DRUG DEVELOPMENT
`AND INDUMHAL
`PHARMACY
`
`Drug Development and Industrial Pharmacy
`
`0 Taylor Francis
`
`Taylor Francis Group
`
`ISSN 03639045 Print 15205762 Online Journal homepage httpwwwtandfonlinecomloViddi20
`
`Trends in Stability Testing with Emphasis on
`Stability During Distribution and Storage
`
`Brahmaiah Kommanaboyina
`
`C T Rhodes
`
`C T Rhodes 1999 Trends in Stability Testing
`To cite this article Brahnnaiah Konnnnanaboyina
`with Emphasis on Stability During Distribution and Storage Drug Development and Industrial
`Pharmacy 257 857868 DOI 101081DDC100102246
`
`To link to this article httpdxdoiorg101081DDC100102246
`
`Published online 06 Oct 1999
`
`I U
`
`MW
`
`geSubmit your article to this journal
`
`I W Article views 660
`
`View related articles C4I
`
`Citing articles 41 View citing articles
`
`Full Terms Conditions of access and use can be found at
`
`httpwwwtandfonlinecomactionjournalInformationjournalCode=iddi20
`
`Download by American Red Cross Mary A Gilligan
`
`Date 26 June 2017 At 1218
`
`Abraxis EX2053
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`Drug Development
`
`and Industrial Pharmacy 257 857868 1999
`
`Trends in Stability Testing with
`Emphasis on Stability During
`Distribution and Storage
`
`Brahmaiah Kommanaboyina and C T Rhodes
`
`Department of Applied Pharmaceutical Sciences University of Rhode
`Island Kingston RI 02881
`
`ABSTRACT
`
`This paper
`
`trends in the stability testing of pharmaceutical
`reviews contemporary
`it consi ders the progrc toward globalization and harmoni
`products In particular
`zati on and i ndi cats stability problems which probably will be the focus of attention
`scientists and regulators in the near future Attention is specifi
`for pharmaceutical
`cally directed to monitoring stability in the channels of distribution
`
`INTRODUCTION
`
`Within the past 25 years or so the stability testing of
`pharmaceutical products has advanced dramatically from
`a somewhat haphazard exercise that showed dramatic
`in quality both within and between various
`
`variations
`
`jurisdictions to an operation based on sound scientific
`principles that shows a significant degree of commonality
`in many parts of the world
`Although pharmaceutical
`and
`regulators
`scientists
`have known for many years that all drug delivery sys
`to de
`temsto a varying degreehave a propensity
`grade and thus show a lower level of fitness for use
`it was only in the 1970s that standardized approaches for
`
`the reliable quantification of the stability of pharmaceuti
`
`cal products began to emerge
`
`To whom correspondence
`
`should be addressed
`
`857
`
`The stability of pharmaceutical
`
`products
`
`is a broad
`
`area that encompasses many potential
`
`routes of degrada
`
`tion Any change that occurs in a pharmaceutical product
`
`to its preparation that adversely affects any
`subsequent
`attribute of the quality of the product
`in terms of its fit
`
`ness for use by a patient
`
`of concern to pharmaceutical
`
`volved in stability
`
`testing
`
`least a matter
`is potentially at
`scientists and regulators in
`
`It
`
`to classify degrada
`is conventional
`and convenient
`tion of pharmaceutical products as being chemical physi
`cal or biological However
`in many instances these dis
`tinctions are not complete For example oxidation in a
`condom chemical
`results in a loss of tensile strength
`physical Also for many drugs or devices more than
`
`one mode of degradation may be possible 1
`
`In general we may classify the adverse effects of the
`
`Copyright CD 1999 by Marcel Dekker
`
`Inc
`
`wwwdekkercom
`
`

`

`858
`
`Kommanaboyina and Rhodes
`
`traction to the use of the same raw materials equipment
`production methods and quality control
`tests at all
`their
`the world Thus such companies have
`in promoting compatibility
`an especially strong interest
`in regulatory policies such as those that control stability
`
`plants throughout
`
`testing
`
`Concepts
`
`STABILITY
`
`Stab lity testing is a routine procedure performed on
`
`drug substances
`
`and products It
`
`is involved
`
`at various
`
`In early stages accel
`
`stages of a products development
`erated stability
`testing at relatively high temperatures
`andor humidities can be used for some drugs as a
