Transcript of Prepared by : Dima Alhashlamoun Doaa Sider Instructor : Mr. Yaseen Qawasmi Drug stability.
- Slide 1
- Prepared by : Dima Alhashlamoun Doaa Sider Instructor : Mr.
Yaseen Qawasmi Drug stability
- Slide 2
- Druges in liquid or solid dosage forms susceptible to chemical
decomposition which leads to : 1) physical changes (discoloration)
2) Chemical changes (loss of potency)
- Slide 3
- To take the precautions to minimise the loss of potency
(activity) of drugs in certin enviromental conditions : 1) Study
the kinetics of the decompostion process. 2) Determine the
shelf-life : time taken for the concentration of the drug to be
reduced to 95% of its value when prepared.
- Slide 4
- Chemical decomposition process Hydrolysis Oxidation Isomerision
Photochemical decomposition Polymerisation
- Slide 5
- I.Hydrolysis The drug is susceptible to this type of
degradation if it is a derivative of carboxulic acid or contains
functional groups based on this moiety
- Slide 6
- Functional groups can hydrolysis Functional group
structureExample ImideGlutethimide LactamPenicillins Cephalosporins
LactonePilocarpine Spironolactone
EsterAspirin,physostigmine,tetracaine,procai ne
AmideErgometrine,benzylpenicllin sodium
- Slide 7
- Hydrolysis in water and catalysed by : 1) Acid catalysis : by
hydrogen ion(H+) or other acidic species. 2) Basic catalysis: by
hydroxyl ion(OH-) or other basic species.
- Slide 8
- Hydrolysis of esters hydrolysis of amide
- Slide 9
- Controlling drug hydrolysis in solution 1) Optimisation of
formulation 2) Modification of chemical structure of drug
- Slide 10
- Optimisation of formulation To stabilise a solution of a druge
which is susceptible to acid-base catalysed hydrolysis : 1)
Detrmine the pH of maximum stability from kinetic experiments at a
range of pH values and to formulate the product at this pH. 2)
Alteration of the dielectric constant by the addition of nonaqueous
solvents such as alcohol, glycerin or propylene glycol.
- Slide 11
- 3) Reducing the solubilty of the drug,by using additives (such
as citrates, dextrose, sorbitol and gluconate for pencillin) (Since
only that portion of the drug which is in solution will be
hydrolysed, it is possible to suppress degradation by making the
drug less soluble) 4)Adding a compound that forms a complex with
the drug. The addition of caffeine to aqueous solutions of some
druges (procain) decreases the base-catalysed hydrolysis. 5)
solubilisation of a drug by surfactants protects against
hydrolysis
- Slide 12
- Modification of chemical structure of drug - The modification (
ex: substituention, elemnation)should increase the drug stability
without reducing the therapeutic effiency. - Hammett linear free
energy relationship Used to measure the effect of substituents on
the rates of aromatic side-chain reactions, such as the hydrolysis
of esters.
- Slide 13
- Hammett linear free energy relationship Logk=logk 0 + Where: k
: the rate constants for the reaction of the substituted k 0 : the
rate constants for the reaction of the unsubstituted : the Hammett
substituent constant ( determined by the nature of the substituents
and is independent of the reaction) : the reaction constant.
(dependent on the reaction, the conditions of reaction and the
nature of the side-chains undergoing reaction).
- Slide 14
- Hammett linear free energy relationship a plot of log k against
the Hammett constant is linear if this relationship is obeyed, with
a slope of .
- Slide 15
- 2. Oxidation oxidation is the next most common pathway for drug
breakdown After hydrolysis. the oxidative process has usually been
eliminated by storage under anaerobic conditions without an
investigation of the oxidative mechanism.
