Use the Accelerated Stability Assessment (ASAP) to ... Stability... · Dowicil 200 Cosmocil Proclin...
Transcript of Use the Accelerated Stability Assessment (ASAP) to ... Stability... · Dowicil 200 Cosmocil Proclin...
Accelerated Stability Assessment:
Stability Studies of in vitro Diagnostic
(IVD) Products
Xiaodong (Jerry) Zhao
Beckman Coulter
Carlsbad, California
Content of this workshop
The importance of the evaluation of product stability
The objectives of product stability studies
The types of common stability studies
The designs of product stability tests
Kinetics parameters in stability tests
Accelerated product stability studies
Principle of accelerated stability studies
Applications of accelerated stability studies
Arrhenius equation: temperature and reaction rate
The empirical Q10 rule
Case studies
Medical products oversight by FDA
IND
NDAIND
BLA
510k
PMA
IDE
FDA
NCTRNational Center for
Toxicological Research
CVMCenter for Veterinary
Medicine
CDERCenter for Drugs
and Evaluation Research
CBERCenter for Biologics and
Evaluation Research
CDRHCenter for Devices and
Radiological Health
CFSANCenter for Food Safety
And Applied Nutrition
Devices
IVD
Drugs Biologics
Food
Drugs
Medical devices*
Biologics
Animal feed and drugs
Cosmetics
Radiation-emitting products*
Combination products
Drug-Device*, Biologic-Device*, Drug-Biologic
Office of Regulatory Affairs (ORA) is the office for all field activities
*
FDA recalls due to noncompliant stability issues
Stability data does not support expiration claims
The incorrect testing method was used
The incorrect expiration date was on the label
Stability data did not support expiration dating
Consequences of non-compliance
Issuance of warning letter
Endure a consent decree
Loss of certification to market the product
Stability characteristics: critical quality
attributes (CQA) of pharmaceutical/diagnostic
products
Assurance of the safety, efficacy and performance of a product during its shelf life
Legal requirement by regulatory agencies (ICH, FDA, WHO) and meeting
cGMP/QSR requirement
Safeguard the reputation of the manufacturer by providing the data to support the
claims of the marketed product
Objectives of stability studies
Establishing storage conditions that define how a product changes over time
under critical environmental factors
Revelation of the chemical nature of the decomposition and the mechanism of
the chemical transformation
Determining product specifications
Selecting container closure system for the product package
Justifying expiry dating of on market product
If the product stability changes beyond the claimed acceptance criteria,
established safety and efficacy claims are no longer applicable
Types of stability studies of IVD products
Shelf-life stability studies
Transport simulation studies
Winter stress cycle
Summer stress cycle
Shock, vibration, drop test
Temperature excursion stability studies (storage)
Freeze-thaw cycle
Extreme high temperature
Anti-microbial stability test
preservative efficacy and microbial count and challenges
Functional performance test
Closed- and open-container (in-use) stability
Claimed shelf-life
At least three lots manufactured under routine production conditions
The study report includes the protocol, lot numbers, acceptance criteria and testing intervals
The accelerated studies are accompanied by real time studies
The conclusion of the study validates the claimed shelf life
In-Use stability
Three lots tested under actual routine use of device (real or simulated). This may include assessing open vial stability, automated instruments, and on board stability.
The study report includes the protocol, lot numbers, acceptance criteria and testing intervals
The conclusion of the study validates the claimed in use stability
Design of stability studies
Full testing design:
Three batches of each strength, each package configuration for all time points
Test all specification parameters
Bracketing design:
Test at the extreme border conditions to support the configurations in between to
reduce the number of stability tests
Matrixing design:
Cover three batches of all conditions
But test a subset of a total number of possible samples for all combinations to
decrease the number of time points of tests
The types of stability parameters to be
considered during shelf-life
Chemical degradation
Each active ingredient stays within the specified limit (>90%)
Physical
Appearance: precipitation, content uniformity, clarity, moisture contents, particle size, package integrity, etc.
