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drug substance and early developed formulation (thermolysis,hydrolysis,oxidation,and photolysis) can be submitted as a draft guidance document in phase 3 application for IND as “result of one- time stress”.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.

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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.