Choosing
`the Right
`Sample Size
`for Integrity
`Testing,
`p.80
`
`Package Testing
`Principles of Proper Aging
`Methods, p. 116
`
`--=-~----1 ■
`
`Novartis Exhibit 2049.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ACCELERATED AGING >>
`
`The Need for
`Specificity in
`Accelerated Aging
`
`To maximize the benefits of copolyester plastics as packaging materials,
`manufacturers need to understand and use proper aging methods.
`
`Glenn Petrie
`
`M edical device manu(cid:173)
`
`facturers invest a
`great deal of time
`and money to ensure that
`their products meet both
`product performance needs
`and FDA guidelines. The se(cid:173)
`lection of the appropriate
`packaging materials and
`forms is among the critical
`decisions that need to be
`made when bringing a prod(cid:173)
`uct to market.
`Manufacturers need pack(cid:173)
`aging materials that provide
`a microbial barrier and last-
`ing device protection over an Materials must provide a microbial barrier over an extended period.
`extended period. Packaging
`with these benefits delivers durability
`and safety from the manufacturer
`through storage and transport to the
`end-user.
`Accelerated aging is a critical test for
`documenting the expiration dates for
`medical products.1 It is essential to un-
`
`derstand how to properly test materials.
`Using copolyester as an example, this
`article focuses on the conditions and re(cid:173)
`quirements for proper accelerated aging.
`
`The Need for Accelerated Aging
`Consideration of key variables at the
`beginning of the packaging specifica(cid:173)
`tion process is essential to guaranteeing
`medical packaging integrity. Aging in(cid:173)
`formation, including physical, thermal,
`and optical performance over time, is
`imperative for ensuring package in(cid:173)
`tegrity. Obtaining this information also
`
`helps to satisfy current FDA validation ~
`requirements and provide evidence of 'g
`sterility and fitness-for-use over a prod- i
`uct's life cycle.
`,;;.
`0
`For example, when a product needs a ~
`five-year shelf life to allow time for dis- 1:i ::;
`tribution, storage, and other constraints, ~
`0
`the quality of the package-device :i
`combination should be monitored. Ob- ~
`serving the effects of time through ~
`accelerated-aging studies on a product- i
`package combination can decrease the ~
`time it takes to introduce a product in i
`the marketplace. Material exposure to ~
`
`0
`
`Glenn Petrie is field marketing devel(cid:173)
`opment manager for medical packag(cid:173)
`ing and tubing, SF&S specialty plas(cid:173)
`tics, engineering, and specialty pro(cid:173)
`grams at Eastman Chemical Co. (New
`York City).
`
`Novartis Exhibit 2049.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ACCELERATED AGING >>
`
`tics, including copoly(cid:173)
`esters, is physical aging.
`As a plastic is held below
`its glass transition (Tg)
`temperature, its physi(cid:173)
`cal properties can im(cid:173)
`prove or deteriorate over
`time. It is essential that
`accelerated-aging studies
`be performed properly
`since each plastic materi(cid:173)
`al ages differently. Fail(cid:173)
`ing to perform or im(cid:173)
`properly conducting
`accelerated-aging testing
`Proper accelerated aging is necessary for ensuring product on a medical device
`product-package combi-
`quality.
`nation can lead to incor(cid:173)
`rect data and quality issues that can
`affect the health and safety of end-users.
`
`Accelerated Physical Aging
`Physical aging is a process of molec(cid:173)
`ular relaxation that occurs in all amor(cid:173)
`phous polymers held below their Tg
`temperature. Aging has been observed
`in polyvinyl chloride (PVC), poly(cid:173)
`styrene, styrene acrylonitrile (SAN),
`and polycarbonate, as well as in
`copolyester polymers. This discussion
`focuses on the effects of aging on
`copolyester polymers.
`When a polymer is rapidly cooled to
`below its Tg level, which occurs in all
`commercial melt-phase processing
`techniques, it freezes into a nonequi(cid:173)
`librium conformation with excess free
`volume. In an attempt to attain equi(cid:173)
`librium, the molecular chains rearrange
`
`themselves into a denser structure, re(cid:173)
`ducing the free volume of the system.
`Although this densification is difficult
`to detect, it directly affects other ther(cid:173)
`modynamic and mechanical properties
`that are easier to measure and can,
`therefore, be used to track the extent of
`aging over time.
