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`Determination of Conditions for the Production Scale
`Sterilization of Prefilled Syringes
`Norihiro Nishimoto and Tatsuyuki Maekawa
`
`PDA J Pharm Sci and Tech
`
`
`
`2003
`
`57,
`
` 378-386
`
`Regeneron Exhibit 1111.001
`Regeneron v. Novartis
`IPR2021-00816
`
` 
` 
`  
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`TECHNOLOGY/APPLICATION
`
`Determination of Conditions for the Production Scale
`Sterilization of Prefilled Syringes
`
`NORIHIRO NISHIMOTO1* and TATSUYUKI MAEKAWA2
`
`1Osaka Pharmaceutical Research Center, Daiichi Pharmaceutical Co. Ltd. 2Tokyo Pharmaceutical Research Center,
`Daiichi Pharmaceutical Co. Ltd.
`
`ABSTRACT: External and internal differences in pressure of prefilled syringes can cause plunger movement during
`sterilization, which might cause drug product contamination. Consequently the pressure inside the autoclave during
`sterilization should be controlled carefully to prevent contamination of the drug product by microorganism and
`particulates. A previously determined theoretical relationship of temperature to pressure in sealed bottles was
`modified for prefilled syringes to take plunger movement into account. This modification yielded a correction factor
`that includes a coefficient of linear thermal expansion for the syringe, thermal expansion of the plunger, and friction
`between the plunger and the syringe wall. To confirm the accuracy of this modified relationship, 100 mL polypro-
`pylene prefilled syringes with butyl rubber plungers, some of which carried pressure and temperature sensors, were
`used to test various sterilization conditions at the experimental scale. The results showed that the major problem in
`establishing the pressure conditions for production scale sterilization is temperature distribution throughout the load.
`However, an over pressure sterilization cycle at 121°C and 0.34 MPa showed the best results. Microbial challenge
`and light-obscuration particle count tests were performed on the syringes from the worst-case location predicted from
`modified relationship; the results show that these conditions preserved the sterility of the drug product and protected
`it from particulate contamination.
`
`Introduction
`
`Sterile parenteral drug products should be terminally
`sterilized by heating in their final container if terminal
`sterilization does not causes unacceptable degradation
`of the products, or if terminal sterilization deprives
`substantial clinical advantage of market presentation
`(1, 2). Recently, many parenteral drugs have begun
`being marketed in plastic containers. Unlike previ-
`ously used packaging materials such as glass or metal,
`plastic can expand or deform under high temperature
`and pressure conditions such as those seem during
`autoclave sterilization. Thus, controlling the chamber
`pressure during the sterilization cycle is important to
`prevent deformation or breakage of such containers.
`This is especially true for prefilled syringes because
`
`to whom correspondence should be ad-
`*Author
`dressed: Daiichi Pharmaceutical Co., Ltd., Osaka
`Pharmaceutical Research Center, 4-38, Aketa-cho,
`Takatsuki-shi, Osaka 569-0806, Japan. Phone: ⫹81-
`Fax: ⫹81-72-682-8975.
`72-685-2836.
`E-mail:
`nishi5og@daiichipharm.co.jp
`
`the plunger is not fixed; if the chamber pressure is not
`adequately controlled, the plunger might be displaced
`or move significantly outward, which might lead to
`microbial and particulate contamination of the pack-
`aged drug product. While high pressure might prevent
`this, an excessively high pressure might cause the
`container to deform or to break. Unfortunately, while
`much is known about optimizing sterilization condi-
`tions for glass and metal containers (3), little informa-
`tion has been reported on optimum conditions for
`prefilled syringe sterilization. Consequently, this study
`was conducted to determine optimum conditions for
`these drug presentations.
`
`R. E. Beck derived an internal pressure-temperature
`relationship for autoclave sterilization of solutions in
`sealed bottles from five events postulated to occur as
`the container is heated:
`
`1. Water evaporates into the headspace.
`
`2. The liquid phase expands as temperature increases.
`
`3. The vapor phase attempts to expand as the temper-
`ature increases.
`
`378
`
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`
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`4. Dissolved gases vaporize and enter the headspace.
`
`T ⫽ temperature
`
`5. The container walls expand reversibly to increase
`the total volume of the container.
