USP Medicines Compendium - Rituximab - 2013-05-30

Published on USP Medicines Compendium (https://https://www.wendangku.net/doc/475375174.html, )

Rituximab

Final Authorized Version 1.0

RITUXIMAB HEAVY CHAIN

QVQLQQPGAE LVKPGASVKM SCKASGYTFT SYNMHWVKQT PGRGLEWIGA IYPGNGDTSY NQKFKGKATL TADKSSSTAY MQLSSLTSED SAVYYCARST YYGGDWYFNV WGAGTTVTVS AASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS

SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKAE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K

RITUXIMAB LIGHT CHAIN

QIVLSQSPAI LSASPGEKVT MTCRASSSVS YIHWFQQKPG SSPKPWIYAT SNLASGVPVR FSGSGSGTSY SLTISRVEAE DAATYYCQQW TSNPPTFGGG TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC

C 6416H 9874N 1688O 1987S 44 Molecular weight, approx. 144,187 Da

Immunoglobulin G 1 (human-mouse monoclonal IDEC-C2B8 γ1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8 κ-chain, dimer;

Immunoglobulin G 1 (human-mouse monoclonal IDEC-C2B8 γ1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8 κ-chain, dimer [174722-31-7].

Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. This IgG1 kappa antibody contains murine light and heavy chain variable regions, and human gamma 1 heavy chain and kappa light chain constant regions. Rituximab is composed of two heavy chains each having 451amino acids and two light chains each having 213 amino acids.Rituximab is a clear colorless liquid.

Performance-Based Monograph

(Contains tests, procedures, and acceptance criteria for the material under test. It also includes the criteria-based procedures to demonstrate that an Acceptable Procedure is equivalent to the Reference Procedures .)

DEFINITION

Rituximab contains recombinant chimeric murine/human monoclonal antibody directed against the CD20 antigen in a sterile solution having measured potency of NLT 80.0% and NMT 125.0% of the stated potency.

IDENTIFICATION ? A. B IOASSAY

Standard solution: USP Rituximab RS in an appropriate diluent

Sample solution: Rituximab diluted in an appropriate diluent similar to that of the Standard solution .System performance requirements and Analysis: Proceed as directed in the Assay for Potency .Acceptance criteria

Measured potency: 80.0%–125.0% of the stated potency ? B. P EPTIDE M APPING

Use a chromatographic system. (Proceed as directed in Biotechnology Derived Articles—Peptide Mapping <1055>.)

Analyze the material to be tested by a chromatographic technique capable of resolving peptides generated from a Trypsin digest. The digest is carried out under reducing conditions which provides NLT 80% digestion. The test procedure used provides a minimum of 90% coverage of the protein sequence.

Standard solution: Digest and dilute a portion of USP Rituximab RS in an appropriate diluent.

Sample solution: Digest and dilute a quantity of Rituximab in an appropriate diluent to obtain a nominal concentration of

Rituximab similar to that of the Standard solution.

Control solution: Digest and dilute a portion of an appropriate control (non-Rituximab monoclonal antibody) in an appropriate diluent to obtain a nominal concentration of the control that is similar to that of Standard solution. [N OTE—The digests described in the Standard solution, Sample solution, and Control solution are conducted at the same time, using the same stock and

concentration of reagents.]

Analytical system: Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>.

System performance requirements

Specificity: The profile obtained from the Standard solution, CDR regions should be identified using a suitable procedure. The peptide profile obtained from the Control solution is distinctly different from that obtained from the Standard solution.

Analysis

Samples:Standard solution and Sample solution

The peptide profiles obtained from the Standard solution are visually compared to the Sample solution.

Acceptance criteria: The profile obtained from the Standard solution is similar to the profile obtained from the Sample solution.

The retention times of the peaks from the Sample solution differ from retention times of the corresponding peaks in the Standard solution by NMT ± 0.2 min.

? C. C APILLARY I SOELECTRIC F OCUSING

Analyze Rituximab using a capillary isoelectrophoretic focusing procedure using a broad range ampholyte (isoelectric point range of 3.0–10.0).

Standard solution: USP Rituximab RS in an appropriate diluent

Sample solution: Dilute a quantity of Rituximab in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution.

Control solution: Dilute a quantity of a non-Rituximab protein (such as Trastuzumab) in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution.

Analytical system: Use a validated procedure. (See Biotechnology-Derived Articles—Capillary Electrophoresis <1053>.)

System performance requirements

Specificity: The isoelectric point obtained from the Standard solution is between 9.1 and 9.5. The isoelectric point obtained from the Control solution should be different from the isoelectric point obtained from the Standard solution.

Analysis

Samples:Standard solution and Sample solution

Compare the isoelectric point from the Sample solution and the Standard solution.

Acceptance criteria: The isoelectric point (pI) of the main peak obtained from the Sample solution differs by NMT ± 0.2 pI units from the corresponding peak from the Standard solution.

ASSAY

? P OTENCY [C OMPLEMENT D EPENDENT C YTOTOXICITY (CDC) A SSAY]

Determine the potency using a suitable CD20 positive cell line (similar to WIL2-S) in a CDC assay with a suitable read out. Perform a comparison of a dilution series of the Sample solution with a dilution series of the Standard solution.

Standard solution: USP Rituximab RS in an appropriate diluent

Sample solution: Rituximab in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution Control solution: Dilute a quantity of an appropriate protein (such as non-specific monoclonal antibody) in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution.

Analytical system: Use a validated procedure. (See Biotechnology-Derived Articles—Biological Assay Validation <1033>.)

System performance requirements

Specificity: The Standard solution provides a significant dose response and the Control solution shows no response.

Precision

Repeatability: NMT 10.0% RSD

Intermediate precision: NMT 15.0% RSD

Linearity: Plot the measured potency versus expected potency. The R2 is NLT 0.95. [N OTE—The slope should be NLT 0.80.] Accuracy: Spike recovery 85.0%–115.0%

Range: Should be wider than 80.0% and above 125.0%.

Analysis

Samples: Standard solution and Sample solution

The potency of the Sample solution is calculated relative to the Standard solution using a suitable parallel line method.(Proceed as directed in Analysis of Biological Assays <1034>.)

Calculate 95.0% confidence limits for each independent determination of the measured potency.

Acceptance criteria

95.0% Confidence limits for independent determination: 74.0%–136.0%

Mean measured potency: 80.0%–125.0% of the stated potency obtained as a mean of a minimum of three independent determinations.

95% Confidence limits of the mean measured potency: 85.0%–115.0%. [N OTE—Measure as many independent Sample solutions as necessary to achieve the 95.0% confidence limits.]

? G LYCAN P ROFILING

Use a procedure that is capable of separating all glycans.

Standard solution: USP Rituximab RS in an appropriate diluent

Sample solution: Rituximab in an appropriate diluent

Resolution solution: Use Standard solution

Control solution: Use a non-glycosylated protein in an appropriate diluent.

Analytical system: Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>. (See Glycoprotein and Glycan Analysis—General Considerations <1084>.)

System performance requirements

[N OTE—Identify the peaks using commercial glycan standards of G0, G0F, G1, G1F, G1F', G2, and G2F, or any other suitable procedure.]

Specificity

Peak profile: The profile obtained from the Resolution solution shows prominent peaks for G0, G0F, G1, G1F, G1F', G2, and G2F.

Resolution: NLT 1.0 between G0–G0F and G2–G2F glycan peaks from the Resolution solution.

Negative control: The Control solution shows no glycan peaks.

[N OTE—The following criteria are with respect to the G0F peak in the Standard solution.]

Precision

Repeatability: NMT 4.0% RSD

Intermediate precision: NMT 5.0% RSD

Accuracy: Probability NLT 0.95 for 90.0%–110.0%

Linearity: R2 NLT 0.99

Range: 80.0%–120.0% of the Acceptance criteria set for oligosaccharides with galactose

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of oligosaccharides with galactose in the Sample solution.

Acceptance criteria

Sum of all oligosaccharides with galactose: NLT 35.0%

? C ATION E XCHANGE C HROMATOGRAPHY(AFTER C ARBOXYPEPTIDASE T REATMENT)

Use the normalization procedure. (See Chromatography <621>.)