`These properties increase in linear
`fashion with the log of aging time. The
`aging process proceeds more quickly
`at higher temperatures closer to the
`copolyester's Tg temperature. These
`trends are consistent with other similar
`viscoelastic molecular relaxation pro(cid:173)
`cesses, such as rheological behavior. As
`with other relaxation processes, time
`and temperature can relate through the
`principle of time-temperature super(cid:173)
`position. Molecular motions that occur
`over a given period of time at one tem(cid:173)
`perature are equivalent to motions that
`occur over a longer time period at
`lower temperatures. Simply stated, an
`elevated temperature acts as a catalyst
`for the rate of motion.
`
`Accelerated Aging of Copolyesters
`Copolyester plastics possess excel(cid:173)
`lent final application properties such
`as long-term clarity and toughness.
`Using accelerated-aging testing on
`copolyesters that are used in medical
`packaging helps manufacturers to cap(cid:173)
`italize on these benefits. The ASTM
`guidelines suggest using an accelerat(cid:173)
`ed aging (QlO) factor of 2.0 as a con(cid:173)
`servative estimate for aging the pack(cid:173)
`aging and device. The guidelines also
`
`an elevated temperature for a short
`period of time ages a package-device
`combination to the same extent as
`would be observed were it exposed to
`room temperature for a longer period of
`time (time-temperature superposition).
`The American Society for Testing and
`Materials (ASTM) has established
`guidelines to contribute to the reliabili(cid:173)
`ty of materials, promote public health,
`
`Accelerated aging is
`a critical test
`for documenting
`the expiration dates for
`medical products.
`
`and improve quality of life. Accelerated(cid:173)
`aging testing is done based on ASTM
`F1980-02 standard guidelines and in(cid:173)
`corporates factors such as time at am(cid:173)
`bient (room) temperature, accelerated(cid:173)
`aging temperature, and ambient
`temperature into a test equation.
`Changes in relative humidity during
`testing away from standard laboratory
`guidelines of 50% rh may affect the
`aging results. The ASTM guidelines
`suggest that low- and high-humidity
`environments might need to be con(cid:173)
`sidered in testing protocols. Industry
`concern over relative humidity effects
`on physical aging has put the standard
`under review. Because the effects are
`not well known, most labs perform
`tests at 50% rh.
`An integral part of this testing on plas-
`
`AGING
`TEMP.
`
`23°c
`(74°F)
`30°c
`(86°F)
`40°c
`(104°F)
`50°C
`(l22°F)
`60°C
`(140°F)
`65°C
`(150°F)
`
`SIMULATED AGE/
`ACCELERATED AGING TIME (HOURS)
`12
`17
`2
`20
`7
`3
`YEARS MONTHS MONTHS MONTHS WEEKS DAYS
`
`165
`YEARS
`
`1,400,000
`
`150,000
`
`15,000
`
`8,800
`
`5,100
`
`500
`
`290,000
`
`30,000
`
`3,000
`
`1,800
`
`1,000
`
`100
`
`48
`
`10
`
`30,000
`
`3,100
`
`300
`
`3,000
`
`310
`
`31
`
`180
`
`18
`
`110
`
`10
`
`1.0
`
`11
`
`1.0
`
`-
`
`-
`
`-
`
`310
`
`99
`
`32
`
`10
`
`3.1
`
`1.0
`
`1.9
`
`0.6
`
`1.1
`
`-
`
`-
`
`-
`
`Table I. Accelerated physical aging data of copolyester Eastar 6763.
`
`Novartis Exhibit 2049.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ACCELERATED AGING>>
`
`for 19 hours. This aging pro(cid:173)
`tocol reasonably represents
`the lifetime of a typical
`copolyester application.
`Aging copolyesters at
`higher temperatur.es for
`longer periods. of time is not
`generally recommended. For
`example, aging for 250
`hours (10 days) at 60°C is
`equivalent to aging for 1.2
`million hours (133 years) at
`room temperature of 23°C.
`Aging for this length of time
`or longer at 60°C may age
`the material tpo long and
`could provide an unrealistic expecta(cid:173)
`tion of properties and aging at stan(cid:173)
`dard room temperature conditions.
`The recommended aging conditions
`for co polyesters are 50°C and 50% rel(cid:173)
`ative humidity. At these conditions, 18
`hours ·is equivalent to 1 year of actual
`aging at room temperature of 23°C.
