rahul-niper
Post on 21-Jun-2015
874 Views
Preview:
DESCRIPTION
TRANSCRIPT
BEST GUIDANCE AND PRACTICES FOR STRESS STABILITY TESTING
RAHUL KUMAR YADAV PA/2010/08
AGENDA………..
1) INTODUCTION
2) IMPORTANCE
3) EXPERIMENTAL DEGISNING
4) ISSUES
5) DIVERSITY IN INDUSTRYIAL APPROACH
6) CONCLUSION
DEFINITION
According to ICH GUIDELINE :“stress stability is designed to help determine the intrinsic stability of the molecule by establishing degradation pathways in order to identify the likely degradation products and to validate the stability indicating power of analytical procedure used” what we do. what is our aim . And what we needs.
And that is why industry adopt different testing procedures and thus difference in quality happen.
HOW
Why and what it provides:To develop and validate stability indicating methods.Degradation pathways and degradation product.Facilitate pharmaceutical development, packagingDetermination of intrinsic stability.Regulatory aspects:
1)Requirements at the IND phase: FDA needs no degradation studies for an IND application, BUT preliminary stress study on drug substance and early developed formulation (thermolysis,hydrolysis,oxidation,and photolysis) can be submitted as a draft guidance document in phase 3 application for IND as “result of one- time stress”.
2)Requirement for marketing application: a full written account of degradation studies
condition Drug substance Drug product
solid Solution/suspension
solid Solution/suspension
Acid/base √ X
Oxidative X √ √ √
Photo stability √ X √ √
Thermal √ √ √
Thermal/humidity √ √
ISSUES…………
1. Stress testing design (i.e. how they design stress testing studies and the approaches used)
2. Stress testing activity (i.e the type of stress testing conducted such as oxidative and the procedures used )
3.Organisation (i.e. how companies are structured to oversee their stress testing activities and resources) 1. Stress testing as a function : No defined stress-testing group Have defined stress-testing groups, but less are in no that are
centralized But the majority whether they have or have not any stress -testing
Group , most stress testing resources report their findings within the analytical chemistry function.
2.Stress testing as a discipline: mostly have a “sop “ And they follow a protocol.
3. Types of stress testing studies performed: Hydrolysis(acid –base –neutral), thermal-humidity ,photo stability, and oxidation are most frequently used tests.Frequency of testing is different for drug product or substanceBut for drug product choice of photo stability testing and thermal-stability testing are most favored.
4. Time of stress testing: Preclinical stage For repetitions: 1)stage of development 2)between preclinical and registration stages 3)between phase-1 and registrations final commercial formulation
5.How stress testing studies are analysed:
Identification : major degraded product Limit : 5-20% degradation Method of analysis: lc-uv, lc-diode, lc-nmr, etc.
ORGANIZATION OF STRESS TESTING
Responsibility: 1)individual 2)a group of scientist Data submission: 1)within the analytical chemistry function 2)head of analytical chemistry function 3) head of early development.Primary reason for testing: 1)method development 2)method validation 3)stability support & distribution 4)regulatory compliance.
method deve
lopment
method va
lidati
on
stabilit
y support&
distrib
ution
preformulati
on and exci
pients co
mpatibilit
y
regulat
ory co
mpliance
oth
er02468
1012141618
Series 1Series 2
RESOURCES PRIMARLY RESPONCIBLE FOR CONDUCTING STRESS TESTING STUDIES BY PHASE
CONDUCTRESORCE
DISCOVERY PRECLINICAL PHASE-1 PHASE-2 PHASE-3 REGISTRATION
SPECILIZEDDEGRADTION GROUP
3 3 4 5 4 4
ROBOTSYSTEM
0 0 0 0 0 0
CONTACTLABORATORY
0 0 0 1 1 1
INDIVIDUAL SCIENTIST
6 15 13 12 12 11
OTHER 1 0 0 0 0 0
N/A 10 2 3 2 3 4
TOTAL 20 20 20 20 20 20
It include: a)method to analyze stress testing sample b)appropriate stage of development to perform stress stability tastings .
