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Review Article

Stability Studies Needed to Define the Handling and Transport Conditionsof Sensitive Pharmaceutical or Biotechnological Products

Claude Ammann12

Abstract Many pharmaceutical or biotechnological products require transport using temperature-

controlled systems to keep their therapeutic properties There are presently no of 1047297cial guidelines for

testing pharmaceutical products in order to de1047297ne suitable transport speci1047297cations After reviewing the

current guidance documents this paper proposes a methodology for testing pharmaceutical products and

de1047297ning appropriate transport conditions

KEY WORDS biotechnological products distribution pharmaceutical products stability temperature

excursions transport

INTRODUCTION

It is considered good practice to test the stability of drugsubstances and drug products according to the InternationalConference on Harmonization (ICH) Q1A to Q1E (1ndash5) orQ5C (6) guidelines or the World Health Organization(WHO) Technical Report Series No 953 2009 Annex 2ldquoStability testing of active pharmaceutical ingredients and1047297nished pharmaceutical productsrdquo (7)

In a standard stability program a stress study is 1047297rst

carried out to determine the drug substances degradationpath and to establish suitable analytical methods Drugsubstance stability studies are then conducted to de1047297nestability under long-term and accelerated storage conditionsIn the next phase of the development plan the drugsubstance is formulated into a drug product and compatibilityof the drug substance with excipients and container parts isthen tested When suitable conditions are determined long-term and accelerated studies commence with the drugproduct The data obtained from these studies are used tode1047297ne the optimal storage conditions and correspondingretest dates for the drug substance or shelf-lives for drugproduct

A major concern of the pharmaceutical industry and

health authorities is to guarantee that drugs are delivered topatients without loss of therapeutic properties An ever-increasing number of therapeutic products developed by thebiotechnological or biologics (vaccines) industries requiretemperature-controlled distribution channels and it is notinfrequent that delays during transport put product quality atrisk when transport times and temperature control cannot bemaintained In these cases the drug may experience ldquotemper-ature excursionsrdquo

Products sensitive to transport conditions need specialcare to ensure that their quality is not impaired by transportoperations When talking about sensitive products oneusually thinks about products that are sensitive to temper-ature but other environmental conditions should also beconsidered including humidity light oxygen shocks pres-sure vibrations and X-rays encountered during shipment bytruck train boat or plane

Two points should be remembered before going anyfurther The 1047297rst is that regulatory authorities require that the

manufacturer ensures product quality not only during storageor transport but until it is used for patient treatment ldquoThestorage conditions and the lengths of studies chosen should besuf 1047297cient to cover storage shipment and subsequent userdquoICH Q1A 217 (1) This requirement is a challenge for themanufacturer since it must be ensured even after controls bythe manufacturer in the supply chain have ended This isusually the case when the product is sold to pharmacists orhospitals for distribution to patients and when patients storethe product at home

The second point is that the drug product manufacturermust decrease the risk of quality defects as much as possibleQuality defects might occur either if the temperature chosenfor the transport of a temperature-sensitive product is outside

the registered storage temperature range or if the transportorganization fails to maintain the planned transport con-ditions Both will increase the degradation of the product sothe manufacturer must balance both situations and choose thebest distribution plan It might be suitable to transport aproduct at room temperature if the studies support thisapproach

An additional economic factor should be consideredThe value of a product ready to be used by the patient has thehighest cost along the whole supply chain When a product isready to be used its value not only includes the aggregatecost of the drug substance the drug product storage anddelivery but also RampD marketing sales taxes and other

1 Claude Ammann Consulting Daillettes 5 1066 Epalinges Switzerland2 To whom correspondence should be addressed (e-mail info

claudeammanncom)

Received 16 March 2011 accepted 2 September 2011 published online 27 September 2011

AAPS PharmSciTech Vol 12 No 4 December 2011 ( 2011)DOI 101208s12249-011-9684-0

1530-9932110400-12640 2011 American Association of Pharmaceutical Scientists 1264

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items If the product is not properly stored during and afterdistribution the loss can be major Failing to address thedistribution channel correctly may have negative consequen-ces to patient health and harm the companys image if arecall is mandated Pro1047297ts may also be impacted by a lack of drug availability

There are no guidelines (such as those on storagestabilities) for testing to determine the suitability of transport

conditions for sensitive products After reviewing the status of the leading pharmaceutical associations regulations andguidelines on transporting drugs this paper will describe testprogram for determining optimal transport conditions thatprovide suf 1047297cient product protection as well as satisfactoryhandling and distribution

