Validation Guide Summary - Saint-Gobain

FLS-5203VS.r1 2664 Gilchrist Road, Akron, OH 44305 Page 1 May 21, 2015 Telephone (330) 798-9240 Fax (330) 798-6968

Validation Guide Summary

Tygon® 2475 Revision: May 21, 2015


Tygon® 2475 Tubing Validation Guide Summary

Table of Contents Page

1. Summary _________________________________________________________________________________________ 3

2. Typical Physical Properties ___________________________________________________________________________ 3

3. Chemical Compatibility ______________________________________________________________________________ 4

4. Biocompatibility, Physiochemical and Extractable Testing __________________________________________________ 5

a. Summary _____________________________________________________________________________________ 5

b. Ames Genotoxicity Test (Saline) ___________________________________________________________________ 6

c. Ames Genotoxicity Test (EtOH) ____________________________________________________________________ 6

d. Hemolysis: Direct Contact ________________________________________________________________________ 6

e. Hemolysis: Indirect Contact ______________________________________________________________________ 7

f. Tests, In Vitro: Cytotoxicity _______________________________________________________________________ 7

g. Tests for Irritation and Delayed-Type Hypersensitivity _________________________________________________ 8

h. Sterility Tests: Bacteriostasis & Fungistasis __________________________________________________________ 8

i. Kinetic LAL Endotoxin ___________________________________________________________________________ 9

j. Biological Reactivity Tests, In Vitro: Agar Diffusion Test ________________________________________________ 9

k. Biological Reactivity Tests, In Vitro: MEM Elution Test _________________________________________________ 9

l. NAMSA Assay for Biological Reactivity – MEM Elution Test ____________________________________________ 10

m. Biological Reactivity Tests, In Vivo ________________________________________________________________ 10

n. Pyrogen Test _________________________________________________________________________________ 11

o. Elastomeric Closures for Injection ________________________________________________________________ 11

p. Physicochemical Tests – Plastics __________________________________________________________________ 12

q. Physicochemical Tests for Plastics Using and Alternative Extract ________________________________________ 12

r. Chemical Identification and Semi-Quantification of Extractables: Post-Gamma Irradiation ___________________ 13

5. Revisions to FLS-5203VS Tygon® 2475 and 2475 I.B. Validation Summary ____________________________________ 16

a. Revision (.r1) 1.27.15 ___________________________________________________________________________ 16

Saint-Gobain Performance Plastics Terms of Use & Confidentiality Statement

PLEASE NOTE: In receiving this Validation Summary you have agreed to possess ONLY ONE COPY of this validation information. You are also agreeing to NOT forward disseminate, either electronically or in print, totally or in part, any of the information contained in this material without the express written consent of Saint-Gobain Performance Plastics Corporation. If you have any questions about these terms please contact: [email protected]


Validation Guide Summary: Tygon® 2475 Tubing 1.0 Summary

Tygon® 2475 High-Purity Tubing is hydrophobic and resists the sorption (absorption/adsorption) of aqueous fluids. This

reduction in sorption minimizes the risk of fluid alteration in single or repeat-use applications. Tygon® 2475 High-Purity

Tubing is entirely free of plasticizers. This unique tubing uses the latest in polymer technology to provide a clear and flexible

tubing choice for sensitive fluid transfer applications. Tygon® 2475 tubing can be cleaned repeatedly without decreasing its

service life. The non-wettable surface of the product facilitates complete drainage of fluid during the cleaning process. In

addition, Tygon® 2475 tubing can be sterilized using gamma radiation or ethylene oxide.

Tygon® 2475 meets all relevant USP Class VI requirements.

Saint-Gobain considers certain information concerning the manufacture of our products to be confidential trade secrets, such

as, product raw materials and formulations. The Drug Master File (DMF) system was developed to permit suppliers to make

this information on their products directly available to FDA for its review of drug company applications that involve the use of

the supplier's material. The DMF number for Tygon®2475 is # 25831.