`worst case evaluation to determine what
`types of deg
`radation products may be found after longterm storage
`those recom
`Testing under
`less rigorous conditions
`mended for longterm shelf storage and slightly elevated
`temperatures can be used to determine a products shelf
`
`studies loss
`
`of the
`
`product as modifying ef
`instability of a pharmaceutical
`ficacy safety or ease of use or patient acceptability In
`is loss of po
`terms of efficacy the most obvious effect
`tency of the drug Indeed for many stability
`in the determination
`of potency is the key factor
`shelf life of the product Usually we regard 90 of label
`claim as being the lowest acceptable value of potency
`Thus for many pharmaceutical products an estimation of
`the time that will elapse when the product
`is stored under
`specified conditions before the potency is less than 90
`of label claim will be central
`to our stability studies
`Important though loss of potency can be there is now
`for some pharmaceutical
`an increasing recognition that
`products other effects of instability may be of equal or
`of greater importance than loss of potency For example
`is toxic it may be that the accu
`if a degradation product
`is of more criti
`mulation of the toxic degradation product
`the active ingredient Al
`than loss of
`importance
`though such occurrences are presently probably relatively
`rare the increasing use of protein drugs for which small
`in structure can have a profound impact on im
`changes
`munogenicity may result in this situation becoming more
`likely and therefore deserving of more attention
`
`cal
`
`In considering
`
`the stability of pharmaceutical prod
`
`the totality of the prod
`to consider
`ucts it
`is essential
`uctdrug excipients pack
`and label All of these ele
`ments can play an important role in the fitness for use of
`
`the drug delivery system For example if migration of a
`plasticizer from the plastic bottle into a label causes the
`ink to become blurred so that
`the legibility of the infor
`is impaired this is a matter of con
`
`mation on the label
`
`cern
`A major factor
`in the improvement of pharmaceutical
`testing has been the development of analytical
`stability
`methods that are suitable for use in a stability indicating
`assay In particular the availability of highperformance
`liquid chromatography HPLC has been a real boon to
`that our definition of a
`is noteworthy
`stability testing It
`stability indicating assay has evolved from a method that
`would allow quantification
`of a drug in the presence of
`its degradation products and excipients to a method that
`
`allows quantification
`
`not only of the drug but also of
`
`major degradation products
`
`In addition
`to technical
`such
`as the
`achievements
`emergence of HPLC for use in stability indicating assays
`have also
`and regulatory developments
`organizational
`in stability testing During re
`been of great significance
`cent years the substantial number of corporate takeovers
`and mergers has increased the number of pharmaceutical
`companies that operate in many areas of the world For
`corporations there is an obvious at
`such transnational
`
`life and expiration dates 2 Stability testing is performed
`the end of their expiration dates 3
`
`to ensure that drug products retain their fitness for use
`
`until
`
`The raison dêtre of pharmaceutical
`
`testing should be
`
`to provide reasonable assurance that
`
`the fitness for use
`
`of products remains at an acceptable level
`throughout
`period during which they are in the marketplace available
`It has been suggested
`
`the
`
`the above definition should be extended so
`
`for supply to the patientconsumer
`by some that
`the patient uses
`it covers the period until
`unit of product However since we cannot control how
`patients store drugs and because we are aware that a sig
`nificant proportion of patients store pharmaceuticals
`in a
`
`that
`
`the last
`
`scien
`quite inappropriate manner many pharmaceutical
`to be impracticable The most
`tists believe this concept
`likely method of improving storage of drug products by
`patients may well be in individual counseling by pharma
`cists
`
`Sabi lity of a pharmaceutical
`
`product may be defined
`as the capability of a particular formulation in a specific