`
`This theoretical relationship of temperature to pres-
`sure was defined from the vapor pressure, density, and
`Henry’s Law constant of the solution; and the coeffi-
`cient of linear thermal expansion of the container (4,
`5). A subsequent experiment confirmed the validity of
`this relationship (6). The derivation of the following
`equation, which expresses these relationships, is given
`in References 4 and 5.
`
`P ⫽ Pvp ⫹ 共P0 ⫺ Pvp0兲
`
`⫻冢
`
`冉 Y0
`再 关1 ⫹ C共T ⫺ T0兲兴3
`
`1 ⫹
`
`H0MWw
`R␳w0T0
`
`1 ⫺ Y0
`
`H0MWw
`R␳w0T
`
`共1 ⫺ Y0兲
`
`⫺
`
`冊
`
`冎 ⫹
`
`␳w0
`␳w
`
`冣
`
`H0
`H
`
`(1)
`
`P ⫽ container pressure at T
`
`Pvp
`
`⫽ vapor pressure of water at T
`
`H ⫽ Henry’s Law constant for air at T
`
`MWw
`
`⫽ molecular weight of water
`
`R ⫽ universal gas constant
`
`␳
`w
`
`⫽ density of water
`
`C ⫽ coefficient of linear thermal expansion
`for the container material or correction
`factor
`
`Vc
`
`⫽ total volume of container
`
`Y ⫽ fraction occupied by air and water va-
`por
`
`subscript 0 ⫽ conditions when the container is sealed
`
`Values for the vapor pressure, the density, and the
`Henry’s Law constant of the solution—and the coef-
`ficient of linear thermal expansion of the container—
`are needed in order to use Eq. 4 to calculate simulated
`internal pressure values. In order to perform computer
`simulation, Beck developed the following equations,
`which empirically fit tables of reported data for the
`vapor pressure, density of water, and the solubility of
`air in water:
`
`(5)
`
`(6)
`
`(7)
`
`Pvp ⫽ e共16.0⫺4967/T兲
`
`⫽ 0.84829 ⫹ 0.0013128T
`
`⫺ 共2.713 ⫻ 10⫺6兲T2
`
`⫽ 1.627 ⫺
`
`223
`T
`
`e⫺关共T⫺273.2兲/45兴2
`
`␳w
`␳w0
`
`H H
`
`0
`
`this equation is applicable only for
`Unfortunately,
`fixed-stopper containers, vials, bottles, plastic bags,
`and others. However,
`in a prefilled syringe,
`the
`plunger can move during sterilization; consequently,
`plunger motion must be considered to estimate the
`internal pressure precisely. An increase in volume
`within the syringe cylinder caused by this motion adds
`to the fifth event originally considered by Beck. Thus
`the total volume can be expressed by the following
`equations:
`
`Vc ⫽ 兵1 ⫹ C共T ⫺ T0兲其3Vc0 ⫹ UcVc0
`
`Uc ⫽
`
`Um ⫻ S0
`Vc0
`
`(2)
`
`(3)
`
`Where Uc is the portion of the syringe volume at T
`caused by the plunger movement from the initial vol-
`ume, Um is the distance traveled by plunger, and S is
`the sectional area of syringe container. Providing that
`the solution is water and that air occupies the head-
`space, Equations 2 and 3 can be substituted into the
`Beck Equation (Eq. 1) to yield:
`
`冉 Y0
`再关1 ⫹ C共T ⫺ T0兲兴3 ⫹ Uc
`
`P ⫽ Pvp ⫹ 共P0 ⫺ Pvp0兲
`H0MWw
`R␳w0T0
`
`1 ⫹
`
`⫻冢
`
`H0MWw
`R␳w0T
`
`where
`
`共1 ⫺ Y0兲
`
`1 ⫺ Y0
`
`冊
`
`⫺
`
`␳w0
`␳w
`
`冎 ⫹
`
`H0
`H
`
`冣
`
`(4)
`
`where H0
`
`⫽ 6.64 ⫻ 104 atm at 20°C.
`
`In this study, the vapor pressure, the density, and the
`Henry’s Law constant of water are also used to cal-
`culate the internal pressure of syringe presentation
`filled with drug solution because the drug solution is
`aqueous.