Standard solution: USP Rituximab RS in an appropriate diluent

Sample solution: Rituximab in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution. Resolution solution: USP Rituximab RS in an appropriate diluent without carboxypeptidase treatment

Analytical system: Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>.

System performance requirements

Specificity

Peak profile: The chromatogram obtained from the Resolution solution shows presence of lysine (K1) variant when compared to the Standard solution.

Resolution: NLT 1.5 between the main peak (K0) and lysine variant peak (K1)

[N OTE—The following criteria are with respect to the main peak (K0).]

Precision

Repeatability: NMT 2.0% RSD

Intermediate precision: NMT 4.0% RSD

Accuracy: Probability NLT 0.95 at 95.0%–105.0%

Linearity: R2 NLT 0.99

Range: 80.0%–120.0% of the Acceptance criteria

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of acidic and basic variants in the Sample solution.

Acceptance criteria

Acidic variants: NMT 20.0%

Basic variants: NMT 20.0%

IMPURITIES

? CE-SDS (UNDER R EDUCING C ONDITION)

Analyze Rituximab using an electrophoretic method capable of giving separation in the range 10–250 kDa followed by UV detection by normalization procedure.

Standard solution: USP Rituximab RS in an appropriate diluent.

Sample solution: Rituximab in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution. Non-glycosylated heavy chain (NGHC) solution: Combine a portion of the Standard solution with PNGase enzyme under suitable conditions to achieve at least 95% deglycosylation.

Resolution solution: 2.0% NGHC spiked in Standard solution

Analytical system: Use a validated procedure carried out under reducing conditions. (See Biotechnology-Derived Articles—Capillary Electrophoresis <1053>.)

Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>. (Although general chapter <10> is directed to chromatographic methods, concepts in the guideline are general.) System performance requirements

Specificity: The electropherogram obtained from the Standard solution includes a peak corresponding to light chain and heavy chain.

Resolution: NLT 1.5 between the NGHC and heavy chain peaks from the Resolution solution

[N OTE—The following criteria are with respect to the NGHC peak in the Standard solution.]

Precision

Repeatability: NMT 2.0% RSD

Intermediate precision: NMT 4.0% RSD

Accuracy: Probability NLT 0.95 at 90.0%–110.0%

Linearity: R2 NLT 0.99

Range: 50.0%–200.0% of the Acceptance criteria

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of NGHC in the Sample solution.

Acceptance criteria

NGHC impurity: NMT 2.0%

? CE-SDS (UNDER N ON-R EDUCING C ONDITION)

Analyze Rituximab using an electrophoretic method capable of giving separation in the range 10–250 kDa followed by UV detection by normalization procedure.

Standard solution: USP Rituximab RS in an appropriate diluent

Sample solution: Rituximab in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution. NGHC solution: Combine a portion of the Standard solution with PNGase enzyme under suitable conditions to achieve at least 95% deglycosylation.

Resolution solution: 2.0% NGHC spiked in S tandard solution under reducing condition

Analytical system: Use a validated procedure carried out under non-reducing conditions. (See Biotechnology-Derived Articles—Capillary Electrophoresis <1053>.)

Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>. (Although MC general chapter <10> is directed to chromatographic methods, concepts in the guideline are general.)

System performance requirements

Specificity: The Standard solution contains a principal peak corresponding to Rituximab.

Resolution: NLT 1.5 between the NGHC and heavy chain peaks from the Resolution solution

[N OTE—The following criteria is with respect to the light chain peak.]

Precision

Repeatability: NMT 2.0% RSD

Intermediate precision: NMT 4.0% RSD

Accuracy: Probability NLT 0.95 at 90.0%–110.0%

Linearity: R2 NLT 0.99

Range: 50.0%–200.0% of the Acceptance criteria

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of impurities in the Sample solution.

Acceptance criteria

Sum of low molecular weight impurities: NMT 8.0%

? S IZE E XCLUSION C HROMATOGRAPHY

Use the normalization procedure. (See Chromatography <621>.)

Standard solution: USP Rituximab RS in an appropriate diluent

Sample solution: Rituximab in an appropriate diluent to obtain a nominal concentration similar to that of the Standard solution. Resolution solution: Dilute USP Rituximab RS in water to obtain a 1.0 mg/mL solution, incubate under UV light (at 254 nm) for 2 h. Analytical system: Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>.

System performance requirements

Specificity

Peak profile: The chromatogram obtained from the Resolution solution shows a high molecular weight (HMW) peak eluting before the main peak.

Resolution: NLT 1.5 between the HMW peak and the main peak from the Resolution solution

[N OTE—The following criteria is with respect to the main peak.]

Precision

Repeatability: NMT 4.0% RSD

Intermediate precision: NMT 4.0% RSD

Accuracy: Probability NLT 0.95 for 90.0%–110.0%

Linearity: R2 NLT 0.99

Range: 50.0%–200.0% of the Acceptance criteria

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of HMW impurities in the Sample solution.

Acceptance criteria

Total impurities: NMT 2.0%

? P ROCESS R ELATED I MPURITIES

Protein A: NMT 10 ppm

Host cell proteins: NMT 100 ppm

Host cell DNA: NMT 10 ng/dose

SPECIFIC TESTS

? M ICROBIAL E NUMERATION T ESTS <61> and T ESTS FOR S PECIFIED M ICROORGANISMS <62>: Total aerobic count does not exceed 1 cfu/mL.

? B ACTERIAL E NDOTOXINS T EST <85>: NMT 0.1 EU/mg of Rituximab

ADDITIONAL REQUIREMENTS

? S TORAGE: Store at 2°–8° C in an airtight container.

? L ABELING: The label states the name, content in mg/mL, and potency of the drug substance.

? R EFERENCE S TANDARDS <11>

USP Rituximab RS

REFERENCE PROCEDURES

(This section provides detailed descriptions of procedures that may be used for the evaluation of the material under test. These procedures have been fully validated, and the data is available on the MC website.)

IDENTIFICATION

? A. P EPTIDE M APPING

Solution A: 0.1% Trifluoroacetic acid in water

Solution B: 0.1% Trifluoroacetic acid in acetonitrile

Solution C: 0.5 M dithiothreitol in water

Solution D: 0.5 M iodoacetamide in water

Solution E: 0.25 M tris buffer in water. Adjust with dilute hydrochloric acid to a pH of 7.5.

Solution F: 6 M guanidine hydrochloride and 1 mM EDTA in Solution E (denaturing buffer)

Solution G: 0.1 M tris buffer in water. Adjust with dilute hydrochloric acid to a pH of 7.8.

Solution H: 2 M urea in Solution G (digest buffer)

Solution I: 0.05 M acetic acid in water

Solution J: 1 mg/mL of trypsin in Solution I

Solution K: 10 mg/mL of USP Rituximab RS in water

Standard stock solution 1: Mix 100 μL of Solution K, 400 μL of Solution F, and 10 μL of Solution C, and incubate at 37° for 30 min. Add 24 μL of Solution D and incubate at room temperature for an additional 30 min in dark. Add 10 μL of Solution C and mix well. Standard stock solution 2: Wash the PD-10 Sephadex G-25 column with 20 mL of water and equilibrate with 35–40 mL of Solution H. Load Standard stock solution 1 on the column, and elute using Solution H in volumes of 700 μL each. Collect 6 independent fractions. Measure the absorbance of each fraction at 280 nm against Solution H. The fraction having an absorbance between 1.3 and 2.0 is used for digestion. [N OTE—If the absorbance of the fraction is more than 2.0, dilute it using Solution H to get an absorbance of 2.0.]

Standard solution: Mix well 50 μL of Standard stock solution 2 and 2 μL of Solution J and incubate for 18–20 h at room temperature. Add 1 μL of trifluoroacetic acid and store the mixture at 4°.

Sample solution: Prepare Rituximab similar to that of the Standard solution. [N OTE—Prepare the Standard solution and the Sample solution at the same time, using the same stock of reagents and concentrations.]

Mobile phase: See Table 1.

Table 1

Time (min)Solution A

(%)

Solution B

(%)

0982

5982

1205545

1250100

1300100

131982

135982

Chromatographic system

(See Chromatography <621>.)

