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Prescription drug products
stability and expirationdates*
UTMB/NASA-JSC Aerospace Medicine Grand Rounds
Houston, TX
Mansoor A. Khan, R.Ph., Ph.D.
Director, FDA/CDER/Division of Product Quality Research
October 27, 2009
Views are my own and does not represent the official policy of the Agency
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Outline
Introduction to FDA and DPQR
Drug product shelf life & expiration date Shelf-Life Extension Program (SLEP)
Repackaged products
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Food and Drug Administration
CDER CBER CDRH CVM CFSAN NCTR
Drugs FoodDevicesBiologics Veterinary
Cosmetics
Combination products
ORA
Field Laboratories
Office of Biotech Laboratories
Office of Testing and Research Laboratories
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DS
Characterization
AnalyticalMethods
DPCell Culture
Stability
Nanoparticles
Liposomes
SR/MR
TDDS
Nasal
Pulmonary
Fast disintegration Solid dispersion
PK/Bioavailability
Excipients
Formulation variables Process variables
Mechanistic evaluations
Optimization &
ANN procedures
Mixing
Milling
Granulation
Drying
Compression
Coating
Packaging
Research in DPQR
Physical Chemical
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Stability, shelf-life, and expiration date
Drug substance and products could degrade by oxidation,hydrolysis, racemization etc.
Factors such as temperature, humidity, light, pH, ionic strength,
buffer strength could enhance the degradation.
It is expected that a well designed formulation and packagingprotects the product from degradation
A shelf-life generally means a product will retain approved specs inthe final packaged container, in stated storage conditions, whentested by validated methods
An expiration date must be placed on container label (21 CFR201.17).
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Levothyroxine Sodium
6
I
O
HO
I
I
ONa
O
I
H NH2 x H2O
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Levothyroxine Stability Indicating Method*
-25
75
175
275
0 5 10 15 20
Time (min)
Peakarea
T4
T3
T2
T0
DIT
MIT
T
heo
Tyr
International Journal of Pharmaceutics, 360:77-82, 2008.
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How is Shelf Life Established?
Applicant conducts systematic stability testing(21 CFR 211.166) according to a prescribedprotocol
Select samples from representative batches
Store samples at defined storage conditions*
Accelerated (40C/75% relative humidity or RH)
Long-term (25C/60% RH)
Intermediate (30C/65% RH), if needed
*(Other stress conditions, e.g., light, acid, base, oxidant, forone-time testing)
Pull samples at predetermined intervals
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How is Shelf Life Established?
Test samples for product attributes susceptible tochange during storage and shipping and likely toinfluence quality, safety, and/or efficacy
Physical attributes, e.g., appearance, particle size
Chemical attributes, e.g., assay, degradants, pH In vitro drug release rate, e.g., dissolution
Biological, e.g., bioassay, and microbiological attributes
Analyze data for each attribute as a function of
time against proposed acceptance criteria Determine if the proposed shelf life can be
supported by available data
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How is Shelf Life Established?Perform regression analysis (if needed)
Time (years)
85
90
95
100
105
110
0 1 2 3 4 5
%
LabelClaim
Raw dataRegression lineTwo-sided 95% confidence limitsLower acceptance criterion
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Stability Test Attributes
Solid Orals
Potency Assay
Impurities
Dissolution
Water Content
Appearance
Injectables
Potency Assay
Impurities
Preservatives
pH
Appearance
Color
Particulates
Powders
Potency Assay
pH Water Content
Appearance
Creams/Ointments
Potency Assay pH
Appearance
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GabapentinExample of a drug product impurity
H2N COOH
Gabapentin
HN C=O
Lactam impurity
* Laboratory efforts: Understand all the variables and their interactions thatenhance the impurity level. DOE experiments to obtain a design space of a unitoperation. Drying and granulation process monitored by Near IR and chemical
imaging.
J. Pharm and Biomed. Analysis, 2008, 46, pp. 181-186.
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Granule Potency at 40 oC/75% RH
70
75
80
85
90
95
100
105
110
0 2 4 6 8 10 12 14
Time (weeks)
Potency(%c
laim)
PVP-W PVP-A
xPVP-W xPVP-A
HPC-W HPC-A
Polx-W Polx-A
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RC-A formation in Granules stored at 40oC/75% RH
0.0
0.4
0.8
1.2
1.6
2.0
2.4
0 2 4 6 8 10 12 14
Time (weeks)
Re
latedCompound
A(%w
/w)
PVP-W PVP-A
xPVP-W xPVP-A
HPC-W HPC-A
Polx-W Polx-A
USP limit
for RC-A
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RC-A formation in Tablets stored at 40
o
C/75% RH
0.0
0.4
0.8
1.2
1.6
2.0
2.4
2.8
3.2
3.6
0 2 4 6 8 10 12 14Time (we eks)
RelatedCompoundA
(%
w/w)
PVP-W PVP-A
xPVP-W xPVP-A
HPC-W HPC-A
Polx-W Polx-A
USP limit for
RC-A
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SLEP: Program Operation
Tests/Test methods/Location of
standards/procedures/research
(when needed)
SLEP
Military/SNS/VA
Contact
Samples
FDA Field Lab
Testing
Samples
Test ResultsFDA SLEP Coordinator
FDA CDER
Chemist Analysis
Data Evaluation, Analysis, and
Estimations of New Expiration
Date
Samples
New Expiration Date
Drug Lot Stored
in
Military/SNS/VA
Stockpile
Lyon et. al., J. Pharm. Sci., 2006, 95, 1549-1560.
