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.

1. Chapter 3
DRUG AND COSMETIC
STABILITY TESTING
Asst. Prof. Ma. Lourdes Licsi- Mojares, R. Ph.
School of Pharmacy
CEU 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 TESTING
It embraces the evaluation /study of
the following changes:
S – SUBJECTIVE
P – PHYSICAL
C - CHEMICAL
M - MICROBIOLOGICAL
6

7. Types of Changes Definition
Subjective Changes that affect the
Changes physiological – psychological
perceptions of the patient
towards the product
Physical Changes Changes that affect the
physical form of the drug
molecule composition
Chemical Changes Changes that affect the
structure of the drug molecule
(break down in the type of
bonds)
Microbiological Changes that involves the
Changes development of
microorganisms into the
product formulation 7

8. Types of Changes Examples
Subjective Changes the color, odor,
Changes texture, size, shape,
consistency and appearance
of the drug product.
Physical Changes Polymorphism, Precipitation,
Sublimation, Evaporation,
Condensation, Crystallization,
Liquefaction
Chemical Changes Oxidation, Hydrolysis,
Chelation, Complexation
Microbiological Contamination of the drug
Changes 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 LIFE
It indicates the period of time
when the formulation or pack is
expected to remain “FIT FOR
USE,” under ordinary conditions
of handling and storage in the
environment (warehouse, home,
supermarket rack or pharmacy
shelf).
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 CLIMATE
Zone II SUB-TROPICAL and
(with possibly high humidity)
MEDITERRANEAN CLIMATE
Zone III HOT and DRY/ HUMID
CLIMATE
Zone IV HOT and VERY HUMID
CLIMATE 29

30. GLOBAL ASSESSMENT OF STABILITY
ZONE % MEAN
TEMPERATURE ANNUAL
rH
RANGE
TEMPERATUR
E
TEMPERATE LT 20.5 – 21 0 C 45% 21 0 C
(I)
MEDITE- 20.5 – 24 0 C 60% 26 0 C
RRANEAN
(II)
HOT AND MT 24 - 31 0 C 40% 31 0 C
DRY (III)
VERY HOT MT 24 - 31 C
O
70% 31 C
0 30

31. INTERNATIONAL CONFERENCE ON
HARMONIZATION ( ICH )
STABILITY ZONES
ZONE TYPE OF CLIMATE
ZONE I TEMPERATE ZONE
ZONE II MEDITERRANEAN / SUB-TROPICAL
ZONE
ZONE III HOT DRY ZONE
ZONE IV HOT HUMID / TROPICAL ZONE
ZONE IV b ASEAN TESTING CONDITIONS
HOT / HIGHER HUMIDITY 31

32. ICH
LONG-TERM STABILITY
TESTING
CLIMATIC TEMPERATURE HUMIDITY MINIMUM
ZONE DURATION
ZONE I 21 0 C (+/- 2 0 C) 45 % rH +/- 5% rH 12 months
ZONE II 25 0 C (+/- 2 0 C) 60 % rH +/- 5% rH 12 months
ZONE III 30 0 C (+/- 2 0 C) 35 % rH +/- 5% rH 12 months
ZONE IV 30 0 C (+/- 2 0 C) 65 % rH +/- 5% rH 12 months
ZONE IV b 30 0 C (+/- 2 0 C) 75 % rH +/- 5% rH 12 months
REFRIGERATE 5 0 C (+/- 3 0 C) NO HUMDITY 12 months
D
FROZEN -15 0 C (+/- 5 0 C) NO HUMIDITY 12 months
32

33. ASEAN MEMBER COUNTRIES
(assigned to Zone IV)
Brunei Darrusalam Myanmar
Cambodia
Philippines
Indonesia
Singapore
Lao PDR (Laos) Thailand 33

34. ICH
ACCELERATED AND
INTERMEDIATE TESTING
CONDTIONS
CLIMATIC TEMPERATURE HUMIDITY MINIMUM
ZONE DURATION
ACCELERATED 40 0 C +/- 2 0 C 75 % rH +/- 5% rH 6 months
AMBIENT
ACCELERATED 25 0 C +/- 2 0 C 60 % rH +/- 5% rH 6 months
REFRIGERATE
D
ACCELERATED 5 0 C +/- 3 0 C NO HUMIDITY 6 months
FROZEN
INTERMEDIATE 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
USED
4. Susceptibility to Oxidation
5. 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 OVERAGE
LIMITS
(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 of
1982
45

46. Chicago Tylenol Murders of
1982
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
Description
Type I Silicone dioxide Highly resistant
Boric oxide Borosilicate
glass
Type II Sodium oxide Soda Lime
Calcium oxide Treated glass
SO2 treatment
Type III Sodium oxide Soda Lime
Calcium oxide Glass
Type 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 inventory
control (in hospitals and drugstores) that
require different types of packaging (such as
strip/ blister packs, disposable plastic
syringes) 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