M
`
`TRANS PERFECT
`
`City of New York, State of New York, County of New York
`
`I, Angela Hirons-Goulbourn, hereby certify that the following proofreading is, to the best
`of my knowledge and belief, a true and accurate translation from German to English of
`the file "Exhibit 1064, Bruno Reuter and Claudia Petersen. "Die Silikonisierung von
`Spritzen: Trends, Methoden, Analyseverfahren," TechnoPharrn 2, Nr. 4 (2012): 238-
`244". I declare that 1 am fluent in German, and further declare that aJI statements herein
`of my own knowledge are true, and all statements made on information and belief are
`believed to be true, and these statements were made with the knowledge that willful false
`statements and the like so made are punishable by fine, imprisonment, or both under
`Section I 001 of Title 18 of the United States Code. I declare under penalty of perjury that .
`the foregoing is true and correct.
`
`Angela H iron s-Goulbourn
`July 15, 2020
`
`LANGUAGE AND TECHNOLOGY SOLUTIONS FOR GLOBAL BUSINESS
`1250 BROADWAY, 6TH FLOOR, NEW YORK, NY 10001 I T 212.689.5555 I F 212. 689.1059 I WWW.TRANSPERFECT.COM
`OFFICES IN 90 CITIES WORLDWIDE
`
`Regeneron Exhibit 1010.001
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Focus Packaging
`
`Syringe Siliconization
`
`Trends, methods, analysis procedmes
`Bmno Reuter, Claudia Petersen . Gerresheimer Bunde GmbH, Bunde
`Correspondence: Claudia Petersen, Gerresheimer Biinde GmbH, 32257 Biinde, Erich(cid:173)
`Martens-Str. 26-32;
`e-mail: c.petersen@gerresheimer.com
`
`Summary
`Ready-to-fill, i.e. sterile, prefillable glass syringes, are washed, siliconized, sterilized
`and packaged by the primary packaging manufacturer. They can then be filled by the
`phamiaceutical companies without any further processing. These days the majority of
`prefillable syringes are made of glass and the trend looks set to continue. The
`s1hcomzat10n ofthe synnge barrel ts an extremely important aspect ofthe product10n
`of sterile, pre fillable glass syringes because the functional interaction of the glass barrel
`siliconization and the plunger stopper siliconization is crucial to the efficiency of the
`entire system. Both inadequate and excessive siliconizalion can cause problems in this
`regard. The use of modem technology can achieve an extremely unifonn distribution of
`silicone oil in glass syringes with reduced quantities of silicone oil. Another option for
`minimizing the amount of free silicone oil in a syringe is the thermal fixation of the
`silicone oil on the glass surface in a process called baked-on siliconiZlltion.
`Plastic-based silicone oil-tree or low-silicone oil prefillable syringe systems are a
`relatively new development. Silicone oil-free lubricant coatings for syringes are also
`currently in the development phase.
`
`Introduction
`
`Primary packaging for inJectables
`almost exclusively comprises a glass
`container (cartridge, syringe, vial) and
`an elastomer closure. Ampoules are an
`exception.
`Elastomers are by nature slightly
`sticky, so all elastomer closures
`(plunger stoppers for syringes and
`cartridges, serum or lyophilization
`stoppers) are s1hcomzed. S11iconizat10n
`prevents the rubber closures from
`sticking together and simplifies
`processing of the articles on the filling
`lines. For example, it minimizes
`mechanical forces when the stoppers
`are inserted. Siliconization is therefore
`essential to process capability.
`
`and cartridges are
`Although syringes
`always siliconized, this applies to a lesser
`extent to vials and ampoules. On
`the
`container the siliconization provides a barrier
`coating he-
`tween
`the glass and drug
`formulation. lt also prevents !he adsorption of
`formulation components on the glass surface.
`The hydrophobic deactivation of the surface
`also improves the containers' drainability.
`In prefillable syringes and cartridges,
`siliconization
`also
`perfonns
`another
`fonction It lubricates the syringe barrel or
`cartridge body enabling the plunger
`to
`glide through
`it. Siliconization of the
`plunger stopper alone would nol provide
`adequate lubrication.
`
`Silicone oils are ideal as lubricants
`because they are largely inert, hydro(cid:173)
`phobic and viscoelastic. Chemical and
`physical requirements for lubricants
`arc set out in the relevant monographs
`of
`lhe American
`(United Stales
`Phannacopoeia, USP) and European
`(Pharmacopoeia Europaea, Ph. Eur.)