2.0 Typical Physical Properties

Property Standard Value or Rating

Durometer Hardness Shore A, 15 Sec. D2240-97 72

Tensile Strength, psi (MPa) D412-97 700 (4.8)

Ultimate Elongation,% D412-97 700

Tear Resistance, lb-f/inch (kN/m) D1004-93 220 (39)

Specific Gravity D792-91 0.9

Water Absorption, %, 24 hours @ 23°C D570-95 <0.01

Compression Set

Constant Deflection, % @ 158°F (70°C) for 22 hours

D395-89

Method B 84

Brittleness by Impact, Temperature, °F (°C) D746-95 -108 (-78)

Maximum Recommended Operating Temp., °F (°C) — 125 (52)

Low Temperature Flexibility, °F (°C) D380-87 -94 (-70)

Dielectric Strength, v/mil (kV/mm) D149-93 587 (23.1)

Tensile Modulus, @ 100% Elongation, psi (MPa) D412-97 350 (2.4)

Tensile Set, % D412-97 187


3.0 Chemical Compatibility

Relative Chemical Resistance Properties

Acids

Concentrated Fair

Medium Excellent

Weak Excellent

Bases

Concentrated Excellent

Medium Excellent

Weak Excellent

Salts Excellent

Alcohols Excellent

Ketones Excellent


4.0 Tygon® 2475 Biocompatibility, Physiochemical & Extractable Testing

4a. Summary

The following is a summary of the validation testing that has been performed on Tygon® 2475 Tubing. Complete test

reports can be found in the Tygon® 2475 Validation Guide. In addition, a letter regarding the animal origin of Tygon®

2475 components and statements of RoHS compliance, latex-free status and shelf-life can be found in the Validation

Guide.

Test Standard Result

Ames Genotoxicity (Saline) ISO 10993-3 Passed

Ames Genotoxicity (EtOH) ISO 10993-3 Passed

Hemolysis: Direct Contact ISO 10993-4 Passed

Hemolysis: Indirect Contact ISO 10993-4 Passed

Tests for In Vitro Cytotoxicity ISO 10993-5 Passed

Tests for Irritation and Delayed-Type Hypersensitivity ISO 10993-10 Passed

Sterility Tests: Bacteriostasis & Fungistasis USP <71> Passed

Kinetic LAL Endotoxin Test USP <85> Passed

Biological Reactivity Tests, In Vitro, Agar Diffusion Test USP <87> Passed

Biological Reactivity Tests, In Vitro, MEM Elution Test USP <87> Passed

NAMSA Assay for Biological Reactivity - MEM Elution Test Passed

Biological Reactivity Tests, In Vivo USP <88> Passed

Pyrogen Test USP <151> Passed

Elastomeric Closures for Injection, USP <381> See Data Summary. 4o

Physicochemical Tests for Plastics USP <661> Passed

Physicochemical Tests for Plastics Using an Alternative Extract (IPA) USP <661> See Data Summary, 4r

Chemical Identification and Semi-Quantification of Extractables:

Post-Gamma Irradiation See Data Summary, 4s


4b. ISO 10993-3 Ames Genotoxicity Test (Saline)

Genotoxicity tests are conducted to detect compounds that could potentially cause genetic damage. Genotoxic compounds can potentially cause cancer or heritable defects in humans. The Ames Genotoxicity Test assesses the ability of potentially genotoxic compounds to reverse genetic mutations in specific reference bacteria, and has been shown to predict potential carcinogenicity and mutagenesis in humans.

Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with ISO 10993-3, 2003, Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity.