Mode: UPLC

Detector: UV 215 nm

Column: 2.1-mm × 10-cm; 130?, 1.7-μm, packing L1 (similar to Waters BEH C18)

Flow rate: 0.3 mL/min

Temperatures

Column oven: 60°

Autosampler: 5°

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Relative retention time of peaks corresponding to CDR regions

Heavy chain CDR regions 1 and 2 should be seen at an RRT (with respect to reference peak around 89 min) of 0.61 and 0.71 respectively within ± 0.02 RRT.

Light chain CDR regions 1, 2 (single peak), and 3 should be seen at an RRT (with respect to reference peak around 89 min) of

0.81 and 0.58 respectively within ± 0.02 RRT.

Analysis

Samples: Standard solution and Sample solution

The peptide profiles obtained from the Sample solution are visually compared to those from the Standard solution.

? B. C APILLARY I SOELECTRIC F OCUSING (CIEF)

Solution A: 0.2 M phosphoric acid in water (anolyte)

Solution B: 0.3 M sodium hydroxide in water (catholyte)

Solution C: 0.35 M acetic acid in water (chemical mobilizer)

Solution D: 0.2 M iminodiacetic acid in water (anodic stabilizer)

Solution E: 0.5 M arginine in water (cathodic stabilizer)

Solution F: 4.3 M urea in water

Solution G: 3.0 M urea in cIEF gel

Solution H: 5 mg/mL of USP Rituximab RS in water

System suitability solution: Mix 200 μL of Solution G, 12 μL of Pharmalyte 3-10, 20 μL of Solution E, 2 μL of Solution D, and 2 μL of each of the pI markers (10.0, 9.5, 7.0, 5.5, and 4.1). Vortex the solution for 15 s and mix well. Transfer 200 μL to a micro vial for analysis.

Standard solution: Mix well 10 μL of Solution H, 200 μL of Solution G, 12 μL of Pharmalyte 3-10, 20 μL of Solution E, 2 μL of Solution D, and 2 μL of each of the pI markers (10, 5.5, and 4.1). Vortex the solution for 15 s and mix well. Transfer 200 μL to a micro vial for analysis.

Sample solution: Prepare Rituximab similar to that of the Standard solution. [N OTE—Prepare the Standard solution and the Sample solution at the same time, using the same stock reagents and concentrations.]

Capillary electrophoresis system

Mode: Capillary isoelectric focusing

Detector: UV 280 nm

Capillary: 30.2-cm × 50-μm (similar to Beckman coulter, Neutral coated)

Effective length: 20 cm

Temperatures

Capillary: 20 ± 2°

Sample: 10 ± 2°

Polarity: Anode at the inlet and cathode at the outlet

Injection time: 25 psi for 99.0 s

Focusing voltage: 25.0 kV for 15.0 min

Chemical mobilization: 30.0 kV for 30.0 min

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

R2: NLT 0.99 from the System suitability solution

pI: Should be between 9.1–9.5 from the Standard solution

Analysis

Samples: System suitability solution, Standard solution, and Sample solution

Plot a curve using the migration time and pI of the markers spiked in the Sample solution. Calculate the pI of Rituximab main peak in the Sample solution.

ASSAY

? P OTENCY

Determination of the biological activity of Rituximab solution based on the cytotoxicity activity (similar to lysis of WIL2-S cells, ATCC No. CRL-8885) in presence of human serum complement using Resazurin sodium staining method.

Medium A: Roswell Park Memorial Institute 1640 (RPMI 1640) with 2 mM glutamine, 2 g/L of sodium bicarbonate, 4.5 g/L of glucose, 10 mM HEPES, 1 mM sodium pyruvate, and 10% fetal bovine serum (FBS)

Medium B: RPMI 1640 with 2 mM glutamine, 2 g/L of sodium bicarbonate, 4.5 g/L of glucose, 10 mM HEPES, 1 mM sodium pyruvate, and 0.1% bovine serum albumin (BSA)

Complement source: Pooled normal human serum. [N OTE—Fold dilution should be estimated by titrating each new lot with the old lot.]

Cell line: WIL2-S, grow cells in Medium A. [N OTE—Cells can be directly thawed and used in the Assay without further sub-culturing.] Cell suspension: 0.7–0.8 ×106 WIL2-S cells/mL in Medium B. [N OTE—Maintain the cells in a uniform suspension during addition.] Standard solution 1: 10 μg/mL of USP Rituximab RS in Medium B

Standard solution 2: 5.0 μg/mL of USP Rituximab RS from Standard solution 1, in Medium B

Standard solution 3: 2.5 μg/mL of USP Rituximab RS from Standard solution 2, in Medium B

Standard solution 4: 1.25 μg/mL of USP Rituximab RS from Standard solution 3, in Medium B

Standard solution 5: 0.625 μg/mL of USP Rituximab RS from Standard solution 4, in Medium B

Standard solution 6: 0.313 μg/mL of USP Rituximab RS from Standard solution 5, in Medium B

Standard solution 7: 0.156 μg/mL of USP Rituximab RS from Standard solution 6, in Medium B

Standard solution 8: 0.078 μg/mL of USP Rituximab RS from Standard solution 7, in Medium B

Sample solution 1: 10 μg/mL of Rituximab in Medium B

Sample solution 2: 5.0 μg/mL of Rituximab from Sample solution 1, in Medium B

Sample solution 3: 2.5 μg/mL of Rituximab from Sample solution 2, in Medium B

Sample solution 4:1.25 μg/mL of Rituximab from Sample solution 3, in Medium B

Sample solution 5: 0.625 μg/mL of Rituximab from Sample solution 4, in Medium B

Sample solution 6: 0.313 μg/mL of Rituximab from Sample solution 5, in Medium B

Sample solution 7: 0.156 μg/mL of Rituximab from Sample solution 6, in Medium B

Sample solution 8: 0.078 μg/mL of Rituximab from Sample solution 7, in Medium B

Analysis

To a suitable 96 well microtitre plate, transfer 50 μL each of Standard solutions1–8 and Sample solutions 1–8 to designated wells for the standard and sample controls (see Design and Development of Biological Assays <1032>). Transfer 150 μL of Medium B to the wells designated as medium control. Transfer 100 μL of Medium B to the wells designated as cell control. Transfer 50 μL of Medium B to the wells designated as complement control. Add 50 μL of Cell suspension to each standard, sample, cell, and complement control wells. Add 50 μL of 5 fold diluted pooled normal human serum to all wells except medium control and cell control. Mix and incubate the plate at 37 ± 1° for a period of 2 h in a humidified incubator with 5% CO

2

. Remove the plate from the incubator and add 20 μL of pre-warmed Resazurin (Sodium) to each well. Gently agitate the plate and incubate for an additional 20± 4 h. Remove the plates from the incubator and allow them to cool to room temperature by placing on a plate shaker for 10–15 min. Determine the potency by measuring the fluorescence (relative fluorescence units, RFU) using a suitable 96 well plate reader using an excitation wavelength of 530 nm and emission wavelength of 590 nm. Generate dose response curves for Standard solutions and Sample solutions using the final concentrations of Rituximab before the addition of alamar blue, i.e., concentrations before the addition of alarm blue. Calculate the relative potency, 95% confidence limits for each sample relative to the standard.

(See Analysis of Biological Assays <1034>.)

System suitability

The ratio between the RFU of highest concentration of the Standard solutions and RFU of the cell control should be ≥ 3.5.

The ratio between the RFU of highest and lowest concentrations in the linear range of the Standard solutions should be ≥ 3.0. [N OTE —Medium control and complement control are included for Assay monitoring purpose only and have no acceptance criteria.]

? G LYCAN P ROFILING—N ORMAL P HASE C HROMATOGRAPHY

Solution A: 0.05 M ammonium formate solution in water. Adjust with dilute ammonia solution to a pH of 4.4.

Solution B: Acetonitrile

Solution C: 10X Glycoprotein denaturing buffer (5% SDS and 0.4 M dithiothretol), Make: New England Biolabs

Solution D: 10X G7 reaction buffer (0.5 M sodium phosphate at pH 7.5), Make: New England Biolabs

Solution E: 10% NP40, Make: New England Biolabs

Solution F (2 AB glycan labeling reagent): Transfer 150 μL of glacial acetic acid to the vial of DMSO and mix well. Transfer 100 μL of DMSO-acetic acid mixture to a vial of tag 2-AB dye (Make: Ludger) and mix gently until dye is dissolved. Add dissolved dye to a vial of sodium cyanoborohydride (Make: Ludger) and mix gently until the solution is completely dissolved. To aid in proper dissolution, heat the final mixture at 65° for 30 s. [N OTE—Use within 60 min.]