REGULATIONS AND GUIDANCE

Signi1047297cant information on transporting medicinal productscan be found in the publications issued by the regulatoryauthorities and pharmaceutical associations This informationis summarized below

ndash ICHmdashWHO

ICH Q1A (212) (1)ndashWHO (212) (7) gives generalguidance on how to perform stress tests The results of suchtests are essential to determine the sensitivity of a drugsubstance to temperature humidity oxidation pH and lightThe results of the stress tests are directly useful when it comesto transporting the drug substance and will help to determineappropriate tests to control transport conditions for the drugproduct

ICH Q1A also describes the recommended conditionsfor performing long-term and accelerated stability tests ondrug substances and drug products (see Fig 1) and givesuseful guidelines on the temperature and humidity conditions

for running these tests Advice is provided to manufacturersfor using these data

ndash ICH Q1A similar to WHO Glossary Acceleratedtesting ldquoStudies designed to increase the rate of chemical degradation or physical change of a drugsubstance or drug product by using exaggeratedstorage conditions as part of the formal stability

studies Data from these studies in addition to long-term stability studies can be used to assess longerterm chemical effects at non-accelerated conditionsand to evaluate the effect of short term excursionsoutside the label storage conditions such as mightoccur during shipping Results from acceleratedtesting studies are not always predictive of physicalchangesrdquo

ndash ICH Q1A chapter 217 similar to WHO 217 ldquoDatafrom accelerated stability studies can be used toevaluate the effect of short term excursions higher orlower than the label storage conditions that mayoccur during the shipping of drug productsrdquo

ndash ICH Q1A chapter 2173 identical to WHO 2173Drug substances intended for storage in a freezerldquohelliptesting on a single batch at an elevated temperature(eg 5degCplusmn3degC or 25degCplusmn2degC) for an appropriate timeperiod should be conducted to address the effect of shortterm excursions outside the proposed label storagecondition eg during shipping or handlingrdquo

ndash ICH Q1A chapter 2275 similar to WHO 2265

Drug products intended for storage in a freezerldquo

In theabsence of an accelerated storage condition for drugproducts intended to be stored in a freezer testing on asingle batch at an elevated temperature (eg 5degCplusmn3degCor 25degCplusmn2degC) foran appropriatetime period should beconducted to address the effect of short term excur-sions outside the proposed label storage conditionrdquo

ndash ICH Q5C (6) Stability of BiotechnologicalBiologicalProducts section 63 Accelerated and Stress Condi-tions ldquoStudies under stress conditions may be useful indetermining whether accidental exposures to condi-tions other than those proposed (eg during trans-portation) are deleterious to the productrdquo

From these sections of the guidelines it can be con-cluded that the manufacturer can use the accelerated stabilitydata to assess the signi1047297cance of temperature excursionsoutside the standard conditions during transport

ndash United States Pharmacopoeia

United States Pharmacopoeia (8) has recently editedvery interesting monographs on the programming of stabilitytests Interested readers can 1047297nd valuable information in thefollowing documents

ndash lt795gt Pharmaceutical CompoundingmdashNonsterilePreparations

ndash lt797gt Pharmaceutical CompoundingmdashSterilePreparations

ndash lt1079gt Good Storage and Shipping Practicesndash lt1118gt Monitoring DevicesmdashTime Temperature

and Humidityndash lt1191gt Stability Considerations in Dispensing Practice

ndash Parenteral Drug Association Technical Report 39Revised 2007 (9)

is certainly the best document to date for planning thetesting of products under temperature cycling conditions andevaluating the impact of temperature excursions Following

Fig 1 Stability tests during the development of a drug product and

those described in ICH guidelines

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during which the product is kept at this value For smalldeviations from the storage conditions and short periods of time the consequences are usually not signi1047297cant Riskanalysis will show which tests should be planned (see Table I)

Temperature is the main focus for testing because almost allpharmaceutical and biotechnological products are sensitive totemperature In addition transport in controlled conditions is notalways reliable There are a number of problems that can arise

amp weather might follow unpredictable changesamp customs procedures might take longer than anticipatedamp accidents might cause disruptionamp route used for transport might not be that anticipatedamp transport might stop at unsuitable placesamp temperature control systems might malfunctionamp communications between the various transport com-

panies might have blocked the product (this couldhappen when the transport is contracted out to achain of transport specialist such as shipper forward-ers ground handlerstransportation service providersconsignee air carrier)

amp temperature sensors might be defectiveamp information on the actual transport conditions might

be inexact or lackingamp other factors

For these reasons the manufacturer should make thebest possible efforts to obtain formulation that is ldquostablerdquounder a broad range of conditions

If this is not possible the next objective should be toassess extensively the limits in which the product can behandled safely

There are natural temperature ranges that could bede1047297ned It will be very unusual to have temperaturesbelow minus100degC or over 100degC in a natural environment In

Antarctica temperature minima have been measured atminus

89degCTemperature maxima have been measured at +58degC inLibya and in Death Valley But even if a product is storedin a closed environment under the sun it will not beheated over 100degC