`
`containerclosure system to remain within its physical
`chemical microbiological
`
`toxicological
`
`therapeutic
`
`protective and informational
`there are exceptions 90 of labeled potency is generally
`recognized as the minimum acceptable potency level 4
`
`specifications
`
`Although
`
`Stability is also defined as the extent
`
`to which a product
`
`retains within specified limits and throughout
`of storage and use ie its shelf life the same properties
`and characteristics that it possessed at the time of its man
`
`its period
`
`

`

`Trends in Stability Testing
`
`859
`
`ufacture
`
`The criteria for acceptable levels of stability
`have been reviewed in the form of a table 56
`
`Factors Affecting Product Stability
`
`Many factors affect
`product including the stability of the active ingredients
`interaction between active and socalled in
`
`the stability of a pharmaceutical
`
`the potential
`
`active ingredients the manufacturing
`
`process the dosage
`form the containerclosure system the environmental
`
`conditions
`
`encountered during shipment storage
`handling and the length of time between manufacture
`
`and
`
`and usage Environmental properties such as heat light
`
`and moisture as well as chemical
`
`factors like oxidation
`
`reduction hydrolysis or racemization can all play vital
`reactions
`roles in pharmaceutical
`stability Degradation
`formulations may depend on such con
`in pharmaceutical
`ditions as concentration of reactants pH radiation tem
`perature catalysts and so on 7 A number of other
`
`factors
`
`are
`
`listed in the literature Of all
`
`the many
`factors that can be involved in drug degra
`dation temperature is the most important one that cannot
`
`environmental
`
`be controlled by package selection 4
`
`The stability of a drug product depends on the raw
`materials used warehouse and transport
`facilities pa
`tientconsumer storage and in vivo stability The effects
`
`of drug product
`
`instability include loss of active drug
`
`in biologi
`
`elegance
`
`eg nitroglycerin tablets increase in concentration of
`active ingredient eg lidocaine gel change
`cal activity eg tablet aging loss of content uniformity
`eg flocculation and impaction in suspensions pres
`ence of pathological microorganisms eg contamination
`of a multiuse cream loss of pharmaceutical
`eg yellowing of direct compression lactose tablets
`containing an amine drug production of toxic decompo
`sition products eg conversion of tetracycline to epian
`for use eg adhesion aging of transdermals 8
`
`hydrotetracycline
`
`and other
`
`factors that change
`
`fitness
`
`Expiration DateShelf Life
`
`An expiration date is defined as the time up to which
`the preparation will remain stable when stored under rec
`ommended conditions Thus an expiration date
`date beyond which it
`the product may
`is predicted that
`no longer retain fitness for use If the product
`is not stored
`
`is the
`
`in accordance with the manufacturers instructions then
`the product may be expected to degrade more rapidly
`Strict adherence to the storage requirements
`specified in
`
`labeling will help ensure product stability
`the product
`to
`the manufacturers labeled expiration date The manufac
`
`is supplied to the user 9
`
`it
`
`Shelf
`
`these storage re
`turers expiration date only applies if
`quirements are met from the time the product
`leaves the
`manufacturer until
`life is the time during which we have reason to
`if stored appropriately will re
`believe that
`tain fitness for use >90 of label claim of potency 10
`The expiration date is also defined as the date placed on
`
`the product
`
`the containerlabels of a drug product designating
`time during which a batch of the product
`
`is expected to
`
`the
`
`stored under defined conditions
`
`remain within the approved shelf life specification
`if
`and after which it may
`not be used 11 The use of kinetic and predictive studies
`for establishing credible expiration dates for pharmaceu
`is now accepted worldwide However
`prior to about 1950 only qualitative or semiquantitative
`methods and procedures were commonly used in pharma
`ceutical studies Stability study requirements
`and proto
`col designs were covered in detail
`in the standard profes
`literature 1013
