ICH, WHO, USFDA GUIDELINES ON STABILITY TESTING AND SHELF LIFE FOR INTERNATIONAL REGISTRATION OF PHARMACEUTICALS

Mr. Ajay Kumar Tiwari, M.PharmLecturerDepartment of Pharmaceutics,School Of Pharmaceutical SciencesJaipur National UniversityJaipur

GLOBALISATION GLOBAL TRADE CUSTOMER QUALITY SERVICE.

WORLD WIDE MARKETING APPLICATIONS MINIMUM ACCEPTABLE STANDARDS EVOLVED BYINTERNATIONAL CONFERENCE ON HORMONISATIONBY SELECTIVE COUNTRIES.

TO ELIMINATE REDUNDANT AND DUPLICATE REQUIREMENTS FOR REGISTRATION IN INDIVIDUAL COUNTRIES (LEGAL).

SIGNIFICANCE:BENEFITS ARE DIRECT IN TERMS OF SAVING- TIME, COST AND RESOURCES

PRE FORMULATION STUDY WITH API FOR

* STORAGE CONDITION* DOSAGE FORM DESIGN* SUITABLE CONTAINERS AND CLOSURES

ICH- EU, USA, JAPAN YRS.ICH 1 NOV. 1991 (BRUSSELS)

ICH 2 OCT. 1993 (FLORIDA)

ICH3 NOV. 1995 (YOKOHOMA)

ICH 4 JUL. 1997 (BRUSSELS)

ICH 5 2000 (JAPAN)DOES NOT SEEK NECESSARILY REGISTRATION FOR EXPORT TO OTHER AREAS OF THE WORLD

HARMONIZATION ONEFFICACYQUALITYSAFETYMULTI DISCIPLINARY

TABLE 1

TABLE 1: UPDATED LIST OF CODES, TOPICS AND CORRESPONDING GUIDELINES DEVELOPED BY ICHCODENAME OF THE TOPICCODENAME OF THE GUIDELINES DEVELOPED UNDER SPECIFIC TOPICSA. EFFICACYE1EXPOSUREE1THE EXTEND OF POPULATION EXPOSURE TO ASSESS CLINICAL SAFETYE2CLINICAL SAFETY DATA MANAGEMENTE2ADEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

E2BDATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS E2CPERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS E3CLINICAL STUDY REPORTSE3STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTSE4DATA RESPONSE STUDIESE4DOSE-RESPONSE INFORMATION TO SUPPORT DRUG REGISTRATIONE5ETHNIC FACTORSE5ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA

E6GOOD CLINICAL PRACTICESE6GOOD CLINICAL PRACTICE: CONSOLIDATED GUIDELINEE7CLINICAL TRAILS IN SPECIAL POPULATIONSE7CLINICAL TRAILS IN SPECIAL POPULATIONS : GERIATRICSE8CLINICAL TRIAL DESIGNE8GENERAL CONSIDERATIONS FOR CLINICAL TRAILSE9STATISTICAL PRINCIPLES FOR CLINICAL TRIALSE10CHOICE OF CONTROL GROUP

B. QUALITYQ1STABILITYQ1ASTABILITY TESTING OF NEW DRUGS AND PRODUCTSQ1BPHOTO STABILITY TESTING OF NEW DRUGS AND PRODUCTS Q1CSTABILITY TESTING FOR NEW DOSAGE FORMSQ2ANALYTICAL VALIDATIONQ2ATEXT ON VALIDATION OF ANALYTICAL PROCEDURESQ2BVALIDATION OF ANALYTICAL PROCEDURE: METHODOLOGYQ3IMPURITIESQ3AIMPURITIES IN NEW DRUG SUBSTANCES

Q3BIMPURITIES IN NEW DRUG PRODUCTSQ3CIMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTSQ4PHARMACOPOEIASQ5QUALITY OF BIOTECHNOLOGICAL PRODUCTSQ5AVIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGINQ5BANALYSIS OF THE EXPRESSION CONSTRUCT IN CELLS SUBSTRATES USED FOR PRODUCTION OF R-DNA DERIVED PROTEIN PRODUCTS

Q5CSTABILITY TESTING OF BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTS Q5DDERIVATION AND CHARACTERIZATION OF CELL SUBSTRATES USED FOR PRODUCTION OF BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTSQ6SPECIFICATIONS FOR NEW DRUG SUBSTANCES AND PRODUCTSQ6ACHEMICAL SUBSTANCESQ6BBIOTECHNOLOGICAL SUBSTANCES

C.SAFETYS1CARCINOGENICITY STUDIESS1AGUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALSS1BTESTING FOR CARCINOGENICITY OF PHARMACEUTICALSS1C / Rev.ADDENDUM TO THE GUIDELINE ON DOSE SELECTION FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALS : ADDITION OF A LIMIT DOSE AND RELATED NOTESS2S2BA STANDARD BATTERY FOR GENOTOXICITY TESTING OF PHARMACEUTICALS

S3KINETICSS3ANOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES S3BPHARMACOKINETICS: GUIDANCE FOR REPEATED DOSE TISSUE DISTRIBUTION STUDIESS4TOXICITYS4ADURATION OF CHRONIC TOXICITY TESTING IN ANIMALS (RODENT AND NON RODENT TOXICITY TESTING)S5REPRODUCTIVE TOXICITYS5ADETECTION OF TOXICITY TO REPRODUCTION FOR MEDICINAL PRODUCTS

S5BAN ADDENDUM TO TOXICITY TO MALE FERTILITYS6SAFETY STUDIES FOR BIOTECHNOLOGICAL PRODUCTSS6APRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY-DERIVED PHARMACEUTICALSD. MULTIDISCIPLINARYM1MEDICINAL TERMINOLOGYM2ELECTRONIC STANDARDS FOR TRANSMISSION OF REGULATORY INFORMATION (ESTRI)M3GUIDELINE FOR THE TIMING OF NON-CLINICAL SAFETY STUDIES FOR THE CONDUCT OF HUMAN CLINICAL TRAILS FOR PHARMACEUTICALSM4THE COMMON TECHNICAL DOCUMENT

THEPHARMACOPOEIAL AUTHORITIES HAVE BEEN CLOSELY INVOLVED WITH THE WORK OF ICHSINCE THE OUTSET AND HARMONIZATION BETWEEN THE MAJOR PHARMACOPOEIAS STARTED BEFORE ICH.

THE ICH STEERING COMMITTEE RECEIVES REGULAR REPORTS ON PHARMACOPOEIAL HARMONIZATION AT ITS MEETINGS.

