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STABILITY OF

PHARMACEUTICAL PRODUCTS

Reference:
Remington: Essentials of Pharmaceutics,
2013, Chapter 4, Stability of Pharmaceutical
Products
藥品安定性問題(實例一)
降脂妥膜衣錠10毫克
Atorin F.C. Tablet
10mg

回收分級 2
文號 105年12月2日 FDA藥字第1050050118號(食藥署藥品組)
發布日期 2016/12/15
發文日期 2016/12/02
產品 降脂妥膜衣錠10毫克 Atorin F.C. Tablet 10mg
許可證字號 衛署藥製字第049543號
批號 AEB011
許可證持有者 健O生物科技股份有限公司
原因
廠商主動通報,說明案內批號藥品於長期安定性試驗結果發現主成分含量低
於原核准規格下限
備註
主成分: ATORVASTATIN (CALCIUM)
適應症:高膽固醇血症、高三酸甘油脂血症。
藥品安定性問題(實例二)
"美O" 美胰持續性藥效錠
30公絲 MEZIDE MR
TABLETS 30MG
"LOTUS"

回收分級 2
文號 105年3月1日 FDA藥字第1050007040號(食藥署藥品組)
發布日期 2016/03/17
發文日期 2016/03/01
產品 "美O" 美胰持續性藥效錠30公絲 MEZIDE MR TABLETS 30MG "LOTUS"
許可證字號 衛署藥製字第046070號
批號 效期106年10月前所有批號
許可證持有者 美O化學製藥股份有限公司
原因 廠商主動通報,說明藥品因長期安定性試驗結果發現不純物含量超出原核准規格
備註 主成分:GLICLAZIDE MICRONIZED
適應症:經飲食及體重控制無法達到理想效果之成人非胰島素依賴型糖尿病 (TYPE
II)。
"

藥品安定性問題(實例三)
信O" 夜舒寧 膠囊 YES-
Z CAPSULES "SL"

回收分級 2
文號 105年12月13日 FDA藥字第1051413384號(食藥署藥品組)
發布日期 2016/12/22
發文日期 2016/12/13
產品 "信O" 夜舒寧 膠囊 YES-Z CAPSULES "SL"
許可證字號 衛署藥製字第047305號
批號 6160839
許可證持有者 信O藥品工業股份有限公司
原因
廠商主動通報,說明案內批號藥品於長期安定性試驗之溶離度試驗結果未符合原
核准規格

備註
主成分: DIPHENHYDRAMINE HCL
適應症:在成人短期使用以緩解入睡之困擾
Introduction
Definitions

- Capability of a particular formulation, in specific


container/closure system, to remain within its physical,
chemical, microbiological, therapeutic and toxicological
specifications.
- A 90% labeled potency generally is recognized as the
minimum acceptable potency level. Consequently, shelf-
life is defined as the time in which 90% labeled potency
remained and all other specification limits are within
acceptance levels.
Regulatory (法規) Requirements

 Stability study requirements and expiration


dating (有效期) of a pharmaceutical product
are covered in the Current Good Manufacturing
Practices (cGMPs; 藥品優良製造規範), the USP
and the FDA and ICH guidelines
USP: The United States Pharmacopeia (美國
藥典)
FDA: Food and Drug Administration
ICH: International Council for Harmonisation
Introduction
Definitions
- By USP <1191>
Stability is defined as the extent to which a
product retains, within specified limits, and
throughout its period of storage and use (i.e.,
its shelf-life), the same properties and
characteristics that it possessed at the time of
its manufacture.
Five types of stability and the corresponding
criteria for Acceptable Levels of Stability:

1. Chemical- Each active ingredient retains its chemical integrity


and labeled potency, within the specified limits.
2. Physical- The original physical properties, including appearance,
palatability(適口性), uniformity(均一性), dissolution(溶離率) and
suspendability (浮懸性) are retained.
3. Microbiologic- Sterility (無菌度) or resistance to microbial
growth is retained according to the specified requirements.
Antimicrobial agents that are present retain effectiveness within
specified limits.
4. Therapeutic- The therapeutic effect (療效) remained unchanged.
(Note: Chemical, physical and toxicity changes could affect
therapeutic effect.)
5. Toxicological- No significant increase in toxicity (毒性) occurs.
(Note: Toxicity could arise from chemical changes, e.g., impurity
growth, and growth of microorganisms.)
Storage Conditions in USP Designations