- Slide 16
- Oxidation process
- Slide 17
- Initiation can be via free radicals formed from organic
compounds by the action of light, heat or transition metals such as
copper and iron which are present in trace amounts in almost every
buffer. The propagation stage of the reaction involves the
combination of molecular oxygen with the free radical R to form a
peroxy radical ROO., which then removes H from a molecule of the
organic compound to form a hydroperoxide, ROOH, and in so doing
creates a new free radical The reaction proceeds until the free
radicals are destroyed by inhibitors or by side-reactions which
eventually break the chain. The rancid odour which is a
characteristic of oxidised fats and oils is due to aldehydes,
ketones and shortchain fatty acids which are the breakdown products
of the hydroperoxides. Peroxides (ROOR,) and hydroperoxides (ROOH)
are photolabile, breaking down to hydroxyl (HO) and or alkoxyl
(RO)radicals, which are themselves highly oxidising species.
- Slide 18
- Drugs susceptible to oxidation 1) Steroid and sterols: are
subject to oxidative degradation through the possession of
carboncarbon double bonds (alkene moieties) to which peroxyl
radicals can readily add. 2) polyunsaturated fatty acids.
- Slide 19
- From druges : 1) cholesterol-lowering agent simvastatin :
contain conjugated double bonds, addition of peroxyl radicals may
lead to the formation of polymeric peroxides, cleavage of which
produces epoxides which may further degrade into aldehydes or
ketones.
- Slide 20
- simvastatin
- Slide 21
- 2) Polyene antibiotics, such as amphotericinB which contains
seven conjugated double bonds (heptaene moiety), are subject to
attack by peroxyl radicals, leading to aggregation and loss of
activity. 3) The oxidation of phenothiazines to the sulfoxide
involves two single-electron transfer reactions involving a radical
cation intermediate The sulfoxide is subsequently formed by
reaction of the cation with water.
- Slide 22
- Slide 23
- 4) ether group in drugs such as econazole nitrate and
miconazole nitrate is susceptible to oxidation. The process
involves removal of hydrogen from the CH bonds in the - position to
the oxygen to produce radicals, which further degrade to
-hydroperoxides and eventually to aldehydes, ketones, alcohols and
carboxylic acids.
- Slide 24
- Stabilisation against oxidation 1) The oxygen in pharmaceutical
containers should be replaced with nitrogen or carbon dioxide. 2)
contact of the drug with heavy-metal ions such as iron, cobalt or
nickel, which catalyse oxidation, should be avoided. 3) storage
should be at reduced temperatures. 4) Using antioxidants.
- Slide 25
- antioxidants - The propagation of the chain reaction may be
prevented or delayed by adding low concentrations of antioxidants
that act as inhibitors. interrupt the propagation by interaction
with the free radical. - The antioxidant free radical so formed is
not sufficiently reactive to maintain the chain reaction and is
eventually annihilated. - Reducing agents such as sodium
metabisulfite may also be added to formulations to prevent
oxidation. These compounds are more readily oxidised than the drug
and so protect them.
- Slide 26
- - Oxidation is catalysed by unprotonated amines such as
aminophylline, and hence amixture of susceptible drugs with such
compounds should be avoided.
- Slide 27
- Structures of some common antioxidants
- Slide 28
- Isomerisation Isomerisation : is the process of conversion of
the drug into its optical or geometric isomers. various isomers of
a drug are frequently of different activity, such a conversion may
be regarded as a form of degradation, often resulting in a serious
loss of therapeutic activity.
- Slide 29
- Racemisation of adrenaline at low pH
- Slide 30
- Isomerisation of vitamin A (Cistrans isomerisation )
- Slide 31
- Photodecomposition occur : during storage during use of the
product. As sunlight is able to penetrate the skin to a sufficient
depth to cause photodegradation of drugs circulating in the surface
capillaries or in the eyes of patients receiving the drug.
Photochemical decomposition
- Slide 32
- Primary photochemical reaction occurs when 1. the wavelength of
the incident light is within the wavelength range of absorption of
the drug (usually within the ultraviolet range, unless the drug is
coloured), so that the drug molecule itself absorbs radiation and
degrades. 2. with drugs that do not directly absorb the incident
radiation, as a consequence of absorption of radiation by
excipients in the formulation (photosensitisers) which transfer the
absorbed energy to the drug, causing it to degrade.
