@Pupnolbut TABLE OF'CONIENTS Certificate of Analysis for Recombinant Human TNF-alpha Analytical Tests N-terminal Sequence HPLC Mass Spectrometry Final SDS-PAGE gel Biological Assay C onstruction of. E. coli expressing Human TNF- alpha FIow Diagram E.coh, DNA testing Sterility Test Mycoplasma Test Certificate of Analysis for all Reagents used in fermentation foldlng/processing and purification
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@Pupnolbut
TABLE OF'CONIENTS
Certificate of Analysis for Recombinant Human TNF-alpha
Description: TNF-u is a pleiotropic pro-inflammatory cytokine secreted by various cells includingadipocytes, activated monocytes, macrophages, B cells, T cells and fibroblasts. It belongs to the TNF
family of ligands and signals through two receptors, TNFRI and TNFR2. TNF-o is cytotoxic to awide variety of tumor cells and is an essential factor in mediating the immune response against
bacterial infections. TNF-c also plays a role in the induction of septic shock, auto immune diseases,
rheumatoid arthritis, inflammation, atrd diabetes. Recombinant human TNF-cr is a soluble 157 aminoacid protein (17.4 kDa) which corresponds to C-terminal extracellular domain of the frrll lengthtransmembrane protein.
Product is produced using non-animal origin reagents.
Molecule: Recombinant Human TNF-o 17.4 V,Da I 157 alrino acid residues
Mycoplasma: Samples are examined in accordance with sTM V-611.3 for agar cultivableMycoplasmas. The assay includes the inoculation of the test article into broth and onto agar withsubsequent incubation at37oC under aerobic conditions, and also inoculation onto agar withincubation at37oC under anaerobic conditions. Negative results after 28 days.
PeproTech lnc., Princeton Business Park, 5 Crescent Ave., Rocky Hill, NJ 08553
E.coli DNA: Sample is examined utilizing 32P-labeled E.coli DNA probe generated kom E.coligenomic DNA. The assay included the test article, test article spike, negative and positive controlsand standards. The test sample was calculated to contain less than 133.4 pg DNA/mt.
Sterility: Samples were performed in accordance with current USP guidelines for sterility. The testsample was examined for sterility by direct inoculation into fluid thioglycollate and soybean-caseindigest broths. The broth cultures were incubated and observed for growth for 14 days. No growthwas observed.
Endotoxin Level: Tested using the Limulus Amebocyte Lysate (LAL) Kinetic-Qcl test kit fromBioWhittaker. Final product endotoxin level is 0.007 EUipg.
N-terminal Sequencing (5 amino acids): V R S S S
Mass Spectrometryz 17310.85 daltons
Purity: > 98yo by SDS-PAGE gel and HPLC analyses.
Formulation: The sterile filtered solution was lyophilized from 10 mM Sodium Phosphate, pH7.4 +0.5 mM DTT.
Reconstitution: Centrifuge the vial prior to opening. Reconstitute in water to a concentration of 0.1-1.0 mg/ml. Do not vortex. This solution can be stored at 2-8oC for up to I week. For extendedstorage, it is recommended to further dilute in a buffer containing a carrier protein (example 0.1%BSA) and store in working aliquots at -20oC to -80oC.
Storage/Stability: The lyophilized protein is stable at room temperature for up to I month. Workingaliquots stored with a carrier protein are stable for at least 12 months at -20oC to -80oC. Avoidrepeated fu eezel thaw cycles.
Biological Activity: The EDso as determined by the cytolysis of murine L929 cells in the presence ofActinomyocin D is < 0.05 ng/ml, corresponding to a specific activity of> 2x 107 units/mg.
Cytotoxicity Assay for h-TNF-cl using 929 cellsSBH Sciences, lnc. - J.W./L.H./J.W. - July 15, 2009
c
C:ytokine: Human TNF+; PeproTech; Ca# G-300-01A; Lot# 0609C25 G0809All run in parallel:Human TNF-u,; PeproTech; Cat# AF-300-01A; Lot# 0609AFC25 G0809
Human TNF-a; PeproTech; Cat# 300-01A; LotE 0805CY25-2 F1609
Human TNF-o; PeproTech; Cat# G-300-0'lA; Lot# 0609C25 G0809
Procedurc: (Reconstituted in water)1) Resuspend 929 cells in culture media containing 10% HS (Gibco lot# 0892684).