Freezer: A place where temperature is maintained


thermostatically between -25 ºC and -10 ºC (-13 ºF
and 14 ºF) (冷凍)
Cold: Any temperature not exceeding 8 ºC (46 ºF). A
refrigerator is a cold place where the temperature is
maintained between 2 ºC and 8 ºC (36 ºF and 46 ºF)
Controlled Cold Temperature: Temperature maintained
thermostatically between 2 ºC and 8 ºC (冷藏)
Cool: Any temperature between 8 ºC and 15 ºC (46 ºF
and 59 ºF)
Room Temperature: The temperature prevailing in a
working area.
Controlled Room Temperature : A temperature
maintained thermostatically between 20ºC and 25ºC
(68ºF to 77ºF).
The usual or customary temperature range is identified as
20 to 25ºC, with the possibility of encountering
excursions (可接受之漂移範圍) in the 15 to 30ºC range.
Articles may be labeled for storage at “controlled room
temperature” or at “up to 25ºC ”, or other wording based
on the same mean kinetic temperature (平均動力學温度).
An article for which storage at controlled room
temperature is directed may, alternatively, be stored in
a cool place, unless otherwise specified in the individual
monograph or on the label.
Warm: Any temperature between 30ºC and 40ºC (86ºF
and 104ºF).
Excessive Heat: Any temperature above 40ºC (104ºF)
Protection From Freezing: Where, in addition to the risk
of breakage of the container, freezing subjects an article
to loss of strength or potency, or to destructive
alternation of its characteristics, the container label
should bear an appropriate instruction to protect the
product from freezing.
Dry Place: denotes a place that does not exceed 40%
average relative humidity (RH) at Controlled Room
Temperature or the equivalent water vapor pressure at
other temperatures
Mean kinetic Temperature (平均動力學温度)

Mean kinetic temperature is defined as a single calculated


temperature at which the degradation of an article would be
equivalent to the actual degradation that would result from
temperature fluctuations during the storage period. It is not
a simple arithmetic mean. The mean kinetic temperature is
calculated from average storage temperatures recorded over
a one-year period, with a minimum of twelve equally spaced
average storage temperature observations being recorded.
Average temperature may be determined using automated
recording devices or as the arithmetic mean of the highest
and lowest temperatures attained during the observation
period as measured on a high-low thermometer. The mean
kinetic temperature is calculated by the following equation:
H / R
Tk 
 e H / RT1  e H / RT2    e H / RTn 
 ln 
 n 
in which TK is the mean kinetic temperature; △H is the
heat of activation, 83.144 kJ·mole-1(eq. to 20
kcal/mole); R is the universal gas constant, 8.3144×10-
3 mole-1 degree-1; T is the average storage
1
temperature during the first time period (e.g., month);
T2 is the average storage temperature during the
second time period; Tn is the average storage
temperature during the nth time period, n being the
total number of average storage temperatures
recorded (minimum of twelve) during the observation
period; and all temperatures (T ) being absolute
temperatures in degrees Kelvin (˚K).
Climatic Zones (氣候區域)

For convenience in planning for packaging and storage,


and for stability studies, international practice identifies
four climatic zones, which are described in Table 1 on
the next slide. The United States, Europe, and Japan are
characterized by zones I and II. The values in Table 1
are based on observed temperatures and relative
humidities, both outside and in rooms, from which mean
kinetic temperatures and average humidity values are
calculated. Derived values are based on inspection of
data from individual cities and on allowances for a
margin of safety in assignment of these specified
conditions.
Note: Using 1991-1995 recorded data Taiwan MKT = 24.5˚C; with
77%RH.
FDA and ICH Guidelines
 Provide recommendations for
 the design of stability studies to establish appropriate expiry
and product storage requirements
 The submission of stability information for Investigational New
Drug (IND), New Drug Application (NDA) and Product License
Application (PLA)
 The following ICH Guidelines are related to stability:
 Q1A(R2) – Stability testing of new drug substances and drug
products
 Q1B – Photostability of new drug substances and drug products
 Q1C – Stability testing for new dosage forms
 Q1D – Bracketing and matrixing design for stability testing for
new drug substances and new drug products
 Q1E – Evaluation of stability data
 Q1F – Stability data package for registration applications in
Climatic Zones III and IV
Product Stability –
Samples of unstable products
Product Stability
Factors affect the stability of a drug product:
 Intrinsic stability (內在穩定性) of the active ingredient(s)
 Potential interaction between active and inactive
ingredients
 Manufacturing process
 Dosage form
 Container-closure system
 Environmental conditions during shipment, storage and
handling
 Length of time between manufacture and usage
Stability Evaluations of Drug Product
Physical Evaluations:
 Appearance, clarity, color, odor, pH, moisture
content, hardness, particle size distribution,
uniformity, viscosity, drug release rate, etc.
Chemical Evaluations:
 Potency (效價), degradation products(降解物含量),
etc.
Microbiologic Evaluations:
 Sterility, antimicrobial effectiveness (防腐劑有效性),
microbial enumeration (含菌量), total aerobic
microbial count (好氧性微生物總數), total
combined molds and yeasts count (黴菌及酵母菌
總數), etc.
Pharmaceutical Dosage Forms
and Stability Testing
Tablets
 Tablet size, shape, weight and
color
 Tablet friability (片劑脆性)test
 Tablet hardness (硬度)test
 Moisture content
Tablets (片劑)
Dissolution testing
 The in vitro test performed to
estimate bioavailability
 Critical for stability testing
 Plot % drug released vs. time
Tablets - Sample Dissolution Profile
Gelatin Capsules (膠囊)