Solution G: 30% Acetic acid in water

Solution H: 96% Acetonitrile in water

Solution I: 80% Acetonitrile in water

Solution J: 3 mg/mL of USP Rituximab RS in water

Solution K: 500,000 units/mL of PNGase enzyme, Make: New England Biolabs

Standard solution: Mix 6.7 μL of Solution J, 1 μL of Solution C, and make up to 10 μL with water. Denature the solution for 10 min at 96 ± 2°. Add 2 μL of Solution D, 2 μL of Solution E, and 2 μL of Solution K to the denatured solution, and make up the final volume to 20 μL with water. Gently mix the solution and incubate for 1 h at 37 ± 2°. Vacuum dry the solution, add 5 μL of Solution F, and mix well.Incubate the solution for 2.5 h at 65 ± 2°. Wash the clean S cartridge (Make: Ludger) with 1 mL of water, 5 mL of Solution G, and 1 mL of Solution B, sequentially. Load the sample onto clean S cartridge. [N OTE—Ensure the disc is in wet condition with Solution B before loading.] Allow the sample to adsorb onto membrane for 15 min. Wash the disc with 1 mL of Solution B followed by 1 mL of Solution H five times. Elute the glycans with three individual aliquots of 0.5 mL of water in individual micro centrifuge tubes. Vacuum dry the eluted glycans. Reconstitute the aliquots in a total volume of 200 μL with Solution I.

Sample solution: Prepare Rituximab similar to that of the Standard solution. [N OTE—Prepare the Standard solution and the Sample solution at the same time, using the same reagents and concentrations.]

Mobile phase: See Table 2.

Table 2

Time (min)Flow rate

(mL/min)

Solution A

(%)

Solution B

(%)

0.010.402080

1320.405347 1370.401000

142 1.001000

142.100.402080

1500.402080

Chromatographic system

(See Chromatography <621>, System Suitability.)

Mode: LC

Detector: Fluorescence

Excitation wavelength: 330 nm

Emission wavelength: 420 nm

Column: 4.6-mm × 25-cm; 80 ?, 5-μm, packing L68 (similar to TOSOH Biosciences, Amide 80)

Temperatures

Column oven: 30°

Autosampler: 5°

Injection volume: 50 μL

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 1.0 between G0–G0F and G2–G2 F glycan peaks from the Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of oligosaccharides with galactose in the Sample solution.

? C ATION E XCHANGE C HROMATOGRAPHY (AFTER C ARBOXYPEPTIDASE T REATMENT)

Solution A: 0.02 M (2-(N-morpholino)ethanesulfonic acid-MES) solution in water. Adjust with dilute sodium hydroxide to a pH of 6.0. Solution B: 0.02 M (2-(N-morpholino)ethanesulfonic acid-MES) solution and 0.4 M sodium chloride in water. Adjust with dilute sodium hydroxide to a pH of 6.0.

Solution C: 5 mg/mL of carboxypeptidase enzyme in water

Solution D: Add 9.0 g of sodium chloride and 7.35 g of sodium citrate tribasic dihydrate to 800 mL of water. Adjust with dilute hydrochloric acid to a pH of 6.5. Add 642 μL of Polysorbate-80 to the solution and make up the final volume to 1000 mL with water. Solution E: 1 mg/mL of USP Rituximab RS in Solution D

Standard solution: Add 2 μL of Solution C to 200 μL of Solution E and incubate for 2 h at 37 ± 2°.

Sample solution: Prepare Rituximab similar to that of the Standard solution. [N OTE—Prepare the Standard solution and the Sample solution at the same time, using the same reagents and concentrations.]

Resolution solution: Standard solution without carboxypeptidase treatment in an appropriate diluent

Mobile phase: See Table 3.

Table 3

Time (min)Solution A

(%)

Solution B

(%)

0.011000

51000 108317 955545 1000100 1020100

102.011000

1151000

Chromatographic system

(See Chromatography <621>, System Suitability.)

Mode: LC

Detector: PDA (280 nm)

Column: 4.0-mm × 25-cm; packing L53 (similar to Dionex, Pro Pac WCX-10)

Flow rate: 0.7 mL/min

Temperatures

Column oven: 30°

Autosampler: 5°

Injection volume: 40 μL

System suitability

Sample: Resolution solution

Suitability requirements

Resolution: NLT 1.5 between the main peak (K0) and lysine variant peak (K1)

[N OTE—Relative retention time of K1 peak relative to Rituximab (K0, retention time = about 42 min): about 1.06.]

Analysis

Samples: Standard solution, Sample solution, and Resolution solution

Calculate the percentage of acidic and basic variants in the Sample solution.

IMPURITIES

? CE-SDS (UNDER R EDUCING C ONDITION)

Use IgG purity/heterogeneity kit, Make: Beckman Coulter

Solution A: 0.10 M tris HCl at pH 9.0 and 1% SDS (Sample buffer), Make: Beckman coulter

Solution B: 10 kDa internal marker, Make: Beckman coulter

Solution C: Molecular weight marker, 10–250 kDa, Make: Beckman coulter

Solution D: β-Mercaptoethanol

Solution E: 3 mg/mL of USP Rituximab RS in water

Solution F: 500,000 units/mL of PNGase enzyme, Make: New England Biolabs

Standard solution 1: Mix 33.3 μL of Solution E, 61.7 μL of Solution A, 2 μL of Solution B, and 5 μL of Solution D. Heat the solution for 10 min at 70°. Transfer 100 μL to a micro vial for analysis.

Standard solution 2: Add 85 μL of Solution A, 2 μL of Solution B, and 5 μL of Solution D to 10 μL of Solution C. Heat solution for 3 min at 96 ± 2°. Transfer 100 μL to a micro vial for analysis.

Sample solution: Prepare Rituximab similar to that of Standard solution 1. [N OTE—Prepare the Standard solutions and the Sample solution at the same time, using the same stock of reagents and concentrations.]

NGHC solution: Mix 33.3 μL of Solution E, 61.7 μL of Solution A, and 5 μL of Solution D. Heat the solution for 10 min at 70°. Cool to room temperature and add 0.38 μL of Solution F. Incubate the solution for 15 h at 37°.

Resolution solution: 2% NGHC spiked in Standard solution 1

Capillary electrophoresis system

Mode: Capillary electrophoresis

Detector: UV 220 nm

Capillary: 30.2-cm × 50-μm (Bare fused silica coated, similar to Beckman coulter)

Effective length: 20 cm

Temperatures

Capillary: 25 ± 2°

Sample: 10 ± 2°

Polarity: Anode at the inlet and cathode at the outlet

Injection time: 5.0 kV for 20.0 s at reverse polarity

Separation voltage: 15.0 kV for 30.0 min at reverse polarity

System suitability

Samples: Standard solution 2 and Resolution solution

Suitability requirements

Resolution: NLT 1.5 between the NGHC and the heavy chain peaks from the Resolution solution

[N OTE—Principal peak of Rituximab heavy chain appears at around 19.7 min.]

R2: NLT 0.99 from Standard solution 2

Analysis

Samples: Standard solution 1, Standard solution 2, Sample solution, and Resolution solution

Calculate the percentage of NGHC impurity in the Sample solution.

? CE-SDS (UNDER N ON-R EDUCING C ONDITION)

Use IgG purity/heterogeneity kit, Make: Beckman Coulter.

Solution A: 0.10 M tris HCl at pH 9.0 and 1% SDS (Sample buffer), Make: Beckman coulter

Solution B: 10 kDa internal marker, Make: Beckman coulter

Solution C: Molecular weight marker, 10–250 kDa, Make: Beckman coulter

Solution D: 0.25 M iodoacetamide in water

Solution E: β-Mercaptoethanol

Solution F: 3 mg/mL of USP Rituximab RS in water

Solution G: 500,000 units/mL of PNGase enzyme, Make: New England Biolabs

Standard solution 1: Mix 33.3 μL of Solution F, 61.7 μL of Solution A, 2 μL of Solution B, and 5 μL of Solution D. Heat the solution for 10 min at 70°. Transfer 100 μL to a micro vial for analysis.

