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Alaa Khedr Ph.D. Professor Faculty of Pharmacy King Abdulaziz University R بسم الله الرحمن الرحيم اللهم صلي.

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Presentation on theme: "Alaa Khedr Ph.D. Professor Faculty of Pharmacy King Abdulaziz University R بسم الله الرحمن الرحيم اللهم صلي."— Presentation transcript:

1 Alaa Khedr Ph.D. Professor Faculty of Pharmacy King Abdulaziz University R بسم الله الرحمن الرحيم اللهم صلي وسلم على سيدنا محمد STABILITY STUDY and EXPIRATION DATE

2 Stability Study and Expiration date Abbreviations APIActive Pharmaceutical Ingredient FDCFixed-Dose Combination FPPFinished Pharmaceutical Product GMPGood Manufacturing Practices ICHInternational Conference on Harmonization MAMarketing Authorization DRADrug Regulatory Authority MCA MCA: Medicine Control Agency FDA FDA: Food and Drug Administration NDA NDA:New Drug Applications ANDA ANDA:Abbreviated New Drug Applications EU EU: European Union EMEA EMEA:European Medicinal Evaluation Agency CPMP:Committee for Proprietary Medicinal Products NTA NTA:Notices To Applicant CDER / CFR CDER / CFR:Code of Federal Register

3 Stability Study and Expiration date Applicable guidelines Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) November 2003, ICH Guidance for Industry Q1E Evaluation of Stability Data U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) June 2004, ICH

4 Stability Study and Expiration date 1- The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended (1) storage conditions, (2) re-test periods and (3) shelf lives to be established Safety and efficacy.

5 Stability Study and Expiration date Written/Approved IQ/OQ/PQ, Data Logger Log sheets Compendia & Company Spcs Approved Docs ICH Stress testing Development Validation Represent. Chromatograms Batch size 3 batches Sampling protocol Purchase USP / Europ. RS Purchase Potential Impurities Storage cabinet Verified Stability Protocol

6 Stability Study and Expiration date Written/Approved Stability Protocol Who doing what? How to do the task Clear interpretation of procedures Stepwise manner Who doing what? How to do the task Clear interpretation of procedures Stepwise manner 1 Stability protocol is a signed/dated and approved document that describe the exact and clear procedure to start the stability testing of drug. The procedure should be described in a sequential stepwise manner, who doing what, how to do the task.

7 Stability Study and Expiration date Info. Source 1= Compendia (USP/BP) Info. Source 2= FDA / ICH guidelines (Limits / general Official Procedure) Info. Source 3= Supplier of raw material Info. Source 4= Company approved specs of API and PFP Info. Source 1= Compendia (USP/BP) Info. Source 2= FDA / ICH guidelines (Limits / general Official Procedure) Info. Source 3= Supplier of raw material Info. Source 4= Company approved specs of API and PFP 2

8 Stability Study and Expiration date IQ/OQ/PQ, Data Logger Log sheets IQ/OQ/PQ, Data Logger Log sheets Documentations are available= IQ/OQ/PQ Data Logger (calibrated)= Temp., Humidity Documents= Log sheets of operation, time, date How to operate the machine= SOP for machine 3

9 Stability Study and Expiration date Stability Cabinets + Data loggers !!!! HPLC Dissolution UV Karl Fisher Balances 3

10 Stability Study and Expiration date 1.A special cabinet for each condition 2.Should be qualified / calibrated 3.Monitor Temp. / humidity vs time. Time 4.Three General conditions required. Stability Cabinets Data loggers Deep freeze + Data loggers !!!! 3

11 Stability Study and Expiration date Data Loggers (Types) sensor probe / thermocouple

12 Stability Study and Expiration date Why we use Data Loggers ? How many sensor probe? How to position sensors? 1.To monitor Both, temperature and Relative Humidity along 24 hours. 2.To ensure consistency of the adjusted Temp. and RH. 3.Should be calibrated by supplier 4.Any deviation for NLT 6 hours, we should stop study and repeat using new samples. 5.Ex: Electricity shutdown, or instrument failer, no enough water inside instrument.