Humidity during transport is generally not critical dueto the very short period of time when the product isstored at highlow humidity But humidity can change thecharacteristics of solids or non-aqueous solutions whichare packed in non-tight containers Preservation of a drugproduct at high or low humidity is a testing condition of the ICHWHO studies and it is usually not necessary torepeatadd this parameter to the transportdistribution

stability program

Light is usually not a testing parameter since productsare shipped in light-resistant internal or external packaging

Oxygen is usually not a testing parameter since productsare stored and transported in air tight containers

A droprise in pressure can damage products if packaginghas not been tested for deformation or leakage under highlowpressure Blisters and sprays are examples of sensitive packaging

Some very interesting information is given in the IATA

document (15)

ldquoNormal or standard atmospheric pressure at sea level isusually de1047297ned at hellip 1013 millibars however this numbervaries greatly due to the weather

Generally speaking cargo compartments on cargo andpassenger aircraft are pressurized to the same levels Thepressure in the each aircraft varies during 1047298ight depend-ing on altitude and pressurization settings Normally thepressure varies from sea level pressure of 1013 millibars toa value no less than 800 millibars hellip

It should be noted that lsquofeeder aircraftrsquo are not subject tothe same pressure situations These trips are potentiallynonndashpressurized and used to transport express air pack-ages to remote areas In this case cargo experiences thesame ambient pressure as the pilotrdquo

ISTA (15) or ASTM (16) propose standard tests for thevibration shock and atmospheric conditioning

Vibrations might damage solid dosage forms duringtransport if they are friable Vibrations have also been shownto increase the appearance of particles in protein-containingsolutions and to in1047298uence their therapeutic properties Forsensitive pharmaceutical or biotechnological products this iscertainly a parameter that has to be evaluated

Shocks can damage products if packaging has not beentested for shock resistance Shock might damage solid dosageforms during transport if they are friable

Radiation can be an issue for biologic products and thosethat have been shown to be sensitive to X-rays during testsusing this method of sterilization

The International Air Transport Association (IATA)document has the following information (17)

17132 Radio Frequency (RF)Most pharmaceutical products are exposed to RF energythroughout the supply chain RF is used as a tool forinventory purposes as well as supply chain visibility This

low energy is considered to be benign However the FDA

Table I Example of Conditions to be Tested for Product Transport

Temperature Humidity Light Pressure Vibrations Shocks X-ray

Solid in bottles + 0 minus minus 0 0 minus

Solid in blisters + 0 minus + 0 0 minus

Liquid in ampoules + minus minus minus 0 + 0

Liquid in bottles + minus minus minus 0 + 0

Liquid in sprays + 0 minus + 0 minus 0

Gel in plastic tubes + minus minus 0 0 minus 0

Cream in plastic tubes + minus minus 0 0 minus 0

(minus) conditions not requiring tests 0 conditions possibly requiring tests (+) conditions de1047297nitely requiring tests

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has requested that pharmaceutical companies perform RFenergy input studies for their Biologics (this is not necessaryfor nonndashbiologics) to see if there is any modi1047297cation to thebiologic that is not typical of heat degradation

17133 X-ray (radiation exposure in airplanes and at airports)Pharmaceutical products can be exposed to X-rays (maninduced and or naturally occurring) throughout the supply

chain Generally speaking the amount of X-rays that aproduct can be exposed to at an airport during screening issigni1047297cantly less than what the exposure would be in the cargohull at 35000 ft If a product is known to be sensitive to X-rayenergies the manufacturer should work with the broker andcustoms to not have product X-rayed at the exit and entreeports and work with the airline to take appropriate precau-tions during air travel Extra shielding might be an appro-priate means of protection against this radiation hellip

STABILITY STRATEGY

The stability manager has to de1047297ne what the scope of thetransport and distribution studies should be and when tocarry them out This information will be used to develop astability plan

When to Run a Stability Test to Assess the Distribution

Conditions

The stability studies covering the companys transportand distribution requirements have to be planned at the rightmoment as part of the overall development plan If they areplanned too early they might be invalid if the formulationthe container or the distribution plans are revised and willthen have to be repeated

In the early phase of the development plan themanufacturer wants to guarantee that the product is com-pliant with the requirements for all preclinical and clinicalstudies If there is insuf 1047297cient data the manufacturer will beforced to use transport and distribution conditions known tobe protective for the product typically these include liquidnitrogen dry ice minus20degC or any other conditions whereproduct stability has been demonstrated during the necessarytime period

Stability studies for a products transport and distributionare reasonably run with the stability of a product prepared forpivotal phase-3 clinical trials At this product developmentstage the manufacturer has already accumulated preliminary

stability data providing an indication of appropriate storageand distribution conditions These have to be challengedsince the processformulationpackagingetc might have beenchanged before starting phase-3 clinical trials