`
`Vol. 57, No. 5, September/October 2003
`
`379
`
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`IPR2021-00816
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`TABLE I
`Syringe Sample
`
`Syringe barrel material
`Plunger material
`Fill solution
`
`Fill temperature
`Fill volume
`Head space gas
`Headspace
`
`Polypropylene
`Butyl rubber
`Water for injection or
`aqueous drug
`solution
`293.15 K
`102 mL
`Air
`2 mL
`
`Although Beck cited only one coefficient of linear
`thermal expansion for polypropylene (4), there is more
`than one kind of polypropylene and the coefficient of
`linear thermal expansion is different for each type (7);
`consequently, a standard ASTM method (8) was used
`to measure the coefficient of linear thermal expansion
`of syringes used in this study. However, the ASTM
`method should be used for materials that have a very
`low thermal expansion and should be performed only
`between ⫺30 and 30°C (8). Therefore, the coefficient
`of linear thermal expansion for these syringes, deter-
`mined by using the ASTM method, could not be used
`in calculations that use high temperature and pressure
`conditions, such as sterilization. Additionally,
`it
`is
`necessary to take into account the thermal expansion
`of the plunger and effect of friction on the plunger to
`predict the internal pressure in the prefilled syringe
`while the plunger is moving.
`
`To overcome the difficulties in determining the coef-
`ficient of linear thermal expansion of the syringe, the
`thermal expansion of the plunger, and the effect of
`friction on the plunger during sterilization, a practical
`method was used to back-calculate the coefficient of
`linear thermal expansion from Eq. 4 using tempera-
`ture, pressure, and plunger movement distance; these
`values could be measured during sterilization cycle.
`However, it should be noted that the coefficient of
`linear thermal expansion calculated from this method
`is not truly a coefficient of linear thermal expansion of
`the syringe container but a correction factor for this
`syringe-and-plunger combination to predict the inter-
`nal pressure, which includes a coefficient of linear
`thermal expansion of the syringe container, thermal
`expansion of the plunger, and frictional resistance of
`the plunger movement.
`
`Materials and Methods
`
`the optimum pressure conditions to
`In this study,
`provide in order to prevent contamination or container
`damage during sterilization were studied using 100
`mL syringes with rubber plungers. Table I shows the
`materials that make up the syringe and the composi-
`tion of the syringe presentation. After the syringe
`barrel and plunger were sterilized at 121°C for 20 min,
`water for injection or an aqueous drug solution was
`filled at 20°C.
`
`The optimum pressure conditions for production-scale
`sterilization were established according to the follow-
`ing steps.
`
`1. Eq. 4 was used to determine the correction factor
`for the syringe and plunger system using tempera-
`ture, pressure, and plunger movement distance val-
`ues measured during experimental-scale steriliza-
`tion tests.
`
`2. The correction factor for syringe and plunger sys-
`tem determined during step 1 was verified on the
`experimental scale.
`
`3. Eq. 4 was used to determine the pressure conditions
`for production-scale sterilization using the correc-
`tion factor determined from experimental-scale
`sterilization tests.
`
`4. The microbial and particulate quality of syringe
`presentation sterilized using the production-scale
`process was evaluated using samples sterilized at
`the worst-case location.
`
`Autoclaves
`
`The experimental-scale autoclave was a water cascade
`autoclave, and the production-scale autoclave was fan-
`mixed air overpressure autoclave (Tables II, III). Fig-
`ure 1 depicts the experimental-scale sterilization cy-
`
`TABLE II
`Experimental-Scale Autoclave
`
`Sterilization
`Method
`Chamber Size
`
`Max Pressure
`
`Water cascade autoclave
`1,000(diameter) ⫻
`1,200(L) mm
`0.49 MPa
`
`380
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`TABLE III
`Production-Scale Autoclave
`
`Sterilization
`Method
`Chamber Size
`
`Max Pressure
`Max Load
`
`Fan-mixed air overpressure
`autoclave
`1,120(W) ⫻ 1,800(H) ⫻
`3,750(L) mm
`0.40 MPa
`6048 syringes (100 mL
`syringe)
`
`the production-scale
`and Figure 2 depicts
`cle,
`sterilization cycle. The experimental autoclave has
`one heating cycle and one cool-down cycle. The pro-
`duction-scale autoclave has three heating cycles, three
`cool-down cycles, and one drying cycle. Since the
`point to be considered was the internal pressure-tem-
`perature relationship, the differences in the steriliza-
`tion method and sterilization cycles were disregarded.