Transfer l00ulAarell in assay plate (6,000 cellslrvell, passage# 2). lncubate overnight 37oC.2) Serial dilute h-TNF-ct in assay media containing 2pglml Actinomycin D (Sigma Cat #A-9415)3) Add 1OOpli\rell serial diluted h-TNF-cr to cells in assay plate. Final volumeftvell is 2001.t1 containing
1pg/ml Aclinomycin D, 10% Horse Serum and h-TNF-a as indicated below.4) Incubate 46 hours.5) Add 30pl of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well.
6) lncubate 37oC and read OD at 490 nm,
Data:
Average Min.OD ( 11 .11 - 100.0 nglml ): 0.476Max Net O.D ( 0.00 ng/ml): 1132
Calculated Net O.D. for ED5g: 0.565
Result: ED56 is 0.033 - 0.049 ng/ml h-TNF-cr
Conc. h-TNF-cr O.D. readinq at 490nm after 6.2 hours RelativeActivitvno/ml Row F Row G Row H Ave. O.D. Net O.D.
lUU.UU33.33't1.11
3.701.23o.4'.1
0.140.050.02
u.4c60.481
0.4840.5140.536o.6240.7701.1021.380
u.4ti90.466
0.4870.5000.5330.5980.7591.0081.302
u.4/o0.4760.4850.5050.5380.6040.7080.971
1.140
U.4OU
0.4740.4850.5060.5360.6090.7461.0271.274
-U.UU6
-0.00'l
0.0100.03't0.0600.1334.2700.551
0 798
o.290.290.300.310.330.380.460.640.79
0.00
0.000.00
1.560
1.573't.652
1.687
1.6381.467
1.598
1.689
1.608 1j32
Gytotoxicity Assay for h-TNF-a using 929 cellsPeproTech; Caff G-300-01A; Lot# 0609C25 G0809
Ecoo{ooo2
1.30
1.10
0.90
0.70
0.50
0.30
0_ 10
-0.100.0'10 0.100 1.000 10.000
h-TNFc (ng/ml) flog scalel
Cytotoxicity Assay for h-TNF-s using 929 cellsSBH Sciences, lnc. - J.W./L.H./J.W. : July 15,2009
B
Cytokine: Human TNF-a; PeproTech; CaS 300-01A; Lo# 0805CY25-2 F1609All run in parallel:Human TNF-o; PeproTech; Cat# AF-300-01A Lot# 0609AFC25 c0809Human TNF-o; PeproTech; Cat# 300-01A; Lot# 0805CY25-2 Fl609Human TNF-o; PeproTech; Cat# G-300-01A; Lot# 0609C25 G0809
Procedure: (Reconstituted in water)1) Resuspend 929 cells in culture media containing 10% HS (Gibco lot# 0892684),
Transfer lO0ulArvell in assay plate (6,000 cells/well, passage# 2). lncubate overnight 37oC.2) Serial dilute h-TNF-cr in assay media containing 2pglml Actinomycin D (Sigma Cat #A-9415)3) Add lO0pllwell serial diluted h-TNF-cr to cells in assay plate. Final volume/well is 200p1 containing
'lpg/ml Actinomycin D, 10% Horse Serum and h-TNF<r as indicated below.4) lncubate 46 hours.5) Add 30pl of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well.6) lncubate 37oC and read OD at 490 nm.
Data:
Result:
Average Min.OD ( 3.7 - 100.0 ng/ml ): 0.474Max Net O.D ( 0.00 ng/ml): 1.134
Calculated Net O.D. for EDs: 0.567
ED5s is 0.030 - 0.045 ng/ml h-TNF-cr.
Conc. h-TNF-cr O.D. readino at 490nm after 6.2 hours RelativeActivitynq/ml Row D Row E Ave. o.Lr. Net o.D.
100.0033.33
11 11
3.701.230.41o.140.05o.o2
0.4690.4730.473o.4u0.5250.5620.7511.014't.275
0.4690.464
0.4760.4830.5190.5810.7330.9561.236
0.4690.469
0.4750.4840.522o.5720.7420.9851.256
-0.005-0.005
0.0010.0100.0480.0980.2680.511
0.782
o.290.29
0.300.300.320.360.460.61
0.780.000.000.00
1.560
1.5731.652
1.687
1.6381.467
1.598
1.689
1.608 't.134
Gytotoxicity Assay for h-TNF-a using 929 cellsPeproTech; CaH 300-01A; Lo# 0805CY25-2 F{609
E
oo{oooz.