WHO ADVOCATED ICH (17 MEMBERS) GUIDELINES TO ALL MEMBERS (191)

GLOBAL GUIDELINES

GLOBAL DOSSIER (DOCUMENT)

REPORTS OF TOXICITY DUE TO DEGRADED PRODUCT[EPIANHYDROTETRACYCLINE FANCONI (RENAL) SYMPTOMS] [DIMER/POLYMER OF PENICILLIN ALLERGY]

EFFECT OF ENVIRONMENTAL FACTORS (TEMP., LIGHT, HUMIDITY) TO BE AVOIDED

QUALITY, SAFETY, EFFICACY DURING SHELF LIFE (EXPIRY DATE) IS MUST

BEFORE APPROVAL, STABILITY DATA AND STORAGE CONDITIONS TO BE SUBMITTED (LEGAL)

ICH DEVELOPED - FOUR STABILITY GUIDELINES

SHELF LIFE BASED ON LONG TERM TESTING AND NOT ON ACCELERATED OR STRESS TESTING

*COMMITTEE FOR PROPRIETORY MEDICINAL PRODUCTS**MINISTRY OF HEALTH & WELFARE

IMPLEMENTATION IN THE THREE REGIONSCODENAME OF THE GUIDELINEDATE OF FINALIZATION BY ICHDATE OF ADOPTION BY CPMP* IN EUDATE OF ADOPTION BY MHW**, JAPANDATE OF PUBLICATION IN FEDERAL REGISTER, USAQ1ASTABILITY TESTING OFNEW DRUG SUBSTANCES AND PRODUCTSOCT. 1993DEC. 1993APR.1994SEP. 1994Q1BPHOTOSTABILITY TESTING OFNEW DRUG SUBSTANCES AND PRODUCTSNOV. 1996DEC. 1996MAY 1997MAY 1997

Q1CSTABILITY TESTING FOR NEW DOSAGE FORMSNOV. 1996DEC. 1996MAY 1997MAY 1997Q5CSTABILITY TESTING OF BIOLOGICAL / BIOLOGICAL PRODUCTSNOV. 1995DEC. 1995JAN. 1998JUL. 1996

DISADVANTAGE : ICH COVERED NEW DRUG SUBSTANCES AND PRODUCTS ONLY.WHO DEVELOPED SEPARATE GUIDELINE FOR STABILITY TESTING OF ESTABLISHED DRUGS IN CONVENTIONAL DOSAGE FORMS.

US FDA WENT AHEAD AND CAME OUT STABILITY TESTING OF SOLID ORAL DOSAGE FORMS, DRUGS CONTAINING IRON FOR INDIANO SPECIFIC GUIDELINES HAS TO FOLLOW ICH FOR MORE EXPORT POTENTIAL

STABILITY DATA GENERATION: Protocol (8 steps)1. TYPE, SIZE AND NO. OF BATCHES:

Drug SubstancesDrug Products (Clinical Formulation) AT LEAST 3 BATCHES (MINIMUM OF PILOT SCALES: SYNTHETIC ROUTE, METHOD OF MANUFACTURE SIMULATING FINAL MANUFACTURE)

QUALITY IS SAME AS THAT TO BE USED IN CLINICAL STUDY (ANY STABILITY DATA OF LAB SCALE MAY BE USED AS SUPPORTING DATA)AT LEAST 3 BATCHES (PREFERABLY 3 DIFFERENT BATCH) OF DRUG PRODUCTS (ONE MAY BE FROM SMALLER: 25,000 TO 50, 000 TABLET OR CAPSULE) (TWO SHOULD BE AT LEAST PILOT SCALE)

QUALITY SAME AS THAT FOR MARKETING (LAB DATA ARE NOT ACCEPTABLE, DATA ON ASSOCIATED FORMULATION OR PACKAGING MAY BE USED AS SUPPORTING DATA)

2. TYPE, SIZE & SOURCE OF CONTAINER AND CLOSURES: DRUG SUBSTANCES: IN PROPOSED BULK CONTAINER AND CLOSURE DRUG PRODUCT: IN PROPOSED DOSAGE FROM CONTAINER AND CLOSURE PROPOSED FOR STORAGE AND DISTRIBUTION MEANT FOR MARKETING

3. STORAGE ORIENTATION FOR FULL INTERACTION: eg.VIAL IN INVERTED POSITION

4. TEST PARAMETERS (ICH Q6):DRUG ASSAYANALYSIS OF DEGRADATION PRODUCTSPHYSICAL, CHEMICAL, MICROBIOLOGICALQUALITY ATTRIBUTES (E.g. TABLET: DISSOLUTION TEST ETC.)LOSS OF PRESERVATIVERELEASE SPECIFICATIONPRESERVATIVE EFFICACY TESTING etc.

US FDA GIVES ELABORATE GUIDELINES: ASSAY AND DEGRADATION PUT TOGETHER BE 100 % OF INITIAL VALUE (MEET ADEQUACY OF MASS BALANCE)

5. TEST METHODS: (ICH Q6)STP BE DEVELOPED FOR ANALYSIS:VALIDATED FOR SPECIFICITY, ACCURACY, PRECISION & LINEARITYLIMITS FOR DETECTION AND QUANTIFICATION PRESCRIBED. (REPLICATION IF NECESSARY)

6. ACCEPTANCE CRITERIA:DERIVED FROM MATERIAL USED IN PRE AND CLINICAL STUDIES AND BIOAVAILABILITY STUDIES.IS FIXED AS NUMERICAL LIMITS.EG.: MOISTURE PICKUP, VISCOSITY, PARTICLE SIZE, ASSAY, DEGRADATION PRODUCTS, IMPURITIES (INDIVIDUAL AND TOTAL UPPER LIMITS)

7. SAMPLING TIME POINTS: (TESTING FREQUENCY)

REAL TIME TESTING (ICH): ON SAMPLES(LONG TERM)

FREQUENCY OF 3 MONTH IN FIRST YEAR (MINIMUM PERIOD FOR INITIAL SUBMISSION)

FREQUENCY OF 6 MONTH IN SECOND YEAR & THEN ANNUALLY (RE TEST PERIOD SUBMITTED DURING ASSESSMENT UP TO PROPOSED SHELF LIFE)

b) ACCELERATED CONDITIONS: (3 POINTS)ICH: 0,3,6 MONTHS IF REQUIRED. ADDITIONAL SAMPLES AT FINAL TIME OR A FOURTH TIME POINT.USFDA: 0,2,4 & 6 MONTHSWHO: 0,1,2,3 APPROPRIATE, 6 MONTHS

c) INTERMEDIATE CONDITIONS: (IF FAILURE OCCUR AT ACCELERATED): FOUR TEST POINTS:0,6,9,12 MONTHS

8. TEST STORAGE CONDITIONS:IN CURRENT PRACTICE:a) ISOTHERMAL CONDITION AND b) CONTROLLED HUMIDITYBOTH a & b (FOR STABILITY STUDIES) MANDATORY

INSTEAD OF MULTI TEMPERATURE TESTING, SINGLE ACCELERATED TESTING IS ACCEPTED (ICH, WHO AND USFDA)HAYNES: 4 CLIMATIC ZONES (TABLE 4) IN WORLDCLIMATIC ZONE FOR WORLD STABILITY TESTING (TABLE 5)

TABLE 4 CLIMATIC ZONES FOR WORLD WIDE STABILITY TESTING

CLIMATIC ZONEMEASURED DATA IN OPEN AIR OC %RH MEASURED DATA IN STORAGE ROOM OC %RHZONE I : TEMPERATE10.9 75 18.7 45ZONE II : SUB-TROPICAL 17.0 70 21.1 52ZONE III : HOT / DRY 24.4 39 26.0 54ZONE IV : HOT / HUMID 26.5 77 28.4 70

MKT = MEAN KINETIC TEMP.