`Although shelf life in some instances may be esti
`mated by accelerated stability testing protocols realtime
`testing is necessary to validate stability
`claims 14 Additional data pertinent
`to shelf life may
`be obtained using the retained samples from market chal
`lenge tests and test distributed samples and from re
`
`tical products
`
`sional
`
`product stability
`
`turned samples 8
`
`STABILITY TESTING METHODS
`
`Real Time Stability Testing
`
`storage
`
`In realtime stability
`testing the duration of the test
`period should normally be long enough to allow signifi
`recommended
`under
`cant product degradation
`conditions Alternatively if a product
`is essentially sta
`ble the test should be conducted for a long enough period
`to indicate clearly that no measurable degradation occurs
`At the least the testing protocol must permit one to dis
`tinguish degradation from interassay variation For exam
`ple data may be collected at an appropriate frequency
`such that a trend analysis may discern instability from
`daytoday imprecision The reliability of data interpreta
`tion can be increased by including in each assay a sin
`gle lot of reference material with established stability
`Sample recovery between assays can be
`normalized to this reference minimizing the impact of
`
`characteristics
`
`systematic drift and interassay imprecision Frequently
`
`however an appropriate reference material
`is not avail
`able for use as a control When one measures the stability
`imprecision may be introduced
`of a reference material
`in both reagents and instrumentation Ideally
`
`by changes
`
`

`

`860
`
`Kommanaboyina and Rhodes
`
`changes
`
`is
`
`reagents should be sufficiently stable that a single lot pro
`the stability
`vides unchanging
`throughout
`performance
`should remain con
`study and instrument performance
`stant However one must monitor system performance
`and discontinuity resulting from
`and control
`for drift
`in both reagents and instrumentation 14
`The time at which the 90 twosided lower confi
`dence bound intersects at the 90 potency level on the
`time is
`stability plot percentage of label claim against
`best termed the conformance period This length of time
`must always be greater than the actual shelf life that
`assigned to the product The conformance period may
`of course be any time interval eg 213 months 387
`months or 695 months The shelf life is rounded down
`from the conformance period to give a convenient
`value
`eg 18 months 3 years or 5 years Full details of
`are given in the FDA guide
`
`the method of calculation
`lines 12
`
`Accelerated Stability Testing
`
`to methods
`by
`Accelerated
`stability testing refers
`which product stability may be estimated by storage of
`the product under conditions that accelerate degradation
`commonly by an increase in temperature Stress condi
`the general head
`fall under
`tions that accelerate change
`ings of temperature light moisture agitation gravity
`pH packaging
`and method of manufacture
`The acceler
`ated method is often used to provide an early indication
`
`the
`
`of product shelf life and thereby shorten the development
`schedule This may permit in some circumstances
`prediction of the stability of the product at ordinary shelf
`temperature from data obtained by stress testing A rea
`sonable statistical
`in accelerated stability pro
`treatment
`jections based on the Arrhenius equation normally re
`quires that at least four stress temperatures be used Many
`testing models are based on the Ar
`accelerated stability
`rhenius equation 1518
`
`k
`
`AeEaRT
`
`where k is a rate constant at temperature T in degrees
`Kelvin Ea is the activation energy and R is the gas con
`stant This equation describes the relationship between
`storage temperature and degradation rate Use of the Ar
`from
`rhenius equation permits a projection of stability
`
`the degradation rates observed at high temperatures for
`some degradation processes 19 When the activation en
`ergy is known the degradation rate at
`low temperatures
`may be projected from those observed at stress tem
`peratures
`
`The classical approach in Arrhenius prediction of drug
`stability uses two sequential steps of linear regression in
`volving a a function of drug content versus time to ob