`Therefore, 92 hours of aging at acceler(cid:173)
`ated conditions. is equivalent to 5 years
`of actual aging at room temperature.
`
`Results
`The testing shows that copolyester
`provides the required package integri(cid:173)
`ty for a minimum of five years if good
`manufacturing practices are followed
`during extrusion, forming, package de(cid:173)
`sign, and sterilization, and if the pack(cid:173)
`aging is stored at room temperature
`under normal conditions and humidi(cid:173)
`ty levels.
`
`Conclusion
`Packaging materials must provide a
`microbial barrier and lasting device
`protection over an extended period of
`time. Accelerated aging for all plastics
`is critical for understanding and docu(cid:173)
`menting expiration dates. Proper test(cid:173)
`ing is essential to maximize the benefits
`of copolyesters.
`
`Reference
`1. Patrick J Nolan, "Common M istakes in
`Valida ting Package Systems," Medical De(cid:173)
`vice & Diagno,tic Indu,try 28, no. 5
`(2006): 112-120. ■
`
`Correct aging information helps satisfy FDA valida(cid:173)
`tion requirements for packaging.
`
`state that each material, such as poly(cid:173)
`carbonate, PVC, and copolyester, has
`a unique QJO factor. The appropriate
`Q JO factor can and should be used if it
`is derived from proper research and
`experimentation.
`A number of trials were conducted
`to induce accelerated aging on Eastar
`6763 , a co polyester used in rigid med(cid:173)
`ical packaging. These examples. were
`designed to illustrate the effects of
`averaging when the wrong QlO factor
`is used. After extensive experimenta(cid:173)
`tion, it was determined that the QJO
`factor for copo lye sters is 9. 8 .. The
`examples demonstrated that using
`the wrong QlO factor can drastically
`alter the outcome and reliability of
`accelerated-aging testing. Q 10 factors
`should be determined experimentally
`for various polymers.
`
`Examples
`The following example illustrates
`how using the wrong QlO factor ages
`plastic longer than may be intended.
`Aging a co polyester package five years
`(43,800 hours) at 60°C before per(cid:173)
`forming shipping validation testing
`with the QlO set at 2.0 inadvertently
`ages the material well past the intend(cid:173)
`ed five years. Using the ASTM equa(cid:173)
`tion t23 = tT x QJO ((T-723)/10) leads
`the manufacturer to deduce that the
`accelerated-aging time duration will be
`3370 hours (140 days). Experimenta(cid:173)
`tion has shown that this process ages
`tho copolyestor almost 2000 years.
`
`Based on this error, the packaging
`would not withstand additional testing.
`However, by using the correct QlO
`value for copolyester and taking rela(cid:173)
`tive humidity and aging temperature
`into consideration, the accelerated(cid:173)
`aging testing can be accurately com(cid:173)
`pleted in just 92 hours with reliable
`results.
`Because of time-temperature super(cid:173)
`position, it is possible to generate data
`as a function of time at different tem(cid:173)
`peratures and then shift the da:ta to(cid:173)
`gether on one common master curve.
`Numerous tests were conducted to de(cid:173)
`termine the mechanical and thermal
`properties of copolyesters as a function
`of aging time and temperature.
`Time-tern pe ra tu re superpositions
`were performed on the data generated
`from these experiments to create mas(cid:173)
`ter curves for each material. Table I
`shows the times and temperatures that
`can be used to perform accelerated(cid:173)
`aging experiments. A product-package
`combination is aged at an elevated tem(cid:173)
`perature for a short period of time to
`simulate aging at a lower temperature
`for an extended period of time.
`For example, using the QlO factor of
`9.8 for copolyestei; one hour at 60°C is
`equivalent to 96 hours at 40°C or 4 700
`hours at 23°C. Likewise, one hour at
`40°Cequals 48 hours at 23°C. Therefore,
`if manufacturers want to simulate the per(cid:173)
`formance of a package after 10 years of
`life (87,600 hours) at 23°C, it should be
`aged at either 50°C for 180 hours or 60°C
`
`Reprint from Medical Device & Diagnostic Industry, October 2006 • Copyright~ 2006 Canon Communications LLC
`
`Publication PPM-219
`
`Novartis Exhibit 2049.004
`Regeneron v. Novartis, IPR2021-00816
`
`