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Chapter 4   drug cosmetic stability
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Chapter 4 drug cosmetic stability

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Introduction to Stability Testing of Drugs and Cosmetics. Includes the 3 types of stability test methods (Real time studies, Accelerated studies and Stress tests). Contains the WHO and ICH Climatic ...

Introduction to Stability Testing of Drugs and Cosmetics. Includes the 3 types of stability test methods (Real time studies, Accelerated studies and Stress tests). Contains the WHO and ICH Climatic Zones for Real time, Intermediate and Accelerated tests). Classification of Packaging materials. Container- Closure Systems.

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  • Appearance - color Physical Attributes – phase separation of suspensions, softening of creams, melting of suppositories, resuspendability or caking of suspensions. Functionality Tests – dose delivery per actuation in aerosols and MDI’s, diffusibility of transdermal patches
  • CLIMATE OR REGION can be used interchangeably.
  • Occurred when seven people died after taking pain-relief medicine capsules that had been poisoned. The Investigation, took place in September and early October 1982, in the Chicago area of the United States. This led to reforms in packaging OTC drugs and to Federal Anti-tampering Laws. On October 5, 1982, it issued a nationwide recall of Tylenol products; an estimated 31 million bottles were in circulation, with a retail value of over US$100 million. The case remains unsolved and no suspects have been charged. A $100,000 reward, offered by Johnson & Johnson, McNeil's parent company, for the capture and conviction of the "Tylenol Killer", has never been claimed.
  • In addition to the primary container, the stability of the product should also be examined in the presence of IV administration components if the product could be exposed to these conditions.
  • Ex.: Pelletized Unit Loads
  • POLYOLEFINS – USED AS SUBSTITUTES FOR PVC.
  • Type NP – Soda Lime Glass Not Suitable Container for Parenterals

Chapter 4 drug cosmetic stability Presentation Transcript

  • 1. Chapter 3 DRUG AND COSMETIC STABILITY TESTINGAsst. Prof. Ma. Lourdes Licsi- Mojares, R. Ph.School of PharmacyCEU Manila 1
  • 2. DRUG /COSMETIC STABILITY THE ABILITY OF A PARTICULAR DRUG OR COSMETIC FORMULATION AND PACK TO REMAIN WITHIN ITS SPECIFICATIONS. (PHYSICAL, CHEMICAL, THERAPEUTIC, TOXICOLOGICAL , MICROBIOLOGICAL) 2
  • 3. STABILITY TESTS / STUDIES IT EMBRACES THE STUDY OF THE CHANGES THAT TAKES PLACE IN A DRUG OR COSMETIC FORMULATION AND PACK WITHIN CERTAIN SPECIFICATIONS, UNDER VARYING ENVIRONMENTAL CONDITIONS. 3
  • 4. FACTORS WHICH ACCELERATE DRUG / COSMETIC STABILITY LIGHT / RADIATION TEMPERATURE MOISTURE / RELATIVE HUMIDITY (rH) AGITATION INVERSION METHOD OF MANUFACTURE GRAVITY 4
  • 5. CONSIDERATIONS IN STABILITY STUDIES Specific compendial requirements Changes / degradations in the physical appearance of the product Loss of activity / potency of the APIs Degree / rate of degradation of the product 5 Loss of elegance
  • 6. STABILITY TESTINGIt embraces the evaluation /study ofthe following changes:S – SUBJECTIVEP – PHYSICALC - CHEMICALM - MICROBIOLOGICAL 6