- Slide 33
- The effect of ultraviolet light on chlorpromazine (CLP).
- Slide 34
- V Polymer produced by the ultraviolet irradiation of
chlorpromazine under anaerobic conditions
- Slide 35
- Stabilisation against photochemical decomposition the use of
coloured glass containers storage in the dark. Amber glass excludes
light of wavelength `470 nm and so affords considerable protection
of compounds sensitive to ultraviolet light. Coating tablets with a
polymer film containing ultraviolet absorbers has been suggested as
an additional method for protection from light. In this respect, a
film coating of vinyl acetate containing oxybenzone as an
ultraviolet absorber has been shown to be effective in minimising
the discoloration and photolytic degradation of sulfasomidine
tablets.
- Slide 36
- Polymerisation Polymerisation is the process by which two or
more identical drug molecules combine together to form a complex
molecule.
- Slide 37
- Dimerisation and hydrolysis of ampicillin.
- Slide 38
- Kinetics of chemical decomposition in solution - Before we can
predict the shelf-life of a dosage form it is essential to
determine the kinetics of the breakdown of the drug under carefully
controlled conditions.
- Slide 39
- Classifying reactions: the order of reaction Reactions are
classified according to the order of reaction: number of reacting
species whose concentration determines the rate at which the
reaction occurs. We will concentrate mainly on: 1) zero-order
reactions, in which the breakdown rate is independent of the
concentration of any of the reactants. 2) first-order reactions, in
which the reaction rate is determined by one concentration term. 3)
Second order reactions, in which the rate is determined by the
concentrations of two reacting species.
- Slide 40
- 1) zero-order reactions - Dx/dy=K 0 - This type of reaction,can
often occur in suspensions of poorly soluble drugs.In these systems
the suspended drug slowly dissolves as the drug decomposes and so a
constant drug concentration in solution is maintained. - Ex :
hydrolysis of acetyl - salicylic acid
- Slide 41
- 2) first-order reactions - Dx/dy=K 1 [A]=K 1 (a-x) - Ex :
hydrolysis of homatropine
- Slide 42
- - pseudo first-order reaction: occurs when one of the reactants
is in such a large excess that any change in its concentration is
negligible compared with changes in the concentration the other
reactants. - Such reactions are often met in stability studies of
drugs that hydrolyse in solution,the water being in such excess
that changes in its concentration are negligible and hence the rate
of reaction is dependent solely on the drug concentration.
- Slide 43
- Second order reactions Dx/dy=K 1 [A][B] Dx/dy=K 1 [A] [B]=K 1
(a-x)(b-x)
- Slide 44
- Complex reactions - There are many examples of drugs in which
decomposition occurs simultaneously by two or more pathways, or
involves a sequence of decomposition steps or a reversible
reaction. - Complex reaction: a. Reversible reactions b. Parallel
reactions c. Consecutive reactions
- Slide 45
- Reversible reactions the kinetics of a reversible reaction
involves two rate constants : - Kf: describe the rate of the
forward reaction - kr: describe the rate of the reverse reaction
For the simplest example in which both of these reactions are
first-order ex: epimerisation of tetracycline
- Slide 46
- Parallel reactions The decomposition of many drugs involves two
or more pathways, the preferred route of reaction being dependent
on reaction condition. Ex: Nitrazepam decomposes in two pseudo
first-order parallel reactions giving different breakdown products
in solution and in the solid state. Decomposition of nitrazepam
tablets in the presence of moisture will occur by both routes, the
ratio of the two products being dependent on the amount of water
present. In other cases decomposition may occur simultaneously by
two different processes, as in the simultaneous hydrolysis and
epimerisation of pilocarpine.
- Slide 47
- Consecutive reactions where each step is a nonreversible
first-order reaction. The hydrolysis of chlordiazepoxide follows a
first-order decomposition
- Slide 48
- Solid dosage forms: kinetics of chemical decomposition 1)
Solids that decompose to give a solid and a gas. 2) Solids that
decompose to give a liquid and a gas.
