ICH-Stability of finished products

ICH guide lines for stability, Accelerated stability testing in expiration dating of pharmaceutical dosage forms.

1. ICH GUIDELINES OF STABILITY STUDIES FOR FINISHED PRODUCTS Presented By: K. ARSHAD AHMED KHAN M.pharm , ( Ph.D ) Assistant Professor Department: PHARMACEUTICS Raghavendra institute of Pharmaceutical education and Research (RIPER) 1

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3. 12-11-2011 3 PHARMACEUTICAL PRODUCT STABILITY Stability of 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 and toxicological specification . Assurance that the packed product will be stable for its anticipated shelf life must come from an accumulation of valid data on the drug in its commercial package. Stability/ compatibility with various solvents, buffered solutions, and excipients considered for formulation developments

4. These stability data involves selected parameters that taken together from the stability profile . Pharmaceutical products are expected to meet their specification for identifying purity, quality and strength throughout their defined storage period at specific storage condition. The stability of pharmaceutical product is investigated throughout the various stages of the development process . The stability of the drug substance is first assessed in the preformulation stage . 12-11-2011 4 PHARMACEUTICAL PRODUCT STABILITY

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6. 12-11-2011 6 IMPORTANCE/ OBJECTIVES: Provide an 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. Establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. Because physical, chemical or microbiological changes might impact the efficiency and security of the final product.

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11. Where and Why? Stability Studies are preformed on ... Drug Substances (DS)  The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form. Drug Products (DP)  The dosage form in the final immediate packaging intended for marketing……. controlled and documented determination of acceptable changes of the drug substance or drug product 12-11-2011 11

12. Stability attributes / What are changes? Physical changes • Appearance • Melting point • Clarity and color of solution • moisture • Crystal modification (Polymorphism) • Particle size Chemical changes • Increase in Degradation • Decrease of Assay Microbial changes 12-11-2011 12

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14. 12-11-2011 14 ICH ICH stands for I nternational C onference on H armonization of Technical Requirements for Registration of Pharmaceuticals for Human use Objectives of ICH • Harmonization of registration applications within the three regions of the EU, Japan and the United States. • ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines. Tripartite guideline on stability testing of new drug substances and products (Q1A) in 1993, has become standard for stability evaluation in Japan, US, Europe.

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17. 12-11-2011 17 Testing scope for Solid dosage Physical-chemical properties – Appearance – Elasticity – Moisture – Hardness – Disintegration – Dissolution Chemical properties – Assay – Degradation Microbial properties Container closure system properties – Functionality tests (e.g. extraction from blister)

18. 12-11-2011 18 Testing scope for LIQUID FORMS for inj. and PARENTRAL Physical-chemical properties – pH – Loss on weight – Color & clarity of solution - Sterility Tests Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties - Pyrogen Testing Container closure system properties – Functionality tests - Leakage test

19. 12-11-2011 19 Testing scope for Oral liquid form Physical-chemical properties – pH – Color & clarity of solution – Viscosity – Particle size distribution (for oral suspensions only) Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties Container closure system properties – Functionality tests

20. 12-11-2011 20 Testing scope for SEMI SOLID FORMS Physical-chemical properties – Appearance, odor, homogeneity, consistency – Loss on weight, Viscosity – Content uniformity (within the container) Chemical properties – Assay – Degradation products & preservatives – Content preservatives – Degradation– Content antioxidants Microbial properties Container closure system properties – Functionality tests

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29. 12-11-2011 29 The design of the stability studies for the FPP should be based on knowledge of the behavior and properties of the API, information from stability studies on the API and on experience gained from preformulation studies and investigational FPPs. The purpose of stability testing is to determine shelf life of a finished pharmaceutical product (FPP). STABILITY STUDIES PROCEDURE

30. 12-11-2011 30 CLIMATIC ZONES The shelf life of a product depends on its storage temperature and humidity, these conditions vary from country to country. The four climatic zones recognized by ICH are Climatic zone Climate Temperature ( o C ) Humidity (% RH) Examples I Temperate 21 60 Canada, Russia, UK, etc., II sub-tropical 26 65 Japan, USA, etc., III Tropical dry 31 60 Australia, Argentina, etc., IV Tropical wet 31 70 India , Indonesia, brazil, etc.,

31. TYPE, SIZE, NUMBER OF BATCHES ICH/ WHO GUIDELINES- At least 3 primary batches of drug product, should be of the same FPP (finished pharmaceutical product), packaged in same container as proposed for marketing 2 out of 3 batches should be pilot scale batches. Stability to be performed on individual strength, dosage form, container type and size of the FPP. 12-11-2011 31

32. 12-11-2011 32 SPECIFICATION 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. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes, preservative content(e.g. antioxidant or antimicrobial preservative) and functionality tests (e.g. for a dose delivery system).