 Mostly hard gelatin capsules (capsule shell contain 13 – 16%


of water)
 Soft gelatin capsule shells contain glycerin and a polyhydric
alcohol (多元醇) such as sorbitol. Sensitive to the water
content in the liquid filling.
 Maintaining water content is critical to capsule stability, use
desiccant or moisture barrier in packaging is important
 Gelatin cross-linking (pellicle薄膜formation) may cause
dissolution test failure. Use of digestive enzyme like pepsin
(胃蛋白脢) is allowed.
Suspensions (懸液劑)

 A stable suspension can be re-dispersed homogeneously with


moderate shaking and can be poured easily throughout its
shelf life
 Particle size distribution, crystal form, physiological availability
of the suspended active ingredient should not change
appreciably
 Flocculated (絮凝狀) suspensions are more stable
 Non-flocculated suspension can have rapid particle
settlement and difficult-to-disperse
 Reduce particle size of the suspended material or increase
the density and viscosity of the vehicle may reduce the
particle settling
 Temperature cycling to determine the tendency for crystal
growth
Solutions (溶液劑)

 Clarity, color, odor


 Crystal or precipitation may form at low temperatures
due to solubility
 pH, pourability, viscosity, isotonicity, specific gravity
 Microbial stability and pyrogen content
 For parenteral (injectable) products
 Sterility
 Particulate matters
 Rate of reconstitution for dry-packaged formulations
reconstituted prior to use
Emulsions (乳劑)
 A stable emulsion can be re-dispersed
homogenously to its original state with
moderate shaking and can be poured at
any stage of its shelf life
Emulsions
 Screening for emulsion formulations
Elevated temperature (e.g., 50-70˚C)
Coalescence (聚結) time
Refrigeration temperature
Freeze/thaw cycles (-10˚C to ambient
temperature)
Ultracentrifuge and measure
creaming rate
Formulation may experience scaling-
up issues (homogenizer types and
batch sizes)
Ointments
/Creams
 Ointment/cream (high viscosity suspensions of
active ingredients in a non-reacting vehicle)
 Ointment: Mineral oil based (e.g.,
Mentholatum® )
 Cream: Water based (e.g., toothpaste)
 Bleeding: e.g., Mineral oil separated from
ointment
 Texture consistency: measured by a
penetrometer, viscometer or rheometer
 Stability testing: color, odor, viscosity, softening
range, consistency, homogeneity, particle size
distribution, crystal form and sterility, etc.
Transdermal Patches
(經皮貼劑)

Stability testing: appearance, assay, impurities, drug


release USP<724> Apparatus 5, backing peel force
Metered-Dose Aerosols
(定劑量氣霧劑)
Metered-Dose Aerosols
 Drug product containing a propellant (推動劑)(e.g., chlorofluor
carbon (CFC) or hydrofluoralkane (HFA)) and drug, and a
mouthpiece (噴嘴)used to present an aerosolized drug to the
patients
 Many drug contact components in a metered-dose inhaler
 Leachable plasticizer is a big concern in selecting
components
 Stability testing: appearance, assay, impurities, plume
geometry (use high speed camera & laser), emitted dose per
unit, particle size distribution by various type of impactors
Dry-Powdered Inhaler
(乾粉吸入劑)

 A dry-powdered inhalation product consists of


drug with excipients delivered in a dry powered
form
 Must reproducibly delivery a specific amount of
drug at a particle size that can be deposited
into the lungs
 Stability testing: appearance, assay, impurities,
emitted dose, particle size distribution of the
emitted dose and water content
Nasal Inhaler