0_001 0.010 0.100 1.000
h-TNF{ (ngrml} flog scalel
10.000 100.000
Cytotoxicity Assay for h-TNF-cr, using 929 cellsSBH Sciences, lnc. - J.W./L.H./J.W. - July 15,2009
A
Cytokine: Human TNF-g; PeproTech; Cat# AF-300-01A; Lot# 0609AFC25 G0809
All run in parallel;Human TNF-g; PeproTech; Cat# AF-300-01A; Lot# 0609AFC25 G0809
Human TNF-g; PeproTech; Cat# 300-01A; Lot# 0805GY25-2 F1609
Human TNF-a; PeproTech; Cat# G-300-01A; Lot# 0609C25 G0809
Procedure: (Reconstituted in water)1) Resuspend 929 cells in culture media containing 10% HS (Gibco lot# 0892684).
Transfer lO0ulArell in assay plate (6,000 cellsArvell, passage# 2). lncubate overnight 37oC.
2) Serial dilute h-TNF-cr in assay media containing 2pg/ml Actinomycin D (Sigma Cat #A-9415)3) Add 100p1/well serial diluted h-TNF-o to cells in assay plate. Final volume/well is 200p1 containing
1pg/ml Ac{inomycin D, 10% l'lorse Serum and h-TNF-cr as indicated below.4) lncubate 46 hours.5) Add 30pl of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well.
6) lncubate 37oC and read OD at 490 nm.
Data:
Average Min.OD ( 11.11 - 100.0 ng/ml ), 0.473Max Net O.D ( 0.00 ng/ml): 1.135
Calculated Net O.D. for EDse: 0.568
Result: EDso is 0.034 - 0.05'l ng/ml h-TNF-o
Conc. h-TNF-a O.D. readinq at 490nm after 6.2 hours RelativeActivityno/ml RowA Row B Row C Ave. O.D. Net O.D.
100.0033.33
11.113.701.23o.41o.140.050.02
U.4OU
0.466
0.4750.4890.5250.5930.7350.9821.214
U.4OU
0.475o.4760.5010.5320.6200.7661.0841.302
0.4710.481
0.4820.5040.5430.6100.7771.0791.285
0.4660.474
0.4780.4980.5330.6080.7591.0481.267
-0.0060.001
0.0050.0250.0610.1 350.2870.5760.794
0.290.29
0.300.310.330.380.470.650.79
0.00
0.000.00
1.560
1.5731.652
1.687
1.6381.467
1.598
1.689
1.608 1-135 1.00
Cytotoxicity Assay for h-TNF-a using 929 cellsPeproTech; Ga# AF-300-0{A; Lot# 0609AFC25 G0809
E
o@*oooz
1.30
1. t0
0.90
0.70
0.50
0.30
0.10
-0.100.000 0.001
Cytotoxicity Assay for h-TNF-cr using 929 cellsSBH Sciences, lnc. -- J.W./L.H./J.W. - July 15,2009
Summary Graph
no/ml
Human TNF-a;PeproTech; Cat*
AF-3OGO1A;Lot# 0609AFC2€
G0809
Human TNF-a;PeproTech; Cat#
300-01A; Lot#0805cY25-2
F1609
Human TNF-a;PeproTech; Cat#G-300-01A; Lot#0609c25 G0809
pACYC177 Plasmid(Gift from New England Biolabs,lnc,)
p ACY C17 7 Residues: 1 588-3322
Synthetic DNA
pUC18 Plasmid(Purchased Commercially)
pUCl 8 Residues: 2622-2300
pUC18 Plasmid(Purchased Commercially)
pUCl 8 Residues: 1926-456
Sequence Name: TNFaPV2KLength:4616
(d83
I/
dEcoO 1 0'PsPOMhAPal:Nhel-Bmtl
urallt
5 rNraPV2K
Page I of I DS Gene 611212012 {2:32:52 PM
Sequence Name: TNFaEFLength: 663
TNFa Expression Fragment