Microbiological
Sterility, resistance to microbial growth
Toxicological
No increase of toxicity
Performance
Unchanged therapeutic and diagnostic activity
The chemical stability of the products:
The factors effecting chemical stability: temperature, moisture, light, oxygen, pH
and package configuration
The chemical transformations during storage: oxidation, hydrolysis, isomerization
5-Chloro-2-methyl-4-
isothiazolin-3-one (CMIT)
2-Methyl-4-isothiazolin
-3-one (MIT)
Proclin 300Dowicil 200 Cosmocil
Polyhexamethylene biguanide (PHMB)1-(3-Chloroallyl)-3,5,7-triaza-
1-azoniaadamantane chloride
S-(+)-Ibuprofen
(S)-(+)-2-(4-Isobutylphenyl)propionic acid
Kinetics of chemical decomposition
The study of the rate of change and the way in which the rate is influenced by the
concentration of reactants, and other factors such as solvents, catalyst, pressure
and temperature
It can be measured by determining the change in the concentration of reactants
or products as a function of time
It allows a prediction of the degree of change at a given time
It gives insight into the mechanism of the reaction
The common degradation reaction in stability studies follows zero- or first-order
kinetics
Zero-order reaction
When the rate of reaction is independent of concentration of reactants. The
reaction follows zero-order kinetics
The rate of the zero-order kinetics is described as
[A]0
Time (t)
[A]
[A]=[A]0-kt
-k = slope90%
50%
A[A] B[B]k
Rate = -d[A]/dt = k [A] 0 = k
-d[A] = k dt
-d[A] = k dt
[A]0-[A]t = kt
t = ([A]0-[A]t)/k
[A]0 = initial concentration
[A]t = concentration at time t
t
0
Calculation of half-life and shelf-life of zero-
order reaction
[A]0
Time
[A]
[A]=[A]0-kt
-k = slope90%
50%
Determination of t1/2: [A]t = [A] 0/2
Substitute in the equation: t = ([A]0-[A]t)/k
t1/2 = ([A]0-[A]t)/k = ([A]0-0.5[A]0) /k = 0.5[A]0/k
Determination of shelf life t90% : [A]t = 0.9[A]0
t90% = ([A]0-[A]t)/k = ([A]0-0.9[A]0) /k = 0.1[A]0/k
k = concentration/time
= (mole/liter) day-1
First-order reaction
When the reaction rate is directly proportional to the first power of the
concentration of a single reactant, the reaction follows first-order kinetics
The rate of the first order reaction is described as
A[A] B[B]k
Rate = -d[A]/dt = k [A]
-d[A]/[A] = k dt
-d[A]/[A] = k t
ln[A]0 - ln[A]t = kt
t = ln([A]0/[A]t)/k
[A]0 = initial concentration
[A]t = concentration at time t
t
0
tln[A]0
Time
ln[A]
ln[A] = ln[A]0-kt
-k = slope
90%
50%
[A]0
[A]
90%
50%
Time
1) Determination of t1/2: [A]t = 0.5[A]0
Substitute in the equation: t = ln([A]0/[A]t)/k
t1/2 = ln([A]0/0.5[A]0)/k = ln2/k = 0.693/k
2) Determination of shelf life t90% : [A]t = 0.9[A]0
t90% = ln([A]0-0.9[A]0) /k = ln1.11/k = 0.105/k
k = time-1 = day-1
[A]0
t
[A]
90%
50%
ln[A]0
time
ln[A]
ln[A] = ln[A]0-kt
-k = slope
90%
50%
Calculation of half-life and shelf-life of first-
order reaction
Real time stability study vs accelerated
stability assessment program (ASAP)
Real time stability conducted at the claimed storage condition:
Store under selected conditions for longer than the expected shelf life (days, weeks, months)
Direct measurement of the real course of the change of the products
Check at regular intervals to see the trend
Benefit: direct conclusion, no calculation
Accelerated stability assessment program (ASAP):
Store the product at the elevated storage temperature, or other stressful environment
The rate of decomposition is increased and the trial period is shortened
Benefit:
Approximate ¼ of expected shelf life
See the impact of any changes much sooner
Application of real-time stability monitoring
A regulatory requirement as part of product license/clearance
As part of a manufacturer’s routine product quality assurance practice
To verify claims following changes to product formulation or manufacturing
As part of a corrective and preventive action (CAPA) plan for the product
(effectivity check)
Application of accelerated stability testing
Assessing the impact of multiple changes to a product formulation; Comparing the
relative effectiveness of different product formulations or container closure systems
This provides an early indication of the product shelf life and shortening of the
development schedule.