Scope

The next point to examine is the scope of the study Theproposed tests should be related to production environment anddistribution channels This can be challenging since typically atthe beginning of the phase-3 clinical trials the manufactureroften has only a very vague idea of what the marketing andrelated production and distribution activities will actually be

after registration and later during its commercializationKnowing the products sensitivity to the parameters of

concern is the 1047297rst objective of the study The correspondencebetween this sensitivity and the required minimum needs fordistribution and subsequent use by customerspatients willdetermine the product distribution conditions

The basic scope of the stability study is to de1047297ne thetransport conditions as proposed in Table II

Having limited understanding of the products propertiesat this point in the development lifecycle means that it mightrequire considerable effort to focus on the right testingconditions that are not too drastic (where the productdeteriorates too much) or too mild (where the product does

not deteriorate and therefore could stand additional stress)Using a mathematical model could help to assess the temper-ature excursion effect on the products potency (18) Thebasic scope can be translated in an alternative scope asdescribed in the Table III

When the scope is clearly de1047297ned and approved it istime to program the studies

Program the Study

The proposed analytical strategy for programming thestudies on transport stability is described in Table IV

Limits of the Study

The stability manager should start by evaluating therange of investigations appropriate for the product underconsideration Is the drug substance already present inanother drug product Is the product a well-known type of product in the company What are the relevant experi-ences available for the present product What are theparameters that impact the quality characteristics Whatare the limits of these parameters Are they limited onboth sides by maximumminimum values Are thereintermediate values that could be relevant Is it a multi-dimensional study Are there potential dependent param-eters What are the limits for the investigations

Stress Studies At the beginning of a drug substancesdevelopment manufacturers conduct stress tests to deter-mine its sensitivity to different environmental conditionsThey usually choose temperature humidity light and

Table II Example of Basic Scope

Set the conditions that are best suited to the

1047297llingpackagingdistribution operations

The company will determine the conditions that are best to handle the product

How can we 1047297ll and pack products that are stored at minus70degC or minus20degC

Assist the QP in evaluating the release of

batches that were subjected to excursions

The company will determine the action plan in case of a temperature deviation

Are there potential deviations that could place the

patient at risk andor damage the product

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oxygen as stress factors and push the studies conditions upto when degradation paths are activated and detectedThese tests will show two main correlated factors

amp the value of analytical methods for detecting productdegradation

amp the nature of the degradation paths

In Fig 2 the drug substance has been placed at 50degC for

3 and 7 days It can be seen on the HPLC traces after 3 daysthat two degradation peaks are built before and after themain peak and that these peaks increase after 7 days

It is of utmost importance to determine the toxicity of degradation byproducts Are they much more toxic than thedrug substance or is their toxicity close to or less than thesubstance The answers to these questions are needed todetermine the speci1047297cations of the drug substance and later of the drug product

The results of these studies give direct indications fortransporting drug substances showing whether special precau-tions should be de1047297ned or if ambient conditions are satisfactory

For drug products the results of stress studies are usuallynot directly interpretable with the exception of the productsthat are similar to the drug substance since the presence of excipients should modify the intrinsic properties of a drugsubstance in a positive way The main focus should be an

understanding of the degradation pathways and of thecorresponding detection methods This knowledge can beused to build formulations that are able to protect the productfrom degradation Additionally it will help the manufacturerto de1047297ne the testing program for the transport conditions

Supportive AcceleratedLong-term Studies Supportiveacceleratedlong-term stability studies show the consequences of temperature on a drug product It would be a great help to havethe ICHWHO stability studies results from early development

Table III Translation of Basic Scope in Alternative Scope

Determine the temperature that the product can support

during

1 h (eg temperature of extreme sensitivity) This scheme will tell the company what the sensitivity of the product is to the

tested parameters and help determine the conditions and methods for 1047297lling

packagingdistributions preparationsdistributionsreceipts1047297nal use

8 h (eg temperature of one shift work 4-h shift plus 2 h

in and out storage)

24 h (eg temperature of daily work)

72 h (eg temperature of standard local transport time)

1 week

2 weeks

1 month

Table IV Stability Study Roadmap

Step Key elements

Establish the limits of the study using present knowledge

(similar project preliminary tests hellip)

Check the data available for the same type of product

Same active as other products already developed Same dosage

form Same packaging

What are the parameters for non-acceptance

Which parameters are importantwhat are the extremesare

intermediates values critical

What is the minmax reasonable temperature

What are the minmax reasonable humidity light oxygen shock

pressure vibrations and X-rays

De1047297ne the standard distribution plan for this product Which are the standard distribution schemes