GAATTCCGCTCTCACCTACCAAACAATGCCCCCCTGCAAAAAATAAATTCATATAAAAAACATACAGATAAI I ll I ll I I ll I I I I I ll llll I I I I I I I lt I I I I tl I I lt t I I I I I I tlt I I ttt tt tlt I ll I I I r lJt
10 20 30 40 50 60 70
Promoter
CCATCTGCGGTGATAAATTATCTCTGGCGGTGTTGACATAAATACCACTGGCGGTGATACTGAGCACAICGI lll I I I I lt I I I I I I ll ll I I I ll I tlll I I I I I I I tll I I I I tt I I lt I I I I I I I I lt ll I I ll I I lt I80 90 100 1 10 120 1 30 140
RBS
--------> MVRSSSRTPSDKPV
ATGTTAACTC-IAGAAGGAGGAATAACATATGGTACGTAGCTCCTCTCGCACTCCGTCCGATAAGCCGGTTGI I I I I I I lll I I I I I I lll ll I I I I ll ll ll I I I I tl lt I I tl I I I I ll ll I I I I I I lt I rt lt I I I lt I I1s0 160 170 180 190 zCA 21A
AH VVAN PAA EGA L QWL N R R AN A L L
CTCATGTAGTTGCTAACCCTCAGGCAGAAGGTCAGCTGCAGTGGCTGAACCGTCGCGCTAACGCCCTGCTGI I I I llll I I I I I lll ll I I I I I I I I llt tl I I I I I lt lt I tt tl I lt I I I I I llt ll I I I I lt I I lr rl I220 230 24A 250 260 27A 280
ANGVELRDNOLVVPS EGLYLIYSOGCAAACGGCGTTGAGCTCCGTGATAACCAGCTCGTGGTACCTTCTGAAGGTCTGTACCTGATCTATTCTCAI I ll I ll I I I I t I I I lll ll I I I I lll ll I I lt I I lt I tt I I I I I lt I I I I I I tt lt I lt I I I I lll I lt I290 300 310 320 330 340 350
VLFKGOGCPSTH VLLCoding Region
NYTI SRIAAGTACTGTTCAAGGGTCAGGGCTGCCCGTCGACTCATGTTCTGCTGAACTACACCATCAGCCGTATTGCTGI I ll ll I I I I I I I I ll ll ll I I ll lli ll I I tl I lt I tlr I I I I lt I I I I I I I I lll I tll tt I lt I I I I I360 370 380 390 400 410 420
I I I ll I ll I I I I I Il I t I I I I I I ll I I I I I I I I ll I I I I I I I I ll tt I I I I I I lt I I I I I I I tlr I I I I I I
430 440 450 460 470 480 4go
AEAK PWYE P I Y L GGVF Q L E KGDR L
GCAGAAGCGAAACCATGGTATGAACCGATcTACCTGGGTGGCGTATTTCAACTGGAGAAAGGTGACCGTcTI I ll I I ll ll I I ll I I I I I I I I ll I I I I I I I I lrr r lr r r I I lt I I I I I tt I lt I I I I I I tl lt lt I I I I I
500 510 52A 530 540 550 560
SAE I N RPDYL D FAE SGOVYFG I I
GTCCGCAGAAATCAACCGTCCTGACTATCTAGATTTCGCTGAATCTGGCCAGGTGTACTTCGGTATTAICGlltl I I ll ll I ll I I I ll ll I ll I I ll I I I I lr r r r r r r r l lt tl I I I I rt ll I I I I I lt tlt I I I I I tt I
570 580 590 600 610 620 630
TerminationAL/
II
C AC TGT AATAAT AAGGATC C AGC T
lr r I I I tl I I lt I lt I I I tt lt tt660650
Page 2 of 2 DS Gene 611212012 {2:30:35 PM
Host Strain PHS1An E.Coli K-12 Derivative
GenotJpe: F= mcrA mcrB IN(rmD rmE)l::Tn10{Hg'}
Phenotype: Increased resistance to HgCl2 (10ug/rnl) relative to W3110Resistant to bactreriophage lambda infection at 30oC.
Sensitive to Ampicillin (100 ug/ml), Kanamycin (25 u{r,r,l), Tetracycline(25 ug/ml), and Chloramphenicol (25 ug/rnl).