 A nasal inhalation product consists of drug with excipients


delivered from a nasal delivery system
 Must reproducibly deliver a specific amount of drug at a
particle size and plume that can be deposited into the nasal
membrane
 Particle size too large → not to be absorbed into the
nasal membrane or run out of nose
 Poor spray pattern → deposit the drug ineffective in the
nasal cavity
 Stability testing: appearance, assay, impurities, spray
content uniformity, particle (droplet) size distribution of the
emitted dose, spray pattern or/and plume geometry, weight
loss, preservative content, sterility and microbial testing
Incompatibility (不相容,配伍禁忌)
 Physical –
interactions which leads to a visible change. It may be in
the form of a gross precipitate, haze or color change.
 Chemical –
is classified as a reaction with no visible change.
 Therapeutic –
is defined as an undesirable pharmacological interaction
between two or more ingredients which leads to (1)
potentiation (增強) of the therapeutic effects of the
ingredients, (2) destruction (破壞) of the effectiveness of
one or more of the ingredients, or (3) occurrence of a
toxic manifestation within the patient.
Mechanisms of Drug Instability (Chemically)
I. Oxidation - Reduction
- Oxidation is a prime cause of product instability, and the
addition of oxygen or the removal of hydrogen is involved.
- When molecular oxygen is involved, the reaction is known
as auto-oxidation.
- Reduction reactions are much less common than oxidative
processes in pharmaceutical practice.

Oxidative reactions generally go by the way of


free radical mechanisms
Free radicals are atoms or molecules with one
or more unshared electrons,

e.g.:

Radicals are unstable reactive species.


General scheme of radical reaction:

Initiation Step

Propagation Step
(Chain Reaction)

Termination Step

In general, the reaction ends as non reactive species


formed.
Oxidation of Oil Solutions

Oil-soluble substances with a high degree of


unsaturation can undergo oxidation.
For example, the polyunsaturated fatty acids in
vegetable oils
CH3(CH2)4CH=CH-CH2-CH=CH-(CH2)7-COOH
Lineoleic acid (亞油酸), cis-double bonds at 9
and 12 positions
Oxidation of Oil Solutions (continued)

These unsaturated fatty acids undergo free radical


reactions in the presence of dissolved oxygen 
peroxides and cleavage to smaller molecular
weight saturated acids. The smaller acids, such as
butyric and valeric acid produce the rancid odor
(油臭味) observed with degradation of fats.

Oil soluble vitamin A and vitamin D, and K


formulations are prone to such oxidation.
Auto-oxidation:
an oxidation reaction initiated under normal
conditions in the presence of the oxygen molecules

Example: Epinephrine (腎上腺素) Adrenochrome (pink color)

The reaction could


be catalyzed by
polyvalent metal
ions (e.g., Cu2+,
Fe2+…). Adding
chelating agents in
the solution may
reduce the
influence.
Methods to Prevent Oxidation

1. In a closed ampoule, one can remove oxygen by


nitrogen gas purge.
2. Eliminate heavy metals with EDTA, a complexation
agent.
3. Control pH – profiles usually have region above or
below a given value where they are fairly stable.
4. Use an antioxidant – compounds with lower oxidation
potentials are more easily oxidized than the drug.
FREE RADICAL SCAVENGERS
Ideal Antioxidant

Stable and effective over a wide pH range


Soluble in its oxidized form
Colorless, Nontoxic, Nonvolatile and
Nonirritating
Effective in low concentrations
Thermal stable
Compatible with the container-closure
system and formulation ingredients
Water-Soluble antioxidants

Ascorbic acid (Vitamin C)


Sodium Bisulfite
Sodium metabisulfite
(Na2S2O5)
Sodium sulfite Ascorbic acid: a sugar acid with
antioxidant properties
Sodium thiosulfate

Sulfite compounds have been implicated as a source


of allergic response in asthmatic and hence are now
being removed from certain products.
Ascorbic acid

Dehydroascorbic acid
Oil-Soluble antioxidants
a-Tocopherol (a form of Vit. E),
Butylated hydroxy toluene (BHT),
Propyl gallate, etc.
a-Tocopherol

Tocols:

R1 = R2 = R3 = H : Tocol
R1 = R2 = R3 = Me, known as a-tocopherol, is designated a-
tocopherol or 5,7,8-trimethyltocol.

Tocopherol(s) is used as a generic descriptor for all mono-, di-, and


tri-methyltocols (i.e., α, β, γ and δ tocopherols). Thus, this term is
not synonymous with the term vitamin E. Vit. E refers to a group of
compounds include both tocopherols and tocotrienols.
Propyl gallate, or propyl 3,4,5-trihydroxybenzoate is an ester
formed by the condensation of gallic acid and propanol. It is an
antioxidant added to foods containing oils and fats to prevent
oxidation.

propyl gallate

Butylated hydroxytoluene (BHT) is a lipophilic (fat-soluble)


phenol, primarily used as an antioxidant food additive as well as in
cosmetics, pharmaceuticals, jet fuels, rubber, petroleum products.