Method includes lc-diode. lc-nmr,lc-mass,tlc,lc-uv,,cappillary electrophoresis
Lc-uv or lc-diode is most accepted Use of lc-nmr is only for special function Lc-mass is for secondary useWhile other are of least use
ACTIVITY:
LC-DIODE ARRAY
LC-UV LC-MS TLC LC-NMR0
2
4
6
8
10
12
14
16
Series 1Series 2
APPROPIATE STAGE OF DEVELOPMENT
PRICLINICAL STAGEDISCOVERY STAGEPHASE-1PHASE2
REPITATION OF TESTING
REPEATIONNOT REPEAT
Acid base testing
drug substance + drug product + drug metabolite.
SOLN .FORM FREQUNCY
SOLID FORM FREQUENCY
pH, and temp. is a important factor .Buffer mainly phosphate when there is need of acidity while also used(64%) in case of basisityUse of co solvent : 1.acetonitrile and methanol Time period: 1) more than 25 days 2) until 5-20% degradation taken place.
ACID-BASE TESTING
Ph range
pH1-8pH 0.1-2 ,5-9 & 12-15pH 1-2 &12-13pH0.1-9pH0.1-4 &10-15pH0.1-1,3-11
Temperature range
temperature >70temprature<70temperature >90temp>80
USE OF OXIDITAVIVE AGENT FOR OXIDATION
65%10%
18%
4% 3%
H2O2 RADICAL INISITOR PRESSURISEDOXYGENTRANSITION METALS BUBBLE OXYGEN
OXIDATION
H2O2 1)concentration---- ----- 1-3% 2)temp.--------------------30°C 3)duration-------------- - -either 1 days or 7 daysRADICAL INITIATOR:AIBN,ACN-WATER 1)temp.--------------------31-40°C 2)duration-------------- -- either 1 days ,7 days or may be 14 days.TRANSITION METAL: 1)cu+3 or fe+3
2)concentration---------- generally 0.05 and 1.0 mm ,but some uses 25 mm 3)temp.---------------------31-40°C 4)duration------------------ from 1 to more than 14 days
PRESSURED OXYGEN: 1)pressure-------150 or 300 psi 2)temp.----------- >50°C 3)duration-------- from 1 to 14 days.
BUBBLED OXYGEN 1)temp.------------30°C 2)duration---------7 days 3)flow rate--------- differ, from 5-10cc/min
THERMAL-HUMIDITY STUDIES
This test is choice for drug substance and drug product.Parameters:1)container: open or closed.
2)temp. : 51-70°C, if not degraded 90°C
3)Humidity : 51-70% most used.
4)duration: 1-3 weeks , 6 weeks or more
And same pattern is followed for drug product.
PHOTOSATABILITY STUDIES
Both for drug substance and drug product
Two light sources: a)visible light : ≥1.2 million lux hour b)UV-light : ≥200 watt h/m2
This is well accepted by ICH guideline But when the matter is use of maximum intensity it varies :
a)visible-light: >10 times of ICH b) UV-light: >2 times of ICH
ICH provides two option for performing the tests
CONTINUE…….
OPTION-1 OPTION-2
--any light sources that provides an output of d65/id65 emission standard -----artificial daylight fluorescent lamp combined of both uv and visible one . xenon or metal halide lamp.---d65,an internationally recognized standards for outdoor light--- similarly id 65 for indoor light
-----any light sources that provide an standard iso10977 and has a range of 320t0 400 nm distribution
----cool white florescent lamp is used
ACCORDING TO ICH Q1B
CONFUSIEST STAGE :
When 1)drug is very stable 2)drug is less soluble
How much stress is applied Because excess stress leads to an unrealistic result
And what is done at each stage of development phase from both a regulatory and a scientific perspective
CLASSIFICATION OF DRUGS
Class I: Extremely labile
Class II: Very labile
Class III: Labile
Class IV: Stable
Class V: Very stable
Class VI: Practically stable
CONCLUSION
“artful science”
“ monographs”
5-20% degradation of the active ingredients .
slightly excess of accelerated storage is recommended,.
major degraded product for ICH impurity threshold limit .
no degradation
REFERENCE:
1) ICH Guideline, “Stability Testing: Photo stability Testing of New DrugSubstances and Products, "November 1996
2) D.W. Reynolds et al., “Available Guidance and Best Practices for Conducting Forced Degradation Studies,” Pharm. Technol. 26 (2), 48–54(2002).
3)Forced Degradation Study By Danw.Reynolds,Kewin L.Facchine.June F.Mullaney.
4) A stress testing benchmarking study by Karen M. Alsante,Linda Martin. And Steven W. Baertschi.
top related