CLIMATIC ZONECALCULATED DATA

OC OC (MKT) %RHDERIVED STORAGE CONDITIONS (FOR REAL TIME STUDIES) OC %RHZONE I : TEMPERATE20.0 20.0 42 21 45 ZONE II : SUB-TROPICAL 21.6 22.0 52 25 60 ZONE III : HOT / DRY26.4 27.9 35 30 35ZONE IV : HOT / HUMID26.7 27.4 76 30 70

TABLE 5. DISTRIBUTION OF WORLD NATIONS INTO DIFFERENT ZONES

REGIONZONE I AND II COUNTRIESZONE III AND IV COUNTRIESEUROPEALL COUNTRIES------AMERICAARGENTINA, BOLIVIA, CHILE, CANADA, MEXICO, URUGUAY, USABARBADOS, BELIZE, BRAZIL, COSTA RICA, DOMINICAN REPUBLIC, ECUADOR, EI SALVADOR, GUATEMALA, GUYANA, HAITI, HONDURAS, JAMAICA, COLUMBIA, CUBA, NICARAGUA, DUTCH ANTILLES, PANAMA, PARAGUAY, PUERTO RICO, VENEZUELA. ALL OF THESE COUNTRIES ARE ASSIGNED TO CZ IV

ASIAAFGHANISTAN, ARMENIA, AZERBAIJAN, CHINA, GEORGIA, IRAN, ISRAEL, JAPAN, KAZAKSTAN, KIRGHIZIA, KOREA, LEBANON, NEPAL, SYRIA, TADZHIKISTAN, TURKEY, TURKMENIA, UZBEKISTANBAHRAIN, BANGALADESH, HONG KONG, INDIA, INDONESIA, IRAQ (III), JORDAN (III), KAMPUCHEA, QATAR, KUWAIT, LAOS, MALAYSIA, MALDIVES ISLANDS, MYANMAR, OMAN, PAKISTAN, PHILIPPINES, SAUDI ARABIA, SINGAPORE, SRI LANKA, TAIWAN, THAILAND, UNITED ARAB EMIRATES, VIETNAM, YEMEN

AFRICAEGYPT, ALGERIA, TUNISIA, LIBYA, MOROCCO, NAMIBIA, RWANDA, SOUTH AFRICA, ZAMBIA, ZIMBABWEANGOLA, ETHIOPIA, BENIN, BOTSWANA (III), BURKINA FASO, BURUNDI, DJIBOUTI, IVORY COAST, GABON, GAMBIA, GHANA, GUINEA, CAMEROON, KENYA, LONGO, LIBERIA, MADAGASCAR, MALAWI, MALI, MAURITANIA, MOZAMBIQUE, NIGER, NIGERIA, SENEGAL, SIERRA LEONE, SOMALIA, SUDAN, TANZANIA, TOGO, CHAD (III), UGANDA, ZAIRE, CENTRAL AFRICAN REPUBLICAUSTRALIAN / OCEANICAUSTRALIA, NEW ZEALANDFIJI, SOCIETY ISLANDS, MARSHOULD ISLANDS, NEW CALEDONIA, PAPUA-NEW GUINEA, SAMOA, TONGA

A. GENERAL CASE: (FOR DRUG SUBSTANCE AND DRUG PRODUCTS)STORAGE CONDITIONS: FOR LONG TERM TESTING

MINIMUM TIME PERIOD FOR INITIAL SUBMISSION: 12 MONTH CONTINUED FOR SUFFICIENT RESTEST PERIOD FOR ASSESSMENT.

ZONE I & IIZONE III & IV (ICH)25O 2O C; 60% R.H 5% R.HZONE III & IV (WHO)30O 2O C; 60% R.H 5% R.H

FOR ACCELERATED TESTING(ICH & WHO)40oC 2oC; 75% R.H 5% R.H;

MINIMUM TIME PERIOD FOR INITIAL SUBMISSION: 6 MONTHS (DATA SUBMITTED AS IMPACT STUDY ABOUT SHORT TERM EXCURSION SIMULATING SHIPPING)

IF THE PRODUCT IS UNSTABLE IN THE ABOVE DURING 6 MONTHSINTERMEDIATE CONDITIONS PERFORMED30oC 2oC; 60% R.H 5% R.H;

MINIMUM TIME PERIOD FOR INITIAL SUBMISSION: AT LEAST 6 MONTHS OUT OF 12 MONTHS

ACCEPTANCE:RESULTS WITHIN SIGNIFICANT CHANGE OTHERWISE NOT MEETING SPECIFICATION.

DEFINITION OF SIGNIFICANT CHANGE:FAILURE TO MEET ACCEPTANCE CRITERIA LIKE APPEARANCECOLOURPHASE SEPARATIONRESUSPENDABILITYCAKINGHARDNESSDELIVERY PER ACTUATION AND AS APPROPRIATE TOPRODUCT TYPE.pH EXCEEDINGDISSOLUTION EXCEEDING FOR 12 DOSAGE UNITSSPECIFIC DEGRADATION EXCEEDINGA 5% POTENCY CHANGE FROM INITIAL ASSAY

B. TO BE STORED IN REFRIGERATOR (FOR DRUG SUBSTANCE AND DRUG PRODUCT)

LONG TERM: 5O 3O C MINIMUM 12 MONTHS FOR INITIAL SUBMISSIONACCELERATED: 25O 2O C; MINIMUM 6 MONTHS

IF SIGNIFICANT CHANGE OCCUR IN ACCELERATED

a. WITHIN 3 MONTHS, TEST NOT TO BE CONTINUED BUT STRESS TEST DATA TO BE SUBMITTED (OUTSIDE LABEL CONDITION) TO COVER SHIPPING CONDITION.

b. BETWEEN 3 AND 6 MONTHS, ANY RETEST PERIOD (FOURTH) BASED ON REAL TIME TESTING.

C. TO BE STORED IN A FREEZER: (FOR DRUG SUBSTANCE AND DRUG PRODUCTS)

LONG TERM: - 20O 5O C, AMBIENT HUMIDITY; MINIMUM 12 MONTHS FOR INITIAL SUBMISSION. RETEST PERIOD DEPEND ON STABILITY IN LONG TERM.