Butylated hydroxytoluene (BHT)


II. Hydrolysis

- The rate of hydrolysis depends on the


temperature and pH of the solution.
- Compounds containing acyl groups attached to
electrophilic species X are subjected to
cleavage when encountering a nucleophilic
substance Y-.
Examples:
Hydrolysis reactions are often pH dependent and are
catalyzed by either hydronium ion or hydroxyl ion
Specific acid catalysis, hydronium ions (H3O+)
Specific base catalysis, hydroxyl ions (OH-)
pH Profiles: Examine the reaction rate constants at various pH conditions

When minimum
reaction rate
constant
observed at the
acid side (pH < 7)
indicates that the
hydroxyl ion has
the stronger
catalytic effect
Hydrolysis of
acetylsalicylic
acid (Aspirin)
Methods to Prevent Hydrolysis

1. Reduce temperature (typically, a 10˚C rise in storage


temperature could double or triple the rate of reaction)
2. Reduce water content or using non-aqueous solvents
3. pH control with a buffer system
4. Chemical structure modification to (a) reduce reactivity or (b) to
reduce the water solubility, e.g., change to less-soluble salt or
forming an ester of the parent compound.
5. Steric and polar complexations have been employed to alter the
rate of hydrolysis. e.g.: (a) cyclodextrin, (b) caffeine complexes
with local anesthetics such as benzocaine, procaine, tetracaine,
etc.
6. Solubilize the drug in a micelle (微胞) formed by surfactants.
e.g.: (a) Tweens, (b) Addition of Na-lauryl sulfate leads to an
18-times increase of the half-life of benzocaine.
III. Decarboxylation

- Decarboxylation usually is not encountered in


pharmacy, as relatively high heats of activation
(25 to 30 kcal/mole) are required for the
reaction.
Example:
p-aminosalicylic acid m-aminopherol + CO2
*This reaction follows first-order kinetics, is
highly pH-dependent and is catalyzed by
hydronium ions.
IV. Racemization

- A process of changing from an optically active


compound into a racemic compound or an optically
inactive mixture of corresponding R and S forms.
- Optical activity of a compound may be monitored
by polarimetry and reported in terms of specific
rotation. Chiral high performance liquid
chromatography (HPLC) could be used to test
enantiomeric purity of a sample.
- In general, racemization follows first-order kinetics
and depends on temperature, solvent, catalyst
and the presence or absence of light.
V. Epimerization
VI. Photochemical Reactions
 A drug can be affected chemically by radiation
of a particular wavelength only if it absorbs
radiation at that wavelength and the energy
exceeds a threshold
 Ultraviolet (UV) radiation, which has a high energy
level, is the cause of many degradation reactions
 Expose to UV illumination may cause photo-
oxidation and photolysis of covalent bonds
 Colored-glass containers are commonly used to
protect light-sensitive formulations
 The ICH Q1B guidance provides a systematic
approach for photostability testing of the drug
products
Photolytic Decomposition

Example: Chlorpromazine  Chlorpromazine sulfoxide


VII. Ionizing Radiation

 g-ray has been used for the sterilization of


certain pharmaceutical products
 At the usual sterilization dose, 2.5 mRad, it
seldom causes appreciable chemical
degradation
 In general, compounds in solid or frozen
state are more resistant to degradation
from ionizing radiation than those in liquid
form, e.g., vitamins
Estimation of Temperature Effect

An Approximation for Estimating the Temperature Effects


Ea (kcal/mole) Q5 (30 to 25 °C) Q10 (35 to 25 °C) Q15 (40 to 25 °C)
10 1.32 1.73 2.24
15 1.52 2.27 3.36
20 1.75 2.99 5.04
25 2.01 3.93 7.55
Q10 Method of Shelf-Life Estimation
Q10 is the ratio of two different reaction rate
constants derived from conditions of different
temperatures with 10 degrees difference,
which is defined as:
K ( T  1 0)
Q1 0 
KT
The Q10 approach, based on Ea, is independent
of reaction order and is described as:
[  Ea / RT ][ 1 /(T 10)1 / T ]
Q10  e
Ea: activation energy;
R: gas constant;
T: absolute temperature.
At temperature around 25 C,
Q10=2, Ea: 12.2 kcal/mole;
Q10=3, Ea: 19.4 kcal/mole;
Q10=4, Ea: 24.5 kcal/mole;
t 90 (T1 )
Q10 Shelf-life estimates: t 90 (T2 )  ( T / 10)
Q10

T is the difference in T1 and T2;

In most of the cases, using the Q10 value of 3 can


make a reasonable estimate.
Temperature Effect on Reaction Rate
In 1889, Arrhenius noted that the variation with
temperature of the rate constant of chemical
reaction could be expressed by:

Ea
k  A exp(  ) (1)
RT
Ea: Arrhenius activation energy
(the difference between the average energy of reactive
molecules and the minimum energy required for reactants
to proceed to products)
Ea
exp(  ) : the Boltzmann factor
RT
(which expresses the fraction of molecules having energies
greater than or equal to Ea )

A: is a factor related to the frequency of collisions.