33. 1. ACCELERATED STABILITY STUDIES Storage condition of 40 C and relative humidity of 75% has been recommended for all the four zones for drug substances and drug products. Studies carried out for 6 months. Accelerated storage conditions must be at least 15 C above the expected actual storage temperature and appropriate relative humidity 12-11-2011 33

34. 2. LONG TERM STABILITY STUDIES Study is performed at 25 C/60% RH or 30 C/ 65% RH. Ideally 12 months data is to be generated but 6 months data is also acceptable in circumstances for submission of registration dossier, continued till end of shelf life. For parentrals stability has to carried out at 2-8 C. Liquid products packed in container with closures need to be stored in inverted position, to allow interaction with closure. (ex: sorption of preservative by rubber in vials) 12-11-2011 34

35. 12-11-2011 35 Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 60% ± 5% R.H or 30°C ± 2°C / 65% ± 5% R.H or 30°C ± 2°C / 75% ± 5% R.H. 12 months Intermediate 30°C ± 2°C / 65% ± 5% R.H. 6 months Accelerated 40°C ± 2°C / 75% ± 5% R.H. 6 months Storage conditions Drug products - General case

36. Drug products - packaged in Semi-permeable containers 12-11-2011 36 Study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C / 40% ± 5% R.H. or 30°C ± 2°C / 35% ± 5% R.H. 12 months Intermediate 30°C ± 2°C / 65% ± 5% R.H. 6 months Accelerated 40°C ± 2°C / NMT 25% R.H. 6 months Aqueous-based products packaged in semi-permeable containers should be evaluated for potential water loss.

37. 12-11-2011 37 Drug substances - intended for storage in a Refrigerator Study Storage condition Minimum time period covered by data at submission Long term 5°C ± 3°C 12 months Accelerated 25°C ± 2°C / 60% ± 5% R.H. or 30 °C ± 2 °C/65% ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH 6 months

38. Drug substances/Product- intended for storage in Freezer 12-11-2011 38 Study Storage condition Minimum time period covered by data at submission Long term -20°C ± 5°C 12 months

39. 12-11-2011 39 TESTING FREQUENCY Frequency of testing at the long-term storage condition should normally be every three months over the first year, every six months over the second year and annually thereafter throughout the proposed shelf-life. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g. 0, 3 & 6 months), from a six-month study is recommended Intermediate storage condition a minimum of four time points, including the initial and final time points (e.g. 0, 6, 9 & 12 months), from a 12-month study is recommended.

40. 12-11-2011 40 Evaluation Physical, Chemical, Biological And Microbiological tests, Container closure system properties Particular attributes of the dosage form Example: dissolution rate for solid oral dosage forms). Significant changes may occur.

41. 12-11-2011 41 SIGNIFICANT CHANGE A change from the initial content of API(s) of 5% or more detected by assay, or failure to meet the acceptance criteria for potency when using biological or immunological procedures. Any degradation product exceeding its acceptance criterion. Failure to meet the acceptance criteria for appearance, physical attributes and functionality test . (e.g. colour , phase separation, resuspendability , caking, hardness, dose delivery per actuation). However, some changes in physical attributes may be expected under accelerated conditions. (e.g. softening of suppositories, melting of creams, partial loss of adhesion for transdermal products)

42. STABILITY Ideally any commercial pharmaceutical product should have a shelf life of 5 yrs and should not fall below 90-95% potency under recommended storage. Various statistical tests are applied to ensure that the amount of drug remaining at the expiry date is above lower acceptable limit. In designing a solid dosage form it is necessary to know the inherent stability of the drug substance, excipients to be used, formulation procedure. 12-11-2011 42

43. Recent development in ICH Guidelines For Climatic Zones III and IV, the following standard conditions are recommended: Long-term testing: 30°C / 65% RH Accelerated conditions: 40°C / 75% RH This means that the "accelerated conditions" remain the same as in the Q1A(R) Guideline and only the "long-term storage conditions" have to be modified. 12-11-2011 43

44. 12-11-2011 44 3. PHOTOSTABILITY TESTING These studies are carried out to investigate effect of light on formulated product. Product is exposed to light, provided by artificial-day light fluorescent lamps, which emit long wave length U. V & visible light. Photostability studies are carried out in stability cabinet at 25 C and light dose of 1.2 million lux hours is used. The product must be stored in the exact same packing used for marketing the product. Photosensitive drugs show reduction in drug assay, colour change & formation of degradative product. Oxidation, and to some extent hydrolysis, is often catalysed by light.