ACCELERATED: 5O 3O C; 60% 5% R.H

STRESS TESTING: 25O 2O C ON A SINGLE BATCH TO COVER OUTSIDE LABEL CONDITION (SHIPPING)D. TO BE STORED IN DEEP FREEZER BELOW - 20O C (FOR DS & DP)TREATED CASE BY CASE BASIS

E. DRUG PRODUCT PACKED IN IMPERMEABLE CONTAINER (ICH / USFDA)

SEMI SOLIDS IN SEALED ALUMINIUM COLLAPSIBLE TUBES,INJECTIONS IN SEALED GLASS AMPOULES

NO MOISTURE OR SOLVENT ENTRY OR LOSS (PERMANENT BARRIERS)

THEREFORE CONDITIONS AS ABOVE (GENERAL REFRIGERATOR, FREEZER AT ANY RELATIVE HUMIDITY).

F. DP PACKED IN SEMI PERMEABLE CONTAINERS: (PLASTIC BAG, LOW DENSITY POLYETHYLENE POUCH FOR LVP, AMPOULES AND VIALS)AQUEOUS BASED PRODUCTS: EVALUATED FOR WATER LOSS UNDER LOW RH

SIGNIFICANT CHANGE: WATER LOSS OF > 5%.AFTER 3 MONTHS STORAGE AT ACCELERATED REQUIRED: THROUGHOUT THE PROPOSED SHELF IT SHOULD BE WITHIN ACCEPTANCE CRITERIA.

ii) NON AQUEOUS BASED PRODUCT:ANY COMPARABLE APPROACH MAY BE FOLLOWED

StudyConditionMinimum Time Period at submissionLong25O 2O C; 40%; R.H 5% R.H 12 monthsIntermediate30O 2O C; 60%; R.H 5% R.H 6 monthsAccelerated40O 2O C; 60%; NMT 25% R.H 6 months (water loss after 3 months)

STABILITY COMMITMENT: FOR DS AND DP

LONG TERM STUDY DATA ON PRIMARY BATCHES:

IF NOT COVERED PROPOSED SHELF LIFE AT TIME OF APPROVAL,STUDY TO BE CONTINUED TO ESTABLISH SHELF LIFE AS WELL AS FOR POST APPROVAL

IF COVERED PROPOSED SHELF LIFE,POST APPROVAL COMMITMENT NOT NECESSARY.

EVALUATION FOR DS AND DP

SHOULD BE SYSTEMATIC APPROACH

IF DATA SHOW LITTLE VARIATION, (APPARENT BY LOOKING): NO FORMAL STATISTICAL ANALYSIS

ACCELERATED STABILITY DATA SHOW MORE STABILITY,SHELF LIFE MAY BE EXTENDED AT APPROVAL TIME (FOR LIMITED CASES)

STABILITY OF DRUG PRODUCT AFTER RECONSTITUTION OR DILUTION TO BE PROVIDED AS SUPPORTIVE INFORMATION

FOR STABILITY TESTING3 TYPES OF EQUIPMENTS

HUMIDITY CUM THERMOSTATIC CHAMBERS

REFRIGERATORS (5O 3O C; 15O 5O C )

THERMOSTATIC CHAMBERS WITH AMBIENT HUMIDITY (25OC, 30OC, 40OC)FOR PRODUCTS IN IMPERMEABLE CONTAINERS, AMPOULE, VIAL, etc. AVAILABLE IN STANDARD COMPANIES:( REF. TABLE 7 )

Table 7 Name & addresses of a few International Vendors for ICH Stability Test Chambers

VENDORS NAMEADDRESSCONTACT PERSON / LOCAL AGENTSENVIRONMENTAL SPECIALTIES LIMITED4412 TYRON ROAD, RALEIGH, NORTH CAROLINA, USA . PHONE. 919/829-9300 toll free 1-800-688-5859, fax:919/829-7357MR. EDWARD P. FRANTZ JR., PRODUCT MANAGER,SALES FAX : 919-833-9476HOTPACK CORPORATION10940 DUTTON ROAD, PHILADELPHIA, PA 19154, USA ph.212-824-1700 fax:215-673-0519 toll free 1-800-523-3608MR. JOE GRIPPI,NATIONAL SALES MANAGER, LOCAL AGENTS: BIONICS EQUIPMENT PTE LTD., 91-44-840512VOTSCH INDESTRITECHNIK(PREVIOUSLY SOLD AS HERAEUS)ASIA PACIFIC REGIONAL OFFICE7L-1 JALAN GOTTLIEB, 10350 PENANG, MALAYSIA FAX: + 60-4-2274831MR. THILO KOPPE, SALES MANAGER ASIA PACIFICWTB BINDER LABORTECHNIK GMBHBERGSTR. 14 D 78532 , TUTTLINGEN, GERMANY, PH. 0049/7461/1792-0; FAX: 0049/7461/1792-0LOCAL AGENTS: S.V. INSTRUMENTS ANALYTICA PVT. LTD., 3269 RANJIT NAGAR, NEAR PUSA GATE, NEW DELHI 110008, PH. 5731571; FAX: 5761571, 5751590SANYO GALLENKAM (USA)900 N, ARLINGTON HEIGHTS RD. SUITE 320, ITASCA IL 60143, USA PH.708-875-3542; FAX: 708-775-0427 TOLL FREE:1-800-528-7083LUNIARE ENVIRONMENTAL1719 RT. 10, SUITE 301PARSIPPANY, NJ 07054, USA 1-800-LUNAIRE (586-2473) FAX 201-540-0367

APPROACH 1: SAMPLES IN REPLICATEANALYSE 1, OTHER KEPT AT LOW TEMPALL SAMPLES ANALYSED AFTER LAST SAMPLES WITHDRAWN.(IMPROVED ASSAY MAY COME LATER).

APPROACH 2: TAKE ONE OR TWO INITIAL SAMPLES. FROZENKEEP FOR ENTIRE SHELF PERIODFOR ASSAYS DONE AT DIFFERENT TIMES, IT IS KEPT AS INTERNAL STANDARD AND MAKE CORRECTIONS IF NECESSARY.

STABILITY DATA IS RECORDED IN AN ORGANIZED WAY AND DOCUMENTED (REF TABLE 8 & 9)

FOR DIFFERENT SCIENTIFIC SITUATIONS ALTERNATIVE APPROACHES MAY BE USED

TABLE 8. COMPARISON OF THE CURRENT AND HARMONIZED PROTOCOLS FOR WORLD WIDE MARKETING.

