Dow C0ming® 3 65,
`35% Dimethicone NF Emulsion
`
`Frequently Asked Questions
`
`DOW CORNING
`
`Regeneron Exhibit 1034.001
`
`

`

`PLEASE READ CAREFULLY:
`
`The information contained in this publication is an accurate
`description of the product’s typical characteristics and is
`designed to supplement the Product Data Sheet and Material
`Safety Data Sheet.
`However, these are only guidelines for its use and it is the
`user’s responsibility to thoroughly test the product in any
`specific application to determine its performance, efficacy
`and safety.
`
`1. What is the formulation of Dow Corning
`365, 35% Dimethicone NF Emulsion?
`The emulsion is composed of 35% Dow C0rning® 360 Medical Fluid,
`350 cSt in water with non-ionic surfactants, Tween® 20 and Triton®
`
`X-100 and the preservatives, sodium benzoate and parabens (propyl
`and methyl p-hydroxy-benzoates).
`Typical mechanical emulsions of this type have a particle size of
`0.1 — 1 micron.
`
`2. What are the most important factors to
`
`consider with respect to the manufacturing
`and testing of Dow Corning 365, 35%
`Dimethicone NF Emulsion?
`
`The emulsion is manufactured at the Dow Corning Healthcare
`Industries Materials Site using a quality system based on bulk
`pharmaceutical cGMPs. The material is manufactured using USP
`purified (but not sterilized) water and is not packaged in an ultra
`clean-room environment — although it is filtered through a 25 micron
`filter. It is therefore labeled “NOT MANUFACTURED OR
`
`TESTED TO BE PYROGEN-FREE”. Dow Corning does not test
`this emulsion for pyrogen levels due to the difficulties associated
`with testing of any material that uses surfactants in the formulation.
`It is the user’s responsibility to determine the safety and efficacy for
`use of the material in their application and this will be addressed
`filrther in the sections to follow.
`
`3. Does Dow Corning perform any
`microbiological testing on Dow Corning
`365, 35% Dimethicone NF Emulsion?
`One of the Lot Acceptance Requirements is microbial testing with a
`specification of less than 100 Colony Forming Units (CFU) per ml.
`Dow Corning also has control measures in place which require any
`colonies found to be identified in order to ensure that they are not
`among those listed in USP <6l> (“Microbial Limits Test”). Any lot
`showing these organisms will be immediately rejected and destroyed.
`Typically, this material does not show any CFUs in the microbial
`count test.
`
`to meet the Dimethicone NF and Dimeticone EP monograph
`requirements. Furthermore, Dow Corning holds a Certificate of
`Suitability for both Ph. Eur. Monographs and a Drug Master File is
`maintained with the United States FDA.
`
`5. Are there any known toxicology concerns
`with Dow Corning 365, 35% Dimethicone
`NF Emulsion?
`
`Dow Corning has a wealth of toxicological information and specific
`questions on toxicology should be addressed to your Customer
`Service Professional or Technical Service Specialist who will direct
`you to the appropriate person Within Dow Corning’s Environmental
`Health & Safety Department.
`
`6. What is the fate in the body of the
`additives used in Dow Corning 365, 35%
`Dimethicone NF Emulsion if they are
`introduced from siliconized articles such
`
`as needles or syringes?
`The components of the surfactant and preservative package used in
`the emulsion are present at levels of fractions of a percent. Typically,
`the product is diluted to 2-3% silicone prior to application, which
`reduces these ingredients to ppm quantities. As a result, any still
`present on the articles are at extremely low levels and unlikely to
`cause any adverse effects (none have ever been reported). Further,
`these additives are commonly used in other industries that produce
`materials that come into human contact, for example food
`applications.
`However, it is recommended that users determine by their own testing
`that these additives will not cause a problem in their specific
`application.
`
`7. If applicable, will the additives used in
`Dow Corning 365, 35% Dimethicone NF
`Emulsion interfere with the customer’s
`
`drug components?
`There have been no reported negative interactions between the
`emulsion components and any particular type of drug or drug
`component (e.g. proteins). As stated above, it is important to
`remember that the recommended application procedure requires that
`the emulsion be diluted with water and this effectively dilutes all the
`emulsifier and preservative components to very low levels. It is
`therefore unlikely that they will interfere with anything in the
`customer’s solutions although of course this must be verified by the
`customer’s own development work. (It is of interest to note that this
`emulsion has been successfully used to treat drug vials to prevent
`protein adsorption onto the vial surface).
`
`4. What are the important regulatory
`considerations for Dow Corning 365, 35%
`Dimethicone NF Emulsion?
`
`8. What are the principal applications and
`considerations for using Dow Corning 365,
`35% Dimethicone NF Emulsion?
`
`There are no guideline USP/NF or Ph. Eur. (“EP”) monographs for
`compositions such as Dow Corning 365, 35% Dimethicone NF
`Emulsion. However, the silicone fluid used as the active material in the
`
`Since the product is a water-based method of delivering silicone fluid,
`it may be employed in siliconization applications Where it is not
`possible to use a solvent as a diluting agent for the fluid. The product
`
`emulsion (Dow Corning 360 Medical Fluid, 350 cSt) has been qualified
`
`Regeneron Exhibit 1034.002
`
`