Standard solution 2: Add 85 μL of Solution A, 2 μL of Solution B, and 5 μL of Solution D to 10 μL of Solution C. Make up the final volume to 100 μL. Heat the solution for 3 min at 96 ± 2°. Transfer 100 μL to a micro vial for analysis.

Sample solution: Prepare Rituximab similar to that of Standard solution 1. [N OTE—Prepare the Standard solutions and the Sample solution at the same time, using the same stock reagents and concentrations.]

NGHC solution: Mix 33.3 μL of Solution F, 61.7 μL of Solution A, and 5 μL of Solution D. Heat the solution for 10 min at 70°. Cool to room temperature and add 0.38 μL of Solution G. Incubate the solution for 15 h at 37°.

Resolution solution: 2% NGHC spiked in Standard solution 1 under reducing condition.

Capillary electrophoresis system

Mode: Capillary electrophoresis

Detector: UV 220 nm

Capillary: 30.2-cm × 50-μm (Bare fused silica coated, similar to Beckman coulter)

Effective length: 20 cm

Temperatures

Capillary: 25 ± 2°

Sample: 10 ± 2°

Polarity: Anode at the inlet and cathode at the outlet

Injection time: 5.0 kV for 20.0 s at reverse polarity

Separation voltage: 15.0 kV for 30.0 min at reverse polarity

System suitability

Samples: Standard solution 2 and Resolution solution

Suitability requirements

Resolution: NLT 1.5 between the NGHC and the heavy chain peaks from the Resolution solution

[N OTE—Principal peak of Rituximab appears at around 28.7 min.]

R2: NLT 0.99 from Standard solution 2

Analysis

Samples: Standard solution 1, Standard solution 2, Sample solution, and Resolution solution

Calculate the percentage of low molecular weight impurities in the Sample solution.

? S IZE E XCLUSION C HROMATOGRAPHY

Solution A: 0.02 M sodium phosphate and 0.3 M sodium chloride solution in water. Adjust with dilute sodium hydroxide to a pH of 6.8. Standard stock solution: 10 mg/mL of USP Rituximab RS in Solution A

Standard solution: 1 mg/mL of USP Rituximab RS in Solution A

Sample solution: 1 mg/mL of Rituximab in Solution A

Resolution solution: Incubate 50 μL of Standard stock solution under UV light at 254 nm for around 2 h. Dilute to 1 mg/mL with Solution A.

Chromatographic system

(See Chromatography <621>, System Suitability.)

Mode: LC

Detector: PDA (280 nm)

Column: 7.8-mm × 30-cm; 250 ?, 5-μm, packing L59 (similar to TOSOH Biosciences G3000SWXL)

Flow rate: 0.5 mL/min

Temperatures

Column oven: 30°

Autosampler: 5°

Injection volume: 30 μL

Run time: 35 min

System suitability

Sample: Resolution solution

Suitability requirements

Resolution: NLT 1.5 between the HMW peak and the main peaks

Relative retention time: HMW peak relative to Rituximab peak (retention time = about 16 min): about 0.85

Analysis

Samples: Standard solution, Sample solution, and Resolution solution

Calculate the percentage of HMW impurities in the Sample solution.

[N OTE—

1.

Protein estimation: Protein estimation is not part of the monograph and there is no acceptance criteria that is

indicated. Manufacturer is left with flexibility of deciding the concentration of Rituximab preparation. Use a validated procedure to estimate the protein content.

2.

Antibody dependent cellular cytotoxicity (ADCC) assay: ADCC assay is not a compendial test as per the monograph. However, the Rituximab preparation must comply with the ADCC activity through analysis of representative batches using a validated procedure or a surrogate test for ADCC assay. Acceptance criteria: NLT 80.0% of USP Rituximab RS.]

Source URL (modified on 2013/05/30 - 5:14am): https://https://www.wendangku.net/doc/475375174.html,/monographs/rituximab-1-0

sap日常维护管理手册

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维护工作职责和内容

维护工作职责和内容 一、基本职责 1、负责整个公司（包含局域网、广域网）的系统安全性。 2、负责日常服务器维护、操作系统、网管系统、邮件系统的安全补丁、漏洞检测及修补、病毒防治等工作。 3、应经常保持对最新病毒的了解，做到预防为主。 4、确保网络通信传输畅通，实时监控整个局域网的运转和网络通信流量情况； 5、掌握主干设备的配置情况及配置参数变更情况，备份各个设备的配置文件； 6、负责网络布线配线架的管理，确保配线的合理有序； 7、掌握用户端设备接入网络的情况，以便发现问题时可迅速定位； 8、掌握与外部网络的连接配置，监督网络通信状况，发现问题及时解决； 二、机房管理职责 1、严禁非机房工作人员进入机房，特殊情况需经负责人批准，并认真填写登记表后方可进入。 2、进入机房人员不得携带任何易燃、易爆、腐蚀性、强电磁、辐射性、流体物质等对设备正常运行构成威胁的物品。 3、未经领导的批准严禁变更机房内的一切设备，或服务器的配置。如有需要应报告领导并填写维护表。 4、外来的一切移动存储禁止在机房内使用。 三、安全管理职责 1、随时监控中心设备运行状况，发现异常情况应立即按照预案规程进行操作，并及时上报和详细记录。 2、严格执行密码管理规定，对操作密码定期更改，超级用户密码由系统管理员掌握。 3、网管人员应恪守保密制度，不得擅自泄露各种信息资料与数据。 4、机房内严禁吸烟、喝水、吃食物、嬉戏和进行剧烈运动，保持机房安静。 5、不定期对机房内设置的消防器材、监控设备进行检查，以保证其有效性。

四、运行管理职责 1、未经负责人批准，不得在机房设备上编写、修改、更换各类软件系统及更改设备参数配置。 2、各类软件系统的维护、增删、配置的更改，各类硬件设备的添加、更换必需经负责人书面批准后方可进行；必须按规定进行详细登记和记录，对各类软件、现场资料、档案整理存档。 五、日常维护职责 1、日常维护中应按规定填写日常维护表。（维护内容见附录） 2、每个月应把常见问题书写成知识档，上传到知识库中。 3．硬件更换应填写硬件更换表以便查阅。

溶出度检查法美国药典USP-711

<711> DISSOLUTION 溶出度 (USP39-NF34 Page 540) General chapter Dissolution <711> is being harmonized with the corresponding texts of the European Pharmacopoeia and/or the Japanese Pharmacopoeia. These pharmacopeias have undertaken to not make any unilateral change to this harmonized chapter. 通则<711>溶出度与欧盟药典和日本药典中的相应部分相统一。这三部药典承诺不做单方面的修改。 Portions of the present general chapter text that are national USP text, and therefore not part of the harmonized text, are marked with symbols to specify this fact. 本章中的部分文字为本国USP内容，并没有与其他药典统一。此部分以（）标注。 This test is provided to determine compliance with the dissolution requirements where stated in the individual monograph for dosage forms administered orally. In this general chapter, a dosage unit is defined as 1 tablet or 1 capsule or the amount specified. Of the types of apparatus designs described herein, use the one specified in the individual monograph. Where the label states that an article is enteric coated and a dissolution or disintegration test does not specifically state that it is to be applied to delayed-release articles and is included in the individual monograph, the procedure and interpretation given for Delayed-Release Dosage Forms are applied, unless otherwise specified in the individual monograph. 本测试用于检测药品口服制剂的溶出度是否符合各论中的规定。本章中，除另有规定外，单位制剂定义为1片或1粒胶囊。对于本章中所述多种仪器，使用各论中规定的种类。除各论中另有规定外，如果检品是肠溶衣片且各论中的溶出度或崩解时限检查项下没有特别指出适用迟释剂的，使用本章中适用于迟释剂的流程和解释。 FOR DOSAGE FORMS CONTAINING OR COATED WITH GELATIN涂有或包含明胶的剂型 If the dosage form containing gelatin does not meet the criteria in the appropriate Acceptance Table (see Interpretation, Immediate-Release Dosage Forms, Extended-Release Dosage Forms, or Delayed-Release Dosage Forms) because of evidence of the presence of cross-linking, the dissolution procedure should be repeated with the addition of enzymes to the medium, as described below, and the dissolution results should be evaluated starting at the first stage of the appropriate Acceptance Table. It is not necessary to continue testing through the last stage (up to 24 units) when criteria are not met during the first stage testing, and evidence of cross-linking is observed. 如果剂型中含有明胶，其不符合验收表中的标准（见判断，速释制剂，延释制剂，缓释制剂），因为存在明胶交联结合作用，它的溶解过程与外加的媒介酶是重复的，见下面的描述，并且溶解结果可以通过适当的验收表的开始的第一阶段标准进行评估。如果溶出结果不满足第一阶段的测试标准，那么就没有必要继续测试到最后阶段，并且也证明了明胶交联结合作用的存在。