The test article was extracted with USP 0.9% Sodium Chloride for Irrigation (NaCl) for 24hrs at 70oC. Triplicate cultures of

five strains of histidine deficient (his-) Salmonella typhimurium were exposed to the resulting extractant. Triplicate

cultures of these strains were also exposed to NaCl as negative controls. As positive controls, cultures of these strains were also exposed to strain-specific known mutagens (sodium azide, 2-nitrofluorene, methylmethane sulfonate, 2-aminoanthracene, benzo[a]pyrene, ICR-191) on triplicate plates.

Results: The mutant strains exposed to the test article extract did not exhibit a statistically significant number of revertant colonies relative to those exposed to the negative controls. The positive controls demonstrated statistically significant reversion in response to exposure to known mutagens, confirming that the test was valid. The test article was therefore deemed non-mutagenic in the test species.

4.c ISO 10993-3 Ames Genotoxicity Test (EtOH)

Genotoxicity tests are conducted to detect compounds that could potentially cause genetic damage. Genotoxic compounds can potentially cause cancer or heritable defects in humans. The Ames Genotoxicity Test assesses the ability of potentially genotoxic compounds to reverse genetic mutations in specific reference bacteria, and has been shown to predict potential carcinogenicity and mutagenesis in humans.

Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with ISO 10993-3, 2003, Biological evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity.

The test article was extracted with 95% ethanol (EtOH) for 24hrs at 70oC. Triplicate cultures of five strains of histidine

deficient (his-) Salmonella typhimurium were exposed to the resulting extractant. Triplicate cultures of these strains were

also exposed to EtOH as negative controls. As positive controls, cultures of these strains were also exposed to strain-specific known mutagens (sodium azide, 2-nitrofluorene, methylmethane sulfonate, 2-aminoanthracene, benzo[a]pyrene, ICR-191) on triplicate plates.

Results: The mutant strains exposed to the test article extract did not exhibit a statistically significant number of revertant colonies relative to those exposed to the negative controls. The positive controls demonstrated statistically significant reversion in response to exposure to known mutagens, confirming that the test was valid. The test article was therefore deemed non-mutagenic in the test species.

4.d ISO 10993-4 Hemolysis: Direct Contact

The Hemolysis test assesses the potential for contact of a given sample with blood to cause the rupture of erythrocytes (red blood cells).


Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with ISO 10993-4, 2002 (as amended 2006), Biological Evaluation of Medical Devices – Part 4: Selection of Tests for Interactions with Blood and ASTM F756-08, Standard Practice for Assessment of Hemolytic Properties of Materials, 2008.

Test samples and controls were prepared by adding a sample of the Negative Control Plastic, positive control (Sterile Water for Injection) or the test article to vials of Calcium- and Magnesium-Free Phosphate Buffered Saline (CMF-PBS). A blank sample containing just CMF-PBS was also prepared. Rabbit blood was added to each vial and the resulting mixture was incubated at 37

oC for 3hrs with periodic inversion. The incubated vials were then centrifuged and the supernatant

was drawn off. Supernatant samples were tested by adding Drabkin’s reagent, letting the samples stand for 15 minutes and then measuring the absorbance of the samples in a spectrophotometer at 540nm to determine the corresponding hemoglobin concentration.

Results: The percent hemolysis resulting from direct contact of the product with rabbit blood was 0.0% above the negative control. Per ASTM F756-08 and ISO 10993-4, a test article is considered non-hemolytic if its % hemolysis is <2.0% above the negative control. The test article was therefore deemed non-hemolytic.

4.e ISO 10993-4 Hemolysis: Indirect Contact

The Hemolysis test assesses the potential for indirect contact of a given sample with blood to cause the rupture of erythrocytes (red blood cells).

Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with ISO 10993-4, 2002, Biological Evaluation of Medical Devices – Part 4: Selection of Tests for Interactions with Blood.