`

`is also widely used for siliconization of glass syringe barrels, which
`are often ultimately sterilized and depyrogenated with dry heat. In the
`case of articles such as rubber stoppers, for which it may not be
`possible to perform depyrogenation, it is very important to consider
`diluting the material with USP Water for Injection (WFI) grade water
`in a clean-room environment to control any bio-burden.
`
`9. What are the principal methods for
`applying Dow Corning 365, 35%
`Dimethicone NF Emulsion to an article?
`
`Application equipment often consists of washing/rinsing/drying
`machines; another application method is to spray a diluted solution of
`the emulsion and equipment for this process has been developed by
`Spraymation Inc. of Florida. (Dow Corning recommends the use of
`appropriate controls in order to limit operator exposure to silicone in
`aerosol spray form). Some articles may be dip-coated in a diluted
`solution of the emulsion while others may be wipe-treated via a
`sponge or other device.
`Whichever method is chosen, it is very important to consider how
`much fluid is applied to an article. The process should be designed to
`deliver the minimum amount needed to achieve the desired
`
`lubrication as any excess may come off the article and become
`suspended in fluids delivered from siliconized articles such as
`syringes.
`
`10. Should Dow Corning 365, 35%
`Dimethicone NF Emulsion be diluted
`before use?
`
`Dow Corning 365, 35% Dimethicone NF Emulsion is manufactured
`with 35% silicone fluid in the formulation and it is recommended
`
`that the emulsion be diluted with sterile, pyrogen-controlled (WFI)
`water to a concentration of l-5% silicone in the final treatment
`
`solution. As stated above, delivery to the surface of just enough
`silicone to achieve the desired lubrication is sufficient.
`
`11. Are there any special considerations to
`keep in mind regarding the use of
`Dow Corning 365, 35% Dimethicone NF
`Emulsion?
`
`The product is an emulsion and therefore has a high tendency to
`separate but can be easily mixed to return the material to its optimum
`useable form. Labels and product information sheets recommend that
`the material be thoroughly mixed before each sampling or use to
`ensure good uniformity. This has been the most common cause of
`problems related to PDMS assays of the product. All original
`containers or extracted samples must be thoroughly mixed before use
`or testing. If PDMS values are out of specification, it is highly
`recommended to try more extensive mixing before rejecting the
`material.
`
`12. Can the silicone fluid delivered by
`Dow Corning 365, 35% Dimethicone NF
`Emulsion be “cured” on an article?
`
`Linear polydimethylsiloxane fluids do not have any (appreciable)
`filnctional groups that allow the fluid to attach to a surface or itself
`be polymerized and thus become “cured”. It is best to think of the
`Dow Corning 360 Medical Fluid delivered by Dow Corning 365,
`35% Dimethicone NF Emulsion as a fluid with the capability of
`spreading from its point of application, especially if applied in
`excess. Some studies (Mundry, Schurreit and Surmann, PDA Journal
`ofPharmaceutical Science & Technology 54: 5, 383 (2000)) have
`indicated that heat treatment can result in a small percentage of fluid
`become “bound” to the surface but it is usual to consider it as non-
`curable and able to be removed from the surface of an article.
`
`1 3. Even if the fluid cannot be “cured”, can it
`be made slightly more durable on a
`surface?
`
`If the article being siliconized can withstand some application of
`heat, it is advantageous to “bake” it after treatment. This will ensure
`complete removal of the water and, on a microscopic scale, allow the
`silicone fluid to become more intimately associated with the
`substrate. The input heat energy assists small aggregates or droplets
`of the fluid to spread out evenly over the surface and create a more
`uniform film. At the same time the “water of hydration” — a layer of
`moisture present on the surface of an article due to humidity from the
`air — is displaced. Heating or baking only needs to be done at a
`temperature and time sufficient to remove this water of hydration
`from the substrate surface. As stated above, no significant chemical
`bonding results, rather a strong physical attraction between the
`surface and initial monolayer of fluid that is thought to be the most
`important for lubrication. Again, it is very important to remember to
`apply only the minimum amount of silicone fluid that is required to
`achieve the desired level of lubrication on the article (which itself
`should be clean and free of contaminants before treatment).
`It is suggested that the baking temperature be kept below 150°C to
`minimize any possibility of oxidation and the formation of
`formaldehyde. Additionally, the time needed for baking is related to
`the temperature used and can be substantially shortened at higher
`temperatures. It is suggested that customers perform their own
`time/temperature studies in order to identify their optimum
`conditions for the part being siliconized.
`
`14. Is there a simple qualitative method that
`can be used to determine if a surface has
`been siliconized and whether the
`treatment is uniform?
`
`A siliconized article can be dipped into a container of a fine powder
`such as talc for a gross verification of whether or not the surface has
`been siliconized. If the treatment has been successful the powder will
`stick to it and the uniformity of the coating can be estimated by
`examining the surface for any areas where the powder did not stick.
`However, in order for this method to be effective, it is important to
`first check that the powder does not stick to the untreated surface;
`furthermore, contamination of the surface can also give misleading
`
`Regeneron Exhibit 1034.003
`
`

