-life.
• Submission data from <3 production batches, set more
production batches on to make up the required three with same
protocol.
• Submission data not from production batches, first 3 production
batches to set on stability through proposed shelf-life long term and
6 months accelerated.
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Stability Studies During Pharmaceutical Product
Lifecycle
File
IND
Drug
Drug
Discovery
Discovery
PrePreclinical
clinical
File
NDA
Phase
Phase II
Phase
Phase IIII
Stability studies to support
formulation development
and clinical studies
Phase
Phase III
III
Approval
Final
Final
Labeling
Labeling
Discussions
Discussions
Stability studies to
support marketing
application
Catalent Pharma Solutions
Phase
Phase IV
IV
PLCM
PLCM
Rx
Rx to
to OTC
OTC
Stability studies to
monitor product quality
and support post
approval changes
50
Stability Studies Post Approval
After approval, routine stability study is conducted to monitor product
quality
•
Only long term condition is required
•
Can drop testing point from standard ICH (through PAS)
•
Can be used to extend expiry (through annual report)
•
May want to add a expiry test point
•
Stability failure can result in field alert* and/or product recalls
21CFR 314.81 Sponsors are required to report to FDA district office within 3 working days of a problem being
identified.
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Stability Studies for Post-Approval Changes
•
change in the manufacturing process;
•
change in the composition of the formulation;
•
change of the immediate packaging;
•
change in the manufacturing process of an API.
Additional stability testing (3 or 6 months long term and
accelerated) are often required to support the changes.
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Stability Studies for Post-Approval Changes
US
EU
Major Changes
Type II
Substantial
Substantial potential
potential to
to
have
have an
an adverse
adverse effect
effect
Moderate Changes
Type IB
Moderate
Moderate potential
potential to
to have
have
an
an adverse
adverse effect
effect
Minor Changes
Type IA
Minimal
Minimal potential
potential to
to have
have an
an
adverse
adverse effect
effect
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Stability Studies for Post-Approval Changes
1.
FDA/CDER (November 1995) Guidance for industry Scale up and post-approval
changes: immediate release solid oral dosage forms.
2.
FDA/CDER (September 1997) Guidance for industry Scale up and post-approval
changes: modified release solid oral dosage forms.
3.
FDA/CDER (May 1997) Guidance for industry Scale up and post-approval changes:
non-sterile semisolid dosage forms.
4.
FDA/CDER (January 1999) Guidance for industry Scale up and post-approval
changes: immediate release and modified release solid oral dosage forms
manufacturing equipment.
5.
FDA/CDER (April 2004) Guidance for industry Changes to an approved NDA and
ANDAs.
6.
CHMP/CVMP (December 2005) Guideline on stability testing for applications for
variations to a marketing authorization CPMP/QWP/576/96 Rev 1
EMEA/CVMP/373/04
7.
EMEA (2006) Guideline on dossier requirement for Type IA and IB notification
8.
WHO (February 2007) Annex 6 variation guidance: guidance on variation to a
prequalified product Dossier
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54
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