`tain the rate constants k at several elevated temperatures
`and b the relationship of logarithm of mean k versus
`
`reciprocal
`
`about
`
`the room temperature
`temperature to predict
`the shelf life of the drug The
`rate constant and hence
`classical approach also provides a wide and unsymmetri
`cal 95 confidence interval for the predicted shelf life
`20 The time for the lower 95 confidence limit curve
`line to reach 90 of the labeled
`the fitted straight
`is assigned as the shelf life of the pharma
`drug content
`ceutical product 2122
`The stress tests used in the current
`
`International Con
`ference on Harmonization ICH guideline eg 40 for
`to be stored at controlled room temperature
`CRT were developed from a model
`that assumes an
`energy of activation of about 83 kJ per mole
`A common practice of manufacturers in pharmaceuti
`is to utilize various
`shortcuts
`such
`
`products
`
`cal
`
`industries
`
`bracket
`
`tables 23 and in the past the Q rule 16
`
`as
`
`Q Rule
`
`The Q rule states that a product degradation rate de
`factor Q10 when the storage temper
`creases by a constant
`ature is decreased by 10°C The value of Q10 is typically
`set at 2 3 or 4 because
`these correspond to reasonable
`activation energies For larger shifts in temperature the
`
`exponentially with temperature
`rate constant changes
`and is proportional to Q10n where n equals the tempera
`ture change °C divided by 10 This model falsely as
`sumes that the value of Q does not vary with temperature
`More detailed treatments
`are given by Anderson
`and
`Scott 14 and Connors Amidon and Kennon 16 This
`technique is not recommended
`
`Bracket Tables
`
`The bracket
`
`table technique assumes that for a given
`analyte the activation energy is between two limits eg
`between 10 and 20 kcal As a result
`a table may be
`constructed showing days of stress at various stress
`temperatures Readers are requested to view the table in
`Ref 14 The use of a 10 to 20 kcal bracket
`table is rea
`
`sonable because
`
`broad experience indicates
`
`that most
`
`analytes and reagents of interest
`
`in pharmaceutical
`
`and
`
`clinical
`
`laboratories
`
`have
`
`activation
`
`energies
`
`in this
`
`range 2324
`For analytes with high activation
`energies
`tables and the Q rule provide useful
`bracket
`information
`when they are applied conservatively Use of published
`
`both
`
`

`

`Trends in Stability Testing
`
`861
`
`energy values can
`
`in projecting prod
`
`or experimentally derived activation
`significantly lower the risks inherent
`uct shelf life
`The Q rule and the bracket
`tables were used in the
`past by some in the pharmaceutical
`industry for the pre
`diction of shelf life of the product These methods are
`in either the ICH or FDA stability guidelines
`
`not official
`
`Retained Sample Stability Testing
`
`One of the most important elements in most stability
`testing of marketed pharmaceutical products is evaluation
`of retained stability samples The usual practice for such
`for which sta
`for every marketed product
`
`studies is that
`
`bility data are required the manufacturer
`selects stability
`least one batch a year
`samples for retained storage for at
`If the number of batches marketed exceeds 50 it
`is proba
`samples from two batches
`bly desirable to take stability
`introduced in the mar
`Often when a new product
`is first
`the manufacturer may decide to take stability sam
`ket
`as increased confidence
`ples of every batch Later
`the number of
`of
`gained in the stability
`
`is
`
`the product
`testing is likely to be progres
`
`batches kept
`
`for stability
`
`are designated as stability
`
`sively reduced so that only 2 to 5 of marketed batches
`sample batches 8
`
`Stability samples are tested at predetermined intervals
`Thus if a product has a 5 year shelf life it
`is conventional
`to test at 3 6 9 12 18 24 36 48 and 60 months This
`data on re
`conventional method of obtaining
`stability
`tained storage samples was termed the constant
`
`interval
`
`method by Carstensen and Rhodes 8 who pointed out
`some disadvantages of this method earlier 2526 These
`authors have proposed use of the fixed date method of
`sample testing which uses a modified form of
`the conventional
`retained sample testing They also pro