Construction of PHS1:
The host strain PHS1 was constructed by inserting the DNA containing the CI857/Cro regulatoryelements of bacteriophage-lambda into E.coli strain W3110, according to the methodologyoutlined in Herrero M., Journal of Bacteriology, Nov., 1990, p.6557-6567 andp.6568-6572.
Specific protocol for the preparation of Host Strain PHS 1 :
1) ADNAfragment(EcoRl-BamHl)consistingofnucleotides34499-39168ofbacteriophagelarnbda-Cl857 was excised from phage DNA and subcloned into the EcoRl-BamHl sites ofpUClSNot using the DH5cr host strain. The resulting plasmid was designatedlambdaRB/pUC18Not.
2) A DNA fragment (Notl) containing the Cl857lCro regulatory elements of bacteriophagelambda was excised from larnbdaRB/pUC18Not and subcloned into the Notl site of pUT/Hgusing Cl l8(lambda-pir) as the host strain. The resulting plasmid was designatedlambdaNot/pUT/Hg.
3) Plasmid lambdaNot/pUTlHg was transfected into E. Coli host strain W3110 using increasedresistance to 10 ug/ml HgCl2 as the initial screen for stable insertion of the transposon intothe host strain. The use of the mercury resistance screen was difficult due to some naturalresistance by the W3110 host strain to HgCl2 at the 10 ug/ml concentration. Ultimately, thestable insertion of the CI857 lCro regulatory elements was confirmed by resistance to lambdainfection at 30oC. and the ability of the resulting strain to regulate, by temperature shiftinduction, the expression of genes residing on plasmids and transcribed by the lambda P1
promoter. The resulting strain was designated PHS 1.
Source of Materials:
E.Coli strain DH5o and Lambda-Cl857 DNA were purchased commercially from LifeTechnologies, Inc..
Plasmids pUCl8Not, pUT/t{g, and E.Coli host C118(lambda-pir).were obtained from Dr. BurtEnsley, Envirogen, lnc., Princeton, NJ who obtained these materials from the lab authoring theaforementioned publication. E.Coli strain W3110 was obtained from Dr. Burt Ensley,Envirogen, Inc., Princeton, NJ.
#PrTnoilbcn
Flow ChartRecombinant Human TNF-alpha
Lot # 0609C25
Flow Diagram:
Fermentation
Cell Disruption and Clarifrcation
Ion Exchange Chromatogaphy
Ion Exchange Chromatography
Formulation and Lyophilization
-C{r-
Client:
Charles River Protocol Number:
Protocol Effective Date:
On-Test Date:
Results:
PeproTech lnc.P O Box 275,5 Crescent Ave.
Rocky Hill, NJ 08553
GP-V614.5
10 DEC 2009
08 MAR 2010
charles riverSUMMARY REPORT
Version 1
Determination of DNA Levels in Samples by Means of DNA Hybridization (E cotiDNA)
Exception Document(s):
None
This report summarizes testing performed at the Charles River Laboratories, lnc., Malvem, PA, facitity, which isoperated in compliance with the applicable requirements of the U.S. Food and Drug Administration's GoodManufacturing Practic,e regulations as found in Title 21 CFR Parts 210 and 211. There were no deviations from thetest method(s) that impacted the quality or integrity of the test result(s).
21r*6f2or aDate
'Vt\nA-azo, b
Sample ldentification SampleNumber
Assay Result
Unspiked Spike Recovery
Human TNF-a G-300-01A
Lot# 0609C25 81910518000
<133.4 pdmlDNA
104o/o
Revision History
Version 1 N/A
Page 1 of 1
35BTechnology Drive, Malvern, PA 19355 o 610.64A.4550 r FAX 6I O.BB9.9O28
\.c<rFcharles river
SUMMARY REPORTVersion 1
Sterility Testing of Final Containers and Biological products (Direct Method)
PeproTech lnc.
PO Box 275,5 Crescent Ave.Rocky Hill, NJ 08553
GP.V66O
06MAB2OOB
05MAR2010
This report summarizes testing performed at the Charles River Laboratories, lnc., Malvem, pA, facility, which isgPeraled in compliance wS. the applicable requirements of the U.S. Food and Drug Administration,s GoodManufacturing Practice regulations as found in Title 21 CFR Parts 210 and 211. There were no deviations from thetest method(s) that impacted the quality or integrity of the test result(s).