The test article was added to a vial containing Calcium- and Magnesium-Free Phosphate Buffered Saline (CMF-PBS) and incubated for 24hrs at 70

oC. Sterile Water for Injection was used as the positive control and CMF-PBS was used as the

negative control. Rabbit blood was added to each vial and the resulting mixture was incubated at 37oC for 3hrs with

periodic inversion. The incubated vials were then centrifuged and the supernatant was drawn off. Supernatant samples were tested by adding Drabkin’s reagent, letting the samples stand for 15 minutes and then measuring the absorbance of the samples in a spectrophotometer at 540nm to determine the corresponding hemoglobin concentration.

Results: The percent hemolysis resulting from indirect contact of the product with rabbit blood was 0.0% above the negative control. Per ASTM F756-08 and ISO 10993-4, a test article is considered non-hemolytic if its percent hemolysis is <2.0% above the negative control. The test article was therefore deemed non-hemolytic.

4.f ISO 10993-5 Tests for In Vitro Cytotoxicity

Cytotoxicity testing assesses the potential of a given material to have a toxic effect on living cells.

Test: Samples of Tygon® 2475 were tested by NAMSA in accordance with ISO 10993-5, 2009, Biological Evaluation of Medical Devices Part 5: Tests for In Vitro Cytotoxicity.

Test samples were immersed in Serum-Supplemented Minimum Essential Medium at 37oC for 24hrs. Positive control

(plasticized vinyl containing 10,10’-oxybisphenoxarsine) and negative control (HDPE) samples were also extracted as above. Duplicates of all three extracts were incubated with L929 mouse fibroblast cells at 37

oC for 48hrs. Cultures were


monitored for cytotoxicity and/or cell lysis and rated on a scale of 0 (No Biological Reactivity) to 4 (Severe Biological Reactivity).

Results: The test article samples and the negative controls scored a Grade 0 for Biological Reactivity after 48hrs. The positive controls scored a Grade 4 at the 48hr mark. Samples are deemed to meet the test requirements if they exhibit a Biological Reactivity of no more than Grade 2 (Mild Reactivity). The test articles are therefore considered non-cytotoxic.

4.g ISO 10993-10 Tests for Irritation and Delayed-Type Hypersensitivity

The tests for irritation and skin sensitization are performed to determine the allergenic potential of a test article on contact with skin.

Test: A sample of Tygon ® 2475 was tested by NAMSA in accordance with ISO 10993-10, 2002, Biological Evaluation of Medical Devices – Part 10: Tests for Irritation and Delayed-Type Hypersensitivity.

Samples of the test article were extracted in USP 0.9% Sodium Chloride (NaCl) or Sesame Oil at 70oC for 24 hours. 30

Hartley guinea pigs (20 experimental, 10 control) were used for these evaluations. On Day 0 (Induction Phase) samples of the test article extracts and positive and negative controls were injected intradermally into the test animals. On Day 7 (Topical Application Phase) the test article extracts and control articles were applied to the test sites and left in place for 48 hours. On Day 23 (Challenge Phase) the test article extracts and control articles were applied to the test sites and left in place for 24 hours. The test and control animals were examined and scored for erythema and edema according to the Magnusson and Kligman Scale at 24 and 48 hours post Challenge Phase.

Results: The skin sites exposed to the test article extracts and the negative control showed no evidence of erythema or edema. The sites exposed to the positive control demonstrated erythema and edema as expected. The test article extracts therefore produced no reaction (0% sensitization) and the test article was not considered a sensitizer.

4.h USP <71> Sterility Tests: Bacteriostasis & Fungistasis

Bacteriostasis and Fungistasis testing is performed to determine whether or not a given test article has the potential to inhibit the growth of bacteria and/or fungi, respectively, and therefore potentially interfere with standard Sterility Tests.

Test: Samples of Tygon® 2475 were tested by NAMSA in accordance with USP 32, NF 27, 2009; <71>: Sterility Tests.