`phannacopoeias [l, 2]. Section 3.1.8 of
`Ph. Eur. also defines a kmemat1c
`viscosity of between 1,000
`and 10,000 mni21s for silicone oils
`used as lubricants f3]. By contrast, the
`monograph for polydimethylsiloxane
`(l'DMS) in the USP [2] permits the
`use of silicone oils with a viscosity of
`20 to 30,000 centistokes. However,
`increasingly stringent quality
`requirements and new bioengineered
`
`238 Petersen and Reuter Siliconization
`
`TcchnoPharm 2, No. 4, 238-244 (2012)
`~ECV. Editio Cantor Verlag, Aulendorf (Germany)
`
`Regeneron Exhibit 1010.002
`
`

`

`HO t CZ3 - 0 - CZ3 - 0 - Ct j OH
`
`I
`CH3
`
`I
`CH3
`
`I
`CH3
`
`n
`
`is generally used for siliconization
`(Fig. 1 ).
`The most frequently used silicone
`oil for the siliconization of prin1ary
`packaging components is DOW
`CORNING® 360 Medical Fluid, which
`has a viscosity of 1,000 cSt.
`PDMS is produced by reducing quartz
`sand to silicone metal. In the next step,
`the silicone reacts directly with methyl
`chloride in a process called Muller(cid:173)
`Rochow synthesis to create methyl
`chlorosilanes. In this process, a mixture
`of different silanes is produced, the
`majority of which (75%--90%) are
`dimethyldichlorosilane (CH3)2 SiC12.
`After distillative separation, the di(cid:173)
`methyldichlorosilane is converted by
`hydrolysis or methanolysis into silanols
`which condense into low- molecular(cid:173)
`weight chains and cycles. In an acidic
`(cationic) or alkaline ( an- ionic)
`catalyzed polymerization,
`polydimethylsiloxanes with hydroxy
`funclions are generaled. Afler the
`addition of trimethy lchlorosilane, they
`are turmshed wrth tnmethylsrloxy end
`groups. The short chain molecules are
`removed from the resulting
`polydisperse polymers by way of va(cid:173)
`porization, leaving deployable PDMS.
`The characteristic aspect of the
`PDMS molecule is the Si-O bond. With
`a bond energy of I 08 kcal/mo!, it is
`considerably more stable than the C-O
`bond (83 kcal/mo!) or lhe C-C boml (85
`kcal/mo!). PDMS is accordingly less
`sensitive to thermal loads, UV radiation
`or oxidation agents. Reactions such as
`oxidation, polymerization or
`depolymerization do not occur until
`temperatures exceeding 130 °C. The
`molecule also typically has a flat bond
`angle (Si-O- Si 130 °C) which has low
`rotation energy and is especially
`flexible (Fig. 2). A high bond lengtl1
`(1.63 A Si-O as compared to 1.43 A for
`C-O) makes the molecule
`comparatively gas-permeable l6J.
`The spiral shaped ( and therefore
`easily compressible) molecule is sur(cid:173)
`rounded by CH3 groups which are
`responsible for the chemical and
`mechanical properties of PDMS. The
`molecule's methyl groups only interact
`
`Fig. 2: 3D-structure of polydimethylsiloxane.
`
`to a very limited extent. This ensures
`low viscosity, even with high molecular
`weights, which simplifies the
`distribution of PDMS on surfaces and
`makes it a very effective lubricant.
`PDMS is also largely inert and
`reactions with glass, metals, plastics or
`human tissues are minimal. The CH3
`groups make PDMS extremely
`hydrophobic. It rs msoluble n{ water,
`but soluble in non-polar solvents [6].
`
`Siliconizcd syringes
`
`As already explained, lhe sy1i11ge sys(cid:173)
`tem only works if the glass barrel and
`plunger stopper sil!conrzation are
`homogenous and optinlally harmonized.
`For needle syringes, siliconization of
`the needle is also essential to prevent it
`sticking to the skin, thereby minimizing
`injection pain. For tl1e so-called oily
`siliconization of the syringe glass
`barrel, DOW CORNING® 360 with a
`viscosity of 1,000 cSt is used. The
`DOW COR- NING® 365 siliconizalion
`emulsion is otten used in the baked-on
`s1lrco1Uzat10n process. The needle 1s
`siliconized using a wipe teclmique
`during ready-to-fill processing. DOW
`CORNING® 360 with a viscositv of
`12,500 cSt is used. Another opti~n is
`the themial fixation of silicone oil on
`the needle during the needle mounting
`process.