Testing at relatively high temperatures and/or humidity in early stages to determine
the type of degradation products which may be found after long-term storage
Establishing knowledge of stability failure modes for design risk analysis
Providing initial estimates of product stability through use of the Arrhenius equation
or other suitable data analysis that is predictive for the product under study.
The results obtained from accelerated testing can be used only as supportive stability
data.
Arrhenius equation: the relationship between the
rate constant and the temperature
lnk1
k2 =T1
1
T2
1
R
Ea
ln k = ln A -Ea
RTk =
-Ea
A·e RT
Arrhenius equation
These equations describe the relationships between the storage temperatures
and the degradation rates.
When the activation energy is known, the degradation rate at low temperature
may be projected from those observed at “stress” temperature.
Accelerated stability testing
A product is stressed at several higher temperatures. The information of the
product decomposition is projected to predict shelf life at the recommended
storage temperature.
For statistical reasons, the treatment in accelerated stability projections is
recommended to be conducted at four different stress temperatures.
The duration of the studies should be adequate to observe significant product
degradation, typically, two to six weeks, depending on the temperatures
selected.
Estimation of shelf-life and expiration date
Stability data collection: six time points in the study.
Data analysis: regression line based on calculation of 95% one-side confidence limit.
Expiry date: Border concentration is considered as the lowest specification limit and the point where the extension line cuts the 95% confidence limit is taken as an expiry date. Beyond this point, the product may no longer retain fitness for use.
Shelf life is the time during which the product will retain fitness for use (>90% of label claim of potency) if stored appropriately as per the manufacturer’s instruction.
Upper 95% CI Line
Lower 95% CI Line
Shelf life: 65 days
Day
Acceptance criteria:>5 mg/dl
An
alyt
e(m
g/d
l)
Iris iChemVELOCITY
Automated urinalysis chemistry solution
iRICELL®—Comprehensive urine testing
solutions
Iris iQ 200
Particle counts in urine by iQ 200
Strip chemistry in urine by iChemVELOCITY
Acceptance criteria of urine chemistry controls:
example of IRISpecCA control
Data analysis of the analytes in the IRISpecCA
control
The Rule of Q10: a useful tool for ASAP
A practical method: Q10 rule
The degradation reaction has to follow zero- or first-order kinetics
The principle of the Q10 rule is based upon the Arrhenius equation
The same model is used to fit each temperature
The duration should be adequate to observe significant product degradation,
typically, two to six weeks, depending on the temperatures selected
The Q10 Rule
Q10 is a number without a unit
Q10 is the factor by which the rate increases when the temperature is raised by
10 degrees
Conventional assumption for typical chemical reaction: Q10 values are ~2
Q10 =k2
k1
10T2-T1
A case study: activation energy of the
chemical transformation with a specified Q10
Ea = =
×T1T2
T2-T1
=k1
k2R×T1×T2×ln
T2-T1
R×lnk1
k2R×ln
1 1T1 T2
k1
k2
=8.314J/molK×298K×308K×ln2
10K= 52.9 kJ/mol
Q10 1.7 2 3
Ea (kJ/mol) 40.7 52.9 84.2
The Q10 Rule: a shortcut method for predicting
shelf-life of the products
Q10 Rule: a common practice of manufacturers for complex processes. But this
is not the official practice of ICH or FDA.
The Q10 rule states that a product degradation rate decreases by a constant
factor Q10 when the storage temperature decreases by 10C. The value of Q10
is typically set at 2 or 3 because these correspond to reasonable activation
energies. This model falsely assumes that the value of Q does not vary with
temperature.
The activation energy assumes the range between 10 and 20 kcal (41.8 kJ to
83.6 kJ) for a chemical decomposition. The use of 10 to 20 kcal is reasonable
because broad experience indicates that most analytes and reagents of interest
in pharmaceutical and clinical laboratories have activation energies in this
range.
A case study: estimation of the shelf-life of iQ
Calibrator with ASAP
T1 T2 T3
Temperature (C) 5 15 25
k (h-1) 1.6x 10-5 3.6x10-5 7.9x10-5
Component Test Specifications
Control KitControl run on
iQ200Pass
iQ Calibrator Coulter Count1200 ± 100
cells/μL
How Q10 value is used in an example
Q10 value is calculated as 2.2 not 2
We had a study run at 25C. We found
the product that tested at 25C expired
after 7 weeks. Based on Q10 = 2.2, we
would project the shelf life at refrigerated
conditions (5C) of 7x2.2x2.2 = 34 weeks
(8.5 month).