Test articles were placed in culture vessels containing Soybean Casein Digest Broth (SCDB) or Fluid Thioglycollate Media (FTM). Corresponding positive controls were prepared using the same media in culture vessels that did not contain samples of test article. The product-containing and positive control flasks were inoculated with Bacillus subtilis (SCDB), Candida albicans (SCDB), Aspergillus brasiliensis (SCDB), Staphylococcus aureus (FTM), Clostridium sporogenes (FTM) and Pseudomonas aeruginosa (FTM). Flasks containing SCDB were incubated at 20

oC - 25

oC and flasks containing FTM were

incubated at 30oC - 35

oC until positive for microbial growth or until five days had passed.

Results: All test article-containing flasks and positive control flasks were positive for microbial growth within three days. The test article was therefore deemed non-bacteriostatic and non-fungistatic.


4.i USP <85> Kinetic LAL Endotoxin

Endotoxins are lipopolysaccharide complexes found in Gram negative bacterial cell walls. They can cause significant illness in humans. The Limulus Amebocyte Lysate (LAL) Gel Clot Test is used to detect and quantify endotoxin levels in test samples.

Test: Samples of Tygon® 2475 were tested by NAMSA in accordance with USP 32, NF 27, 2009; <85> Bacterial Endotoxins Test; Guidelines of Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological products and Medical Devices, December 1987.

The test article was immersed in Water for Injection for one hour at 37oC. A positive product control (PPC) was prepared

by adding a 0.1ml of the 5.0 EU/ml endotoxin standard to 0.9ml of test article. LAL Reagent water (endotoxin-free) was used as negative controls. Test article samples, PPC samples, and negative control samples were added to a microtiter plate and incubated at 37

oC for 10 minutes. After incubation 0.1ml of LAL was added to each well and the plate was

placed in a plate reader. The absorbance was measured at 405 nm.

Results: The positive product controls demonstrated that the product did not interfere with the test. The endotoxin level in the test article extract was determined to be below the limit of detection for this assay, i.e. <0.005 EU/ml or <0.0225 EU/device. The test articles were certified endotoxin-free.

4.j USP <87> Biological Reactivity Tests, In Vitro – Agar Diffusion Test


Test: Samples of Tygon® 2475 were tested by NAMSA in accordance with USP 32, NF 27, 2009; <87> Biological Reactivity Tests, In Vitro.

Duplicate test article, negative control (HDPE) and positive control (latex) samples were placed in separate wells containing solidified agarose overlaying a L929 mouse fibroblast monolayer. The culture plates were then incubated at 37

oC in 5% CO2 for 24hrs. After the incubation period cultures were examined macroscopically and microscopically for

cell decolorization and potential cell lysis and rated on a scale of 0 (No Biological Reactivity) to 4 (Severe Biological Reactivity).

Results: The test article samples scored a Grade 0 for Biological Reactivity after 24hrs. The negative controls scored a Grade 0. The positive controls scored a Grade 3 at the 24hr mark. Samples are deemed to meet the test requirements if they exhibit a Biological Reactivity of no more than Grade 2 (Mild Reactivity). The test articles are therefore considered non-cytotoxic.

4.k USP <87> Biological Reactivity Tests, In Vitro – MEM Elution Test


Test: Samples of Tygon® 2475 were tested by NAMSA in accordance with USP 32, NF 27, 2009; <87> Biological Reactivity Tests, In Vitro.


Test samples were immersed in Serum-Supplemented Minimum Essential Medium at 37oC for 24hrs. Positive control

(plasticized vinyl containing 10,10’-oxybisphenoxarsine) and negative control (High Density Polyethylene) samples were also extracted as above. Duplicates of all three extracts were incubated with L929 mouse fibroblast cells at 37

oC for

48hrs. Cultures were monitored for cellular degeneration and malformation and rated on a scale of 0 (No Biological Reactivity) to 4 (Severe Biological Reactivity).

Results: The test article extracts and negative controls scored a Grade 0 for Biological Reactivity after 48hrs. The positive controls scored a Grade 4 at the 48hr mark. Samples are deemed to meet the test requirements if they exhibit a Biological Reactivity of no more than Grade 2 (Mild Reactivity). The test articles are therefore considered non-cytotoxic.