`The goal of syringe barrel
`siliconizalion is lo obtain the mosl even
`anti-friction coating possible along the
`entrre length of the syrmge m order to
`minimize breakloose and gliding forces
`when the plunger stopper is deployed
`(Fig. 3).
`
`Fig. 1 Polydimethylsiloxane.
`
`drugs are now trucing siliconization
`technology to its limits. Non(cid:173)
`homogenous siliconization which can
`occur when simple coating techniques
`are used on longer syringe barrels can,
`in some cases, lead lo mechanical
`problems. These include the incomplete
`dramage otthe syrmge man auto(cid:173)
`injector or high gliding forces.
`Silicone oil droplets are always
`observed in filled syringes. The ni:unber
`of silicone oil droplets increases in line
`with the quantity of silicone oil used.
`Droplets which are visible to the naked
`eye could be viewed as a cosmetic
`defect. At sub-visual level, the issue of
`whether silicone oil particles could
`induce protein aggregation is currently
`under discussion 141.
`·
`In light of this development, there
`is an obvious trend towards optimized
`or alternative coating techniques.
`A !tempts are heing made to achieve the
`most uniform possible coating with a
`reduced quantity of silicone oil and to
`minimize the amount of free silicone oil
`by way of baked-on siliconization. In
`this context, reliable analysis
`technologies that can be used to make
`qualitative and quantitative checks on
`the coating are absolutely essential.
`Alternative coating techniques are also
`being developed.
`
`Silicone oils and their properties
`
`Silicone oils have been used for half a
`century in numerous pharmaceutical
`applications. For example, they are
`used as lubricants in pharmaceutics
`production and as inert phannaceutical
`base materials ( e.g. sotl capsule walls)
`[5]. Trimethylsiloxy end-blocked
`polydimethylsiloxane (PDMS,
`dimethicone) in various viscosities
`
`TechnoPharm 2, No. 4, 238-244(2012)
`©ECV • Edilio Cantor Verlag, Aulendorf(Germany)
`
`Petersen and Reuter Siliconiza Lion 239
`
`Regeneron Exhibit 1010.003
`
`

`

`Focus Packaging
`
`tage. It prevents the drug solution from
`interacting with the glass sur- face and
`rules out related problems such as the
`loss of active ingredients through
`adsorption or pH value changes due to
`alkali leaching. Prefillable glass
`syringes are on 1y manufactured from
`high quality type 1 borosilicate glass.
`However, sodium ions can still leach
`out of the glass surface if the syringe
`contains an aqueous solution and is
`stored for a long period of time. This
`leads to higher pH values which could
`be problematic m unbuffered systems.
`Acidic environments foster this process.
`
`Si-O-Na + H20 <--> SiOH + NaOH
`
`In alkaline environments, on the other
`hand, an etching process is observed.
`
`2NaOH + (SiO2)X---, Na2Si03 + H2O
`
`Aqueous solutions with a high pH
`value cannot therefore be stored for
`long periods of time in borosilicate
`glass containers. They have to be
`lyophilized and reconstituted before
`use. In extreme cases, the etching of the
`glass surface can cause delamination.
`Hydrophobic deactivation of the
`container by siliconization effectively
`protects the glass surface.
`
`Optimized siliconization
`
`For the above-mentioned reasons, the
`main objective in siliconization is to
`achieve the most homogenous possible
`coating with the minimum possible
`quantity of silicone oil. Tnitially it is
`necessary to establish the minimum
`quantity of silicone oil which will
`reliably satisfy the quality requirements
`of the application. In the production of
`ready-to-fill syringes, siliconization
`generally takes place after washing and
`drymg. Fixed nozzles pos1tioned at
`finger flange level under the syringe
`barrel spray the silicone oil onto the
`inside sur-foce. In longer syringes, the
`silicone oil is sometimes unevenly
`distributed and the concentration of the
`silicone oil is lower at one end of the
`syringe (lucr tip/needle end). The use of
`diving nozzles can considerably im(cid:173)
`prove the evenness orthe coating across
`the entire length of the syringe body. In
`this process, the nozzles are inserted
`into the syringe to apply the silicone oil
`(finely atomized) in motion. The result
`is practically linear as is shown by the
`closely bundled gliding forces in the
`force path diagram (Fig. 4).