Shelf Life of iQ Calibrator
Time Point and Run Date
QC Release
24-Jul-15
Month 2
23-Sept-15
Month 4
17-Nov-15
Month 6
13-Jan-16
Month 8
15-Mar-16
Month 9
08-Apr-16
Days from Manufacture: 11 72 127 184 246 270
Daily Control Run
(Must Pass)Pass Pass Pass Pass Pass Pass
iQ Calibrator Coulter Count
(1200 ± 100 cells/μL)1196 1153 1142 1160 1108 1104
Q10 =k2
k1
10T2-T1
=0.0000360.000016
1015-5
= 2.25
Q10 =k3
k2
10T3-T2
=0.000079
0.000036
1025-15
= 2.19
A case study: Bilirubin failure happens prior to
the end of expiry of CA control
Bilirubin is the leading cause of the stability issues of CA control
Bilirubin is an analyte in urine from the
catabolism of red blood cells
Heme Biliverdin Bilirubin
Biliverdin
ReductaseHeme
Oxygenase
[O]
Bilirubin is sensitive to oxygen and light
Bilirubin is sensitive to oxidation during the reagent manufacturing and storage.
Bilirubin can be oxidized in the presence of dissolved oxygen (DO)
Design change in the filling process
Oxygen removal
Sparging Argon into the bottle while filling the reagent
Filling more reagent to limit the head-space in the bottle
106mL/123mL 120mL/123mL 123mL/123mL
Parameters used for evaluation of the stability
Bilirubin
Reflectance on the device
UV-Vis Absorption on the spectrophotometer
Dissolved Oxygen (DO)
DO probe
Bilirubin
Biliverdin
HPLC trace
The reported value of Bilirubin is correlated
with both analyte and degradation product
y = -48.499x + 62.174R² = 0.951
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
50.00
0.0000 0.1000 0.2000 0.3000 0.4000 0.5000 0.6000 0.7000 0.8000
Refl
ecta
nce f
rom
iQ
Velo
cit
y
Bilirubin (459 nm)
#7 DN LFR 45CMean BIL %R vs. Bilirubin A 459 nm
y = 114.89x + 13.273R² = 0.9626
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
50.00
0.0000 0.0500 0.1000 0.1500 0.2000 0.2500 0.3000
Refl
ecta
nce f
rom
iQ
Velo
cit
y
Biliverdin (365 nm)
#7 DN LFR 45CMean BIL %R vs. Biliverdin A 365 nm
Dissolved oxygen (DO) vs Bilirubin content
Dissolved oxygen (DO) is largely consumed by the components in the closed
container after 14 days. Bilirubin content is stabilized after the dissolved oxygen
is removed after 14 days at 45 C.
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Day 0 Day 7 Day 14 Day 21 Day 30
Abso
rbance (
459 n
m)
Mean DO BIL 459nm
1.00
0.80
0.40
0.00
0.20
DO
(m
g/L)
0.60
Prediction of the shelf life with ASAP data
according to the Q10 Rule
Shelf Life Current Unsparged Overfilled
ASAP at 45C
(Days)14 days 7 days 21 days
Projected for 5C
(Months)
224 days = 7.4 mo
(RTS 7)
112 days = 3.7 mo
(RTS 4)>336 days = 11 mo
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
Day 0 Day 7 Day 14 Day 21 Day 30 Day 60 Day 90 Day 120
Test Case #6 Unsparged 45C
Mean 4.0 mg/dL 2.0 mg/dL
] Acceptance criteria
Reflecta
nce
of B
IL(%
)
Q10 = 2
Q40 = 24=16
Preliminary study conclusions with ASAP
45C stress is informative of product stability:
Current conditions showing initial failures in the 14-21 day range
Unsparged failed at 7 days
Overfill was stable to 21 days
35C is expected to produce more differentiation but may take longer
These results suggest that increasing filling volume is the best approach
Summary of the workshop on ASAP
Stability studies can be complex and need science-based decisions
ASAP can provide estimates of the kinetic parameters for the rates of
decompositions
The results of ASAP can be used to characterize the relationship between the
degradation and storage conditions
The results supply critical information in the design and analysis of long-term
stability studies under ambient and refrigerated conditions
All studies require detailed information about the products to establish the end
of shelf-life parameters
Follow guideline, use standard model to predict shelf-life claims