STORAGE CONDITION TEMP. OC HUMIDITY (%RH)TESTING INTERVAL (MONTHS) 1 2 3 6 9 12 18 24 30 36 48 60A. CURRENT WORLD WIDE STABILITY TESTING PROTOCOL 2 X X X X X X X X X X X 5 X X X X X X X X X X X 8 X X X X X X X X X X X 15 X X X X X X X X X X X 20 X X X X X X X X 25 60 X X X X X X X X X X X 25 75 X X X X X X X X X X X X 30 40 X X X X X X X X X X X

30 70 X X X X X X X X X X X 40 25 X X X X X X X X X X 40 75 X X X X X X 40 90 X X X X 50 X X X 60 X X X 70 XB. WORLD WIDE STABILITY PROTOCOL FOR MARKETING APPLICATIONS: HARMONIZED PROTOCOL 2 X X X X X X X X X 25 60 X X X X X X X X X 30 60 X X X X X X X X X 40 75 X X X

TABLE 9. SAMPLE FORMAT SHEET FOR RECORDING STABILITY INFORMATION

STABILITY RAW DATAPRODUCT NAME / STRENGTH :STUDY NUMBER : DATE STUDY STARTED :BATCH NUMBER : BATCH SIZE :DATE OF MANUFACTURE : MANUFACTURER / SITE :CONTAINER / SIZE / SUPPLIER :CLOSURE COMPOSITION / SUPPLIER : SEAL SUPPLIER :DATE PACKAGED : PACKAGER / SITE :STORAGE CONDITION : STORAGE ORIENTATION : CHAMBER # : SHELF # : LOCATION :

ATTRIBUTESMETHODSPECIFICATIONTIME (MONTHS)Sop #(LOW / HIGH)0369121824etcAPPEARANCEASSAYDEGRADATIONPRODUCT ADEGRADATIONPRODUCT BDEGRADATIONPRODUCT CETC.

CONDUCT OF STABILITY STUDY AND RECORDING OF STABILITY DATA: SAMPLE IN SELECTED STORAGE CONDITIONS.SAMPLING AT PRESCRIBED INTERVALS.. ANALYZING IMMEDIATELY(IF FORCED, FROZEN IMMEDIATELY TILL ANALYSIS)

AVOIDANCE OF CALENDRIC ASSAY BIAS ( DAY TO DAY VARIABILITY)

ICH GUIDELINES OF PHOTOSTABILITY TESTING DONE ON BOTH DRUG SUBSTANCE AND PRODUCT (ICH QIB). AT LEAST ONE PRIMARY BATCHLIGHT SOURCE ARTIFICIAL DAY LIGHT FLUORESCENT LAMP / XENON OR METAL HALIDE LAMP (SIMILAR TO D65/ID65 EMISSION STANDARD) EXPOSURE OF SAMPLE TO COMBINATION OF COOL LIGHT FLUORESCENT LAMP AND A NEAR UV LAMP (FROM 320NM TO 400 NM)

EXPOSE SAMPLES TO OVERALL ILLUMINATION OF NOT LESS THAN 1.2 MILLION LUX HOURS AND AN INTEGRATED NEAR UV LIGHT OF NOT LESS THAN 200 WATT HOURS/SQUARE METER ( SIDE BY SIDE SAMPLES BE EXPOSED TO A VALIDATED ACTINOMETRIC SYSTEM)

Start Directly ExposedAcceptable Change?Marketing PackAcceptable Change?Immediate PackAcceptable Change?Redesign Package or ReformulationMarketing pack Change?Immediate pack Change?Formulation Change?Test EndTest EndTest EndYesYesYesYesYesNoNoNoDECISION FLOW CHART FOR PHOTO STABILITY TESTING OF DRUG PRODUCTS:

ICH GUIDELINES (QIA)STATISTICAL TREATMENTSTABILITY DATA FROM THREE BATCHES SUBJECT TO STATISTICAL TEST TO CHECK WHETHER TO POOL OR NOT DIFFERENT POSSIBILITIES OF CONCENTRATION - TIME DATA

STATISTICAL SIGNIFICANCE:t Table At A p VALUE OF 0.25 (p VALUE FOR LEVEL OF SIGNIFICANCE OF REJECTION OF MORE THAN 0.25)

IF DATA IS NOT REJECTED, THREE DATA ARE POOLED

IF P VALUE LESS THAN 0.25 , DECISION MADE BY JUDGEMENT, ESTIMATES ARE MADE FORM WORST BATCH

WE HAVE POOL OF THREE BATCH OR A INDIVIDUAL WORST BATCH

DATA HAS FIVE POINTS (INITIAL, 3,6,9 & 12 MONTHS)

NOW, SHELF LIFE IS ESTIMATED BASED ON 95%ONE SIDED CONFIDENCE LEVELS (NOW INCLUDED IN USFDA ALSO)Q

Time (Months)Read time (Shelf life) taken for 90% Label claimLinear Regression Line (50% Confidence Limit Line)One sided 95% confidenceAlong regression line 100 95 90Not statistically significant

EXTRAPOLATION BEYOND EXPIRY DATA IS DISCOURAGED. ACTUAL STABILITY DATA UPTO GRANTED EXPIRATION TIME IS REQUIRED

ADDITIONAL GUIDELINES BY USFDAEXPIRY DATE BEGIN FROM QUALITY CONTROL RELEASE OF THE BATCH ------- DATE OF RELEASE NOT TO EXCEED 30 DAYS FROM PRODUCTION DATE IRRESPECTIVE OF PACKAGING DATE

EXPIRY DATE IS UPTO LAST DAY OF MONTH (ALTHOUGH THERE IS NO SUDDEN DEATH)

ADDITIONAL POINTS:SOFTWARE PACKAGES TO HANDLE STATISTICAL DATA AS PER ICH OR FDA ARE AVAILABLEDRUG FORMULATION STABILITY PGM (STAB) DEVELOPED BY US FDA AVAILABLE FREE OF CHARGE ( INTERNET SITE www.fda.gov)SOFTWARE (SAS): COMMERCIAL PACKAGE AVAILABLE J.T. CARSTENSEN, 1995, DRUG STABILITY PRINCIPLES AND PRACTICES, 2ND EDN. MARCEL DEKKER, NEW YORK.P.WESSELS ET AL., STATISTICAL EVALUATION OF STABILITY DATA FOR PHARMACEUTICAL PRODUCTS FOR SPECIFICATION SETTING DRUG. DEV. IND. PHARM 24, 313 (1998) EQUATION FOR CALCULATING CONFIDENCE LIMIT AND ANOTHER DETAILS AVAILABLE.COMMON STATISTICAL PACKAGE (SIGMASTAT): USEFUL FOR CALCULATING LIMITS OF REGRESSION LINE.

SUMMARY ICH GUIDELINES : ONLY FOR NEW DRUG SUBSTANCES AND PRODUCTS. WHO GUIDELINES: FOR ESTABLISHED DRUG IN CONVENTIONAL DOSAGE FORM ALLOWS 24 MONTHS SHELF LIFE STUDY..NO SUGGESTION OF STATISTICAL TREATMENT.

