Drug stability in dosage forms ( 2102)

1. Drug stability in dosage forms (2102) Howida Kamal Ibrahim, Ph.D Rehab Shamma, Ph.D Master degree in pharmaceutical sciences (Pharmaceutics) Master degree in pharmaceutical sciences (Industrial Pharmacy) Diploma of industrial pharmacy

2. Drug stability in dosage forms Drug substance Chemical degradation Physical degradation • Hydrolysis • Oxidation • Dehydration • Photodegradation • Transitions in crystalline states • Formation & growth of crystals • Moisture adsorption • Sublimation

3. Drug stability in dosage forms Drug substance Dosage form Drug substance Excepients Physical degradation Drug/Excepient interaction Biological degradation Packaging

4. Drug stability in dosage forms • Introductory overview • Reaction orders • Factors affecting reaction rate • Accelerated stability testing • Pre formulation • Kinetics of physical degradation • Physical testing of dosage forms • Packaging • Stability guidelines

5. Drug Stability, Principles and Practices By: J.T. Carestensen C.T. Rhodes

6. Introductory Overview • Stability is an essential quality attribute for drug products • Conformance period, shelf life and expiration date. • Modes of degradation • Potential adverse effects of instability in pharmaceutical products • The scope of stability concerns • Reasons for stability testing • The essential elements of a high-quality and cost effective stability program • Some possible strategies to improve shelf life

7. Stability is an essential property of drug products and the assignment of a shelf life is a routine regulatory requirement.

8. Stability is an essential property of drug products and the assignment of a shelf life is a routine regulatory requirement.

9. Conformance period, shelf life and expiration date Conformance period: is defined by the most vulnerable time-dependant quality attribute. Shelf life is = or < the conformance period and is usually a convenient round number. Expiration date on a product label is the date at which the shelf life ends for this batch (on storage at the recommended storage conditions). It is given only the month and the year (April’ 09) For 5-year shelf life, the practice is to give expiration dates for months of January or July.

10. Potential adverse effects of instability in pharmaceutical products Modes of degradation • Chemical • Physical • Biological (especially microbiological)

11. Potential adverse effects of Instability in pharmaceutical products • Loss of active • Increase in active concentration • Formation of toxic degradation products • Loss of content uniformity • Alteration in bioavailability • Decline of microbiological status • Loss of package integrity • Loss of pharmaceutical elegance and patient acceptability • Reduction of label quality • Modification of any factor of functional relevance

12. Potential adverse effects of Instability in pharmaceutical products Loss of active 110 % of labeled claim 100 90 6 12 18 24 Time (months)

13. Potential adverse effects of Instability in pharmaceutical products Loss of active 110 Linear regression % of labeled claim 100 90% confidence zone 90 95% one-sided lower confidence limit for the mean 6 12 18 24 Time (months) Least squares regression analysis Order of the reaction

14. Potential adverse effects of Instability in pharmaceutical products Loss of active Shelf life values are assigned to a product rather than a batch ?

15. Potential adverse effects of Instability in pharmaceutical products Increase in active concentration 95% one-sided upper confidence limit for the mean 110 % of labeled claim Linear regression 100 90 6 12 18 24 Time (months) Least squares regression analysis

16. Potential adverse effects of Instability in pharmaceutical products Formation of toxic degradation products If a drug degrades to a molecular species that is toxic Ex. 4-Epianhydrotetracycline from tetracycline 4-Epianhydrotetracycline exhibit a 250-fold higher toxicity Potential levels of toxic degradation products are of considerable importance for the approval of stability overages for new products

17. Potential adverse effects of Instability in pharmaceutical products Loss of content uniformity Suspensions are the drug delivery systems that most likely to show a loss of content uniformity as a function of time • Stability study should include physical such as: • Ease of re-dispersion • Sedimentation volume

18. Potential adverse effects of Instability in pharmaceutical products Alteration in bioavailability Bioavailability and bioequivalence are of great importance to evaluate the drug product quality Bioavailability (rate and extent of drug absorption) In vitro dissolution is an appropriate test to predict any possible clinically relevant modification of bioavailability or bioequivalence

19. Examples of bioavailability alterations problems: Hardening of the surface of tablets Pellicle formation with hard gelatin capsules a skin-like film on the gelatin capsules

20. Potential adverse effects of Instability in pharmaceutical products Decline of microbiological status The microbial status of all pharmaceutical products should be evaluated with time Sterile products Non-sterile products Should be free from all forms of life (vegetative & sporing) Extent of total bioburden Exclusion of pathogens

21. Potential adverse effects of Instability in pharmaceutical products Decline of microbiological status Change of microbial status with time ↑ of present m.o by reproduction >maximum permitted bioburden Ingress of m.o due to loss of package integrity Package integrity tests Quality of raw materials Manufacturing facility Manufacturing operation

22. Potential adverse effects of Instability in pharmaceutical products Decline of microbiological status In some parts of the world, Biological problems are not limited to the microbial one but rats, roaches, ants and other non-microbiological organisms can be responsible for stability problems