美国药典(USP)规定的色谱柱编号

美国药典(USP)规定的色谱柱编号 L1和L8是美国药典(USP)规定的色谱柱编号，其实就是ODS柱和NH2柱。下面是USP规定的编号所对应的色谱柱类型。 L1：十八烷基键合多孔硅胶或无机氧化物微粒固定相，简称ODS柱 L2：30～50m m表面多孔薄壳型键合十八烷基固定相，简称C18柱 L3：多孔硅胶微粒，即一般的硅胶柱 L4：30～50m m表面多孔薄壳型硅胶柱 L5：30～50m m表面多孔薄壳型氧化铝柱 L6：30～50m m实心微球表面包覆磺化碳氟聚合物，强阳离子交换柱 L7：全多孔硅胶微粒键合C8官能团固定相，简称C8柱 L8：全多孔硅胶微粒键合非交联NH2固定相，简称NH2柱 L9：强酸性阳离子交换基团键合全多孔不规则形硅胶固定相，即SCX柱 L10：多孔硅胶微球键合氰基固定相（CN），简称CN柱 L11：键合苯基多孔硅胶微球固定相，简称苯基柱 L12：无孔微球键合季胺功能团的强阴离子交换柱 L13：三乙基硅烷化学键合全多孔硅胶微球固定相（C1），简称C1柱 L14：10m m硅胶化学键合强碱性季铵盐阴离子交换固定相，简称SAX柱 L15：已基硅烷化学键合全多孔硅胶微球固定相，简称C6柱 L16：二甲基硅烷化学键合全多孔硅胶微粒固定相 C2柱 L17：氢型磺化交联苯乙烯-二乙烯基苯共聚物,强阳离子交换柱 L18：3～10m m全多孔硅胶化学键合胺基（NH2）和氰基（CN）柱 L19：钙型磺化交联苯乙烯－二乙烯基苯共聚物，强阳离子交换柱 L20：二羟基丙烷基化学键合多孔硅胶微球固定相（Diol），简称二醇基柱 L21：刚性苯乙烯－二乙烯基苯共聚物微球填料柱

ORACLE数据库日常维护与管理手册

全球眼?（MEGAEYES）网络图像管理系统2.0 ORACLE日常维护与管理手册 北京互信互通信息技术有限公司 2004-08-08

目录 全球眼?（MEGAEYES）网络图像管理系统2.0 (1) 1引言 (3) 1.1 目的 (3) 1.2 范围 (3) 1.3 参考资料 (3) 2日常维护与管理说明 (3) 2.1 运行环境 (3) 2.1.1硬件环境 (3) 2.1.2软件环境 (3) 2.2 数据库日常维护 (4) 2.2.1数据库初始设置 (4) 2.2.2每日工作内容 (5) 2.2.3每周工作内容 (6) 2.2.4每月工作内容 (7)

1引言 1.1目的 对于重要的商业系统来说，数据库系统的正常运行是保证商业应用平稳运行的关键。但是数据库在运行过程中可能会因为种种原因发生问题。这时，数据库的管理与日常维护工作将变得尤为重要。 为了指导数据库管理员做好日常维护工作，保证数据库系统的正常运行，特制定本文档。当然，数据库的日常维护是复杂和繁琐的，本文仅涉及一些常见的数据库日常维护的内容，在实际工作中，数据库管理员还需要做更多的工作。 1.2范围 本文档使用的人员：数据库维护管理人员和相关人员。 本文档涉及内容：oracle数据库的日常维护与管理解决方案。 1.3参考资料 中国电信网络视频监控技术（暂行）规范 2日常维护与管理说明 2.1运行环境 程序的运行环境包括硬件运行环境和软件运行环境。 2.1.1硬件环境 ◆CPU类型：Intel及其兼容系列CPU ◆内存容量：剩余内存要达2G以上 ◆硬盘容量：剩余硬盘容量要达1G以上 ◆网卡类型：100M网卡 2.1.2软件环境 ◆操作系统：RedHat Linux AS 3.0 ◆数据库：Oracle9i Database Release 2 (9.2.0.4.0) for Linux x86

安全管理员日常维护规范

密级： 文档编号： 项目代号： Epson Security Framework Policy 安全管理员日常维护规范 V 1.0 保密申明 这份说明书涉及到EPSON的商业机密的信息。接受这份说明书表示同意对其内容保密，未经书面请求并得到EPSON的书面认可，不得复制，泄露或散布这份说明书。如果你不是有意接受者，请注意对这份说明书内容的任何形式的泄露、复制或散布都有可能引起法律纠纷。

文档控制 版本控制

目录 1目的 (4) 2范围 (4) 3内容 (4) 4安全维护工作细则 (4) 4.1 维护安全设备的工作细则 (5) 4.1.1 防病毒日常维护细则 (5) 4.1.2 防火墙日常维护细则 (11) 4.1.3 VPN日常维护细则 (16) 4.1.4 安全评估日常维护细则 (18) 4.2对主机系统的日常工作细则 (20) 4.3 对网络设备的日常工作细则 (21) 4.4 编写安全报告工作 (23) 4.5 安全加固文档的更新 (24) 4.6 对地市安全现状进行审计和评估 (25)

1目的 为规范EPSON的安全日常维护工作的计划和工作内容管理，明晰EPSON ISD部门的技术人员日常在安全维护时的工作细则，加强对日常安全维护，促进安全维护规范化，特制定本文档。 2范围 本策略适用于EPSON拥有的、控制和管理的所有信息系统、数据和网络环境，适用于属于EPSON范围内的安全维护人员，包括ISD部门的技术负责人、安全管理员、系统管理员、网络管理员和数据库管理员。 3内容 用户系统安全维护管理工作中，日常安全维护工作细则是根据和遵循本岗位职责要求而制定的，运维人员必须认真遵循本岗位安全职责规定，然后遵照日常安全工作细则的规定进行安全管理和维护工作，并根据工作实际情况，制定并遵守相应的安全设备配置和实施细则和安全技术、安全事故的操作流程，做好安全维护管理工作。 4安全维护工作细则 系统一线和二线维护人员和安全管理员的日常维护工作总则： 1.负责用户与信息安全相关工作的具体实施和有关信息安全问题的 处理； 2.根据用户的信息安全需求，定期提出用户的信息安全整改意见， 上报信息安全管理机构； 3.根据信息安全事件的处理情况和对于用户信息安全检测的结果， 定期编制用户的信息安全状况报告；

日常维修项目工作标准、内容及维保

电梯日常维修工作标准 一、概况： 仪化生活区现有电梯23部，其中20层/20站VVVF型三菱电梯8部，11层/11站GPS-Ⅱ型三菱电梯12部，9层/9站奥的斯OH5000型电梯3部，我公司电梯维修队维修人员通过加强电梯日常巡检和维修保养，发现故障及时修理,以保证电梯的正常运行，保证居民的使用。 二、维修保养的内容及要求：（见附表）

生活区高层住宅给排水系统日常维修工作内容 仪化生活区现有高层住宅19栋，其中层高为九层的三栋，层高为二十层的四栋，层高为11层的十二栋，共有居民1076户。为使高层居民的正常生活不受影响，维修公司根据各项公用设施、设备的管理要求，对给排水系统按期进行检查、维护、保养，出现故障时及时维修，以确保高层住宅供水、排水系统的正常运行。 一、供水系统工作内容及运行保障要求 （一）概况 生活用水系统5个，其中浦东高层2个，白沙高层1个，迎江西村1个，浦西村1个。包括（1）水泵13个；（2）供水水箱4个；（3）电气控制系统5套；（4）阀门98只；（5）稳压灌4只。 （二）检查工作内容 （1）水泵每周检查内容 1、对水泵进行手动盘车; 2、泵体清洁； 3、轴承盒内加入钙基黄油； 4、检查填料室内是否正常； 5、检查联轴器的橡胶弹性圈是否正常； 6、检查泵的温度； 7、泵房的清洁卫生工作。 （2）水箱季度冲洗 每季清洗水箱一次； （3）电气控制系统周检查内容 1、检查控制柜能否正常工作； 2、对变频器经常报故障、开关经常跳或者不能合闸、元器件老化等及时更换及维修。（4）阀门每周检查： 1、阀体及阀件清洁; 2、检查阀杆与启密件是否牢靠不脱落; 3、检查阀体是否有渗漏及损坏; 4、检查密封垫片是否密封及损坏. （5）稳压灌每周检查: 1、罐体清洁; 2、检查是否损坏及渗漏.