R: the gas constant (8.314 joule/mol-K or 1.987 cal/K-mole).
Relation between activation energy and energy
levels of reactants, products and activated complex.
The logarithmic form of the Arrhenius equation:
E
ln k  ln A  a (2)
RT
If this equation is valid, a straight line is obtained
on plotting ln k against the reciprocal of the
absolute temperature.

From the slope of ln k vs. 1/T, we can estimate the


value of activation energy, Ea.
Differentiating Eq (2) with respect to temperature
gives:
d ln k Ea
 (3)
dT RT 2

and, then integrating the limits of k2 and k1 at


temperatures between T2 and T1 yields:

k2 Ea T2  T1
ln  ( ) (4)
k1 R T1T2

For estimating the long-term storage for a material is by


extrapolating data from studies performed at elevated
conditions.
An understanding of potential activation energy is
needed to make the long-term stability prediction.
This equation makes it possible to calculate Ea for
reaction when rate constants are known at two
temperatures, or to calculate rate constant at one
temperature if Ea and the rate constant at another
temperature are known.

Most solvolytic reactions of pharmaceuticals exhibit


activation energy in the range of 8 to 20 kcal/mole.

For Ea=8 kcal/mole, temperature increased from 25 C


to 35 C, can result in 1.5-fold increase in k.

For Ea=20 kcal/mole, temperature increased from 25


C to 35 C, can result in 3-fold increase in k.
Pharmaceutical Containers
 Pharmaceutical Container: A device that holds the drug and is,
or may be, in direct contact with the preparation.
 Immediate container: in direct contact with the drug all the
time. Liner and closure are considered to be part of the
container system.
 Container should not: Interact physically or chemically with
the formulation so as to alter the strength, quality, or purity
of its contents beyond permissible limits.
 Packaging components are subject to physical and chemical
changes that may be time-temperature dependent.
 Use “well-closed container” or “tight container” to prevent:
contamination by extraneous materials, loss of contents,
efflorescence (風化), deliquescence (潮解) or evaporation.
 Container/closure integrity (CCI) test, extractable and
leachable (E/L) tests of the packaging materials
Primary Packaging
- Critical to Stability Testing
Secondary and Tertiary Packaging
– may be required in stability testing
Glass
 Type I (borosilicate glass): has high hydrolytic
resistance, suitable for the products for parenteral
administrations (injectables)
 Type II (treated soda-lime glass): has a moderate
to high hydrolytic resistance and may be used for
parenteral products if stability data demonstrate
suitability
 Type III/Type NP (soda-lime glass): has moderate
hydrolytic resistance, typically for oral or topical
preparations
 Use colored glass for light sensitive products,
however, for the injectable products, colored
container may cause problem in detecting color
change and particulate matter in the formulation.
Plastics

 Plastic containers:
 Polyethylene (PE), Polystyrene (PS),
Polyvinyl Chloride (PVC),
Polypropylene (PP), etc.
 Blister packages
 PVC, PVDC (Polyvinylidenechloride),
Aclar (Polychlorotrifluoroethylene,
PVC-CTFE)
 Plastic composition, processing,
cleaning procedures, contacting media,
inks, adhesives, adsorption and
permeability affect the suitability of
plastic for pharmaceutical usage
Barrier Properties –
Moisture Vapor Transmission Rate (MVTR) in
g/m2/day @38°C/90%RH)
Cold Form Aluminium 0.00
Aclar ® 33C 0.08
Aclar ® UltRx2000 0.11 - 0.12
Aclar ® 22C 0.22
Aclar ® SupRx 900 0.23 - 0.26
Aclar ® 22A 0.31 - 0.34
PVC/80g PVDC 0.31
Aclar ® Rx160 0.39 - 0.42
Aclar ® 33C 0.42
PVC/60g PVDC 0.47 - 0.6
PVC/40g PVDC 0.7 - 0.75
PP 0.7 - 1.47
PVC 2.4 - 4
 Aclar ® is a registered trade mark of Allied Signal
Metals