- Slide 49
- Solids that decompose to give a solid and a gas Ex :
p-aminosalicylic acid, which decomposes to a solid (p- aminophenol)
and a gas (carbon dioxide) The decomposition curves which result
from such a reaction show either: (a) an initial rapid
decomposition followed by a more gradual decomposition rate. - The
shape produced called topochemical (contracting geometry). - The
model used in the treatment is that of a cylinder or sphere. - it
is assumed that the radius of the intact chemical substance
decreases linearly with time.
- Slide 50
- Slide 51
- - For the contracting cylinder model, the mole fraction x
decomposed at time t is given by (1 x) 1/2 = 1 (K/r 0 )t Example of
this type decompostion of aspirin at elevated tempreture. - For the
contracting sphere model (1-x) 1/3 = 1- (k/r 0 )t - A similarity
between these and the first-order rate equations, this similarity
might account for the fact that many decompositions in solid dosage
forms appear to follow first-order kinetics.
- Slide 52
- Solids that decompose to give a liquid and a gas - An example
of a solid in this category is p- aminobenzoic acid, which
decomposes into aniline and carbon dioxide. - Decomposition causes
a layer of liquid to form around the solid which dissolves the
solid. - The decomposition curves show an initial lag period which
corresponds to the establishment of the liquid layer. - Beyond this
region, the plot represents the first-order decomposition of the
solid in solution in its liquid decomposition products. - There are
thus two rate constants, that for the initial decomposition of the
solid itself, and that for the decomposition of the solid in
solution.
- Slide 53
- Factors influencing drug stability For Liquid dosage forms: 1)
PH 2) Temperture 3) Ionic strength 4) Solvent effect 5) Oxygen 6)
Light 7) Surfactant
- Slide 54
- PH Studying the influence of pH on degradation rate: - a pH
rate profile : the hydrolysis rate of the drug in a series of
solutions buffered to the required pH is measured and the
hydrolytic rate constant is then plotted as a function of pH. -
this will almost certainly be influenced by the buffers used to It
is probable that a different pH rate profile would be obtained
using a different buffer.
- Slide 55
- Slide 56
- Acidic and alkaline pH influence the rate of decomposition of
most drugs. Many drugs are stable between pH 4 and 8. Weekly acidic
and basic drugs show good solubility when they are ionized and they
also decompose faster when they are ionized. Reactions catalyzed by
pH are monitored by measuring degradation rates against pH, keeping
temperature, ionic strength and solvent concentration constant.
Some buffers such as acetate, citrate, lactate, phosphate and
ascorbate buffers are utilized to prevent drastic change in
pH.
- Slide 57
- - So if the pH of a drug solution has to be adjusted to improve
solubility and the resultant pH leads to instability then a way out
of this tricky problem is to introduce a water miscible solvent
into the product. It will increase stability by: - reducing the
extreme pH required to achieve solubility - enhancing solubility -
reducing the water activity by reducing the polarity of the
solvent. For example, 20% propylene glycol is placed in
chlordiazepoxide injection for this purpose
- Slide 58
- Temperture - Increase in temperature usually causes a very
pronounced increase in the hydrolysis rate of drugs in solution. -
Such studies are usually carried out at high temperatures, say 60
or 80C, because the hydrolysis rate is greater at these
temperatures and can therefore be measured more easily.
- Slide 59
- - The equation which describes the effect of temperature on
decomposition, and which shows us how to calculate the rate of
break down at room temperature from measurements at much higher
temperatures, is the Arrhenius equation. - When it is clear from
stability determinations that a drug is particularly unstable at
room temperature, then of course it will need to be labelled with
instructions to store in a cool place. This is the case, for
example, with injections of penicillin, insulin, oxytocin and
vasopressin.
- Slide 60
- Ionic strength electrolytes add to drug solutions to control
their tonicity, but we must pay attention to any effect they may
have on stability. The equation which describes the influence of
electrolyte on the rate constant is the BrnstedBjerrum equation:
Logk= logk 0 +2AZ A Z B 1/2 In this equation: - zA and zB are the
charge numbers of the two interacting ions - A is a constant for a
given solvent and temperature. - is the ionic strength of the
solution.