VARIOUS CONDITIONS ARE-MOIETY IS KNOWN TO BE STABLESTABILITY STUDIES CARRIED OUT AS PER ACCELERATED STUDY FOR ZONE III AND IV WITH NO SIGNIFICANT CHANGESUPPORTING DATA INDICATE SIMILAR FORMULATION ASSAYED FOR SHELF LIFE OF 24 MONTHS OR MORE.MANUFACTURER CONTINUE REAL TIME STUDY UNTIL PROPOSED SHELF LIFE IS CONVERED

GUIDELINES ARE GUIDELINES..DIFFICULTIES AND COMPLEXITIES MAY ARISE.ALTERNATE APPROACHES ARE POSSIBLE..IT SHOULD BE CONVINCING WITH GUARANTEE FOR PROTECTION (GOAL OF REGULATORY AUTHORITIES ALSO)

STABILITY DATA HANDLING AND SHELF LIFE ESTIMATIONCONVENTIONAL (NOW IT IS STRESS TESTING)

MULTI TEMPERATURE ACCELERATED TESTING USING CLASSICAL ARRHENIUS APPROACH EFFECT OF TEMPERATURE ON REACTION VELOCITY:K = S.e-Ha/RT

K = Specific Rate DegradationR = Gas Constant (1.987 cal. Deg 1mole-1Ha = Heat Of ActivationT = Absolute Temperature (=oC + 273)S = Frequency Factor = 8.314 x 107erg. Mole 1 deg-1it is: log K = -Ha/2.303 R.1/T + log S= Plot log K (vs) 1/T; Slope is -Ha/2.303R; Ha Is calculated

K VALUE AT LOW TEMPERATURE MAY BE OBTAINED (Ref. Fig 1)

Fig 180oC70oC60oC50oC40oC30oC25oC20oC80oC70oC60oC50oC40oC25oCDays to 90% log scale1/TLog K1/T40oC50oC60oC70oC80oC90%100%Time in days% Drug conc. (log scale)Fig 3Fig 2

PRIMARY DATA FOR MULTI TEMPERATUREINITIAL CONCENTRATION = aK=2.303/t log a/a-x FIRST ORDER KINETICS

TEMP.CONCENTRATION AT DIFFERENT TIMEK VALUES2 HOURS6 HOURS12 HOURS24 HOURS(a-x)40oC50oC60oC

ANOTHER METHOD:PLOT TIME (DAYS) VS LOG % CONC.REMAINING

READ DAYS TO 90% (LOG SCALE) (REF. FIG 2)

---------PLOT THIS WITH 1/T (REF. FIG 3)

T 90% IS READ DIRECTLY.EXCESS QUANTITY OF DRUG (OVER AGE) TO BE ADDED TO MAINTAIN 100% OF LABELED AMOUNT DURING SHELF LIFE (NOT FOR POTENT DRUGS)

DISADVANTAGES ONLY FOR DRUGS UNDERGO DEGRADATION WITH TIMENOT POSSIBLE TO FIND OUT ORDER OF REACTIONCHANGE IN DEGRADATION MECHANISM ABOVE CRITICAL TEMPERATURE IS IGNORED

HENCE ACCELERATED STABILITY TESTING IS : SUPPORTING ROLE NOW FOR NDA; O.K. ONLY FOR QUALITY CONTROL MEASURES.

STORAGE CONDITION IS NECESSARY DURING SHELF LIFE: TO BE MENTIONED IN LABEL.

ICH: STORAGE TEMPERATURE SPECIFIC RANGE BASED ON NATIONAL / REGIONAL REQUIREMENTS (AMBIENT / ROOM TEMPERATURE CONDITION NOT ALLOWED).

WHO: STORE 2 8OC (UNDER REFRIGERATION, NO FREEZING)STORE BELOW 8OC (UNDER REFRIGERATION)STORED BELOW - 8OC TO - 20OC(IN FREEZER)STORE BELOW -18OC (DEEP FREEZER)STORE UNDER NORMAL CONDITION (IN DRY, WELL VENTILATED PREMISE OF 15 - 25OC UPTO 30OC ; EXTRANEOUS ODOUR, CONTAMINATION, INTENSE LIGHT TO BE EXCLUDED).STORAGE CONDITION AT THE COUNTRY OF USE ALSOFOLLOW F.I.F.O (FIRST IN FIRST OUT SYSTEM)ALSO F.I.F.E.O (FIRST IN FIRST EXPIRY OUT)

STRESS TESTING FOR DS AND DP: (DATA OUTSIDE LABELED CONDITION )

SINGLE BATCH OF MATERIAL EFFECT OF ACCELERATED TEMPERATURE (EG. 50O, 60O.) HUMIDITY (75% RH OR ABOVE), OXIDIZATION, PHOTOLYSIS, HYDROLYSIS OVER DIFFERENT pH WITH SOLUTION OR SUSPENSION

TO ESTABLISH INTRINSIC STABILITY BY STUDYING DEGRADATION PATHWAYS AND MECHANISMS, DEGRADATION PRODUCTS AND TO ESTABLISH SUITABLE ANALYTICAL PROCEDURE AND ITS VALIDATION (THEREFORE STRESS TESTING WILL NOT PREDICT PHYSICAL CHANGES). SINCE IT MAY OCCUR DURING SHIPPING.

ALTHOUGH PRODUCTS OF HIGHER STRESSES UNLIKELY IN STORAGE CONDITION, (RESULT FROM INTEGRAL PART OF SUBMISSIONS).

THE CONTENT OF AMPOULES ARE ANALYSED AT DIFFERENT TIME INTERVALS

AMPOULE CONTAINING O2 ABOVE THE SOLUTIONAMPOULE MARKAMPOULE CONTAINING NITROGEN GAS ABOVE THE SOLUTIONAMPOULE MARK1.EXPOSED TO LIGHTA1EXPOSED TO LIGHTB12.EXPOSED TO HEATA2EXPOSED TO HEATB23.STORED IN DARKA3STORED IN DARKB3

THE RESULTS ARE SUMMARIZED AS FOLLOWS:

DECOMPOSITION IN ALL THE AMPOULES IRRESPECTIVE OF THE AMPOULES HAVING OXYGEN OR NITROGEN ABOVE THE SOLUTION INDICATES HYDROLYTIC DECOMPOSITION.

DEGRADATION BY OXIDATION IS INDICATED BY THE DECOMPOSITION IN ONLY THREE GROUPS OF AMPOULES (A1,A2 AND A3) CONTAINING OXYGEN IRRESPECTIVE OF EXPOSURE TO LIGHT, HEAT OR DARKNESS.

A PHOTOCHEMICAL REACTION IS INDICATED BY THE DECOMPOSITION ONLY IN AMPOULES A1 AND B1 GROUPS EXPOSED TO LIGHT.

THERMAL DECOMPOSITION IS INDICATED BY THE DECOMPOSITION ONLY IN A2 AND B2 AND NOT IN ALL THE OTHER AMPOULES.

IN A SIMILAR WAY, THE EFFECT OF PH ON DECOMPOSITION OF DRUG SOLUTIONS CAN BE CARRIED OUT.

BRACKETING AND MATRIXING DESIGNSFOR STABILITY TESTING OFNEW DRUG SUBSTANCES AND PRODUCTS (ICH Q1D)BRACKETING is the design of a stability schedule such that only the extremes of certain design factors are tested at all time points.