`Studies on 1 ml long syringes have
`revealed considerable potential for
`reducing the amount of silicone oil
`required. In the experiment, the
`quantity of silicone oil per syringe
`could be reduced by 40% without any
`impairment of the system's functional
`properties (Fig. 5).
`
`¢
`.~
`1113
`Fig. 3: Extrusion force profile of a prefilJable
`syringe.
`
`Inadequate siliconization of the
`syringe barrel, particularly the existence
`of unsiliconized areas, can cause slip(cid:173)
`stick effects that impair the syringe's
`function. The forces in the injection
`process can then be too h1 gh or the
`eulire system cau fail. Since iua<le4 uale
`siliconization and gaps in the coating
`are often found on the lower end of the
`syringe (luer tip/needle end), it is
`possible that the syringe will not be
`completely emptied. Such defects can
`remam undiscovered, particularly m
`auto-injectors since these are closed
`systems. The result could be that an
`inadequate dosage of the medication is
`administered.
`The obvious solution is lo increase
`the amount of silicone oil used to
`achieve a homogenous coating. How(cid:173)
`ever, as already mentioned, increasing
`the amount of silicone oil used is also
`associated with higher quantities of
`silicone particles in the solution. With
`protein-based drugs, in particular,
`undesirable interactions with silicone
`oil particles cannot be ruled out Sub(cid:173)
`visual silicone oil particles are thought
`to promote protein aggregation which
`can increase the severity of immune
`responses and reduce the drug ' s
`tolerability. How- ever, the underlying
`mechanism is not yet fully understood.
`There is a discussion as to whether
`protein aggregation is influenced by
`additional motion, e.g. shaking the
`syringe [7]. Experiments have also
`shown that when silicone oil in excess
`of l mg/syringe is used the additional
`silicone oil does not further reduce
`gliding forces.
`The interior siliconization of glass
`syringe barrels has another advantage
`
`240 Petersen and Reuter Siliconization
`
`TechnoPharm 2, No. 4, 238-244 (2012)
`!dECV . Edilio Cantor Verlag, Aulendorf(Germany)
`
`Regeneron Exhibit 1010.004
`
`

`

`Focus Packaging
`
`Fixed nozzle
`=2.1 N
`"- F
`avbreakloose force
`- F owghding fme = 2.4 N
`
`Diving nozzle
`- F avbreaklooseforce= 1.7 N
`"-F
`. .
`-0.SN
`aw gliding force
`
`m ~ 0.8 mg, v ~ 300 mm/min, empty I ml long LC syringes
`Fig. 4: Comparison of extrusion force profi1es diving nozzle vs. fixed nozzle.
`Standard 1ml long syringe*
`Fixed nozzle
`m= 0.8 mg
`V = 100 mm/min
`BF mean= 2.5 N
`EFmean = 1.7 N
`
`l!Ei
`
`,.
`
`-
`
`In praclice !he calculation of!he
`optimum quantity of silicone oil has to
`take syringe volume, plunger stopper
`type (coated/ uncoated), plunger
`stopper placement method (seating
`tube/ vacuum) and application
`requirements (injection systems) into
`account. Plunger stoppers from
`different suppliers not only differ in
`terms of the type of rubber used and
`their design, they are also coated with
`silicone oils of different viscosities. The
`siliconization methods also differ
`considerably. These vanables can have
`a bigger impact on the syringe system's
`timctional properties than the syringe
`siliconization of different suppliers, as
`shown by Eu et al. [8].
`
`Baked-on siliconization
`
`Another key advancement in
`siliconization technology is the baked(cid:173)
`on siliconization technology. It involves
`the application of silicone oil as an
`emulsion which is then baked on to the
`glass surface in a special kiln at a
`specific temperature and for a specific
`length of time.
`In the baked-on process, both hydrogen
`and covalent bonds form be- tween the
`glass surface and the
`polydimethylsiloxane chains. The
`bonds are so strong that part of the
`silicone oil cannot be removed with
`solvent and a permanent hydrophobic
`layer is created (Fig. 6). In addition, the
`average molecule weight increases as a
`result of polymerization and the
`vaporization of short chain polymers.
`The resulting, extremely thin layer of
`silicone in conjunction with the low
`quantity of silicone oil used in the
`emulsion minimizes free
`silicone in the syringe and ensures that
`the required quality of finish is
`achieved. The layer thickness measures
`15-50 nm. By comparison, the average
`layer thickness with oily siliconization
`is 500-1,000 nm.