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Group 1A: Products with No Failures ( 10 lots tested)Drug Product Dosage Form Tested Mean
Amoxicllin Sodium Tablets 21 23
Ciprofloxacin Tablets 242 55
Diphenhydramine HCl Syringe-Needle a 12 76
Doxycycline Hyclate Capsules b 13 50
Doxycycline Hyclate Powder b 31 27
Halothane Liquid 12 67
Mannitol Injection-Solution 10 66
Morphine Sulfate Syringe-Needle c 13 89
Naloxone HCl Injection-Solution 10 77
Oxacillin Sodium Powder 13 56
Potassium Iodide Tablets d 12 69
Sodium Bicarbonate Injection-Solution 37 55
Sodium Chloride Irrigation e 16 72
Sodium Nitrite Injection-Solution 10 89
Sodium Thiosulfate Injection-Solution 14 131
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Cefoperazone Sodium Powder 4 46 Assay
Cephapirin Sodium Powder 13 74 Potency
Cimetidine HCl Injection-Solution c 7 42 Assay
Dextrose (5%) Injection-Solution 22 65 Assay; Appearance i
Flurazepam HCl Capsules 3 35 Appearance
Morphine Sulfate Autoinjector d 3 32 Degradant
Ophthalmic Irrigating Solution 6 52 Low pH
Pancuronium Bromide Injection-Solution 13 79 Assay (1)
Ringers, Lactated andDextrose
Injection-Solution 13 53 Assay k ; Assay, Appearance
Sodium Chloride Injection-Solution e 41 50 Assay; pH
Sodium PolystyreneSulfonate
Powder 3 55 Water Content
Sulfadiazine Silver Cream 37 57 High pH & Assay
Tetracycline HCl Capsules 11 50 Dissolution ; Degradant
Thiopental Sodium Powder 12 54 Low pH ; Appearance
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SLEP Participants Current DoD participants
US Army US Air Force US Navy US Marines
CDC/Strategic National Stockpile (SNS) since 2004
Dept. of Veterans Affairs (VA) since 2005
Only Federal agencies that sign an MOA with DOD mayparticipate in SLEP
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SLEP Challenges
Protocols/Procedures
References standards Specialized equipment
Lab research when needed
Record keeping Knowledge Management
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0
1
2
3
4
5
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Distance (mm)
Force(Kg)
1975
19992004
FDA Shelf Life Research Example
0.0
0.51.0
1.5
2.0
2.5
3.0
3.5
4.0
1975 1999 2004
Manufacture Year
H
ardness
(kp)
Force
Empty Capsule Cap
Tablet Hardness
Tester (n = 10)
Force-Displacement Cap Crushing Strength
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Research Lessons
Learned Actual shelf life may be much longer thanindicated by expiration date on the productoriginal label.
Shelf life varies greatly between lots.
Continued testing and systematic evaluationis required to ensure product quality.
Analyses of the successes and failures canhelp in applying this information to new
product development.
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Repackaged Product Background
The draft guidance, CPG 7132.b11, specifiesconditions where it may be possible to assign upto 12 months expiration dating to non-sterilesolid and liquid oral dosage form drug productsrepackaged into unit dose containers for Class A,
without conducting new stability studies.
According to USP, a unit dose container is designated Class A if not more
than 1 of 10 containers exceed 0.5 mg/day in moisturepermeation rate, and none exceeds 1 mg/day. a unit dose container is designated Class B if not more
than 1 of 10 containers exceed 5 mg/day in moisturepermeation rate, and none exceeds 10 mg/day.
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Two repackaging firms say a draft FDA guidanceshould be revised to allow one year dating on opendose packages using Class B material.
('http://www.fdaweb.com/start.php?sa=v&aid=D5100826&cate=&stid=4LnsBWacYRN0k')FDA Webview, Sept 12, 2005
http://www.fdaweb.com/start.php?sa=v&aid=D5100826&cate=&stid=4LnsBWacYRN0khttp://www.fdaweb.com/start.php?sa=v&aid=D5100826&cate=&stid=4LnsBWacYRN0khttp://www.fdaweb.com/start.php?sa=v&aid=D5100826&cate=&stid=4LnsBWacYRN0khttp://www.fdaweb.com/start.php?sa=v&aid=D5100826&cate=&stid=4LnsBWacYRN0k8/2/2019 Drug Shelf Life
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Unit Dose Products Selected
Ranitidine HCl Syrup, 15 mg/mL
Metoprolol tartrate tablets, USP 50 mg
Phenytoin sodium suspension, USP 125mg/5 mL
Gabapentin capsules, 300 mg
Furosemide tablets, USP, 40 mg
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Original packaging tablets
Time 0
Repackaged tablets
Stored at 40C
75%RH for 4 Weeks
Original packaging tablets
Stored at 25C 60%RH for
4 Weeks
Repackaged tablets
Stored at 25C60%RH for 4 Weeks
Original packaging tablets
Stored at 40C 75%RH for
4 Weeks
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Overall Conclusions Drug product degrade by several different type of reactions
It is important to monitor several product attributes in addition to the amountof main drug
The stability of a product beyond expiration is not evaluated. Some productcould be dangerous if used after expiration
SLEP program is restricted to certain federal agencies at this time
Repackaged metoprolol tartrate tablets Product integrity compromised ataccelerated conditions.
Repackaged Phenytoin Sodium Suspension Product uniformity, potency,and dissolution compromised at initial time point itself
Repackaged Ranitidine HCl Syrup, Furosemide Tablets, and GabapentinCapsules no stability issues in the conditions of experiment