`posed a much more radical
`and
`termed this
`change
`method stabi I ity testi ng by eval uati on of market sampl es
`This method involves taking samples already in the mar
`ketplace and evaluating stability attributes 2729 This
`since it chal
`type of testing is inherently more realistic
`lenges the product not just in the idealized retained sam
`ple storage conditions but also in the actual marketplace
`
`stability
`
`Cyclic Temperature Stress Testing
`
`temperature stress testing method as ex
`The cyclic
`plained by Carstensen and Rhodes 30 may provide evi
`the instability not available from isothermal
`
`dence about
`
`tests This type of testing is a very useful component
`the gamut of tests available to the pharmaceutical
`scien
`testing 129 used in development or
`
`tist
`
`for stability
`
`in
`
`troubleshooting but not for routine testing of marketed
`product The cyclic temperature stress tests should be de
`signed based on knowledge of the product so as to mimic
`storage The period of
`likely conditions
`in marketplace
`the cycle most
`favored is 24 h since the diurnal rhythm
`on earth is 24 h thus marketed pharmaceuticals
`are most
`likely to experience such a cycle during storage 3132
`Carstensen and Rhodes 32 derived an equation re
`to time based on a sine wave
`lating temperature change
`the maximum and mini
`function It was proposed that
`mum temperatures for the cyclic stress testing should be
`selected on a product byproduct basis and taking into
`account such factors as recommended
`storage tempera
`
`tures for the product and specific chemical and physical
`degradation properties It was also recommended that the
`test should normally have about 20 cycles
`
`MEAN KINETIC TEMPERATURE
`
`Concepts
`
`it
`
`whether
`
`For a USPNF product
`is expected that when prop
`can meet monograph specifica
`erly stored the product
`tions at any time during its shelf life From time to time
`have expressed concerns about
`health care practitioners
`stresses to which drug products
`the environmental
`lifetime and about
`the products
`exposed throughout
`the integrity of the prod
`the exposure will affect
`uct The concerns include transportation
`and storage of
`drug products by manufacturers wholesalers and phar
`macies Thus the stability of the pharmaceutical
`is an attribute that must be known The USPNF recog
`and thus
`nized that storage temperature affects stability
`defined the storage conditions
`The amendment of the USP definition of Controlled
`Room Temperature
`in November
`a re
`quirement for a mean kinetic temperature calculated at
`not more than 25°C The definition of Controlled Room
`Temperature is as follows 3334
`
`are
`
`article
`
`1993 includes
`
`A temperature maintained thermostatically that
`encompasses the usual and customary working en
`vironment of 20°C to 25°C that results in a mean
`kinetic temperature calculated to be not more than
`25°C and that allows for excursions between 15°C
`and 30°C that are experienced in pharmacies hos
`pitals and warehouses Articles may be labeled for
`storage at controlled room temperature
`or at
`up to 25°C or other wording based on the same
`mean kinetic temperature
`
`

`

`862
`
`Kommanaboyina and Rhodes
`
`The relationship between CRT and mean kinetic tem
`perature MKT for storage and distribution of pharma
`
`ceutical articles is given special attention in official publi
`cations 1135 Since degradation
`rate constants
`are
`the amount of degradation varies
`temperature dependent
`with the temperature during a storage period The use of
`MKT originally proposed by Grimm and Shepky 36 has
`as a convenient method of
`become generally
`
`accepted
`
`quantifying storage temperatures as they relate to degra
`
`dation
`
`The equation for the determination of MKT known
`as the Haynes formula is derived from the Arrhenius
`equation relating the degradation rate constants at differ
`ent temperatures to the activation energy 37 The MKT
`concept can be applied to many areas of pharmaceutical
`shippers hos
`distribution manufacturers warehouses
`and community pharmacies emergency vehicles
`vehicles and so on The mean ki
`sales representatives
`netic temperature is the single calculated temperature at
`which the total amount of degradation over a particular
