Stability protocols for different dosage forms by sachin jain


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Stability protocols for different dosage forms by sachin jain

  2. 2. OVERVIEW 1 • Introduction to stability 2 • Stability testing & product development 3 • Essential definitions 4 • Stability testing protocols & report 5 • Stability protocols of API 6 • Stability protocols for diff. dosage forms • Evaluation of stability results 7 8 • conclusion2 5/25/2012
  3. 3. INTRODUCTION TO STABILITY STABILITY : Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its • Physical • Chemical • Microbiological • Therapeutic • Toxicological Specifications.3 5/25/2012
  4. 4. POTENTIAL INSTABILITY ISSUES OF FPP’s  Loss/increase in concentration of API  Formation of (toxic) degradation products  Modification of any attribute of functional relevance  Alteration of dissolution time/profile or bioavailability  Decline of microbiological status  Loss of package integrity  Reduction of label quality  Loss of pharmaceutical elegance and patient acceptability4 5/25/2012
  5. 5.  Stability testing is an integral part of pharmaceutical development.  It is an evolutionary concept covering the life cycle of pharmaceutical product development.  In early discovery phase the primary focus is to generate stability characteristics of a chemical /biological entity.  In later stages ,the goal is to establish shelf life for formulations packaged in final package intended for commercial introduction.5 5/25/2012
  6. 6. STABILITY TESTING PRINCIPLES CAN BE SUBDIVIDED IN TO VARIOUS STAGES OF DRUG DEVELOPMENT  Discovery phase  Pre clinical stage  Pre-IND stage  IND stage  Product development stage  NDA stage  Approved product stage  Revised product stage6 5/25/2012
  7. 7. DISCOVERY PHASE • To help select the most satisfactory chemical entity possessing the right pharmacological, toxicological & pharmaceutical profile. • The pharmaceutical profile is mostly focused towards the optimum chemical and physical stability characteristics. • To select the right physical form(base, salt ,ester). • These studies help establish the boundaries with in which one must operate to design formulations.7 5/25/2012
  8. 8. PRE CLINICAL STAGE • The development of early dosage form for pre clinical testing in humans require an extensive stability evaluation. • Preliminary stability testing on all formulations must be carried out using stability indicating assays in accordance with GLPs. • It requires an entrance assay prior to the initiation of toxicological testing and an exit assay, must be performed at the end of the studies.8 5/25/2012
  9. 9. PRE-IND STAGE Pre-formulation & stability evaluation of chemical entity is carried out according to ICH guidelines. DOSAGE FORM PARAMETERS SOLID Temperature, humidity, photo degradation. Solutions pH, ionic strength, additives In addition to normal preformulation evaluations ,forced degradation studies under highly stressed stability conditions is under taken.9 5/25/2012
  10. 10. IND STAGE • Accelerated and normal storage temperature testing of drug substance and for clinical formulation must be initiated. • The goal of these studies should be to generate information to insure that the clinical formulations are likely to remain stable during the planned clinical studies.10 5/25/2012
  11. 11. PRODUCT DEVELOPMENT STAGE • Intermediate stability testing is done in this stage. • Interim stability testing is conducted to establish the maximum time for which a drug product can be stored in interim containers for further processing.11 5/25/2012
  12. 12. NDA STAGE • Formal stability program is established for generation of stability data for registration applications. • The stability of drugs should be evaluated in containers used for marketing. • Care should be exercised in selection of the size, surface-to volume ratio of the container.12 5/25/2012
  13. 13. APPROVED PRODUCT STAGE • The goal of the stability evaluation program during this phase is to confirm or extending the expiration date. • The commitment in this stage mandates that any batch that is found out of specification will be with drawn from the market.13 5/25/2012
  14. 14. REVISED PRODUCT STAGE • Most products undergo post approval changes. • They may be internally driven or externally driven. • Internally driven : changing size & shape of dosage forms, changes in package design and others. • Externally driven : deletion of dyes, formulation changed and others14 5/25/2012
  15. 15. STABILITY PROTOCOL AND REPORT 1. Batches tested 2. General information 3. Container/closure system 4. Literature and supporting data 5. Stability-indicating analytical methods 6. Testing plan 7. Test parameters 8. Test results 9. Other requirements (post-approval commitments) 10. Conclusions15 5/25/2012
  16. 16. ESSENTIAL DEFINITIONSRe-test dateThe date after which samples of an API should be examined to ensure that thematerial is still in compliance with the specification and thus suitable for use in themanufacture of a given FPP.Shelf life (expiration dating period, conformance period)The time period during which an API or a FPP is expected to remain within theapproved shelf-life specification, provided that it is stored under the conditionsdefined on the container label.16 5/25/2012
  17. 17. Formal stability studies Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of an API or the shelf life of a FPP. Stress testing – forced degradation (API) Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. Stress testing – forced degradation (FPP) Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photostability testing and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation17 5/25/2012 development.