4.l NAMSA Assay for Biological Reactivity - MEM Elution Test


Test: Samples of Tygon® 2475 were tested by NAMSA based on their protocol for cytotoxicity testing via MEM Elution.

The test article was sterilized via ethylene oxide and degassed prior to analysis. Test samples were immersed in Serum-Supplemented Minimum Essential Medium (MEM) at 37

oC for 24hrs. A positive control (plasticized vinyl containing

10,10’-oxybisphenoxarsine) sample was also extracted as above. The negative control sample consisted of Serum-Supplemented MEM incubated at 37

oC for 24hrs. Duplicates of the test article and positive control extracts and the

negative control were incubated with L929 mouse fibroblast cells at 37oC for 72hrs. The positive control well was

examined after 24hrs of incubation and the negative control and test article extract wells were examined at 24, 48 and 72hrs of incubation. Cultures were monitored for cytotoxic effect, as determined by presence or absence of a confluent monolayer, vacuolization, cellular swelling and/or crenation, and by the percent lysis observed. Based on these observations samples were classified as Non-Toxic, Intermediate or Toxic.

Results: The test article extract and the negative control samples were classified as Non-Toxic based on the lack of cytotoxic effects observed microscopically at 24, 48 and 72hrs. The positive control samples were classified as Toxic at the 24hr mark. Samples are deemed to meet the test requirements if they meet the requirements for classification as Non-Toxic. The test articles are therefore considered non-cytotoxic.

4.m USP <88> Biological Reactivity Tests, In Vivo

The USP Class VI Plastics Test assesses the potential toxicity of a given test article by introducing a sample into live animals systemically, intracutaneously and through implantation. Test animals are then monitored for signs of irritation and/or toxicity.

Test: Samples of Tygon® 2475 were tested by NAMSA in accordance with USP 32, NF 27, 2009; <88> Biological Reactivity Tests, In Vivo.

Test articles were immersed in USP 0.9% Sodium Chloride (SC), Sesame Oil (SO), 1 in 20 Alcohol in Saline (AS) or Polyethylene Glycol 400 (PEG) at 70

oC for 24hrs. The test article extracts and corresponding controls (samples of each

extractant that had not been exposed to the test article) were injected systemically into mice and intracutaneously into rabbits and the animals were observed for 72 hours for signs of skin reactivity or toxicity. In addition, the test article was implanted into the paravertebral muscles of rabbits, which were then observed for 5 days for macroscopic signs of hemorrhage, necrosis, discoloration, encapsulation and/or infection.


Results: None of the animals injected systemically with test article extracts or controls exhibited any signs of toxicity. Similarly, none of the animals injected intracutaneously with test article extracts or controls exhibited any signs of erythema, edema or clinical toxicity. Further, none of the implanted animals exhibited any signs of toxicity at the implantation sites relative to the control sites. The test article therefore met the requirements of the USP Class VI Test for Biocompatibility.

4.n USP <151> Pyrogen Test

The rabbit pyrogen test is performed to qualitatively determine whether a given test article contains pyrogens. Pyrogens can provoke a significant febrile reaction in a human patient who receives a parenteral drug product that has come into contact with a contaminated test article.

Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with USP <151> Pyrogen Test and ISO 10993-11, 2006, Biological Evaluation of Medical Devices – Part 11: Tests for Systemic Toxicity.

The test article was sterilized via ethylene oxide and then immersed in Sterile, Non-Pyrogenic 0.9% Sodium Chloride for Injection (SNPS) at 70

oC for 24 hours. The resulting extract was administered to test subjects (rabbits) via IV injection at a

dose of 10 mL per kg of body mass. The body temperatures of the animals were measured 30 minutes prior to injection and again every 30 minutes between the 1 hour and 3 hours marks post-injection.