Tin and aluminum tubes with


internal linings
Tin tubes can be coated with
wax or vinyl linings
Aluminum tubes are available
with lining of epoxy or phenolic
resin, wax, vinyl or a
combination of resin and wax
Closures

 Closures for the formulations must be studied


together as a portion of the stability program
 Container/closure integrity (CCI) test is critical for the
sterile products, e.g., injectable solutions
 Rubber
 Stoppers, cap liners, dropper
 Sorption of the active ingredient, preservative
may cause stability problem
 Extractable/leachable from rubber should be
studied, especially for injectable and inhalation
products
 Use of polytetrafluoroethylene (PTFE) coated
rubber stopper may prevent sorption and
leaching
INTERNATIONAL COUNCIL FOR
HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF
PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINE


STABILITY TESTING OF NEW DRUG
SUBSTANCES AND PRODUCTS

Q1A(R2)
Stability Test Conditions for Drug Substances of
General Case

Study Storage condition Minimum time period


at submission

Long term* 25ºC ± 2ºC/60% RH ± 5% RH 12 months


or
30ºC ± 2ºC/65% RH ± 5% RH
Intermediate** 30ºC ± 2ºC/65% RH ± 5% RH 6 months

Accelerated 40ºC ± 2ºC/75% RH ± 5% RH 6 months

*It is up to the applicant to decide whether long term stability studies are
performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.
**If 30°C  2°C/65% RH  5% RH is the long-term condition, there is no
intermediate condition.
Stability Test Conditions for Drug substances
intended for storage in a refrigerator

Study Storage condition Minimum time period


at submission
Long term 5ºC ± 3ºC 12 months

Accelerated 25ºC ± 2ºC/60% RH ± 6 months


5% RH
Stability Test Conditions for Drug substances
intended for storage in a freezer

Study Storage condition Minimum time period at


submission

Long term -20ºC ± 5ºC 12 months


Stability Test Conditions for Drug Products
of General Case

Study Storage condition Minimum time


period at
submission
Long term* 25ºC ± 2ºC/60% RH ± 5% RH 12 months
or
30ºC ± 2ºC/65% RH ± 5% RH
Intermediate** 30ºC ± 2ºC/65% RH ± 5% RH 6 months

Accelerated 40ºC ± 2ºC/75% RH ± 5% RH 6 months

*It is up to the applicant to decide whether long term stability studies are
performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5%
RH.
**If 30°C  2°C/65% RH  5% RH is the long-term condition, there is no
intermediate condition.
Stability Test Conditions for Drug Products
intended for storage in a refrigerator

Study Storage condition Minimum time


period covered by
data at
submission
Long term 5ºC ± 3ºC 12 months

Accelerated 25ºC ± 2ºC/60% RH ± 5% 6 months


RH
Stability Test Conditions for Drug Products
intended for storage in a freezer

Study Storage Minimum time


condition period covered by
data at submission
Long term -20 ºC ± 5 ºC 12 months
Stability Test Conditions for Drug Products
Packaged in Semi-permeable Containers

Study Storage condition Minimum time


period at
submission
Long term* 25ºC ± 2ºC/40% RH ± 5% 12 months
RH or
30°C ± 2°C/35% RH ±
5% RH
Intermediate** 30ºC ± 2ºC/65% RH ± 5% 6 months
RH
Accelerated 40ºC ± 2ºC/not more 6 months
than (NMT) 25% RH
*It is up to the applicant to decide whether long term stability studies are
performed at 25  2°C/40% RH  5% RH or 30°C  2°C/35% RH  5% RH.
**If 30°C  2°C/35% RH  5% RH is the long-term condition, there is no
intermediate condition.
Example of an approach for determining
water loss:
For a product in a given container closure system,
container size, and fill, an appropriate approach for
deriving the water loss rate at the reference relative
humidity is to multiply the water loss rate measured at an
alternative relative humidity at the same temperature by a
water loss rate ratio shown in the table below. A linear
water loss rate at the alternative relative humidity over the
storage period should be demonstrated.
For example, at a given temperature, e.g., 40 ºC, the
calculated water loss rate during storage at NMT 25% RH
is the water loss rate measured at 75% RH multiplied by
3.0, the corresponding water loss rate ratio.
Alternative Reference Ratio of water loss
relative humidity relative humidity rates at a given
temperature
60% RH 25% RH 1.9

60% RH 40% RH 1.5

65% RH 35% RH 1.9

75% RH 25% RH 3.0


Predicting Shelf Life of Drug Product

 The shelf life of a commercial drug product


must be determined in the commercial
container closure at the defined storage
conditions
 INTERNATIONAL CONFERENCE ON
HARMONISATION (ICH) and FDA guidance
require at least 12 months stability data at
the time of New Drug Application (NDA)
submission
 The ICH Q1E guideline recommends how
the 12 months may be used to predict
long-term stability
Shelf-Life Prediction using
Assay Test Results
Shelf-Life Prediction using
Degradation Test Results
Example: Product Stability Test