23. Potential adverse effects of Instability in pharmaceutical products Loss of package integrity Example: loss of back-off-torque for a plastic screw cap

24. Potential adverse effects of Instability in pharmaceutical products Loss of pharmaceutical elegance and patient acceptability Loss of pharmaceutical elegance includes any aspect of the product that might suggest that the product is somehow substandard or variable

25. Potential adverse effects of Instability in pharmaceutical products Loss of pharmaceutical elegance and patient acceptability ease of use loss of label adhesion speckling on tablet surface Batch to batch variations in appearance, taste or smell

26. Potential adverse effects of Instability in pharmaceutical products Reduction of label quality Any legibility problem

27. Potential adverse effects of Instability in pharmaceutical products Modification of any factor of functional relevance Any time dependant change of any functionally relevant attribute of a drug product that adversely affects safety, efficacy, patient acceptability or ease of use Example: adhesion aging of a transdermal patch

28. The scope of stability concerns • Bulk drug substance and excepients • Research and development formulation • Clinical trials materials • Marketed product • Product in the channel of distribution • Product under the control of the patient • In vivo stability • Reformulation, change of manufacturing site, troubleshooting, complaints

29. The scope of stability concerns (Raw materials) Bulk drug substance and excepients Just-in-time method In-house testing by the manufacturer Drug excepients Pharmacopeias No standards Comprehensive data due to manufacturers’ competitions Handbook of pharmaceutical excepients

30. The scope of stability concerns Research and development formulation No universally accepted procedures of evaluating stability of R&D formulae Accelerated testing Comparison with similar market products

31. The scope of stability concerns Clinical trials materials • FDA has issued specific requirements during clinical trials • All efforts are devoted to produce data that will convince a regulatory authority that a particular formulation, process and shelf life for a new or reformulated product are acceptable

32. The scope of stability concerns Marketed product The manufacturer continues stability studies by storing samples in stability storage areas and testing them to generate reliable stability data to assure that the marketed product continues to justify the assigned shelf life.

33. The scope of stability concerns Product in the channel of distribution Products could be subjected to instability issues during distribution Dropping off a truck back Staying in direct sun or freezing cold Regulations ?

34. The scope of stability concerns Product under the control of the patient Patient counseling Stress stability testing

35. The scope of stability concerns In vivo stability pH sensitive drugs (in the GIT)

36. The scope of stability concerns Reformulation, change of manufacturing site, troubleshooting, complaints An intermittent new study after marketing for a variety of reasons Complains of patients and health professionals Unexpected stability problems Change process Change site of manufacturing Change formulation

37. Stability testing

38. Stability testing aims to ensure the quality, safety and efficacy of drug products up to their expiration date. This means that all organoleptic, physiochemical, chemical and microbial test results must be within the shelf life tolerance ranges up to the end of the shelf life. Stability testing accompanies the development of a medicinal product from the first preliminary trials with the drug substance up to continuous production.

39. Reasons for stability testing • Our concern for patients’ welfare • To protect the reputation of the producer • Requirements of regulatory agencies • To provide a database that may be of value in the formulation of other products

40. Reasons for stability testing patients’ welfare Cost associated problems Discomfort Toxic degradation products Inconvenience Sub-potent levels

41. The over all stability programme can be divided into six steps:

42. Each stage covers 11 basic principles: • Selection of batches and samples • Test criteria • Analytical procedures • Specifications • Storage conditions • Testing frequency • Storage period • Number of batches • Packaging materials • Evaluation • Stability information

43. The essential elements of a high-quality and cost effective stability program • Commitment of the organization to quality • Firm grasp of underlying scientific theory • Up- to- date knowledge of all relevant policies of regulatory agencies and applicable pharmacopoeial standards • Effective communication between R&D, production, QC/ QA, complaints, and regulatory affairs • A general understanding of the limitations of the analytical methods used in the stability testing program • Careful monitoring of the stability budget • Managerial skills to coordinate and optimize the program

44. Some possible strategies to improve shelf life • Formulation • Process • Sampling and analytical • Statistical

45. Some possible strategies to improve shelf life • Formulation • Process • Sampling and analytical • Statistical

46. Some possible strategies to improve shelf life • Formulation The overage 110% 100% 90% 80% % Labeled Claim 0 100 200 300 400 Time (days)

47. Example Calculate the overage required to extend the shelf life of this product from ….. to ….. months. 110% 100% 90% 80% % Labeled Claim 0 5 10 15 20 25 30 35 Time (months)

48. Some possible strategies to improve shelf life • Formulation • Process • Sampling and analytical • Statistical

49. Some possible strategies to improve shelf life 3. Sampling and analytical 110 % of labeled claim 100 90% confidence zone 90 6 12 18 24 Time (months) Least squares regression analysis

50. Some possible strategies to improve shelf life 3. Sampling and analytical 110 % of labeled claim 100 90% confidence zone 90 6 12 18 24 Time (months) Least squares regression analysis