  • 7. Types of Changes DefinitionSubjective Changes that affect theChanges physiological – psychological perceptions of the patient towards the productPhysical Changes Changes that affect the physical form of the drug molecule compositionChemical Changes Changes that affect the structure of the drug molecule (break down in the type of bonds)Microbiological Changes that involves theChanges development of microorganisms into the product formulation 7
  • 8. Types of Changes ExamplesSubjective Changes the color, odor,Changes texture, size, shape, consistency and appearance of the drug product.Physical Changes Polymorphism, Precipitation, Sublimation, Evaporation, Condensation, Crystallization, LiquefactionChemical Changes Oxidation, Hydrolysis, Chelation, ComplexationMicrobiological Contamination of the drugChanges product with bacteria and /or fungi. 8
  • 9. SIGNIFICANT CHANGE THE FAILURE OF A DRUG SUBSTANCE TO MEET ITS SPECIFICATIONS. 9
  • 10. SIGNIFICANT CHANGE INCLUDES: A 5% CHANGE IN ASSAY, FROM ITS INITIAL VALUE. THE FAILURE TO MEET ITS ACCEPTANCE CRITERIA FOR POTENCY WHEN USING BIOLOGICAL OR IMMUNOLOGICAL PROCEDURES 10
  • 11. SIGNIFICANT CHANGE INCLUDES: ANY DEGRADATION PRODUCT’S EXCEEDING ITS ACCEPTANCE CRITERION. FAILURE TO MEET THE ACCEPTANCE CRITERION FOR; 1. APPEARANCE 2. PHYSICAL ATTRIBUTES 3. FUNCTIONALITY TESTS 11
  • 12. SIGNIFICANT CHANGE INCLUDES: FAILURE TO MEET THE ACCEPTANCE CRITERION FOR pH. FAILURE TO MEET THE ACCEPTANCE CRITERIA FOR DISSOLUTION IN 12 UNITS. 12
  • 13. SIGNIFICANCE OF STABILITY TESTS It intensifies the degradation loss with time. Prediction of shelf life and expiry date of a product. Determines the appropriate storage condition of a formulation / pack. Validation of a particular method, procedure or system. 13
  • 14. SHELF LIFEIt indicates the period of timewhen the formulation or pack isexpected to remain “FIT FORUSE,” under ordinary conditionsof handling and storage in theenvironment (warehouse, home,supermarket rack or pharmacyshelf). 14
  • 15. EXPIRY / EXPIRATION DATE The direct application and / or interpretation of the knowledge gained through stability testing. It limits the period during which a pharmaceutical /cosmetic /veterinary preparation may be expected to have its labeled potency, provided it has been stored as directed on its labeling. 15
  • 16. PHYSICAL STABILITY ITS PRIMARY SIGNIFICANCE APPEARANCE A drug/ cosmetic product is expected to look fresh, elegant, professional no matter how long it stands on display in the pharmacy shelves and supermarket racks. 16
  • 17. PHYSICAL STABILITY ITS PRIMARY SIGNIFICANCE UNIFORMITY (In vitro / In vivo BA/BE) An assurance that the patient will receive the proper amount of API’s in each dose of the drug product. 17
  • 18. PHYSICAL STABILITY ITS PRIMARY SIGNIFICANCE AVAILABILITY The API/s must be made available to the patient throughout the expected shelf life of a drug / cosmetic preparation. 18
  • 19. TYPES OF STABILITY TESTS / STUDIES ACCELERATED / SHORT TERM STUDIES Its purpose is to; 1. predict the shelf life 2. establish the expiration date 19
  • 20. TYPES OF STABILITY TESTS / STUDIES ACCELERATED / SHORT TERM STUDIES Designed to increase the rate of chemical degradation and physical change of the drug using exaggerated /harsher storage conditions, as part of the formal stability test program. 20