 Product: Injectable solution, 100 mg/mL, 2


mL/vial
 Recommended storage condition:
Refrigeration (2-8°C)
Example: Product Specification
Test Acceptance Acceptance Criteria
Criteria (Release (Stability specification) Analytical
specification) Procedure
1. Appearance Clear, Light yellow Clear, Light yellow oily Visual
oily solution solution
2. Identification The eluted time of HPLC
sample is the same
as that of standard
by HPLC
3. Volume NLT 2 mL USP
4. Assay Between 95.0% to Between 90.0% to HPLC
105.0% of label 110.0% of label claim
claim
5. Related substances HPLC
5.1 Individual unknown impurity NMT 0.2% NMT 0.2%
5.2 The total unknown impurities NMT 1.0 % NMT 1.0 %
5.3 Impurity A NMT 0.2% NMT 0.4%
5.4 Impurity B NMT 0.2% NMT 0.5%
5.5 Impurity E NMT 1.0% NMT 4.0%
5.6 Total Impurity NMT 2.0% NMT 5.0%
6. Particulate Matters USP<788>
6.1 ≧10μm NMT 6000/container NMT 6000/container

6.2 ≧25μm NMT 600/container NMT 600/container


7. Sterility Sterile Sterile USP<71>
8. Bacterial endotoxins NMT 36 EU/mL NMT 36 EU/mL USP<85>
Example: Product A Stability Protocol -
Storage Conditions and Test Intervals

Stability
Sample Initiation
Testing Points Date
Study Storage Condition Storage
(months)
Positions

Normal and Month


Long-
5˚C±3˚C Upside-down 1,2,3,6,9,12,18,24 Day,
Term
Positions Year

Normal and Month


Accele- 25˚C±2˚C, 60%±5%
Upside-down 1, 2, 3, 6 Day,
rated R.H.
Positions Year
Example: Stability Protocol (Sample set
up) & Data Table
Product name Product A Injection 75mg/mL, 2mL/vial
Storage Condition 5oC, upside-down position
Lot No. 1030601
Batch size 50 L Primary Package Type I Glass Vial/Stopper

Dosage form Injection Manufacturing date Jul. 16, 2014

Sep. 22, Oct. 22, Nov. 20,


Sampling Date Jul. 16, 2014 Feb. 24, 2015
2014 2014 2014
Test Item M0 M1 M2 M3 M6
Specification

Clear and Light yellow


1.Appearance Compliance Compliance Compliance Compliance Compliance
solution
The eluted time of sample is
2.Identification the same as that of Compliance Compliance Compliance Compliance Compliance
standard by HPLC

3.Volume NLT 2mL Compliance N.A. N.A. N.A. N.A.

Between 90.0% and 110.0%


4.Assay 100.7% 98.1% 99.2% 98.6% 97.9%
of label claim.
5.Related
substances
5.3 Impurity A NMT 0.4% <0.04% <0.04% 0.04% 0.04% 0.06%
5.4 Impurity B NMT 0.5% <0.04% <0.04% <0.04% <0.04% <0.04%
5.5 Impurity E NMT 4.0% 0.17% 0.17% 0.25% 0.27% 0.36%

6.Particulate Matter

6.1 ≥10 μm NMT 6000/container 10/container N.A. N.A. N.A. 72/container

6.2 ≥25 μm NMT 600/container 0/container N.A. N.A. N.A. 4/container


7.Sterility Sterile Sterile N.A. N.A. N.A. Sterile
8.Bacterial
NMT 36EU/mL < 36 EU/mL N.A. N.A. N.A. < 36 EU/mL
endotoxins
Example: Shelf-Life Prediction using
Assay Test Result

Shelf life Estimation with upper and lower acceptance criterion based on assay
at 5C/60%RH
115.00

110.00

105.00
Assay (%)

100.00
Regression line
95.00 Lower confidence limit
Upper confidence limit
90.00

85.00

80.00
0 5 10 15 20 25 30 35 40
Time point (months)
Example: Shelf-Life Prediction using
Degradation Test Result

Shelf life Estimation with upper acceptance criterion based on a degradation


product at 5C/60%RH
5.00

4.50
Upper acceptance criterion
4.00

3.50
Imp E level (%)

3.00

2.50 Regression line

2.00
Upper confidence limit
1.50

1.00

0.50

0.00
0 10 20 30 40 50 60
Time point (months)