`
`pital
`
`period is equal to the sum of the individual degradations
`that would occur at various temperatures Thus the MKT
`may be considered an isothermal storage temperature that
`simulates the nonisothermal effects of storage tempera
`ture variation 3839 It
`is not a simple arithmetic mean
`is always higher than the arithmetic mean tempera
`ture 39
`
`It
`
`Calculation of Mean Kinetic Temperature
`
`Although there is general recognition in North Amer
`ica the European Union and Japan of the utility of the
`MKT concept
`the ex
`some debate about
`there is still
`act method by which this value should be calculated al
`though in many instances the differences in mode of cal
`culation will have little significant effect on the numerical
`
`value obtained
`
`USP Method
`
`The USP method of calculation 40 is shown below
`The mean kinetic temperature is calculated from the aver
`age storage temperatures recorded over a 1 year period
`and the running average calculated from the average of
`weekly high and low temperatures recorded over the pre
`ceding 52 weeks
`the exposure of the pharmaceuticals
`If
`is for a shorter period as in doctors cars patients cars
`cars etc then it
`is advised to cal
`sales representatives
`culate the MKT with frequent
`recording of the tempera
`ture profile
`
`The mean kinetic temperature is calculated by Haynes
`
`equation
`
`IVI K I =
`
`AHR
`
`1neAHRTI
`
`eAIIRT2
`
`eA11RTnn
`
`where M KT is the mean kinetic temperature AH is the
`energy of activation 83144 kJmol R is the universal
`gas constant 00083144 kJmoldegree T1 is the arith
`metic mean of the highest and lowest
`temperatures re
`time period eg the first week
`corded during the first
`T2 is the arithmetic mean of the highest and lowest tem
`time period eg
`peratures recorded during the second
`second week Tn is the arithmetic mean of the highest
`temperatures recorded during the nth time pe
`and lowest
`riod eg nth week n being the total number of average
`storage temperatures recorded 52 during the annual ob
`temperatures T being absolute
`temperatures in degrees Kelvin K
`servation period and all
`
`In reality of course not all pharmaceutical
`products
`are characterized by degradation energy of activation of
`83 kJmol This is the average
`value based on work by
`Grimm and Shepky 36 and Kennon 24 Ideally the
`value of activation energy AH to be used in the calcula
`tion should be determined experimentally for any given
`product Among various pharmaceutical
`forms
`dosage
`energy may vary from 5 to 240 kJmol
`the activation
`in MKT that
`results from this variation of
`The change
`activation energies is probably relatively small
`instances 39
`
`in many
`
`FDA Method
`
`The FDA recommends the method of entering both
`the individual highest and the lowest
`temperatures rather
`
`for the calculation
`
`of
`
`than averages
`in the equation
`MKT This results in entering 104 data points in contrast
`to USPs 52 points 13 Bailey and Medwick 40 dis
`cussed the characteristics of methods used to calculate
`MKT The USP and the FDA methods of calculation of
`MKT were compared by the authors taking into consid
`eration the different values for the activation energy 41
`are electronically recorded at many
`temperatures
`the values are used in the calcu
`times during a day and all
`lation of MKT then there is no difference between the
`USP and FDA methods
`
`If
`
`Mail Order Temperature Excursions
`
`Factors that may affect
`include the specific nature of the prod
`during shipment
`in environ
`and variations
`the types of packaging
`
`the stability of a drug product
`
`uct
`
`

`

`Trends in Stability Testing
`
`863
`
`mental conditions during transport Since many pharma
`ceutical products are distributed through the US Postal
`Service USPS a study was performed by Black
`Layloff 42 that
`revealed the interior temperature of a
`black mailbox was 58°C in an ambient
`temperature of
`38°C in St Louis Missouri This result indicates
`products distributed through the postal
`pharmaceutical
`service may be exposed to temperatures that significantly
`exceed
`standards
`those normally specified in stability
`
`and
`
`that
`
`This is especially likely to be a problem for temperature
`
`sensitive labile products