- Slide 61
- Solvent effects K is a constant for a given system at a given
temperature. We can see that a plot of log k as a function of the
reciprocal of the dielectric constant, , of the solvent should be
linear with a gradient of magnitude Kz A z B and an intercept equal
to the logarithm of the rate constant in a theoretical solvent of
infinite dielectric constant.
- Slide 62
- If the charges on the drug ion and the interacting species are
the same, then we can see that the gradient of the line will be
negative. In this case, if we replace the water with a solvent of
lower dielectric constant then we will achieve the desired effect
of reducing the reaction rate. If the drug ion and the interacting
ion are of opposite signs, however, then the slope will be positive
and the choice of a nonpolar solvent will only result in an
increase of decomposition.
- Slide 63
- Oxygen Since molecular oxygen is involved in many oxidation
schemes, we could use oxygen as a challenge to find out whether a
particular drug is likely to be affected by oxidative breakdown. We
would do this by storing solutions of the drug in ampoules purged
with oxygen and then comparing their rate of breakdown with similar
solutions stored under nitrogen. Formulations that are shown to be
susceptible to oxidation can be stabilized by replacing the oxygen
in the storage containers with nitrogen or carbon dioxide, by
avoiding contact with heavy metal ions, and by adding
antioxidants
- Slide 64
- Light Photolabile drugs are usually stored in containers which
exclude ultraviolet light, since exposure to light in this
wavelength range is the most usual cause of photodegradation Amber
glass is particularly effective in this respect because it excludes
light of wavelength of less than about 470 nm. As an added
precaution, it is always advisable to store photolabile drugs in
the dark.
- Slide 65
- k obs = k m f m + k w f w k obs, k m and k w are the observed,
micellar and aqueous rate constants, respectively, and f m and f w
are the fractions of drug associated with the micelles and aqueous
phase, respectively. The value of k m is dependent on the location
of the drug within the micelle. Surfactants
- Slide 66
- A solubilisate may be incorporated into the micelle in a
variety of locations. Nonpolar compounds are thought to be
solubilised within the lipophilic core and, as such, are likely to
be more effectively removed from the attacking species than those
compounds that are located close to the micellar surface.
- Slide 67
- Where the drug is located near to the micellar surface, and
therefore still susceptible to attack, the ionic nature of the
surfactant is an important influence on decomposition rate. For
base-catalysed hydrolysis, solubilisation into anionic micelles
affords an effective stabilisation due to repulsion of OH - by the
micelles. Conversely, solubilisation into cationic micelles might
be expected to cause an enhanced base-catalysed hydrolysis. Many
drugs associate to form micelles in aqueous solution and several
studies have been reported of the effect of this self- association
on stability.
- Slide 68
- Semisolid dosage forms
- Slide 69
- The chemical stability of active ingredients incorporated into
ointments or creams is frequently dependent on the nature of the
ointment or cream base used in the formulation. Such dilution is,
unfortunately, common practice in cases where the practitioner
wishes to reduce the potency of highly active topical preparations,
particularly steroids. The pharmaceutical and biopharmaceutical
dangers of this procedure have been stressed. Of particular
interest here are the problems of drug stability which can occur
through the use of unsuitable diluents.
- Slide 70
- the dilution of betamethasone valerate cream with a cream base
having a neutral to alkaline pH. Under such conditions, conversion
of the 17-ester to the less-active betamethasone 21-ester can
occur. Similarly, diluents containing oxidising agents could cause
chemical degradation of fluocinolone acetate to less-active
compounds.
- Slide 71
- Solid dosage forms
- Slide 72
- Moisture Water-soluble drugs present in a solid dosage form
will dissolve in any moisture which has adsorbed on the solid
surface. The drug will now be in an aqueous environment and its
decomposition could be influenced by many of the factors which
affect the liquid dosage forms. moisture is considered to be one of
the most important factors that must be controlled in order to
minimise decomposition.