How many how long how large exposures to temperature outside

storage temperature can be projected

Assess the related risk What is standard practice of use by patientsWhat are the main risks How can we mitigate the risks

Establish the safety margin that apply to the product What are the parameters for non-acceptance

What is the error on the analytical results

What safety margin applies if the distribution plan goes wrong until

the product is no good anymore

Write a stability plan to cover the full range of the project Long term accelerated cycling excursions special points

Combination studies (cycling+ long termaccelerated hellip)

Additional studies (vibration radiation hellip)

Is DOE useful

Run the plan and draw conclusions

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batches or other supportive data since this could make it possibleto model product stability For liquid products using the long-term and accelerated data can help determine the Arrhenius pre-exponential A and Activation Enthalpy dHa parameters Basedon these a mathematical simulation of the product degradationcan be run showing the product stability performances (18)

Distribution Channels

With these initial data based on the available experiencethe stability manager and the distribution manager can study thebest routestransport conditions for distributing the productfrom initial product storage down to patient administrationThey will study the answers to questions such as ldquoWhich is thebest option for the packaging Is a thermostatized pack better

that a thermostatic container 1047297lled with standard boxes Whichroad to follow If the product has to be stored in a freezer howcan it be handled for 1047297lling and labelingrdquo

Different situations for the handling of medicinal productswhen packed in their 1047297nal container need to be considered asillustrated in Table V for a product to be stored underrefrigeration

In the previous example the conditions for formulation

1047297lling and intermediate storage should be studied independ-ently since the packaging of bulk product is not the same asdrug product

Safety Margin

The next question pertains to the risk attaching to thedistribution channel What to do in the worst case How longcould the transport last At what temperature How longcould the user store the product At what temperatureKnowing all this makes it possible to de1047297ne the safety margin

The safetymarginwill depend on thetype of product (a solidmight be less sensitive to unexpected degradation than a liquiddue to the speed of reactions in solid phase versus liquid phase)

The safety margin should also take into account theuncertainty regarding the tests results (assessing the error on thetemperaturetesting methodtime) and the companys risk policy

The safety margin could be in different forms

amp Percentage of time (set the of 1047297cial limit at x of realexperimental time when degradation is observed)

amp Percentage of product (set the of 1047297cial limit at y of the real experimental quantity where toxicity isobserved)

The safety margin might also be dependent on thenumber of experiments available the 1047297rst batch placed instability will not provide as much con1047297dence as the tenth Themargin might be modi1047297ed over time as experience grows

Fig 2 Degradation study example of HPLC traces after 3 and

7 days at +50degC compared with the initial data

Table V Example of a Product to be Stored Under Refrigeration

Step Temperature Study

Formulation of the drug product Room temperature Bulk stability study

Storage of drug bulk product 2ndash8degC Bulk stability study

Preparation of the product for 1047297lling Room temperature Bulk stability study

Filling of the product Room temperature Bulk stability study

Storage of 1047297lled drug product 2ndash8degC Long term

Preparation of the product for the packaging Room temperature Accelerated and cycling

Packaging of the product Room temperature Accelerated and cyclingStorage of packed drug product for step 1 2ndash8degC Long term

Preparation of the product for the transport Room temperature Accelerated and cycling

Transport of drug product 1 to 2 2ndash8degC Long term

Storage of drug product for step 2 2ndash8degC Long term

Preparation of the product for the transport Room temperature Transport study

Transport of drug product 2 to3 Room temperature Transport study

Storage of drug product for step n 2ndash8degC Long term

Preparation of the product for the transport Room temperature Transport study

Transport of drug product n-1 to n Room temperature Transport study

Use of the product by the consumer Room temperature Stability in-use cycling and accelerated

Extraordinary situations

Temperature excursions Temperature excursionsCycling studiesadditional studies

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STABILITY PLAN

Once these preparatory steps are 1047297nished the stabilityplan can be written Note that the ICHWHO long-term andaccelerated stability conditions start with a 1-month testingtimeframe This period is not adapted to handling operations

Knowing the projected properties of the product and theanticipated distribution channels the stability manager will beable to write a plan demonstrating that the studies correctlysupports the distribution channels and also adequately supportsdeviations that could occur during the products transport

Different types of studies are suitable for de1047297ningproducts sensitivity to distribution

ndash Temperature excursion studies and cycling studies (egPDA technical report 39 (19))

ndash Freeze-thaw studies are another type of study that canbe valuable for biologics or biotechnological productssince their structure might be changed by freezingthawing conditions Presence of particles has also

been observed after such temperature variationsndash Real time studies such as those performed with a

temperature program simulating the real transportconditions eg during summer and winter times arebest suited when the manufacturer knows quiteaccurately what are the distribution channels