美国药典USP31 71 无菌检查法中文版

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小型机日常维护手册

IBM P750小型机 日常维护手册 一、服务器硬件运行状态检查 1.当服务器处于启动和正常工作状态时，其前面板上的状态灯（与电源灯并排）和各硬盘的状态灯 （一排小灯，与各硬盘位置一一对应）应显示为绿色。 2.当服务器的状态灯出现橙黄色时，说明有硬件告警，此时要检查服务器的电源、接线、硬盘等。 如果有硬件故障则需要立即进行更换和更正，如果查不出具体问题，则需要联系相关专家进一步诊断。 3.当硬盘工作正常时，与各硬盘对应的硬盘灯会呈绿色，如无读写，则绿灯一直亮，如该硬盘有读 写操作，则绿灯会不规则闪烁，当硬盘损坏时，则硬盘状态灯将熄灭，或者呈闪烁状态：以1～3秒的频率有规律地、不停地闪烁。 如果发现有服务器硬件状态灯不正常的情况，请及时联系我公司工程师，以便及时进行诊断并解决故障。 二、HMC（硬件管理平台）管理与操作 HMC的两种访问途径： 1、在机房直接通过显示器和键盘进行管理维护等相关操作 2、通过web远程访问，登录HMC web管理界面，访问地址为： 1、登录HMC 浏览器访问连接HMC后，首页界面如下图所示。 点击下图所示链接，进入HMC验证登录界面。 输入用户名与口令，登录HMC。 用户名：hscroot 口令： 成功登录到HMC管理界面如下图所示。 2、注销HMC 在HMC console右上角有（hscroot | help | log off）链接，单击log off，会出现如下图所示注销界面：选择Log off，系统返回到HMC初始登录界面状态。

3、重启HMC 左边导航栏中选择HMC Management shut down or Restart，如下图所示，对HMC进行正常重启及关机操作。 请谨慎对HMC进行关机和重启操作！ 4、状态栏功能 状态栏位于HMC左下角位置，如下图所示，负责监控并反映管理系统资源状态和HMC状态。单击每个图标状态可以列出详细状态，你可以查到更详细的帮助信息： ：非法操作，如果任何被管理的主机执行了非法操作，这个图标将会变亮。 ：黄灯警告, 如果任何被管理的主机有错误并有黄灯被点亮，这个图标也将会变亮 ：报错日志：日志中有报错信息，这个图标将会变亮，此项与 ：摘要，摘要中会将有用信息做统计并显示在工作栏中。 5、Service Management 导航栏中Service Management强大的管理功能给用户日常维护提供了更简单直观的界面，如下图所示， 但日平时最常用的子项是Manage Serviceable Events，如下图步骤可以对HMC所管理的设备进行日常错误及时直观的观察，以确保IBM小型机能正常工作，下图就是基本的操作方法图示： Service ManagementManage Serviceable Events 6、Service Plans-分区管理与操作 如何查看小型机资源配置： 如上图红色标注所示，选中所需查看主机（备注：请不要同时选中多台主机及多个分区）,在下拉菜单中选中“Properties”，打开参数窗口，通过“Properties”可以查看主机运行状态，CPU,内存，I/0等重要硬件系统参数，如下图所示。 同理，在分区区域中先中每分区后的Properties选项，便可以直观方便的掌握分区状态和资源配置信息。 如何开关机及激活分区： 关机。 开机。

日常维修工作流程

日常维修工作流程 文稿归稿存档编号：[KKUY-KKIO69-OTM243-OLUI129-G00I-FDQS58-

日常维修工作流程 一、维修部维修人员每天保持维修房、维修场地干净；工具、材料归类摆放，科学有序。 二、维修人员每天对机电设备进行常规性维护保养，确保所有机电设备健康运作。作业项目安全、规范、美观。 三、维修人员应对所有机电设施例行检查。例行检查根据检查对象的不同每天、每两天或每周不等的时间段进行一次，两人合作进行，对检查中发现的问题，应在《日常维护巡查记录》上登记清楚。能够自己随时处理的问题应随时处理，自己无法随时处理时，应向主管领导做口头或书面报告，及时安排处理。 另外，维修人员应结合日常维修工作对供电、供水、排水网络进行随机检查，发现问题及时处理或向主管领导报告。 四、例行检查的内容为： 1、供电系统是否存在隐患，有无危及供电安全现象。 2、供水系统（包括纯净水制水设备）是否存在隐患，有无危及供水安全现象。 3、公司各部分排水系统是否畅通，是否有水管跑冒滴漏和污水外溢现象。 4、供蒸汽管道、阀门、仪表是否正常。 5、天燃气设备运转是否正常，监测设备是否正常，要做定期检测。 6、锅炉运行状况，及时检查，每天听取锅炉工的工作汇报。 7、宿舍有无私拉乱扯危及用电安全行为。 8、所有公共照明灯电源线是否老化破皮，有无危及员工安全现象。 9、有无其他影响公司形象容需要整改的事项。

10、生产车间每一条生产线的机械电气设备的运行情况，每天早晨上班或车间下班 后对机械进行润滑保养。（把多余的润滑油用抹布擦拭干净，以免污染产品） 11、污水处理系统是否正常运行，建立维护档案 五、维修部保证所有使用工具的安全性。维修过程，应严格遵守安全规程，防止发生意外事故。 六、任何维修工作结束后，均应清点工具，清理现场，清除垃圾，经检查、测试全部符合质量后方能送电、送水，交付使用。 七、对所完成的工作应记录在维修记录上，对未完成项目要写明原因及下步处理意见。 八、维修人员应对所维修项目负责，对不负责任、敷衍了事造成返工的，追究维修人员责任，对因返工造成材料浪费的，予以相应处罚。 九、维修人员在休班期间，如遇公司工作需要到现场处理，应以公司利益为重，积极配合。 十、以上巡视工作，都要认真填写有关《***巡查记录表》。 记录表要及时存档，妥善保存，以备核查。 十一、公司对以上工作做随机巡视监督，若发现工作敷衍，将对维修部进行严厉惩罚 2017年4月21日

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usp美国药典结构梳理

USP35-NF-30结构整理 vivi2010-10-02 USP总目录： 1 New Official Text修订文件 加快修订过程包括勘误表，临时修订声明（IRAS），修订公告。勘误表，临时修订声明，修订公告在USP网站上New Official Text部分刊出，勘误表，临时修订公告也会在PF上刊出2front matter前言 药典与处方集增补删减情况，审核人员，辅料收录情况 3凡例

药典， 1标题和修订 2 药典地位和法律认可 3标准复合性 4专论和通则 5 专论组成 6 检验规范和检验方法 7 测试结果 8 术语和定义 9 处方和配药 10 包装存储与标签 4通则 4.1章节列表 4.2一般检查和含量测定（章节编号小于1000）