`
`Measuring Internal Pressure, Internal Temperature,
`and Plunger Movement Distance
`
`Initially, one syringe was outfitted with temperature
`and pressure sensors to conduct measurement. A pres-
`sure logger (EBI-125A-PT, ebro Electric GmbH & Co.
`KG; Ingolstadt, Germany) was attached on the fitting
`side, and a T-type thermocouple was inserted through
`the plunger (Figure 3). Silicone caulking was used to
`seal the sensors to the syringe. Two syringes were
`sterilized at the same time to measure internal pres-
`sure,
`temperature, and plunger movement distance.
`One was fitted with the pressure logger and the ther-
`mocouple. The other was fitted with the scale and
`
`Figure 2
`
`Schematic diagram of the production-scale steril-
`ization cycle.
`
`placed close to the sensor-equipped syringe to mea-
`sure the plunger movement distance. Pressure and
`temperature data were collected every 10 s using the
`pressure logger and the Validator KL (GE Kaye In-
`struments, Inc.; North Billerica, MA) were analyzed
`with Excel 95 (Microsoft Corporation; Redmond,
`WA).
`
`Results and Discussion
`
`Determination of the Correction Factor
`
`The experimental-scale sterilization process was used
`to determine the correction factor for this syringe and
`plunger set. The first pressure condition examined was
`designed to make the plunger move markedly; the
`coefficient of linear thermal expansion at 20°C mea-
`sured by the ASTM method was used to set
`this
`condition. After the sterilization cycle was finished,
`the correction factors at each temperature point were
`back-calculated from Eq. 4 using internal pressure,
`
`Figure 1
`
`Figure 3
`
`Schematic diagram of the experimental-scale ster-
`ilization cycle.
`
`Syringe equipped with pressure and temperature
`loggers.
`
`Vol. 57, No. 5, September/October 2003
`
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`
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`Figure 4
`
`Figure 6
`
`Correction factor for 0 mm plunger movement.
`
`internal temperature, and the plunger movement dis-
`tance data collected during the sterilization cycle. The
`method of least squares was used to describe the
`correction factor as a function of temperature from
`plots of the correction factors at each temperature
`point. The equation for the coefficient of linear ther-
`mal expansion for polypropylene container was an
`exponential equation in the Beck paper (4); however,
`in the present study a low correlation coefficient was
`obtained using an exponential equation. Since a high
`correlation coefficient was obtained empirically with a
`third-order equation, the correction factor was deter-
`mined using a third-order equation (Figures 4 and 5).
`The reason why a third order equation is needed might
`be that three specific values, a coefficient of linear
`thermal expansion of the syringe container, the ther-
`mal expansion, and friction effect of the plunger, are
`thought to make up this factor. Therefore, two values
`for plunger movement, 0 mm (no movement) and 1
`mm away from the fitting, were prepared.
`
`Figure 5
`
`Correction factor for 1 mm plunger movement.
`
`Calculated pressure, measured pressure, and mea-
`sured temperature values for a desired plunger
`movement of 0 mm.
`
`Verification of the Correction Factor
`
`To achieve the intended plunger movement, the pres-
`sure conditions for the sterilization were set using the
`internal syringe pressure calculated from Eq. 4 using
`the correction factors. For plunger movements of 1
`mm, the plunger was made to move gradually 1 mm
`away from drug solution at a temperature from 100 to
`121°C, and was maintained in this position for the
`entire exposure cycle. Since a sterile product should
`have a positive pressure, the pressure during the cool-
`down cycle was preset higher than the internal pres-
`sure, which pushes the plunger back towards the fit-
`ting.
`
`After programming pressure control conditions into
`the experimental-scale autoclave, sterilization was
`performed to collect data on internal pressure, internal
`temperature, and plunger movement distance in order
`to verify the correction factors. During sterilization at
`the experimental scale, the intended plunger move-
`ments for both 0 mm and 1 mm were confirmed, and
`the internal pressures calculated from internal temper-
`ature data were compared to the internal pressures
`measured with the pressure logger (Figures 6 and 7).