- Slide 73
- The effect of water vapour pressure on the decomposition of
aminosalicylic acid.
- Slide 74
- Excipients Excipients such as starch and povidone have
particularly high water contents (povidone contains about 28%
equilibrium moisture at 75% relative humidity). However, whether
this high moisture level has an effect on stability depends on how
strongly it is bound and whether the moisture can come into contact
with the drug. Magnesium trisilicate causes increased hydrolysis of
aspirin in tablet form because, it is thought,of its high water
content.
- Slide 75
- Chemical interaction between components in solid dosage forms
may lead to increased decomposition.
- Slide 76
- Reactions showing the postulated transacetylation between
aspirin and paracetamol and the direct hydrolysis of
paracetamol.
- Slide 77
- Development of free salicylic acid in aspirin
paracetamolcodeine and aspirinphenacetin codeine tablets at
37C.
- Slide 78
- Temperature The drug or one of the excipients may, for example,
1.melt or change its polymorphic form as temperature is increased,
2.it may contain loosely bound water which is lost at higher
temperatures. 3.the relative humidity will change with temperature
and so we must take care to keep this at a constant value.
- Slide 79
- Light and oxygen the stability problems which arise with drugs
which are susceptible to photodecomposition or oxidation. water
contains dissolved oxygen and so the presence of moisture on the
surface of solid preparations may increase the oxidation of
susceptible drugs; such drugs must, therefore, be stored under dry
conditions.
- Slide 80
- 1. Effect of temperature on stability the basic method of
accelerating the chemical decomposition by raising the temperature
of the preparations. Stability testing and prediction of
shelf-life
- Slide 81
- 1. The order of reaction can be determined by plotting
stability data at several elevated temperatures according to the
equations relating decomposition to time for each of the orders of
reaction, until linear plots are obtained. 2. calculate values of
rate constant at each temperature from the gradient of these plots
3. plot the logarithm of k against reciprocal temperature according
to the Arrhenius equation:
- Slide 82
- The required value of k can be interpolated from this plot at
room temperature, and the activation energy Ea can be calculated
from the gradient, which is Ea/ 2.303R. Values of Ea are usually
within the range 5096 kJ mol -1.
- Slide 83
- Example :
- Slide 84
- Expiry date calculation Once the rate constant is known at the
required storage temperature, it is a simple matter to calculate a
shelf-life for the product based on an acceptable degree of
decomposition. The equations which we can use for 10% loss of
activity are obtained by substituting x=0.1a in the zero- and
first-order equations giving
- Slide 85
- where [D] 0 is the initial concentration of drug. t 0.9 is
usually used as an estimate of shelf-life, other percentage
decompositions may be required, for example when the decomposition
products produce discoloration or have undesirable side-effects.
The equired equations for these may be derived by substituting in
the relevant rate equations.
- Slide 86
- Example :
- Slide 87
- Slide 88
- Suspensions stability testing of suspensions is the changes in
the solubility of the suspended drug with increase in temperature.
With suspensions, the concentration of the drug in solution usually
remains constant because, as the decomposition reaction proceeds,
more of the drug dissolves to keep the solution saturated. this
situation usually leads to zero-order release kinetics.
- Slide 89
- Solid state The main problems arising in stability testing of
solid dosage forms are: (a) that the analytical results tend to
have more scatter because tablets and capsules are distinct dosage
units rather than the true aliquots encountered with stability
studies on drugs in solution. (b) that these dosage forms are
heterogeneous systems often involving a gas phase (air and water
vapour), a liquid phase (adsorbed moisture) and the solid phase
itself. The compositions of all of these phases can vary during an
experiment.
- Slide 90
- The first of these problems can be overcome by ensuring
uniformity of the dosage form before commencing the stability
studies. The problems arising from the heterogeneity are more
difficult to overcome.
- Slide 91
- The main complicating factor is associated with the presence of
moisture. moisture can have a significant effect on the kinetics of
decomposition and this may produce many experimental problems
during stability testing. For example, what happen with gelatin
capsules.