检查和含量分析的一般要求 检查和含量分析的仪器， 微生物检查，生物检查和含量测定， 化学检查和含量测定， 物理检查和测定 4.3一般信息（章节号大于1000） 5食物补充剂通则 6试剂（试剂，指示剂，溶液等） 7参考表 性状描述和溶解性查询表（按字母顺序） 8食品补充剂各论（字母顺序） 9NF各论（辅料标准） 10 USP各论 11术语 附件：通则的章节中文目录（使用起来比较方便，直接找对应章节号即可）一、通用试验和检定 （1）试验和检定的总要求 1 注射剂 11 参比标准物 （2）试验和检定的装置 16 自动分析方法 21 测温仪 31 容量装置，如容量瓶、移液管、滴定管，各种规格的误差限度

41 砝码和天平 （3）微生物学试验 51 抗菌效力试验 55 生物指示剂：耐受性能试验 61 微生物限度试验 61 非灭菌制品的微生物检查：计数试验 62 非灭菌制品的特定菌检查，如大肠杆菌、金葡菌、沙门氏菌等 71 无菌试验 （4）生物学试验和检定 81 抗生素微生物检定 85 细菌内毒素试验 87 体外生物反应性试验：检查合成橡胶、塑料、高聚物对哺乳类细胞培养的影响 88 体内生物反应性试验：检查上述物质对小鼠、兔iv、ip或肌内植入的影响 91 泛酸钙检定 111 生物检定法的设计和分析 115 右泛醇检定 121 胰岛素检定 141 蛋白质——生物适应试验，用缺蛋白饲料大鼠，观察水解蛋白注射液和氨基酸混合物的作用 151 热原检查法 161 输血、输液器及类似医疗装置的内毒素、热原、无菌检查 171 维生素B12 活性检定 （5）化学试验和检定 A 鉴别试验 181 有机含氮碱的鉴别 191 一般鉴别试验 193 四环素类鉴别 197 分光光度法鉴别试验 201 薄层色谱鉴别试验 B 限量试验

系统管理员日常维护操作手册

系统管理员日常维护操作手册一、日常维护

一、服务器日常开关机器规定 （一）、开机步骤 1、开启服务器电源，系统将自动启动server2008操作系统，注意操作系统 启动过程中的系统提示信息，如果有异常的提示必须作好数据库操作启动的日志记录,并联系硬件维护人员。 2、待服务器操作系统正常启动后，使用administrator身份登陆到服务器， 启动自动过费程序。 3、服务器的任何异常提示，请及时联系硬件公司检查,个人及其他非专业人 员勿进行操作,以免造成数据丢失； 4、一般服务器至少20天左右要进行一次系统的关机动作。对于专用服务器 则不需要进行此操作。 （二）、系统运行过程中的数据库维护操作 5、每天必须做好数据库的日常备份工作，同时必须进行数据库至少存放在服 务器的2个地方，或者备份到U盘或其他电脑上,同时保存好备份数据。 6、拷贝数据库备份文件的U盘或其他存储工具,必须先在其他电脑杀毒后,在 到服务器使用,禁止其他未杀毒U盘在服务器使用,避免服务器中毒! （三）、服务器的关机操作步骤

7、点击开始菜单中关机按钮,进行正常关机,关机前先关闭应用程序,禁止 强制关机! 二、数据库备份原则说明 1、以上操作的意义为： 每天在服务器上执行数据备份以保证数据的安全性。防止硬件故障等突发原因引起的系统崩溃。 系统安全稳定性依赖于规范的操作。非正常操作（如：未正常关机,直接关电。强制关机）都会给系统带来损害。 2、建议备份方案： 每月盘点后：数据库备份并且将备份保存一年。 3、注意事项： 在使用过程中如果发生断电或硬件故障等意外情况而造成前后台死机，应先尝试开启服务器,如服务器不能开机,需及时联系硬件公司与蓝崎公司售后人员,大面积的死机可能由服务器故障引起，也可能由于网络（网线、HUB）等故障引起，出现问题时要注意区分，以便迅速有效的解决问题。

USP美国药典 233元素杂质-检查法

á233? ELEMENTAL IMPURITIES—PROCEDURES INTRODUCTION This chapter describes two analytical procedures (Procedures 1 and 2) for the evaluation of the levels of the elemental impuri-ties. The chapter also describes criteria for acceptable alternative procedures. By means of validation studies, analysts will confirm that the analytical procedures described herein are suitable for use on specified material. Use of Alternative Procedures The chapter also describes criteria for acceptable alternative procedures. Alternative procedures that meet the validation re-quirements herein may be used in accordance with General Notices and Requirements 6.30, Alternative and Harmonized Meth-ods and Procedures . Information on the Requirements for Alternate Procedure Validation is provided later in this chapter.Speciation The determination of the oxidation state, organic complex, or combination is termed speciation . Analytical procedures for spe-ciation are not included in this chapter, but examples may be found elsewhere in USP–NF and in the literature. PROCEDURES ? C OMPENDIAL P ROCEDURES 1 AND 2 System standardization and suitability evaluation using applicable reference materials should be performed on the day of analysis. Procedure and detection technique:Procedure 1 can be used for elemental impurities generally amenable to detection by inductively coupled plasma–atomic (optical) emission spectroscopy (ICP–AES or ICP–OES). Procedure 2 can be used for ele-mental impurities generally amenable to detection by ICP–MS. Before initial use, the analyst should verify that the proce- dure is appropriate for the instrument and sample used (procedural verification) by meeting the alternative procedure vali-dation requirements below. Sample preparation:Forms of sample preparation include Neat , Direct aqueous solution , Direct organic solution , and Indi- rect solution . The selection of the appropriate sample preparation depends on the material under test and is the responsibil-ity of the analyst. When a sample preparation is not indicated in the monograph, an analyst may use any of the following appropriately validated preparation procedures. In cases where spiking of a material under test is necessary to provide an acceptable signal intensity, the blank should be spiked with the same Target elements , and where possible, using the same spiking solution. Standard solutions may contain multiple Target elements . [N OTE —All liquid samples should be weighed.]Neat:Used for liquids or alternative procedures that allow the examination of unsolvated samples. Direct aqueous solution:Used when the sample is soluble in an aqueous solvent. Direct organic solution:Used where the sample is soluble in an organic solvent. Indirect solution:Used when a material is not directly soluble in aqueous or organic solvents. Total metal extraction is the preferred sample preparation approach to obtain an Indirect solution . Digest the sample using the Closed vessel diges-tion procedure provided below or one similar to it. The sample preparation scheme should yield sufficient sample to allow quantification of each element at the limit specified in the corresponding monograph or chapter. Closed vessel digestion:This sample preparation procedure is designed for samples that must be digested in a Concen-trated acid using a closed vessel digestion apparatus. Closed vessel digestion minimizes the loss of volatile impurities. The choice of a Concentrated acid depends on the sample matrix. The use of any of the Concentrated acids may be appropri-ate, but each introduces inherent safety risks. Therefore, appropriate safety precautions should be used at all times. [N OTE —Weights and volumes provided may be adjusted to meet the requirements of the digestion apparatus used.] An example procedure that has been shown to have broad applicability is the following. Dehydrate and predigest 0.5 g of primary sample in 5 mL of freshly prepared Concentrated acid . Allow to sit loosely covered for 30 min in a fume hood.Add an additional 10 mL of Concentrated acid , and digest, using a closed vessel technique, until digestion or extraction is complete. Repeat, if necessary, by adding an additional 5 mL of Concentrated acid . [N OTE —Where closed vessel digestion is necessary, follow the manufacturer’s recommended procedures to ensure safe use.] Alternatively, leachate extraction may be appropriate with justification following scientifically validated metal disposition studies, which may include animal studies, speciation, or other means of studying disposition of the specific metal in the drug product. Reagents:All reagents used for the preparation of sample and standard solutions should be free of elemental impurities,in accordance with Plasma Spectrochemistry á730?. ? P ROCEDURE 1: ICP–OES Standardization solution 1: 1.5J of the Target element(s) in a Matched matrix Standardization solution 2:0.5J of the Target element(s) in a Matched matrix Sample stock solution:Proceed as directed in Sample preparation above. Allow the sample to cool, if necessary. For mer-cury determination, add an appropriate stabilizer. Sample solution:Dilute the Sample stock solution with an appropriate solvent to obtain a final concentration of the Target elements at NMT 1.5J . Blank: Matched matrix 298 á233? Elemental Impurities—Procedures / Chemical Tests USP 40