  • 21. TYPES OF STABILITY TESTS / STUDIES ACCELERATED / SHORT TERM STUDIES It involves the use of EXAGERRATED / HARSHER conditions of temperature and moisture, to test the stability of formulations. 21
  • 22. WALK – IN STABILITY ROOM 22
  • 23. STABILITY CHAMBERS 23
  • 24. 24
  • 25. TYPES OF STABILITY TESTS / STUDIES LONG TERM / REAL TIME STUDIES The product is exposed under the USUAL / NORMAL conditions of humidity and temperature. Makes use of WHO / ICH Global Zones or Climatic Zones. 25
  • 26. TYPES OF STABILITY TESTS / STUDIES LONG TERM / REAL TIME STUDIES Its purpose is to determine the appropriate storage conditions of the product. It monitors the degradation of the actives under real conditions and real time. 26
  • 27. TYPES OF STABILITY TESTS / STUDIES LONG TERM / REAL TIME STUDIES Experiments on the physical, chemical, biopharmaceutical and microbiological characteristics of the drug, during and beyond the expected shelf life and storage periods, under storage conditions expected in the intended market. 27
  • 28. STABILITY REFRIGERATORS 28
  • 29. CLIMATIC ZONES and CONDITIONS ( World Health Organization)Zone I TEMPERATE CLIMATEZone II SUB-TROPICAL and (with possibly high humidity) MEDITERRANEAN CLIMATEZone III HOT and DRY/ HUMID CLIMATEZone IV HOT and VERY HUMID CLIMATE 29
  • 30. GLOBAL ASSESSMENT OF STABILITY ZONE % MEAN TEMPERATURE ANNUAL rH RANGE TEMPERATUR ETEMPERATE LT 20.5 – 21 0 C 45% 21 0 C(I)MEDITE- 20.5 – 24 0 C 60% 26 0 CRRANEAN(II)HOT AND MT 24 - 31 0 C 40% 31 0 CDRY (III)VERY HOT MT 24 - 31 C O 70% 31 C 0 30
  • 31. INTERNATIONAL CONFERENCE ON HARMONIZATION ( ICH ) STABILITY ZONES ZONE TYPE OF CLIMATEZONE I TEMPERATE ZONEZONE II MEDITERRANEAN / SUB-TROPICAL ZONEZONE III HOT DRY ZONEZONE IV HOT HUMID / TROPICAL ZONEZONE IV b ASEAN TESTING CONDITIONS HOT / HIGHER HUMIDITY 31
  • 32. ICH LONG-TERM STABILITY TESTINGCLIMATIC TEMPERATURE HUMIDITY MINIMUMZONE DURATIONZONE I 21 0 C (+/- 2 0 C) 45 % rH +/- 5% rH 12 monthsZONE II 25 0 C (+/- 2 0 C) 60 % rH +/- 5% rH 12 monthsZONE III 30 0 C (+/- 2 0 C) 35 % rH +/- 5% rH 12 monthsZONE IV 30 0 C (+/- 2 0 C) 65 % rH +/- 5% rH 12 monthsZONE IV b 30 0 C (+/- 2 0 C) 75 % rH +/- 5% rH 12 monthsREFRIGERATE 5 0 C (+/- 3 0 C) NO HUMDITY 12 monthsDFROZEN -15 0 C (+/- 5 0 C) NO HUMIDITY 12 months 32
  • 33. ASEAN MEMBER COUNTRIES (assigned to Zone IV)Brunei Darrusalam MyanmarCambodiaPhilippinesIndonesiaSingaporeLao PDR (Laos) Thailand 33
  • 34. ICH ACCELERATED AND INTERMEDIATE TESTING CONDTIONSCLIMATIC TEMPERATURE HUMIDITY MINIMUMZONE DURATIONACCELERATED 40 0 C +/- 2 0 C 75 % rH +/- 5% rH 6 monthsAMBIENTACCELERATED 25 0 C +/- 2 0 C 60 % rH +/- 5% rH 6 monthsREFRIGERATEDACCELERATED 5 0 C +/- 3 0 C NO HUMIDITY 6 monthsFROZENINTERMEDIATE 30 0 C +/- 2 0 C 65 % rH +/- 5% rH 6 months 34
  • 35. TYPES OF STABILITY TESTS / STUDIES STRESS TESTS Purposes: 1. Elucidate degradation pathways 2. Identify the products of degradation 3. Validate analytical procedures 35
  • 36. TYPES OF STABILITY TESTS /STUDIES STRESS TESTS : PARAMETERS USED 1. Temperature of 50 0 C, 60 0 C onwards in 10-degree increments. 2. RH greater than 70%, where appropriate. 3. Light Testing 36
  • 37. TYPES OF STABILITY TESTS / STUDIES STRESS TESTS : PARAMETERS USED4. Susceptibility to Oxidation5. Susceptibility to Hydrolysis (across a wide pH range) 37