`Baked-on siliconization reduces the
`measurable quantity of free silicone
`
`~-
`
`'
`
`...,._
`
`-
`
`"
`
`z t 1:1~ I
`.
`+ - --
`i'f
`Standard Im I long syringe*
`!=
`Diving nozzle
`,~
`m= 05 mg
`..
`.... _
`V = 100 mm/min
`,_
`' '-·
`,.
`'
`"
`BF mean= 1.7 N
`Fzg. 5: Extrusionjorce profile after optimized siliconizatio n.EFmean = 0.5 N
`
`i
`
`.
`
`• • IIC .- ,t,SIO]n
`
`• CH.. c;;Hp,t CH,a()
`
`Gins surface
`
`S11icone cit
`
`Hvct rog,en bOncfll'III anct
`partly coval ent bindings
`
`Fig. 6: Baked-on siliconization.
`oil to approx. 10% of the normal value. As a result, there are fewer sub-visual and
`visual silicone oil particles in the solution. This siliconization process is therefore
`recommended for use with sensitive protein formulations. It is also advantageous
`for ophthalmological preparations which are associated with very stringent
`requirements as regards particle contamination.
`Another benefit is the stability of the mechanical properties of the filled
`syringe throughout its shelflife. The ribs of a plunger stopper press into the
`silicone layer when a syringe with oily siliconization is stored for long periods of
`time and the glass comes into direct contact with the rubber. Since elastomers are
`always slightly sticky, the break loose forces increase over the storage period. With
`baked-on siliconization, how- ever, this phenomenon is not observed to the same
`extent (Fig. 7). The breakloose force remains practically constant over the entire
`storage period.
`
`242 Petersen and Reuter Siliconization
`
`TechnoPharm 2, No. 4, 238-244 (2012)
`!dECV . Edilio Cantor Verlag, Aulendorf(Germany)
`
`Regeneron Exhibit 1010.005
`
`

`

`Analysis methods
`
`Focus Packaging
`Oily siliconized syringe
`Storage
`
`Baked-on siliconized syringe
`
`The optimization of the siliconization
`process necessitates reliable qualitative
`and quantitative analysis methods.
`Online methods for the one-hundred
`percent control of siliconi zation during
`production are not currently available.
`In process control, random samples are
`taken and several destructive and non(cid:173)
`destructi ve methods are used.
`In the glass dust test, the
`siliconization is made visible by dusting
`it with finest glass particles (I' ig. 8).
`This destructive method is simple but
`time-consuming. It is also associated
`with the problems that the quality of the
`siliconization is subjectively evaluated
`and the results are affected by
`temperature and air humidity.
`
`syringe
`Fig. 8:_ Glass dust _test: left -
`sthcomzed with a d1v111g nozzle tig_ht -
`syringe siliconized with a fixed nozzle.
`
`Direct rubber/glass contact leads to higher
`breakloa.e tbrces over the storage penod
`
`TI1c baked-on siliconization provides a pcnnancnt
`coating
`Break.loose fo rces remain stable over the storage
`peri od
`
`Fig. 7: Comparison of syringes wiih oily and
`
`baked-on si/iconizaiion.
`
`Another non-destructive technique such
`as the one developed by Zebra Science
`(Fig. 11 ) is based on digital image
`processing. The entire inside surface of
`the syringe barrel is imaged to visualize
`typical siliconization surface structures.
`The technology captures these visual
`cues as a duect 111d1cation of suttic1ent
`silicone oil presence and poorly
`siliconized areas (Fig. 11.1).
`
`,_.,_,.,.. .. -...
`
`111..-.it•Ji'ba•
`
`Mi
`~
`
`1't a,
`
`:, - ~
`... "'
`... "'
`
`IIH
`
`-
`""
`
`~'101.:1
`
`,,n
`
`Fig JO: Silicone layer thickness
`measurement with the Layer Explorer
`RaplD (own data).
`
`Measuring the gliding force is an
`indirect method of determining the
`evenness of the siliconization (Fig. 9).
`
`Fig. 9: G/idingforce measurement.
`
`This process is also destructive and
`associated with problems. For example,
`the results are influenced by the
`positioning of the plunger stopper and
`there is no standard for extrusion speed.