45. PHOTOLYTIC STABILITY If light exposure causes unacceptable amount of change in the product, redesigning of packaging is required to increase light protection. Many drugs fade or darken on exposure to light and this leads to an aesthetic problem which can be controlled by using 1. Amber Glass Container 2. Opaque Container 3. Incorporating a Dye 12-11-2011 45

46. 4. STRESS TESTING In early stages of development during preformulation phase, qualitative assessment of susceptibility to hydrolysis, oxidation, light degradation, effect of pH and solid-state stability is performed Helps to identify the likely degradation products and establish degradation pathways and intrinsic stability of molecule. Stress testing is carried out on single batch. 12-11-2011 46

47. Forced degradation studies Acidic & Basic conditions. Dry heat exposure UV radiation exposure Influence of temperature Influence of ionic strength 12-11-2011 47

48. 12-11-2011 48 CHEMICAL DEGRADATION STUDY Hydrolysis- usually drugs such as esters, amides and lactams undergo hydrolysis. Oxidation Reduction- loss of electrons, gain of electrons. Auto oxidation also is responsible. Eg - tetracyclines , vit A, vit D, morphine. Photolysis - Compounds such as ascorbic acid, riboflavin, cyanacobalamine , folic acid undergo degradation on exposure to light. Sometimes coupled with thermal reactions. Isomerisation -Compounds get converted into a less effective form. Eg -Adrenaline solutions at low pH lose activity since its levo form is more stable than dextro form

49. ELEVATED TEMPERATURE STUDIES Tests are usually performed at 40 ,50 ,60 C in conjunction with ambient humidity for 30 days. Higher temperatures are also used, samples kept at highest temperature examined for chemical and physical changes at weekly intervals- if no change is seen after 30 days at 60 C, then Stability prognosis is excellent. Arrhenius Treatment is used to determine the degradation rate at lower temperature. 12-11-2011 49

50. STABILITY UNDER HIGH HUMIDITY CONDITIONS In presence of moisture, many drug substances hydrolyze react with other excipients or oxidize. These tests are performed by exposing the drugs to different relative humidity conditions Preformulation data of this type is helpful in determining if the material should be protected and stored in a controlled low-humidity environment or if aqueous based granulation should be avoided. 12-11-2011 50

51. STABILITY TO OXIDATION Stability to oxygen must be evaluated to establish that the final product should be packaged under inert atmosphere or it requires an antioxidant. This is investigated by comparing solutions heated with and with out flushing of oxygen The samples are kept in desiccators at 40% oxygen atmosphere for rapid evaluation. Process is repeated 3-4 times to assure 100% of desired atmosphere. 12-11-2011 51

52. EFFECT OF pH Most of the drugs are stable at pH 4 – 8. Effect of ph on stability is studied by heating solutions which are buffered at a range of pH values. Weakly acidic and basic drugs are most soluble in ionized form and instability is likely as they are charged. STABILITY TO HYDROLYSIS This is assessed by heating solution sin water, dilute acid and dilute base. 12-11-2011 52

53. Accelerated stability studies 12-11-2011 53 OBJECTIVE: To predict the shelf life of a product by accelerating the rate of decomposition, preferably by increasing the temperature SALIENT FEATURES: Gross picture on the stability Properties of degradation Mechanism of chemical reaction Establish an analytical method for estimation of drug & degraded product The temperature effect on the chemical degradation is estimated To establish efficacy, safety and toxicity

54. SHELF LIFE Self life (referred to as expiration dating period) is the time period during which a drug product is expected to remain within the approved specification for use, provided that it is stored under the conditions defined on the container label. 12-11-2011 54

55. SHELF LIFE 12-11-2011 55

56. References: http:// www.ich.org/products/guidelines/quality/article/quality-guidelines.html Aulton’s Pharmaceutics The Design & Manufacture of Medicines, Edited By Michael E. Aulton , Third Edition, Published by Churchill Livingstone Elsevier, Page No. 661 to 665 Essentials of Physical Pharmacy By C. V. S. Subrahmanyam , Page no. 51-65 Futscher , N.; Schumacher ,P.; Pharm. Ind. 34, 479 - 483 (1972) Grimm , W.; Krummen , K.; Stability Testing in the EC, Japan and the USA Wissenschaftiche Verlagsgesellschaft mbH, Stuttgart (1993) Grimm , W.; Drugs made in Germany 28, 196 - 202 (1985) and 29, 39 - 47 ( 1986) Dietz , R.; Feilner, K., Gerst, F.; Grimm, W.; Drugs made in Germany 36, 99 - 103, (1993) Haynes , J.D.; J. Pharm. Sci. 60, 927 - 929 (1971 ) 12-11-2011 56

57. Thank you……….! 12-11-2011 57