  • 38. STABILITY TEST SCHEDULES Within the 1 st year of study – every 3 months Within the 2 nd year of study – every 6 months Over the 3 rd year of study and above - Annually 38
  • 39. MANUFACTURING OVERAGES OVERAGING ADDITION OF AN EXCESS OF AN ACTIVE IN AN UNSTABLE DRUG PREPARATION TO COMPENSATE LOSS DURING MANUFACTURE OF THE PREPARATION. IT SHOULD BE WITHIN LIMITS COMPATIBLE WITH THERAPEUTIC REQUIREMENTS. 39
  • 40. CONDITIONS / SITUATIONS AT WHICH OVERAGING IS JUSTIFIABLE The labile / unstable active cannot be possibly standardized. The overage allows an even equilibrium of the content of the actives within acceptable limits. 40
  • 41. CONDITIONS / SITUATIONS AT WHICH OVERAGING IS JUSTIFIABLE Clinical studies show that the overage is therapeutically safe. The lower limit proposed for the decrease in strength, applies only at the end of the validity period for unstable formulations. 41
  • 42. MANUFACTURING OVERAGELIMITS (based on % labeled potency) ANTIBIOTICS NMT 3 % VITAMINS NMT 30% DRY, SOLID DOSAGE NMT 15% FORMS LIQUIDS NMT 20% SUPPOSITORIES, NMT 25% SEMI-SOLIDS , AEROSOLS 42
  • 43. CONTAINER – CLOSURE SYSTEMS ICH Guidelines for Pharmaceutical Development outlines the requirements for container – closure systems for drugs and biologics. 43
  • 44. Chicago Tylenol Murders of 1982 The poisonings were code-named “TYMURS” by the FBI. This involved “Extra Strength” Tylenol capsules (McNeil Consumer Healthcare) were laced by “potassium cyanide .” 44
  • 45. Chicago Tylenol Murders of1982 45
  • 46. Chicago Tylenol Murders of1982 46
  • 47. CONTAINER – CLOSURE SYSTEMS The choice of materials for primary packaging should be justified. A possible INTERACTION between the formulation and the container or label should be considered. 47
  • 48. CONTAINER – CLOSURE SYSTEMS The container – closure system should maintain the integrity of the formulation throughout the shelf life of the product. 48
  • 49. PACKAGING MATERIALS CLASSIFICATION PRIMARY / IMMEDIATE PACK Materials which comes in direct contact with the drug/cosmetic formulation. It is the immediate container itself, used to contain or hold the product. 49
  • 50. BOSTON-ROUND BOTTLES, amber 50
  • 51. BOSTON-ROUND BOTTLES, clear 51
  • 52. FRENCH SQUARE BOTTLES, clear 52
  • 53. STANDARD WIDE-MOUTH BOTTLE, clear 53
  • 54. PACKER BOTTLES, WIDE-MOUTH, amber 54
  • 55. BLAKE WIDE-MOUTH HDPE BOTTLE 55
  • 56. LEAK-RESISTANT NARROW- MOUTH PET BOTTLE 56
  • 57. LEAK-RESISTANT NARROW-MOUTH PET BOTTLES, amber 57
  • 58. PACKAGING MATERIALS CLASSIFICATION SECONDARY PACK Packaging “outside” of the primary pack. It is also used to group primary packs together. 58
  • 59. PACKAGING MATERIALS CLASSIFICATION SECONDARY PACKAGING MATERIALS Unit Labels Unit Boxes Drug Inserts Cotton Plugs Tape Seals Tamper-Evident Seals Pamphlets Brochures 59
  • 60. PACKAGING MATERIALS CLASSIFICATION TERTIARY PACK Used for bulk product handling, warehouse storage and transport shipping. 60
  • 61. CONTAINER – CLOSURE SYSTEMS: PROBLEMS Adsorption of INSULIN and some small molecules has been demonstrated to readily occur in polyvinyl chloride (PVC) bags and tubing when these drugs were present as additives in IV admixtures. 61
  • 62. CONTAINER – CLOSURE SYSTEMS: PROBLEMS Thermoplastic polymers poses certain issues as primary packaging materials for ophthalmic solutions and some SVP’s . 62