- Slide 92
- To reduce some of these problems, particularly those associated
with moisture, during stability testing, the following have been
suggested: (a) the use of tightly sealed containers, except where
the effect of packaging is to be investigated (b) that the amount
of water present in the dosage form should be determined,
preferably at each storage temperature (c) that a separate, sealed
ampoule should be taken for each assay point and water
determination, thus avoiding disturbance of water equilibrium on
opening the container.
- Slide 93
- - Light Photostability testing of drug substances 1. the sample
is irradiated at all absorbing wavelengths using a broad-spectrum
light source. 2. Those drugs or formulations which are shown to be
photosensitive are then subjected to more formal photostability
testing in which they are challenged with light of wavelength
comparable to that to which the formulations are exposed in
practical situations. 3. During their shelf-life it is most likely
that the products will be exposed to fluorescent light, direct
daylight and daylight filtered through window glass, and the
stability testing procedures are designed to cover these
possibilities 2. Other environmental factors affecting
stability
- Slide 94
- - Moisture content The stability of solid dosage forms is
usually very susceptible to the moisture content of the atmosphere
in the container in which they are stored - Oxygen Exaggeration of
the effect of oxygen on stability may be achieved by an increase in
the partial pressure of oxygen in the system.
- Slide 95
- Protocol for stability testing The stability test protocol
should be found on : Drug substance is a pure material which exerts
a pharmacological action Drug product is a finished end product
which may contain one or more drug substances in combination with
excipients meant for use by humans and animals
- Slide 96
- Drug substances Stability information from accelerated and
long-term testing is required to be provided on at least three
batches manufactured to a minimum of pilot plant one tenth that of
the batch . The containers to be used in the long-term evaluation
should be the same as, or simulate, the actual packaging used for
storage and distribution.
- Slide 97
- The testing should be designed to cover those features
susceptible to change during storage and likely to influence
quality, safety and/or efficacy, including, as necessary, the
physical, chemical and microbiological characteristics. The length
of the studies and the storage conditions should be sufficient to
cover storage, shipment and subsequent use.
- Slide 98
- long-term testing The specifications for the long-term testing
are a temperature of 25 2C and 605% relative humidity (RH) for a
period of 12 months. accelerated testing For accelerated testing
the temperature is specified as 40 2C and RH as 75 5% for a period
of 6 months. if a significant change occurs during this period,
additional testing at an intermediate temperature (such as 302C,60%
5% RH) should be conducted for drug substances. Significant change
at 40C75% RH or 30C60% RH is defined as failure to meet the
specification. Temperature sensitive drugs that should be stored at
a lower temperature, is tested under these conditions
- Slide 99
- The long-term testing is required to be continued for a
sufficient period beyond 12 months to cover all appropriate re-test
periods. under the long term conditions this will normally be every
3 months over the first year, every 6 months over the second year
and then annually.
- Slide 100
- The conditions and time periods for long-term and accelerated
storage testing are the same as those outlined above for drug
substances but with special considerations arising from the nature
of the drug product. For example, If it is necessary to store the
product at a lower temperature because of its heat sensitivity then
consideration should be given to any physical or chemical change in
the product which might occur at this temperature; for example, -
suspensions or emulsions may sediment or cream, - while oils and
semi-solid preparations may show an increased viscosity. Drug
product
- Slide 101
- In the case of drug products, significant change at the
accelerated condition is definedas A 5% potency loss from the
initial assay value of a batch Any specified degradant exceeding
its specification limit The product exceeding its pH limits
Dissolution exceeding the specification limits for 12 capsules or
tablets Failure to meet specifications for appearance and physical
properties, e.g. colour, phase separation, resuspendability,
delivery per actuation, caking and hardness
- Slide 102
- If significant change occurs at 40C75% RH then it is necessary
to submit a minimum of 6 months data from an ongoing one-year study
at 30C60% RH using the same criteria for significant change.
- Slide 103