J?,WzonDate
tqru*-rlUh
Client:
Protocol Ntrmber:
Protocol Effective Date:
On-Test Date:
Results:
Sample ldenttficatlon SampleNumber Assay Resuh
Human TNF-a G-3OS01A Lot# 0609C2S 81910 sl8000 No Growth
Exceptio n Document(s):
None
Date
_ arufi{Lxt2
Revision History
Page 1 of 'l
35STechnology Drive, Malvern, PA 19355 r 610.640.4550 o FAX 610.889.9028
-C{-
Client:
Protocol Numbor:
Protocol Effective Date:
On-Test Date:
Rcults:
PeproTech lnc
PO Box 275, 5 Crescent Ave.Rocky Hill, NJ 08553
GP-V611.3
15 AUG 2007
02 MAR 2010
charles riverSUMMARY REPORT
Version {
"Polnts to Consided' Testing forthe Presence of Agar cultivable and NonCultivable Mycoplaemas
Exception Document(s):
None
This report summarizes testing performed at the Charles River Laboratories, lnc., Malvern, PA, facility, which isoperated in compliance with the applicable requirements of the U.S. Food and Drug Administration's GoodManufacturing Practice regulations as found in Title 21 CFR Parts 210 and211. There were no deviations from thetest method(s) that impacted the quality or integrity of the test result(s).
Sample ldentification SampleNumber
Asay ResultMycoplasma
Human TNF-a G-300-01A Lot# 0609C25 81910 518000 Not Detected
et ftpL?flaDate
0b tfrlzithDate
Date
Revlslon History
Version I N/A
Page 1 of 1
35STechnology Drive, Malvern, PA 19355 . 610.640.4550 . FAX 610.889.9028
9sPBecton Diekinson and CoryanyBD Diagaostic SystensPO Box 999Sparks MD 21152-0999 US
Certificate of Analysis
Page: 1 of 2
Product NareCatalog NumberBatch NumberExpiration Date
PAIL YEAST EXTRACT 1OKG
21"2730 Manufacture Date z 2008/07/1,282137 90201,3/06/30
01. Dehydrated Appearance: Light to medium beige, to medium tan,free-flowing, homog:eneous.
02. Solubility: 1 and 2% solutions, solub.l-e in distilled or deionizedwater.
03. Solut.ion Appearance 1%: Light-medium amber, c1ear, may have a veryslight precipitate.
04. Solut.ion Appearance 2eoi Medium amber, c1ear, may have a veryslight precipitate.
05. Coagulable Protein: Not present06. Cultural Response: A solution of 1% Yeast Extract plus 0.5? sodium
chloride was prepared and the pH was adjusted to '7 .2 t 0.2 usingdilute NaOH. The medium was di-spensed into tubes and sterilized.Tubes were inoculated with the test organisms and incubated at35 *. 2"C for 18-48 hours.
TEST ORGANISMS ATCC@ RECOVERYNeisseria meningitidis 13090 fair to goodStaphylococcus aureus 25923 goodStreptococcus pneumoniae 6305 good
07. There are no animal sourced ingredients or anj-mal- derived reagentsused in the manufacture of this product.
08. Residual Solvents (CPMP/ICH/283/95): Typical analysis for YeastExtract indicates that there is less then 3880 ppm of cyclohexane.No other solvents were detected during analysis.
The test methods for characteristics listed below are:Nitrogen (Kjeldahl)
The Batch Number on this certificate is synonymous with the Lot Numbershown on the product labe1"
Creation Date: 2008/08/L2 l6:41:36
/ S mf Dickinson and consrany
BD Diagmostic SystemsPO Box 999Sparks MD 21152-0999 US
Certificate of Analysis
Page:-2 of 2
Product NameCatalog NnrnlcerBatch NunberExpiration Date
PAIL YEAST EXTRACT 1OKG212730 Manufacture Date : 2008/07/1,282L37 9020L3/06/30
BD Diagnostic Systems (BDDS) is an ISO 13485:2003 and ISO 9001-:2000Registered facility. BDDS products are manufactured in facilitiesregistered with the United States Food and Drug Administration (FDA),and are regulated by the FDA's Quality System Regulations (QSRs) . Thisproduct met BDDS string:ent quality standards at time of batch/:.otrelease. Any test resul-ts reported on t.his certif icate were obtainedat. time of release.