  • 63. PHARMACEUTICAL GLASS Composed primarily of SILICON DIOXIDE TETRAHEDRON, which is modified with oxides such as; sodium aluminum potassium boron magnesium iron 63
  • 64. Glass Type Composition General DescriptionType I Silicone dioxide Highly resistant Boric oxide Borosilicate glassType II Sodium oxide Soda Lime Calcium oxide Treated glass SO2 treatmentType III Sodium oxide Soda Lime Calcium oxide GlassType NP Sodium oxide Soda Lime Calcium oxide Glass not suitable for Non – containers of parenteral parenterals 64
  • 65.  The product maybe protected by the use of amber or light resistant glass container instead of a flint / colorless glass. FLINT / COLORLESS glass – light transmission value is above 470 mu AMBER / LIGHT RESISTANT glass – light transmission value is above 300 mu 65
  • 66.  High molecular weight polymers, include: a. POLYETHYLENE (PET) b. POLYSTYRENE (PS) c. POLYPROPYLENE (PP) d. POLYVINYL CHLORIDE (PVC) e. POLYOLEFIN 66
  • 67.  Lightness of weight, resistance to impact, lower transportation costs and lower losses due to less container damages. Versatility in container design and consumer acceptance / preference. Serves a dual function of both package and applicator for ophthalmic, otic and nasal solutions; and topical lotions. 67
  • 68. The advent of newer techniques in drug distribution, dispensing and inventorycontrol (in hospitals and drugstores) thatrequire different types of packaging (such asstrip/ blister packs, disposable plasticsyringes) for unit dose drug delivery. a. collapsible PET bags for IV fluids b. collapsible tubes for ointments c. plastic vials for capsules and tablets d. compact-type container for oral contraceptives 68
  • 69.  PERMEABILITY of plastic containers to atmospheric gasses and to moisture. LEACHING of the constituents from the plastic container into the formulation. SORPTION (ab and/or ad) of drug molecules or ions on the plastic materials. 69
  • 70.  Used as jars and tubes for disperse systems having a consistency of a soft paste, gel, cream or ointment. Aluminum and plastic-coated aluminum are the trend now in producing jars and collapsible tubes. 70
  • 71. 71
  • 72.  When in contact with the liquid contents, it may cause the absorption of the active/s, preservatives and other formulation components. Extraction of one or more components of the rubber closure into the solution  Maybe corrected by: 1. Use of epoxy-clinging material 2. Use of teflon (tetrafluoroethylene polymer). 72
  • 73. PROOF-READING LABEL AND BOXES PARAMETERS TEXT COLOR SIZE THICKNESS GRAIN DIRECTION SEALABILITY / ADEQUATE PASTE CLEANLINESS SURFACE FINISH SHAPE 73
  • 74. PHYSICAL INSPECTION OF CONTAINERS PARAMETERS SHAPE VOLUME FINISH OPENING DIAMETER HEIGHT WEIGHT THICKNESS 74
  • 75. PHYSICAL INSPECTION OF CONTAINERS PARAMETERS COLOR CLARITY LEAK TORQUE PRINT PEELING OF PAINT CLEANLINESS LIGHT TRANSMISSION STRESS CRACK RESISTANCE 75
  • 76. INSTRUMENTAL METHOD OF ANALYSIS OF CONTAINERS IDENTIFICATION INFRA-RED PROPERTIES THERMAL ANALYSIS EXTRACTABLE SUBSTANCES NON-VOLUMETRIC RESIDUE MOISTURE CONTENT RESISTANCE TO WATER ATTACK WATER VAPOR PERMEATION / TRANSMISSION 76
  • 77. DESIRABLE PROPERTIES OF CLOSURES FIT THE TREAD OF THE CONTAINER SIT ON THE CONTAINER WITHOUT TILTING PRODUCE NO LEAKS REASONABLY TIGHT-FITTING ELEGANT LOOKING SHOULD NOT ROTATE CONTINUOUSLY 77