MATRIXING is the design of a stability schedule such: that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested.

BRACKETINGSAMPLES ON THE EXTREMES ARE TESTED AT ANY TIME FOR STABILITY Eg. (A) CONTAINER SIZE (B) DOSAGE STRENGTHS.

STABILITY OF INTERMEDIATE SAMPLES ARE REPRESENTED BY THE EXTREMES.

CONDITION: (a) FOR MATERIAL OR CONTAINER COMPOSITION AND TYPE OF CLOSURE ARE SAME FOR ALL. (b) FOR STRENGTH TO BE CLOSELY RELATED IN COMPOSITION (TABLETS WITH DIFFERENT COMPRESSION WEIGHTS / CAPSULE WITH DIFFERENT FILL WEIGHTS BUT SAME COMPOSITION)

MATRIXING:(STATISTICAL DESIGN)

FRACTION OF TOTAL NUMBER OF SAMPLES TESTED AT ANY SPECIFIED SAMPLING POINT & AT SUBSEQUENT SAMPLING POINT, DIFFERENT SETS OF SAMPLES OF TOTAL NUMBERS

RESULT WILL REFLECT ON STABILITY OF ALL SAMPLES

DIFFERENCES IN THE SAMPLES OF SAME PRODUCT MAY BE DIFFERENT

WHEN MORE THAN ONE VARIABLE, REDUCED TESTING DESIGN OF MATRIX DICTATED BY ALL FACTORS DESIGN TO BE DISCUSSED WITH LICENSING AUTHORITIES IT IS ESSENTIAL ALL BATCHES ARE TESTED INITIALLY AND END OF LONG TEST TERM TESTING

EXPORT OF BULK & FORMULATIONS(RS. IN CRORES)HOWEVER 2% OF WORLD CONTRIBUTIONREASON : STRINGENT REGULATORY & APPROVAL REQUIREMENTSTABLE - 3

YEARFORMULATIONSBULK DRUGSTOTAL92-93553.70856.061410.0393-94771.801009.601781.4094-951336.30842.802179.1095-961028.001518.002536.002005 2006900016,00025,000

BENEFITS OF HARMONISATIONSAVING OFTIMERESOURCESCOST (SAVINGS OF 2/3 COST OF IN DUPLICATION TEST FOR OTHER COUNTRIES)POTENTIAL EXPORT POSSIBILITY IN THE GLOBAL TRADEINDIA IS FAST PICKING UP.

KINETICS AND DRUG STABILITYGENERAL CONSIDERATIONS AND CONCEPTSRatevelocity with which the chemical reaction occurs. drug A drug BIf the amount of the drug A is decreasing with respect to time (i.e. the reaction is going in a forward direction:

The negative sign concentration of drug A decreases with time.Since the amount of drug B is increasing with respect to time, the rate of the reaction : The positive sign the concentration of the product B increases with time.Usually, in pharmacokinetics, only the parent (or pharmacologically active) drug is measured experimentally. metabolites / products of the decomposition of the drug may not be known or may be very difficult to quantitate. Hence, The rate of a reaction is determined experimentally by measuring the disappearance of drug A at given time intervals.

Order of a reactionIf C is the concentration of drug A, the rate of decrease in C (of drug A) can be expressed by a general expression as function of time, t as: dC/dt=-kCn Where k = rate constant and n = order of the reaction.If n = 0 then the reaction is called a zero-order reaction,if n = 1 then the reaction is called a first-order reaction.if n = 2 then the reaction is called a second order reaction.If a reaction is:aA + bB Productand if the reaction rate = k [A] a [B]b then the reaction is said to be (a + b) order.

Molecularity of a reactionover all reaction take place by several steps. Each step elementary step. order of each elementary step the number of reactant molecules taking part in that reaction, hence, the order of an elementary step called the molecularity of the reaction.Specific rate constantThe constant k associated with a single step (elementary) reaction called a specific rate constant for that reaction. If the specific rate constant of an elementary reaction is changed by some factors (like temperature, light, catalyst, solvents etc.) overall reaction rate will also change.

Zero-Order ReactionsIf the concentration of drug A is decreasing at a constant time interval t. then the rate of disappearance of drug A is expressed as:

dC/dt= -koThe term k0 is the zero-order rate constant and is expressed in units of concentration / time[e.g. (mg/ml)/ min).] C = k0 t + C0where C0 is the concentration of drug at t= 0. Half life of the reaction:At t = t1/ 2 C = C0.Replacing t and C in above eq. C0. = k0 t1/ 2 + C0.or,t1/ 2 = c0/2ko Graphical representation

Fig: Plot of Conc vs. timeFig. Rate vs. time

1st Order ReactionsIn first order reaction the rate of reaction is proportional to the concentration of the drug remaining and can be expressed as:dC/dt=- kC1dC/C= - k.dtC = C0 e k tlog C = -kt/2.303 + log C0Half life of the reactiont1/2 = 0.693/k

Graphical representation

k is the specific reaction rate,A is a constant known as the Arrhenius factor or Frequency factorEa is the energy of activationR is the universal gas constantT is the absolute temperatureINFLUENCE OF TEMPERATURE AND OTHER FACTORS ON REACTION RATEInfluence of temperatureThe speed of many reaction increases about two to three times with each 100 C rise in temperature. The effect of temperature on a rate constant of a reaction is given by the equation, first suggested by Arrhenius,A plot of log k vs 1/T yields a slope equal to Ea / 2.303 R from which the value for the energy of activation ( Ea) and Arrhenius factor (A) can be calculated.So Ea = Slope x 2.303 Rand A = 10 intercept

Influence of light (Photoreaction)Light energy (like heat) provide the activation energy necessary for a reaction to occur. The energy unit of light radiation is photon = equivalent of 1 quantum of energy.The photochemical reaction rate depends on the wavelength of light, intensity of light and the number of photons actually absorbed by the material.Examples: Ergosterol, under UV light, transforms into Vitamin D.Oxidation of benzaldehyde by light.Adriamycin, furosemide, menadione, nifedipine, sulfacetamide, theophylline etc. undergoes photo-degradation.

Study of photo reactions are required to prepare suitable packaging material for the product e.g. color-glass bottles or paper box or aluminium foil etc.