Results: The three test rabbits showed a rise of 0.3oC, 0.0

oC and 0.0

oC in body temperature post-injection. A test article

is considered pyrogen-free provided that none of the test subjects display an increase in body temperature of more than 0.5

oC post-injection, therefore the test articles were deemed pyrogen-free.

4.o USP <381> Elastomeric Closures for Injection

Testing of elastomeric closures for use with containers for injectables is performed to assess the suitability of the test article for use in contact with drug products for parenteral administration in humans.

Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with USP 31, NF 26, 2008; <381> Elastomeric Closures for Injections.

The test article extract was prepared by immersing the test article sample in purified water and autoclaving at 121oC for

30 minutes, then rinsing twice with purified water. The test article was subsequently immersed in 200 ml of fresh purified water and autoclaved at 121

oC for 2 hours. The test extract was then tested for Turbidity, Reducing Agents,

Heavy Metals, pH Change and Total Extractables per USP <381>.

Results: The test results are summarized in the table below.


Parameter Results

Turbidity < 0.01 NTU

Total Extractables < 1 mg solids per 200 ml extract

Reducing Agents 0.01 ml

Heavy Metals < 0.1 ppm

pH Change pH units

4.p USP <661> Physicochemical Tests for Plastics

Physicochemical testing is performed to assess the suitability of the test article for use in contact with drug products for parenteral administration in humans.

Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with USP 32, NF 27, 2009; <661> Containers, Physicochemical Tests – Plastics.

The test article was immersed in USP Purified Water for 70oC for 24hrs. The extract was then tested for Non-Volatile

Residue, Residue on Ignition, Heavy Metals as Lead and Buffering Capacity per USP <661>.

Results: The test results are summarized in the table on the following page.

Assay Assay Results Limits Based on Area

Non-Volatile Residue 3 mg ≤ 15 mg

Residue on Ignition < 3 mg ≤ 5 mg

Heavy Metals < 1 ppm ≤ 1 ppm

Buffering Capacity < 1.0 ml ≤ 10 ml

The test article sample met the criteria established per USP <661> for all of the tests performed, as shown above.

4.q USP <661> Physicochemical Tests for Plastics Using an Alternative Extract

Physicochemical testing is performed to assess the suitability of the test article for use in contact with drug products for parenteral administration in humans.

Test: A sample of Tygon® 2475 was tested by NAMSA in accordance with USP 32, NF 27, 2009; <661> Containers, Physicochemical Tests – Plastics.


The test article was immersed in Isopropyl Alcohol (IPA) at 70oC for 24hrs. The extract was then tested for Non-Volatile

Residue per USP <661>.

Results: The test results are summarized in the table below.

Assay Assay Results

Non-Volatile Residue 16 mg

4r. Chemical Identification and Semi-Quantification of Extractables: Post-Gamma Irradiation

Extractable testing is performed to determine the chemical compounds that will migrate from a given material under aggressive yet relevant extraction conditions. The results of extractable testing can be used to guide the design of an appropriate leachable study.

Test: Samples of Tygon® 2475 that had been gamma irradiated at 25-40 kGy were analyzed by Saint Gobain Research – Shanghai. Test article samples were prepared according to SOP: SGRS-03-3003-02-070-01 <Sample Preparation for Extractable and Leachable Tests>. Test articles were extracted in either Purified Water or 70% Ethanol with agitation at 70

oC for 24 hrs. Samples were extracted by immersion at a ratio of 6 cm

2/ml.