13 Stability Study and Expiration date Why we defined some products to be photosensitive, to which degree ? (use UV-A, 200 watts hours/m 2 ) Illumination : 1.2 million Lux hours Humidity range : 40% to 95% ± 2% RH Temperature range : 10 0 c to 50 0 C, ± C -- Use calibrated machine (candles/inch = ?) 3. Exposure time limit = ? (according to the limit of potential degradation products formed, and quinine HCl standard) Photostability Cabinets At least one primary batch Should be tested 3

14 Stability Study and Expiration date ICH Stress testing Development Validation Represent. Chromatograms ICH Stress testing Development Validation Represent. Chromatograms 4

15 Stability Study and Expiration date Stability indicating Analytical Method The method is able to discriminate between principle drug and the degradation products and/or impurities Method: Compendial methods are claimed to be stability indicating Rules: ICH stress Guideline Plus: Photodegradation products & reconstitution testing Monitoring: Peaks of Potential impurities & Degradation products (previously define the cause)

16 Stability Study and Expiration date Rules of Stress testing: -- expose drug subs. To abnormal environmental variables. -- Forced degradation to NLT 90%. -- Do not degraded the drug completely ? To provide selectivity of the method. Example of STRESS TESTING OF BETAHISTINE HCl Representative chromatograms of betahistine hydrochloride; heated in solid state [a], boiled in 1M NaOH [b], boiled with 1M HCl [c], extracted from tablet powder exposed to UV light [d], extracted from Betaserc tablets [e], and left to stand in 0.1% H 2 O 2 solution [f]. heated NaOH HCl UV light Betaserc tablets H2O2H2O2

17 Stability Study and Expiration date Chromatographic parameters* of TIA degraded with 1M HCl, (detection; UV at 254 nm, claimed TIA concentration is 250 ng/μL). n = 3. RT (min) (RSD) Area (RSD) Width (min) % Amount ± SD K R (RSD) αAsN (0.14) (0.06) ± (0.02) (0.88) ± (0.02) (0.27) (0.75) ± (0.26) (0.15) (0.58) ± (0.12) (0.11) (0.55) ± (0.08) (1.20) (1.00) ± (0.95) (0.02) 7442 (0.65) ± (0.01) * k capacity factor; α, selectivity coefficient; R, resolution; and As, peak asymmetry; N, USP plate count. Analytical Method Performance How to present the analytical HPLC method PERFORMANCE PARAMETERS

18 Stability Study and Expiration date Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets: appearance hardness friabilitymoisture content dissolution time degradants assay microbial purity S TABILITY - INDICATING QUALITY PARAMETERS What are the

19 Stability Study and Expiration date Batch size 3 batches Sampling protocol 5 Drug Product

20 Stability Study and Expiration date How many batches should be tested ? Batch size = ? Product unit Which Batches should be tested ? When should we repeat stability testing? How many batches should be tested ? Batch size = ? Product unit Which Batches should be tested ? When should we repeat stability testing? Selection of batches: 5

21 Stability Study and Expiration date Selection of batches: How many batches should be tested ? three, using 3 different batches of starting drug substance Batch size = ? Product unit Two pilot scale batches, third smaller if justified) Which Batches should be tested ? Stability studies should be performed on each individual strength and container size. When we should repeat stability testing? How many batches should be tested ? three, using 3 different batches of starting drug substance Batch size = ? Product unit Two pilot scale batches, third smaller if justified) Which Batches should be tested ? Stability studies should be performed on each individual strength and container size. When we should repeat stability testing? [1] In case of failed stability..! [2] Modification? using raw material from different manufacturer, excepients type/ratio change manufacturing procedure modified. change of package, closure. [3] Application For ANDA (Pharm. Bioeq) !! 5

22 Stability Study and Expiration date The stability testing should be conducted on the dosage form stored in the proposed containers / closure system for marketing. Container / closure systems:

23 Stability Study and Expiration date Purchase USP / Europ. Reference Standard) Purchase Potential Impurities Stored in Special Storage cabinet + log book (amount used, when, for what?) Verified (Melting point, IR, HPLC-RT as per USP/BP) Purchase USP / Europ. Reference Standard) Purchase Potential Impurities Stored in Special Storage cabinet + log book (amount used, when, for what?) Verified (Melting point, IR, HPLC-RT as per USP/BP) 6

24 Stability Study and Expiration date Major Variables Temperature Relative Humidity Light (Photostability) Stability after Reconstitution (dilution)

25 Stability Study and Expiration date Typical storage condition and study duration [a] General Case (PERMEABLE) [b] Drug Products packaged in IMPERMEABLE containers [c] Drug Products packaged in SEMIPERMEABLE containers [d] Drug Products intended for storage in refrigerator [e] Drug Products intended for storage in freezer [f] Drug Products intended for storage below -20 ºC