`To observe the effects experienced by the packaged
`pharmaceuticals during the shipment and distribution the
`USP recorded the temperatures
`and humidities experi
`enced by packages during mailorder distribution using
`packaging temperature and humidity monitoring devices
`and shipping packages to different parts of the country
`On return of the packages the MKT was calculated Re
`sults of the study showed that only 84 of the packages
`experienced temperature variations within the excursions
`allowable under the CRT The remaining packages were
`exposed to temperatures significantly above the accepted
`excursion range While 655 of the packages experi
`enced warm conditions 30°C 40°C during the ship
`the remaining 261 experienced excessive heat
`ment
`In addition MKT calculations
`>40°C conditions
`showed that 311 of
`the packages had MKT values
`25°C for periods of 19 to 21 days Significant
`spikes in relative humidity RH experienced were also
`reported 43
`The USP team of scientists also tried to determine the
`
`above
`
`extent of physical
`
`and chemical
`
`changes experienced by
`
`findings demonstrating
`
`preparations exposed to typical ship
`the pharmaceutical
`ping conditions Monitoring devices were used for the
`study Results of
`temperature and humidity variations
`indicated that about 40 of the articles
`during shipment
`than 25°C 44 The data
`experienced an MKT greater
`presented agreed with previous
`the pharmaceuticals
`
`that
`
`experienced significant
`
`fluctua
`
`Recognizing
`
`tions in temperature and humidity during shipment
`that some products will be especially
`the USP proposed a
`change
`sensitive to temperature
`definition for labile preparations
`and the shipping and
`for such preparations 45
`the labeling requirements
`The data profile of the temperatures experienced dur
`
`ing the shipment and distribution can be obtained using
`such electronic indicators as TempTale 3 Sensitech Inc
`Beverly MA TempTale H Sensitech and Cox Lynx
`Cox Recorder Belmont NC and chemical
`indicators
`such as time temperature indicator TTI Lifeline Tech
`nology Inc Morris Plains NJ and Monitor Mark 3M
`
`St Paul MN The functioning of
`the indicators was
`studied by C C Okeke et al 43 It has also been re
`the MKT in Sudan is in
`ported by Carstensen et al
`excess of that stipulated for the dry hot climate zone
`46
`
`that
`
`STORAGE CONDITIONS
`
`Concepts
`
`fall
`
`the shelf
`
`The USP compendia monographs specify storage re
`quirements that are to be maintained throughout
`life shipment distribution and storage of the article The
`USP storage requirements
`into two major categories
`specific and nonspecific 3347 Many monographs
`in
`clude specific storage conditions such as Store in a cool
`place A survey conducted by the USP revealed that
`there exist products that do not have any specific storage
`conditions 48 The USP General Notices
`section ad
`dresses these types of compendial monographs in the dis
`cussion of storage under nonspecific conditions
`The storage conditions under the specific requirements
`are defined using the following terms freezer cold cool
`room temperature controlled room temperature warm
`excessive heat and protection from freezing The storage
`
`under nonspecific conditions
`cles regardless of quantity for which no specific storage
`
`section states that for arti
`
`directions or limitations are provided
`
`in the individual
`
`monograph it
`
`is to be understood that conditions of stor
`
`age and distribution including the shipment of articles
`to the consumer include protection from moisture stor
`age at controlled room temperature and when necessary
`protection from light 33
`The length of the stability studies and the storage con
`ditions should be sufficient
`shipment
`to cover storage
`
`and subsequent use eg reconstitution or dilution as rec
`ommended in the labeling The accelerated and long
`and the minimum time period at
`term storage conditions
`submission are listed below
`
`Conditions
`
`Longterm testing 25°C it 2°C
`60 it 5 RH
`testing 40°C it 2°C
`75 it 5 RH
`
`Accelerated
`
`Minimum
`
`Time Period
`
`at Submission
`
`12 months
`
`6 months
`
`When significant
`testing additional
`
`occurs due to accelerated
`change
`testing at an inte