  18. 18. API FPP (Active pharmaceutical (Finished pharmaceutical ingredient) product)18 5/25/2012
  19. 19. STABILITY PROTOCOL - API19 5/25/2012
  20. 20. Guidelines for drug substance (API) and drug product(FPP)20 5/25/2012
  21. 21. STRESS TESTING IN API Stress testing of the API can help identify the likely degradation products, which, in turn, can help establish the degradation pathway. stress testing may be carried out on a single batch of the API. It should include the effect of temperature, humidity. Storage conditions Testing period* pH ± 2, room temperature 2 weeks pH ± 7, room temperature 2 weeks pH ± 10-12, room temperature 2 weeks21 H2O2, 0.1-2% at neutral pH, room 2 weeks 5/25/2012 temperature
  22. 22. FORMAL STABILITY STUDIESIn general an API should be evaluated under storage conditions (with appropriatetolerances) that test its thermal stability and, if applicable, its sensitivity tomoisture. The storage conditions and the lengths of studies chosen should besufficient to cover storage and shipment. Minimum time period Type of study Storage condition covered by data at submission 25°C ± 2°C/60% RH ± 5% RH Long term or 12 Months 30°C ± 2°C/65% RH ± 5% RH 30°C ± 2°C/65% RH ± 5% RH 6 Months Intermediate22 Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 Months5/25/2012
  23. 23. Photostability testing of new drug substances & products Photostability testing studies include: •Test on drug substance. •Test on exposed drug product outside the immediate pack. •Test on drug product in the immediate pack. •Test on drug product in the marketing pack. Light source Option 1: Artificial daylight lamp combining both visible & UV output similar to D65 & ID65. Option 2: Cool white fluorescent & near UV lamp23 5/25/2012
  24. 24. CONTAINER CLOSURE SYSTEMS The containers should be tested in all directions i.e. up right ,inverted ,on the side positions. This is done for long term and accelerated stability testing. This is to ensure that there are no adverse effects from any interaction is produced.24 5/25/2012
  25. 25. Testing frequency To establish the stability profile of drug substance For long-term storage 12 month study ◦ Testing frequency For intermediate storage 0 3 6 9 12 12 month study For accelerated storage - Testing frequency 6 month study 0 6 12 ◦ Testing frequency 0 3 6 (initial) (final) If significant change occur - A 4th time point can be included If significant change occur ◦ Increase the testing by adding sample at final time point25 5/25/2012 ◦ Include 4th time point in study design
  26. 26. STORAGE CONDITIONS AND STABILITY ZONES Based on the analysis the world is divided in to 4 climatic zones.26 5/25/2012
  27. 27. STABILITY RESULTS• A storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API.• A re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label.• An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 2oC and 65 5% RH for 2 years and at 40 2oC and 75 5%RH for 6 months.27 5/25/2012
  28. 28. EVALUATION – BEST CASE 1. No significant change at accelerated conditions within six (6) months. 2. Long-term data show little or no variability and little or no change over time. 3. Accelerated data show little or no variability and little or no change over time. 4. Statistical analysis is normally unnecessary. 5. Proposed retest period or shelf life = double of period covered by long-term data 6. A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data28 5/25/2012
  29. 29. Stability-indicating quality parameters 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 friability moisture content dissolution time degradation assay microbial purity29 5/25/2012
  30. 30. DOSAGE FORM CONSIDERATION Dosage form Evaluation Tablets Appearance,colour,odour,assay,degradation products,dissolution,moisture and friability. Hard gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial limits Soft gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial limits,pH,leakage. Emulsions Appearance,colour,odour,assay,degradation products, microbial limits,PH,viscosity,preservative content and distribution of dispersed phase globules.30 5/25/2012
  31. 31. Dosage form Evaluation Oral solutions Appearance,colour,odour,assay,degradation products, PH,microbial limits, preservative content. Oral suspensions Appearance,colour,odour,assay,degradation products, PH,microbial limits, preservative content,redispersibility,rheological properties, mean size and distribution of particle. Oral powders Appearance,colour,moisture,and reconstitution time. Inhalations and nasal sprays Appearance,colour,odour,assay,degradation products, dose content uniformity, microscopic evalution,water content, leak rate, microbial limits.Topical,opthalamic,ointments,creams,lotions,paste Appearance,clarity,colour,homgeneity,odour,ph,resus s,gels,solutions. pendibility,viscosity,particle size 31 5/25/2012 distribution,assy,degraation products,preservatives,microbial limits, weight loss.
  32. 32. CONCLUSION Stability studies should be planned on the basis of pharmaceutical R&D and regulatory requirements. Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date. The shelf life (expiry date) of FPPs is derived from formal stability studies. Variability and time trends of stability data mustbe evaluated by the manufacturer in order to propose a retest date or expiry date.32 5/25/2012
  33. 33. REFERENCES  Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C. T. Rhodes  Statistical Evaluation of Stability Data: Criteria for Change-over-time and Data Variability (PDA Journal of Pharmaceutical Science and Technology, Vol. 57. No.5, Sept./Oct. 2003, pp. 369-377)33 5/25/2012