26 Stability Study and Expiration date Typical storage condition and study duration StudyStorage condition Minimum time period Frequency of sampling (months) Long-term 25 2 C / 60 % RH 5% RH or 30 2 C / 65 % RH 5% RH 12 months0,3,6,9,12,18,24 Intermediate 30 2 C / 65 % RH 5% RH 6 months0,3,6,12 Accelerated40 2 C / 75 % RH 5% RH6 months0,1,2,3,6 [a] General Case (PERMEABLE containers to moisture) It is up to the applicant to decide the tem/RH for long term. If 30 2 C / 65 % RH 5% RH is the long term, then NO INTERMEDIATE cond.

27 Stability Study and Expiration date Typical storage condition and study duration StudyStorage condition Minimum time period Frequency of sampling (months) Long-term 25 2 C or 30 2 C 12 months0,3,6,9,12,18,24 Intermediate 30 2 C 6 months0,3,6,12 Accelerated40 2 C6 months0,1,2,3,6 [b] Drug product packaged in IMPERMEABLE containers (to moisture or solvent loss) [b] Drug product packaged in IMPERMEABLE containers (to moisture or solvent loss) Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.

28 Stability Study and Expiration date Typical storage condition and study duration StudyStorage condition Minimum time period Frequency of sampling (months) Long-term 25 2 C / 40% RH 5% RH or 30 2 C / 35% RH 5% RH 12 months0,3,6,9,12,18,24 Intermediate 30 2 C / 65 % RH 5% RH 6 months0,3,6,12 Accelerated40 2 C / NMT 25 % RH6 months0,1,2,3,6 [c] Drug products stored in SEMIPERMEABLE containers It is up to the applicant to decide the tem/RH for long term. If 30 2 C / 35% RH 5% RH is the long term, then NO INTERMEDIATE cond. potential water loss Aqueous-based products packaged in semipermeable containers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. 5% loss of water (after 3 months) is considered significant change.

29 Stability Study and Expiration date Typical storage condition and study duration StudyStorage condition Minimum time period Frequency of sampling (months) Long-term 5 3 C 12 months0,3,6,9,12,18,24 Accelerated25 2 C / 60 % RH 5% RH6 months0,1,2,3,6 [d] Drug products intended for storage in a REFRIGERATOR [e] Drug products intended for storage in FREEZER StudyStorage condition Minimum time period Frequency of sampling (months) Long-term C 12 months0,3,6,9,12,18,24 [f] Drug products intended for storage BELOW -20 C Drug products intended for storage below -20°C should be treated on a case-by-case basis.

30 Stability Study and Expiration date THE SIGNIFICANT CHANGES

31 Stability Study and Expiration date THE SIGNIFICANT CHANGE IS DEFINED AS

32 Stability Study and Expiration date The assay value is still within the limits but the change during stability is more than 5.0% Example –Release assay limit: 95.0 – 105.0% –Release assay: 101.0% (within spec) –6-Month assay: 95.5% (within spec) –Loss in potency: 5.5%. –This is a significant change. E XAMPLE OF F AILED STABILITY

33 Stability Study and Expiration date Stability Data and Report

34 Stability Study and Expiration date attaché Real Chromatogramsattaché Records Ex: Karl fisher data, tablet weight.. Attaché auto dissolution readingsAttaché Cabinet temp./RH chart data. Batches tested Product name. Name and potency of active ingredient. Validated Stability indicating assay method Batch size. Batch number. Manufacturing site. Manufacturing date. Date stability study was started. Date sample(s) was withdrawn from chamber. Date of sample analysis. Storage conditions (e.g., 40 C / 75% RH). Container / closure system. Supplier and manufacturer of active ingredient(s). Supplier and manufacturer of container / closure system. Supplier and manufacturer of packaging components, cartons, etc. Cumulative tabulation of all tests result. Literature reviewRecords, reports, and certificates Conclusion, QA approval and Decision Stability Data and Report

35 Stability Study and Expiration date Additional or New Stability Data is Required if; Change in the route of synthesis of an API Change in composition of the FPP Change in immediate packaging of the FPP In case of failed stability, (chemical, instrumental, regulatory) using raw material from different manufacturer, excepients type/ratio change manufacturing procedure modified. change of package, closure.

36 Stability Study and Expiration date


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