Reactant (solvent ) Product

The following facts are found:If polarity of product > polarity of reactant then reaction rate increases if the solvent is more polar.If polarity of product < polarity of reactant then reaction rate increases if the solvent is less polar.Influence of solvent

Influence of catalytic speciesThe rate of a reaction is influenced by the presence of a catalyst. Equillibrium constantCatalyst : a substance that influences the rate of a reaction but itself remain unchanged chemically.increases both forward and backward reaction rate, hence cannot change K.does not affect the yield of the product also.Only makes the reaction faster.Negative catalyst: reduces the rate of reaction.e.g. Phosphoric acid reduces the reaction rate of H2O2 H2O + O2.Inhibitor: A substance that reduces the rate of reaction and itself gets changed chemically.Homogeneous catalysis: If the catalyst and the reactants remain in the same phase.e.g. Hydrochloric acid catalyses the hydrolysis of sugar.Heterogeneous catalysis: If the catalyst and the reactants are in separate phases.e.g. Platinum powder is suspended in reaction medium of hydrogenation reaction.Catalyst poison: Substances those reduces the action of catalyst.e.g. Copper acts as catalyst in hydrogenation of ethylene. Carbon monoxide acts as poison of copper.Promoters: Substances those increases the activity of a catalyst.e.g. Ferric ion (Fe3+) acts as catalyst in decomposition of hydrogen peroxide. Cupric ion (Cu++) act as promoter to ferric ion.

ACCELERATED STABILITY STUDYAccelerated stability testing:Instabilities in modern formulations are often detectable only after considerable storage periods under normal conditions.To reduce the time required to obtain information, various tests that involve storage of the products under conditions that accelerate decomposition have been introduced.

Objectives of accelerated stability tests:the rapid detection of deterioration in different initial formulations of the same product this is used in selecting the best formulation from a series of possible choices;the prediction of shelf life, which is the time a product will remain satisfactory when stored under expected or directed storage condition; andthe provision of rapid means of quality control, which ensures that no unexpected change has occurred in the stored product.All these objectives based on obtaining a more rapid rate of decomposition by applying to the product a storage condition that places a higher stress or challenge to it when compared with normal storage conditions.

Common high stresses or challenges:(a) TemperatureAn increase in temperature causes an increase in the rate of chemical reactions. The products are therefore stored at room temperatures greater than room temperature. The nature of the product often determines the range covered in the accelerated test.Samples are removed at various time intervals and the extent of decomposition is determined by analysis. (b) HumidityStorage of the product in atmospheres of high humidity will accelerate decomposition that result from hydrolysis. Marked acceleration will be obtained if a naked product (i.e. not enclosed in a container) is subjected to these tests. This type of stability tests are useful in determining the degree of protection that should be afforded by the container.(c) LightA source of artificial light is used to accelerated the effect of sunlight or sky light. the source should emit a similar distribution of radiant energy to that in sunlight because photochemical reactions involve the absorption of light of definite wavelengths.Day light fluorescent lamps provide a satisfactory source.

THE PREDICTION OF SHELF-LIFE:Say, the room temperature = 250C

Method 1: Prediction from Arrhenius plot:Concentration of undecomposed drug is plotted against time (hr) at various temperature above room temperature (250C)The stability constants at various temperatures are plotted in Arrhenius plot (i.e. log k vs 1/T).From the Arrhenius plot the stability constant at room temperature i.e. (k 25) is determined by extrapolation.

Let us assume that when the drug is 10% decomposed it is to be said that the product has expired.i.e.at time t = 0 hourdrug concentration remaining = 100%at time = t hourdrug concentration remaining = 90%

Now we have to calculate the time t.

If the product is kept at room temperature (250C) then the following equation from 1st order kinetics may be used:log C = log Co (k25 /2.303) x tor, t= (2.303 / k25)=(2.303/k25) log (Co / C)= (2.303/k25) log (100/90)Since k25 value is known, therefore t can be calculated.

Method -II: Simplified techniques for stability prediction:

Free and Blythe describe such technique for liquid products where the decomposition behaves according to the general kinetic laws.In this case log(% of drug remaining) is plotted against time (in days).From the graph the time for the potency (concentration) to fall to 90% of the original value (i.e t90% ) are read at different temperature.Then the log (t90%) is plotted against (1/T) and the time at 250C gives the shelf life of the product (in days).Expiry time = Time required for 90% degradation at room temperature (i.e. 250C) = t25.

REFERENCESSARANJIT SINGH, UNDERSTANDING ICH HARMONIZATION PROCESS. THE EASTERN PHARMACIST, 60 (474), 21 (1997).SARANJIT SINGH, ICH GUIDELINES THE LATEST DEVELOPMENT. THE EASTERN PHARMACIST, 60 (479), 41 (1997).SARANJIT SINGH, AN UPDATE ON ICH PROCESS. THE EASTERN PHARMACIST, 61 (487), 43 (1998).SARANJIT SINGH, DRUG STABILITY GUIDELINES FOR INTERNATIONAL REGISTRATION OF PHARMACEUTICLAS, PHARMATIMES, 28 (8), 29 (1997).

W. R. FAIWEATHER, T. Y. D. LIN AND R. KELLY, REGULATORY DESIGN AND ANALYSIS ASPECTS OF COMPLEX STABILITY STUDIES, J. PHARM. SCI. 85, 1322 (1995)J. D. HAYNES, WORLD-WIDE VIRTUAL TEMPERATURES FOR PHARMACEUTICAL PROCESS STABILITY TESTING. J. PHARM. SCI. 60, 927 (1971)W. GRIMM, EXTENSION OF THE INTERNATIONAL CONFERENCE ON HARMONIZATION TRIPARTITE GUIDELINE FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS TO COUNTRIES OF CLIMATIC ZONES III & IV. DRUG DEV. IND. PHARM. 24, 313 (1998)SARANJIT SINGH, DRUG STABILITY TESTING LABORATORY: TIME TO CHANGE THE PRIMITIVE LOOK. THE EASTERN PHARMACIST, 37 (435), 53 (1994)

W. R. YOUNG, ACCELERATED TEMPERATURE PHARMACEUTICAL PRODUCT STABILITY DETERMINATIONS. DRUG DEV. IND. PHARM., 16, 551 (1990)J. T. CARSTENSEN, 1995,DRYG STABILITY PRINCIPLES AND PRACTICES, 2ND ED., MARCEL DEKKER, NEW YORK.P. WESSELS, M. HOLZ, F. ERNI, K. KRUMMEN AND J. OGROKA, STATISTICAL EVALUATION OF STABILITY EVALUATION OF STABILITY DATA FOR PHARMACEUTICAL PRODUCTS FOR SPECIFICATION SETTING, DRUGDEV. IND. PHARM., 24 313 (1998)ICH GUIDELINES ARE AVAILABLE AT http:/www.fda.gov/guidance

ICH Q1B PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS (Nov. 1996)ICH Q1C STABILITY TESTING FOR NEW DOSAGE FORMS (Nov. 1996)ICH Q3A IMPURITIES IN NEW DRUG SUBSTANCES (JAN 1996)ICH Q3B IMPURITIES IN NEW DRUG SUBSTANCES (NOV 1996)ICH Q5C QUALITY OF BIOTECHNOLOGICAL PRODUCTS; STABILITY TESTING OF BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTS (JULY 1996)

ICH Q6A SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS: CHEMICAL SUBSTANCES (DEC 2000)ICH Q6B SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS: BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTS (AUGUST 1999)

*****************COMMITTEE FOR PROPRIETORY MEDICINE**************************************************************************