`Because each calculated internal pressure was approx-
`imately equal to the measured internal pressure, both
`correction factors were thought to be appropriate.
`
`Application to Production-Scale Sterilization
`
`The smallest plunger movement possible was prefer-
`able to protect against microbial and particulate con-
`tamination. Although the control pressure for 0 mm
`
`382
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`ference caused a large pressure difference from the
`cool-down to the drying cycle. Providing that
`the
`control pressure was set equal to the internal pressure
`calculated from the maximum temperature, an excess
`of pressure was exerted at
`the minimum pressure
`point. It is impossible to calculate the movement of the
`plunger toward the fitting accurately because Eq. 4
`does not take into account the compressibility factor of
`the headspace gas and the solution. However, experi-
`mental scale studies confirmed that the plunger move-
`ment toward the fitting caused by this excess pressure
`was small. Therefore, the internal pressure calculated
`at
`the maximum temperature was used to set
`the
`pressure for the production scale tests.
`
`The pressure conditions for the production-scale ster-
`ilization were set on the basis of the maximum tem-
`perature throughout the load (Figure 11). Chamber
`pressure minus calculated pressure at each point, of
`which negative value means that the plunger moves
`opposite to the drug solution side, are also shown in
`Figure 11. The plunger moved away from the fitting
`after reaching the maximum temperature point. Be-
`cause the container-plunger interface is a difficult site
`to sterilize, the distance moved during the cool-down
`cycle should be smaller than that on the exposure
`cycle. However, the calculation indicated only 0.3 mm
`movement; consequently, it is thought this does not
`affect the microbial and particulate quality. Addition-
`ally, variations inside the autoclave might also affect
`plunger motion;
`therefore,
`the pressure conditions
`were finalized after the microbial and particulate qual-
`ity tests at the maximum and minimum temperature
`point in the payloads were conducted.
`
`Figure 8
`
`Position of thermocouples inserted into a maximum
`load of syringe presentations for the maximum load
`in the production-scale autoclave.
`
`Figure 7
`
`Calculated pressure, measured pressure, and mea-
`sured temperature values for a desired plunger
`movement of 1 mm.
`
`plunger movement was about 0.03 MPa higher during
`the exposure cycle than that for 1 mm plunger move-
`ment (Figures 6 and 7), the production-scale autoclave
`could withstand the maximum pressure for the 0 mm
`plunger movement conditions, 0.34 MPa at 121°C.
`Therefore, the production-scale autoclave was set to
`pressure conditions to provide 0 mm plunger move-
`ment.
`
`However, when establishing pressure conditions at the
`production-scale autoclave, the temperature distribu-
`tion throughout the payload must be considered. To
`ensure that plungers in all prefilled syringes in the
`payload do not move opposite to drug solution, the
`pressure for all cycles must be set equal to the internal
`pressure calculated from the maximum temperature
`throughout the payload. When applying the maximum
`temperature to calculate the control pressure, the in-
`ternal pressure of all syringe products on the load
`cannot be more than the control pressure.
`
`In a maximum load, 6048 syringes, 47 thermocouples
`were inserted into syringe presentation and positioned
`throughout the payload to investigate the temperature
`distribution (Figure 8). A Portable Validator and Vali-
`dator KL (Kaye Instruments, Inc.; North Billerica,
`MA) with T-type thermocouples were used for mea-
`suring temperature. The results showed that the tem-
`perature distribution through the payload was small
`from the heating to the exposure cycles, but large in
`the cool-down and drying cycles (Figure 9). The max-
`imum, mean, and minimum internal pressures of sy-
`ringe products were calculated from the measured
`temperatures (Figure 10). The large temperature dif-
`
`Vol. 57, No. 5, September/October 2003
`
`383
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`Figure 9
`
`Temperature distribution at 47 sites in a maximum prefilled syringe payload at the production-scale sterilizer.
`
`Evaluation of Syringe Product Samples Sterilized on
`the Production-Scale Autoclave
`
`A microbiological challenge test was conducted to
`confirm the effectiveness of the sterilization cycle.
`Bacillus stearothermophilus was inoculated into sy-
`ringe presentations at a population of 1 ⫻ 106 spores/
`container. Three B.