Additional Tests for Transport

Testing required to assess transport effects on theproduct should be distinguished from tests aiming to evaluatethe effect of temperature excursions outside the statedtemperature ranges

The manufacturer de1047297nes transport conditions based onthe available data from his experience Having performed a

risk analysis he de1047297nes the transport conditions guaranteeingthat product quality meets the requirements when theproduct is used by the patient as prescribed This is usuallyreferenced in a table such as the one presented in Table VI

Tests such as those described by the PDA (9) documentunder temperature cycling or in the article of Bishara (14) areexamples that can be indicative for the manufacturer lookingfor a set of conditions to be followed

If the chosen transport temperature differs from thelong-term storage temperature the conditions must be fullytested and shown to be suitable for the desired purpose Toreach this goal it might be necessary to conduct tests to assessthe suitability of transporting the product at a controlled

temperature The simplest situation is when products aretransported between two sites such as manufacturing anddistribution sites in this case manufacturers can simulatetransport conditions knowing time and transport roads andusing meteorological extremes between the starting andrecipient locations Classical studies use two pro1047297les onesimulating winter conditions and one simulating summerconditions Product is placed in the chosen transport con-tainer during a period of time corresponding to the longestanticipated transport duration Temperature is cycled atvalues simulating daily and night external temperatures asthey have been measured during previous transports orrecovered from meteorological historical data

A special situation occurs when the starting location is in

the Northern hemisphere and the receipt location in theSouthern hemisphere or the reverse In this case mixedtesting conditions should be used simulating the actualseasonal conditions at the starting and recipient locationsThese types of pro1047297les are called summer-winter or winter-summer pro1047297les (see Fig 3)

Table VI Summary Table

Temperature range degC Time

lt8 36 months

8ndash13 36 months

13ndash23 3 months

23ndash27 1 month

27ndash32 2 weeks

32ndashminus

38 1 week38ndash42 3 days

42ndash50 2 days

50ndash62 1 day

62ndash79 8 h

gt79 Do not use

Fig 3 Transport temperature pro1047297les

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When the pro1047297les are de1047297ned the product packed in itstransport box is tested for a de1047297ned period in theseconditions The product temperature should remain withinthe speci1047297ed limits at all times

The other situation is represented by transport of productsfrom a distribution center to many uncontrolled recipientlocations In this case there is no real model and it is theresponsibility of the manufacturer to ensure that the instructions

given to the distribution channel are clear enough to ensure thequality of the product Stability tests as described above andother tests are to be used as described below

Additional tests should be considered when risks relatedto the vibrations or radiations are identi1047297ed ISTA (15) orASTM (16) propose standard tests for vibrations shocks andatmospheric conditioning

These tests should simulate as closely as possible theprojected transport scheme But it is important to have along-term vision to extend the transport schemes to newdistribution channels as marketing will boost sales

Additional Tests for Temperature Excursions

Tests to assess the consequences of temperature excursionsare different in that they are carried out to check the effects of additional stress on the product such as those resulting from adramatic situation outside the standard conditions

Preparing them is dif 1047297cult since no one knows whatwill happen in the next deviation situation Some sugges-tions are to consider the MKT approach and to evaluatethe range where the product can keep its properties whenstressed by temperature excursions The MKT is anindirect approach as it gives an evaluation of the temper-ature supported by the product which is not a represen-tation of the stress supported by the product it gives no

information allowing the person in charge to evaluate theconsequences of the deviationAnother approach is to use a mathematical evaluation of

the product degradation during the temperature excursion asrecently described (18) This paper presents a mathematicalapproach to dealing with temperature excursions It is based onexisting tools such as the Arrhenius equation and the 1047297rst-orderkinetic equation The aim is to help the Quali1047297ed Person (QP)decide whether to release a product that has experienced atemperature excursion The available stability data are workedout and completed with additional short tests This evaluationmakes it possible to determine the potential degradation thathas occurred during the temperature excursion

If this approach is not practicable the standard develop-

ment methods Design of Experiment (DoE) or ldquoTrial andErrorrdquo approach based on the available experience can beused Some guess studies such as ldquoTemperature Excursionsrdquocan help the manufacturer to identify possible limits andrespond to temperature deviations

Combination Studies A related question is the need forcombination studies Each stress condition imposed on theproduct will increase the degradation mechanisms that affectits quality Some of these will have a negligible effect butothers will have signi1047297cant consequences For example if theproduct is subject to transport outside its storage conditions itis important to ensure that the expiry date as determinedduring long-term studies remains valid Studies with this aim

are best run as combination studies where the product issubjected to transport conditions eg at the beginningmiddle andor end of long-term stability studies

Similarly temperature excursions studies should beperformed at different time points of the long-term study tosimulate the real-life conditions