`

`Steris Corporation
`5960 Heisley Road
`Mentor
`
`OH 44060-1834
`
`Phone: 1-800 444 9009 or +1 (440) 354 2600
`Fax:
`+1 (440) 350 7077
`
`These detergents are widely used in pharmaceutical facilities to
`remove PDMS from equipment. Dow Corning uses CIP 100 in its
`emulsion processing units that see extensive exposure to PDMS.
`
`indications so care must be taken. Items tested in this way should be
`discarded afterwards.
`
`15. What quantitative analytical methods may
`be used to determine the amount of
`
`silicone fluid applied to a surface?
`Fourier-Transform Infrared Spectroscopy (FTIR) has been used to
`quantify the amount of silicone fluid applied to an article. However,
`this method generally requires that a number of articles be extracted
`in order to get enough PDMS to quantify from the spectrum and
`standards must be used. This does not therefore generally allow exact
`determination of the amount applied to any one article.
`Another more specific method that can be applied is Flame
`Absorption Atomic Spectroscopy (FAAS) which quantifies Si based
`on a stande curve. FAAS may also require multiple articles be
`extracted to achieve sufficient concentration to make a determination.
`
`Comparative testing of siliconized versus non-siliconized items is of
`course an obvious method of qualitative and quantitative assessment.
`
`1 6. Can articles treated with dow corning
`365, 35% dimethicone nf emulsion be
`sterilized, and by what methods?
`Siliconized articles may be sterilized by the usual methods such as
`steam autoclaving, dry heat, radiation, and ethylene oxide (ETO). If
`ETO is used, proper out-gassing must be completed before the article
`is suitable for use. It has been found that sterilization by radiation
`generally has no affect on the fluid with doses up to 2.5 Mrad for the
`appropriate amount of time. However, higher doses and times have
`the potential to affect especially the higher viscosity fluids by causing
`some cross-linking that will result in an increase in molecular
`weights and viscosities. This may affect the lubrication properties of
`the article so it is recommended that articles be tested for proper
`lubrication after the sterilization process.
`
`17. How can Dow Corning 365, 35%
`Dimethicone NF Emulsion be removed
`
`from surfaces that may have been
`accidentally coated?
`The most effective cleaning agents for PDMS are aliphatic and
`aromatic organic solvents but many have hazards associated with
`flammability and/or toxicity. Dow Corning® Q7-9180 Silicone Fluids
`(or industrial grade Dow Corning® OS Fluid equivalents) have also
`been used for cleaning PDMS from surfaces but it should be noted
`that they are also flammable.
`If a water-based detergent is desired for cleaning and use in clean-
`room areas, it is recommended that Steris Corporation be contacted
`to obtain either CIP 100® detergent (potassium hydroxide based) or
`CIP 200® detergent (phosphoric acid based):
`
`Regeneron Exhibit 1034.004
`
`

`

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