`stearothermophilus challenge
`samples were placed at the maximum and minimum
`temperature points in the payload and sterilized. All
`microbiological challenge samples exposed to the ster-
`ilization process were negative after seven days incu-
`bation in soybean casein digestion media cultures in-
`cubated at 55°C (Table IV).
`
`A light obscuration particle count test was performed
`to ascertain the protection from particulate contami-
`
`nation. An APSS-200 Liquid Sampling System (Par-
`ticle Measuring Systems, Inc.; Boulder, CO) was used
`for the measurement. Samples sterilized at the maxi-
`mum and minimum temperature points in the payload,
`and unsterilized samples, were measured three times
`(Table V). Particle count values from before and after
`sterilization were statistically the same. Additionally,
`there was no difference in the particle count between
`the maximum and minimum temperature points in the
`payload. The data show that these pressure conditions
`provide acceptable microbial and particulate quality.
`
`Conclusion
`
`The Beck equations were modified for use with pre-
`filled syringes, which permitted prediction of plunger
`
`Figure 10
`
`Calculated pressure and measured temperature at
`the production-scale autoclave.
`
`Measured chamber pressure, calculated pressure
`and pressure differences at the production-scale
`autoclave.
`
`Figure 11
`
`384
`
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`TABLE IV
`Microbiological Challenge Test Results for Production-Scale Sterilization
`
`Max Temperature
`Point
`⫺
`⫺
`⫺
`
`⫺
`⫺
`⫺
`
`⫺
`Sample Lot #1
`⫺
`Sample Lot #2
`⫺
`Sample Lot #3
`⫹ ⫽growth ⫺ ⫽no growth.
`
`Min Temperature
`Point
`⫺
`⫺
`⫺
`
`⫺
`⫺
`⫺
`
`⫺
`⫺
`⫺
`
`Positive
`Control
`⫹
`⫹
`⫹
`
`Negative
`Control
`⫺
`⫺
`⫺
`
`motion under a variety of sterilization conditions. The
`accuracy of these conditions was then validated. Fol-
`lowing verification of accuracy, a best-overpressure
`cycle was established and run in the production scale
`autoclave. Using the worst-case predictions from the
`modified Beck equations, sterilization, maintenance of
`sterility, and protection from particulate contamina-
`tion were demonstrated for sterilized prefilled sy-
`ringes.
`
`Acknowledgements
`
`The authors gratefully thank Mr. Steven E. Johnson
`for editing this manuscript.
`
`Appendix
`
`the Ideal Gas Law and
`In the Beck paper (4, 5),
`Henry’s Law with Equations A1 and A2 were applied
`to the mass balance for air, Eq. A3. Then Eq. A4 was
`obtained.
`
`P ⫽ Pair ⫹ PVP ⫽
`
`nagRT
`Vc
`
`⫹ PVP
`
`Vl ⫽
`
`␳w0
`␳w
`
`Vl0
`
`nag ⫹ nal ⫽ nag0 ⫹ nal0
`
`(A1)
`
`(A2)
`
`(A3)
`
`TABLE V
`Particle Counts of Syringe Product Samples Sterilized on a Production-Scale Autoclave
`
`Particle Count [particles/mL]
`
`Sterilized
`
`Not Sterilized
`
`Max
`Temperature
`
`Min
`Temperature
`
`5
`
`5
`
`9
`
`Mean
`
`1.0
`0.1
`
`Mean
`
`0.6
`0.0
`
`Mean
`
`0.7
`0.2
`
`SD
`
`0.6
`0.1
`
`SD
`
`0.4
`0.1
`
`SD