Scheduling the Studies for Storage Transport

and Temperature Excursions

Having a comprehensive view of the activities to becarried out will help the stability manager to be moreef 1047297cient Studies can be scheduled logically considering thenumber of samples to be placed in different conditions andthe time when the analysis will be performed There areexcellent reviews on this activity elsewhere (19)

The best plan is to run the studies in two phases

amp The 1047297rst phase consists of assessing short-timesensitivity (up to one month) and establishes if the initialestimate was within the target range

amp The second phase is to run the full set of tests takinginto account the 1047297ndings of the 1047297rst phase

BUILDING STABILITY KNOWLEDGE OR HAVING A

CLEAR VISION OF THE STABILITY PROPERTIES

For Product Distribution

How to interpret the available stability dataThe goal is to assure patients and health authorities

that the manufacturer can control product quality untiluse To achieve this goal the manufacturer should buildknowledge and understand how to control product degra-

dation or conversely to understand the reasons underlyingthe presence of an unacceptable amount of degradationproducts

He should 1047297rst determine what is the acceptable amountof degradation products and in what conditions they will beformed As described above temperature is the mostimportant parameter for most of the sensitive products

The main information is the temperaturetime relationshipand the manufacturer will 1047297nd out that certain periods of timeare more relevant than others (see Table III) Fixing thestandard operational times will decrease the number of observations to the minimal amount For example it is dif 1047297cultto handle a medicinal product in less than 1 h Handling a batchof thousands of units (eg taking it out of the storage room

preparing dispatch loading a truck) lasts at least this period of time Labeling this same batch on an automatic machine will lastone shift or more Transporting a batch from one manufacturingsite to a distribution site abroad might last a couple of days

It is now time to determine the temperature limit atwhich the product can be placed until it is degraded at theacceptable value This can be done by using the mathematicalmodel described in Ref (18)

At the beginning of product development knowledge isscarce and the picture is all dark gray (see Fig 4a) De1047297ningthe theoretical upper limit of product stability using themathematical model presented elsewhere will be of greatvalue and will allow the manufacturer to better understand

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Fig 4 Example showing how to build stability knowledge a At the beginning b With the preliminary mathematical model and safety margin

c With the ICHWHO stability program d With the preparationdistribution plan e With a full set of tests

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the product The data from early stability tests will bevaluable to plan the initial evaluations If in addition themanufacturer de1047297nes the safety margins that apply to theproduct the range in which the product can be handled safelycan be clearly de1047297ned (see Fig 4b)

The ICHWHO stability data guidelines de1047297ne appropriate

temperature ranges for the different study ranges minus

20degCplusmn5degC+5degCplusmn3degC 25degCplusmn2degC 30degCplusmn2degC 40degCplusmn2degC (see Fig 4c) Themanufacturer will have a better view within the tested rangesand 1047297nd how to organize the manufacturing and transportoperations (see Fig 4d) But there will still be a lack of information outside these ranges

Additional studies should focus on clarifying the rangesin which the manufacturer needs information to deal withtransport and temperature excursions (see Fig 4e) Usingstandard periods of time (see Table III) the manufacturer willdetermine the parameters of the tests to be conducted Theproduct will be placed at the upper temperature of each rangeand tested for degradation during the time that has beendetermined If the degradations value is at or below the limitthe manufacturer can reasonably 1047297x the limits for accepting atemperature deviation Obviously all stability-determiningparameters must be evaluated

This is how manufacturer can build his stability knowledgeWhen this set of analysis is complete the 1047297nal version

has to be settled and will be useful for temperature excursioninvestigations

For Temperature Excursion

This same representation can be useful for decisionsrelating to temperature excursions The information is

reported directly on the product temperature pro1047297le Thedecisions that have to be taken are supported by real data

In the example below one batch of product has beenstored at 34degC for 8 h (see Fig 5a) The person in charge canreport this value in the table and show that the quality of theproduct is still within the accepted values of the parameter

tested In the second example one batch has been stored for10 days at 34degC (see Fig 5b) Here it is clear that the qualityof the product is endangered by this temperature excursionThe other tests parameters which are relevant for stabilitystudies still have to be evaluated before releasing or rejectingthe batch

Fig 5 Example showing how to use the stability knowledge in case of temperature excursions a

With temperature excursion forless than 8 h at 34degC b With temperature excursion for 10 days at 34degC

Fig 6 Label of IATA the exact transport information has to be

printed in the white section

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FINAL CONSIDERATIONS

After all the tests have been performed and evaluatedthe company will obtain a table similar to Table VI

These are the speci1047297cations that are supported by thedata and include the safety margin They show the authoritiesthat the manufacturer has adequate control of the productstability pro1047297le that will be included in the application for

marketing approvalThese values must be restrictively provided to persons

who have a limited view of the full batch history and areunaware of the product properties This will prevent theuncontrolled risk that a stakeholder or patient takes a wrongdecision based on his partial and incomplete knowledge