`A feeding speed of 100 mm/min is otlen
`taken for empty syringe systems; and up
`to 380 mm/min for tilled systems.
`Relatively fast quantitative and
`non-destructive results can be obtained
`with retlexometry. _For example, the
`Layer Explorer UT (Fig. 10) which is
`manufactured by ra pID scans the syringe
`body line-by-line. It can measure layer
`thicknesses of 15 nm to several thousand
`11111 with a precision of 5 11111 (Fig. l 0.] ).
`Scanning a 40 mm syringe with the
`Layer Explorer takes approximately 1
`minute.
`
`Techn oPharm 2, No. 4, 238-244 (2012)
`©ECV . Editio Cantor Verlag, A ulendorf(Germany)
`
`Petersen and Re1rter Siliconization 243
`
`Regeneron Exhibit 1010.006
`
`

`

`Focus Packaging
`Outlook
`
`There is a trend towards reduced(cid:173)
`silicone systems or baked-on
`siliconization in glass syringe finishing.
`Im- proved analysis techniques and a
`better understanding of the phenomena
`involved support optimized use of
`silicone oil.
`New issues are arising as a result of the
`use of innovative materials or coatings.
`In light orthe increasing complexity of
`de- vices and the more wide-spread
`incidence of biopharmacutics with
`specific requirements, new alternative
`materials for primary packaging
`products are becoming increasingly
`interesting. For example, the inside
`surfaces of vials and syringes can be
`coated with pure SiO2 in a plasma
`process to m1111m1ze thetr mteractton
`with drugs. Plastic systems based on
`cyclic olefins (COP/COC) are also
`gaining in significance for prefilled
`syringes and vials. COP syringes such
`as the ClearJect TasPack TM by Taisei
`Kako Co. Ltd have glass-like
`transparency. Additionally, they have a
`higher break resistance, their pH
`stability range is larger and there is no
`metal ion leaching. Excellent dosage
`precision is also very important in
`packaging for bio-pharmaceuticals. In
`most cases siliconization is also
`essential in COP syringes.
`Silicone oil-free systems are a
`brand new
`
`Fzg. 10.1 : S1l1cone layer thickness measurement
`wzth the Layer Explorer (own data)
`
`Fi1;. 11: ZebraScience visualization of
`siliconization (Source: Gerreshezmer Bunde)
`
`Fig. 11.1: Visualizatzon of syringe barrel
`siliconizalion (Zebra Science)
`
`It delivers fast qualitative results and is
`suitable for empty and filled syringes.
`However, empty syringes should be
`measured immediately after siliconization
`because even just half an hour after
`siliconization
`the distribution of the
`silicone provides a cumplelely differenl
`picture and it takes a very expe rienced
`person to interpret the results properly.
`Unfortunately, this method is also
`not fast enough to facilitate 100% online
`control
`during
`the washing
`and
`siliconization process.
`
`approach. The gliding properties of the
`fluoropolymer coating on specially
`developed plunger stoppers climmatc
`the need to siliconize plastic syringes.
`There are as many innovative ideas for
`the development of primary packaging
`products as there are innovative drugs
`and syringe systems.
`
`Literature
`l l J United States Pharmacopoeia 35
`NF 30. Dimethicone, The United
`States Pharmacopeial Convention
`Inc, Rockville, USA, 2011
`[2] Pharmacopoea Europaea. 7th
`edition. Dimethicone, Deutscher
`Apotheker Verlag, Stuttgart, Germany,
`2011,p. 2788
`l 3 J Pharmacopoea Europaea. 7th
`edition. 3.1.8 Silicone oil for use as a
`lubricant, Deutscher Apotheker Verlag,
`Stuttgart, Germany, 2011 , p. 486
`[4] Jones LS, Kautinann A, Middaugh
`CR Silicone Oil induced aggregation
`of pro- tcins. J Pharm Sci 2005;
`94( 4 ):918-927
`[5] Colas A, Siang J, Ulman K.
`Silicone in Phaimaceutical
`Applications Part 2: Silicone
`Excipients. Dow Corning Corpo(cid:173)
`ration, Midland, USA, 2001
`[6] Colas A. Silicone in Pharmaceutical
`Applications. Dow Corning
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`244 Petersen and Reuter Siliconization
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`TechnoPharm 2, No. 4, 238-244 (2012)
`©ECV . Edilio Cantor Verlag, Aulemlorf(Germany)
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`Regeneron Exhibit 1010.007
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