`
`0.6
`0.2
`
`3
`
`3
`
`6
`
`Mean
`
`1.3
`0.1
`
`Mean
`
`1.3
`0.1
`
`Mean
`
`0.1
`0.0
`
`SD
`
`0.2
`0.0
`
`SD
`
`0.2
`0.0
`
`SD
`
`0.1
`0.1
`
`3
`
`3
`
`6
`
`Mean
`
`1.2
`0.2
`
`Mean
`
`1.3
`0.1
`
`Mean
`
`0.2
`0.1
`
`SD
`
`0.3
`0.2
`
`SD
`
`0.2
`0.0
`
`SD
`
`0.1
`0.1
`
`Sample Lot #1
`
`Sample Lot #2
`
`Sample Lot #3
`
`n
`
`⭌10␮m
`⭌25␮m
`n
`
`⭌10␮m
`⭌25␮m
`n
`
`⭌10␮m
`⭌25␮m
`
`Vol. 57, No. 5, September/October 2003
`
`385
`
`Regeneron Exhibit 1111.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`on March 31, 2022Downloaded from
`
`P ⫽ Pvp ⫹ 共P0 ⫺ Pvp0兲
`H0MWW
`R␳W0T0
`
`1 ⫹
`
`⫻冢
`
`H0MWW
`R␳W0T
`
`共1 ⫺ Y0兲
`
`冉 Y0
`再 关1 ⫹ C共T ⫺ T0兲兴3 ⫹ ec
`
`1 ⫺ Y0
`
`冊
`
`⫺
`
`冣
`
`H0
`H
`
`冎 ⫹
`
`␳W0
`␳W
`
`(A8)
`
`共P ⫺ PVP兲YVc
`RT
`
`⫹
`
`共P ⫺ PVP兲共1 ⫺ Y兲Vc␳w
`HMWw
`共P0 ⫺ PVP0兲Y0Vc0
`RT0
`共P0 ⫺ PVP0兲共1 ⫺ Y0兲Vc0␳w0
`H0MWw
`
`⫽
`
`⫹
`
`where nag is the moles of air present in the liquid
`phase and nal is the moles of air present in the vapor
`phase. Changing Eq. A4, container pressure, P, can be
`written as follows:
`
`(A4)
`
`References
`
`1. EMEA-CPMP/QWP/054/98. Decision Trees For
`the Selection of Sterilisation Methods. April 2000.
`
`2. FDA Draft. “Sterile Drug Products Produced by
`Aseptic Processing,” September 2002.
`
`3. PDA. “Industrial Moist Heat Sterilization In Auto-
`claves,” PDA Technical Monograph No.1 (Revi-
`sion Draft 13); December 2002.
`
`(A5)
`
`4. R. E. Beck, Autoclaving of Solutions in Sealed
`Containers: Theoretical Pressure-Temperature Re-
`lationships. Pharmaceutical Manufacturing 18 –23,
`June (1985).
`
`P ⫽ PVP ⫹ 共P0 ⫺ PVP0兲
`
`⫻冤Y0Vc0
`
`⫹
`
`(1⫺Y0)Vc0␳w0
`H0MWw
`(1⫺Y)Vc␳w
`⫹
`HMWw
`
`RT0
`YVc
`RT
`
`冥
`
`Here, the liquid volume, Vl, is also expressed as (1 ⫺
`Y)Vc, therefore Eq. A2 becomes Eq. A6.
`
`共1 ⫺ Y0兲Vc0␳w0 ⫽ 共1 ⫺ Y兲Vc␳w
`
`(A6)
`
`The volume of headspace, YVc, can be rewritten as the
`total volume of container minus the liquid volume:
`
`5. R. E. Beck, Letter to the editor. Pharmaceutical
`Manufacturing 12, September (1985).
`
`6. M. A. Joyce, J. W. Lorenz, Internal Pressure of
`Sealed Containers During Autoclaving. Journal of
`Parenteral Science & Technology 44, 320 –323
`(1990).
`
`YVc ⫽ Vc ⫺ Vl ⫽ 关1 ⫹ C共T ⫺ T0兲兴3Vc0
`
`7. S. Yukio, “Plastic Data Book,” Kogyo-Cyosakai:
`Tokyo, Japan, 1999; p. 54.
`
`⫹ ecVc0 ⫺
`
`␳w0
`␳w
`
`共1 ⫺ Y0兲Vc0
`
`(A7)
`
`The following equation is obtained by substituting
`Equations A6 and A7 into Eq. A5:
`
`8. Standard Test Method for Coefficient of Linear
`Thermal Expansion of Plastics Between ⫺30°C
`and 30°C. In Annual Book of ASTM Standards
`American Society for Testing and Materials: Phil-
`adelphia, PA, 1997; pp 80 – 83.
`
`386
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Regeneron Exhibit 1111.010
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`
`
`on March 31, 2022Downloaded from
`
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`Regeneron Exhibit 1111.011
`Regeneron v. Novartis
`IPR2021-00816
`
`  
` 
`  
`