The labeling should be clear and a proposal has beenprovided by the IATA (15) in its regulation eg see Fig 6

By keeping track of the handling conditions and bysumming the time at each temperature the manufacturer canassess whether the batch is acceptable for use by the patient

Temperature excursions are examined in the light of theavailable data set If a mathematical model has been

developed it can assist evaluation of the consequences onthe criticality of the excursion

CONCLUSION

The manufacturer must ensure that products delivered topatients comply with the marketing authorization Forproducts sensitive to transport conditions this means thatthe manufacturer has to control the product stability pro1047297leand choose the correct storage conditions and appropriatetransport systems When the transport conditions deviatefrom the speci1047297ed values there is a sound basis to decidewhether to release or to reject the batches

The storage conditions are best determined in accordance

with the ICHWHO stability testing programsTransport conditions have to be determined considering

the risks of product degradation If the product is verysensitive to one or more parameters the manufacturer haslittle margin to set the transport conditions Tight limitsidentical or close to those of the storage conditions will berequired On the other hand if the product is somewhatresistant to extended parameters for a short period of time itis in the interest of the manufacturer and the users to haveextended transport conditions In the example of a refriger-ated product the chosen transport conditions could be ldquoroomtemperaturerdquo or ldquocontrolled room temperaturerdquo allowing theproduct to be transported in conditions that are not toodif 1047297cult to guarantee for the many transport operations thatare necessary to reach the patients The risks of deviationsare diminished without increasing the risk to the patients

The preliminary information needed to optimize trans-port conditions is knowledge about product sensitivity to therelevant transport parameters Tests in addition to thoseproposed by the ICHWHO guidelines should be planned tocomplete the picture

ACKNOWLEDGMENT

The author would like to acknowledge Dr Manuel ZahnManaging Director 3R Pharma Consulting GmbH Dr SteveButcher and Dr Eugene Helsel Senior Director QualityStemedica Cell Technologies Inc San Diego CA forreviewing the article and their very appreciated and friendlysupport

REFERENCES

1 Stability testing of new drug substances and productsmdashQ1A (R2)(ICH) International Conference on Harmonization Originallypublished 1994 revised 2003

2 Stability testing photostability testing of new drug substances andproductsmdashQ1B(ICH) InternationalConference on Harmonization6 November 1996

3 Stability testing for new dosage formsmdashQ1C (ICH) InternationalConference on Harmonization 6 November 1996

4 Bracketing and matrixing designs for stability testing of new drugsubstances and productsmdashQ1D (ICH) International Conference

on Harmonization 7 February 20025 Evaluation forstability datamdashQ1E(ICH) International Conference

on Harmonization 6 February 20036 Quality of biotechnological products stability testing of biotechno-

logicalbiological productsmdashQ5C (ICH) International Conferenceon Harmonization 30 November 1995

7 Technical Report Series No 953 Annex 2 Stability testing of active pharmaceutical ingredients and 1047297nished pharmaceuticalproducts WHO 2009

8 US Pharmacopoeia USP current version9 Technical Report no 39 Cold chain guidance for medicinal

products maintaining the quality of temperature-sensitivemedicinal products through the transportation environmentPDA Originally published 2005 revised 2007

10 Technical Report no 46 Last mile guidance for good distribu-tion practices for pharmaceutical products to the end user PDA

200911 Temperature controlled pharmaceutical distribution main-taining the quality of temperature sensitive products in thesupply chain Representative FDA Hotel Fira PalaceBarcelona IBC Informa life sciences 26ndash29 September2006

12 Temperature Controlled Pharmaceutical Distribution ConferenceRepresentative FDA Amsterdam IBC Informa life sciences 9ndash10October 2007

13 Seevers RH Bishara RH Harber PJ Lucas TI Designing stabilitystudies for timetemperature exposure American PharmaceuticalOutsourcing 2005 6(5) 18 20 21 23 55

14 Lucas TI Bishara RH Seevers RH A stability program for thedistribution of drug products pp 68ndash73 sl PharmaceuticalTechnology July 2004

15 Guidelines for selecting and using ISTA test procedures andprojects ISTA current

16 International standards ASTM current17 Perishable cargo regulations chapter 17 9thedition IATA July 200918 Ammann Claude A mathematical approach to assessing temper-

ature excursions in temperature-controlled chains EuropeanJournal of Parenteral and Pharmaceutical Sciences 200813(2)57ndash9

19 Handbook of stability testing in pharmaceutical developmentregulations methodologies and best practices Huynh-Ba Kim(Ed) sl Springer 2009

1275Stability Studies for Sensitive Pharmaceutical Products