The test article extracts were analyzed to identify and semi-quantify any extractable compounds present, using the following analytical techniques:

Gravimetric analysis for non-volatile residue (NVR) following USP 36 , NF 31, 2013; <661> Containers,

Physicochemical Tests – Plastics

Total organic carbon (TOC) for DI Water extract only following USP 36, NF 31, 2013; <643> Total Organic Carbon

Inductively coupled plasma/atomic emission spectroscopy (ICP-AES) for analysis of trace metals following SGRS-03-

3003-02-072-01

Headspace gas chromatography/flame ionization detector (GC/FID) for volatile organic compounds (VOC) for Purified

Water extract only, and semi-volatile organic compounds (SVOC) for both extracts following SGRS-03-3003-02-073-

01

Gas chromatography/mass spectrometry (GC/MS) for semi-volatile organic compounds (SVOC) following SGRS-03-

3003-02-073-01

All analytic methods employed in this study have a minimum detection limit of 1 µg/ml for the chemical compounds that are known to be potential extractables.

Results: The results are summarized in the tables below.


Table 1: Results Summary

Solvent NVR

(µg/ml)

TOC

(

(µg/ml)

VOC ( (µg/ml)

SVOC (µg/ml)

Metals (µg/ml)

Purified Water 15.6 4.72 4.5 None 1.36

70% Ethanol 192.4 NA 1.2 90.1 36

Table 2: Metals Analysis by ICP-AES

Element Purified Water

(µg/ml) 70% Ethanol

) (µg/ml)

Aluminum ND* ND*

Antimony ND* ND*

Arsenic ND* ND*

Barium ND* ND*

Beryllium ND* ND*

Boron ND* ND*

Cadmium ND* ND*

Calcium 0.02 0.1

Chromium ND* ND*

Cobalt ND* ND*

Copper ND* ND*

Iridium ND* ND*

Iron ND* ND*

Lead ND* ND*

Magnesium ND* ND*

Manganese ND* ND*

Mercury ND* ND*

Molybdenum ND* ND*

Nickel ND* ND*

Osmium ND* ND*

Palladium ND* ND*

Platinum ND* ND*

Potassium ND* ND*

Rhodium ND* ND*

Ruthenium ND* ND*

Selenium ND* ND*

Silicon 1.25 35


Sodium 0.09 0.9

Thallium ND* ND*

Titanium ND* ND*

Tungsten ND* ND*

Vanadium ND* ND*

Zinc ND* ND*

* ND = Not Detected at Reporting Limit

Table 3: GC-MS Analysis of Volatile Organic Compounds (VOC)

Solvent Compounds Detected Retention Time

(min) Results (µg/ml)

CAS #

Purified Water None NA NA NA

70% Ethanol None NA NA NA

Table 4: Headspace GC/FID Analysis of Volatile Organic Compounds (VOC) in Purified Water Extract


(min)

Results

(µg/ml) CAS #

Purified Water

unknown 1.358 0.7 NA



Table 5: GC-MS Analysis of Semi-Volatile Organic Compounds (SVOC)


(min)

Results

(µg/ml) CAS #

Purified Water None

70% Ethanol

Benzene, 1,3-bis(1,1-dimethylethyl) 8.771 14.8 1014-60-4

2,5-Cyclohexadiene-1,4-dione,2.6-bis(1,1-dimethylethyl)

10.34 0.9 719-22-2

Phenol, 2,4-bis(1,1-dimethylethyl) 10.552 65.0 96-76-4

Oxidized Irgafos 168 26.851 10.3 NA


5.0 Revisions to FLS-5218VS Tygon® 2475 + 2475IB BDF Validation Summary

5.a. Revisions 5.21.15: (.r1)

Front Cover: Updated date and revision number

Table of Contents: Addition of test: Chemical Identification and Semi-Quantification of Extractables: Post-Gamma

Irradiation and confidentiality statement. Adjusted page numbers.

4a. Summary: Addition of test: Chemical Identification and Semi-Quantification of Extractables: Post-Gamma

Irradiation to chart

4p. Removed Chromotography (Drug Preservative Binding) and renumbered test results.

4q. Removed reference to Turbidity in text and chart

4r. Chemical Identification and Semi-Quantification of Extractables: Post-Gamma Irradiation Addition of new

testing Information

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