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rs_synthesis_technical_standards_-2010

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rs_synthesis_technical_standards_-2010

    Confidential - Technical Standards of RS Synthesis Title: XXXXXX Process Procedures

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-01

    Prepared by: Production Dept. Drafted by/date:

    Dept. Review/date: QA Review/date:

    Approved by/date: Date of Effectiveness:

    Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    Purpose: Prepare a normative document for the entire process of XXX production, specify each production process and control, and standardize the production operations so as to ensure the liability and reproducibility of the production and the product quality.

    Scope: This document shall be applicable to the production of the API of XXX .

    Responsibility:

    1 The Manager of the Production Department shall take the responsibility to organize the compilation of this process procedure and supervise the execution of this procedure.

    2 The Chief Engineer shall be responsible for the technical review on this process procedure.

    3 The Manager of the Quality Control Department shall be responsible for approval of this process procedure.

    4 The operation staff in the Production Department shall be responsible for the implementation of this process procedure.

    5 The QA of the Quality Control Department shall take the responsibility to supervise and instruct the operation staff in the Production Department to implement this process procedure and standardize their operations.

    Procedure:

    1. Product Overview

    1.1 Name of product

    1.1.1 Common name of the drug: acetate XXX

    1.1.2 English name :

    1.1.3 Customer Language name:

    1.1.4 Chemical structural formula:

    1.1.5 Molecular formula:

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-02 Prepared by: Production Dept. Drafted by/date:

    Dept. Review/date: QA Review/date:

    Approved by/date: Date of Effectiveness: Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

1.1.6 Molecular weight:

    1.1.7 Specification: 1g/vial

    1.1.8 Product code: CY-XX

    1.1.9 Storage: keep in shade, airtight and under the temperature of XX?.

    1.1.10 Term of validity: 18 months for the time being. 1.2 Primary use: polypeptide hormone medicine. 1.3 Approval No.: XXXXXX.

    nd1.4 Production workshop: this product is produced in the workshop on the 2 floor of the production area

    (K3-101&K3-102 system).

    2. Material Quality Standards

    2.1 Brief quality requirements on the raw materials: No Name of Raw Material Brief Quality Standard

    1 XXX Resin Purchased from a qualified supplier

    Meeting the standards specified in Qa-TS-4301-X Fmoc-amino 2 Fmoc-Thr(tBu)-OH acid inspection quality standard

    Meeting the standards specified in Qa-TS-4301-X Fmoc-amino 3 Fmoc-XXX-OH acid inspection quality standard

    Meeting the standards specified in Qa-TS-4301-X Fmoc-amino 4 Fmoc-XXX-OH acid inspection quality standard

    Meeting the standards specified in Qa-TS-4301-X Fmoc-amino 5 Fmoc-XXX-OH acid inspection quality standard

    Meeting the standards specified in Qa-TS-4301-X Fmoc-amino 6 Fmoc-XXX-OH acid inspection quality standard

    Meeting the standards specified in Qa-TS-4301-X Fmoc-amino 7 Fmoc-(D)Phe-OH acid inspection quality standard

    Meeting the standards specified in Qa-TS-4301-X Fmoc-amino 8 Fmoc-XXX-TA acid inspection quality standard

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-03 Prepared by: Production Dept. Drafted by/date: Dept. Review/date: QA Review/date: Approved by/date: Date of Effectiveness: Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    9 HOBt Meeting standards in XXXXXX 10 XXX Meeting standards in XXXXXX 11 DMF Meeting standards in XXXXXX 12 XXX Meeting standards in XXXXXX 13 XXX Meeting standards in XXXXXX 14 DCM Meeting standards in XXXXXX 15 XXX Meeting standards in XXXXXX 16 XXX Meeting standards in XXXXXX 17 TFA Meeting standards in XXXXXX 18 PhSMe Meeting standards in XXXXXX 19 XXX Meeting standards in XXXXXX 20 XXX Meeting standards in XXXXXX 21 Et2O Meeting standards in XXXXXX 22 XXX Meeting standards in XXXXXX 2.2 Packing materials

    Type Name Brief Quality Standards

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-04 Prepared by: Production Dept. Drafted by/date: Dept. Review/date: QA Review/date: Approved by/date: Date of Effectiveness: Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    Meeting the standards specified in Qa-TS-5022-X mould vial inspection and quality Mould vial standard. Internal Meeting the standards specified in Qa-TS-5003-X medicinal butyl rubber stopper Medicinal butyl packing inspection and quality standard. rubber stopper materials Plastic-aluminum Plastic-aluminum cap Meeting the standards specified in Qa-TS-5042-X φ32

    cap inspection and quality standard.

3 Technical Process

    3.1 Flow chart of chemosynthesis

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-05 Prepared by: Production Dept. Drafted by/date: Dept. Review/date: QA Review/date: Approved by/date: Date of Effectiveness: Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    XXX-XXX Resin

    Wash with DMF and/or DCM

     Drain

    Coupling with AAn Fmoc-AAn-OH+DIPEA Reaction Step1-3 SStep1-3StepStep1 Kaiser Test n=3 Sub test

    -Fmoc 20%DBLK

     Wash with DMF and/or DCM N ?3 Drain

    H-Pro-ZXX- Resin

    Fmoc-AAn-OH+HOBt+DIC/or Coupling with AAn PyBOP+HOBt/or HATU/HOAt Reaction Step 4---24 Kaiser Test Continue?

    negative

    20%DBLK -Fmoc

    n<24 n=24

    XXX-XXX

    Peptide-Resin

    Purify

    Cleavage

    XXX-XXX TFACrude Peptide Reaction

    A

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-06 Prepared by: Production Dept. Drafted by/date: Dept. Review/date: QA Review/date: Approved by/date: Date of Effectiveness: Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    3.2 Flow chart of technological process (Class 300,000 Class 10,0000 * Class 1,000,000 FFU)

    Fmoc- XXX XXX Resin XXX Resin

    Fmoc Deprotection

    H-XXX-XXX Resin

    Fmoc- XXX-OH

    Fmoc- XXX-xxx-XXX Resin

    Fmoc Deprotection

     H-XXX-xxx-XXX Resin

    Fmoc-XXX-OH

    Fmoc-XXX-xxx-XXX-CTC Resin

    Test Substitutability

    Perform peptide resin synthesis one by one from C to N

    Recycle condensation, washing, deprotection and washing

    Fully protected peptide resin

    TFA cleavage Sediment, centrifugal separation, drying

    Crude peptide Crude product test

    Dissolve, filter

    HPLC reverse phase purification

    Salt conversion purification

     Concentration under reduced pressure

     Lyophilization

    API finished product test

    API storage (refrigerated and in shade)

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-07 Prepared by: Production Dept. Drafted by/date: Dept. Review/date: QA Review/date: Approved by/date: Date of Effectiveness: Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    Fmoc-XXX-XXX Resin XXX Resin +Fmoc-XXX-OH

     检测替代度 Test

     Peptide Resin Perform polypeptide synthesis with

     automatic peptide synthesizer Cleavage, side chain deprotection Crude peptide

     Dissolution

     HPLC reverse phase purification

     Sephadex G-10 desalting

    Acetic acid XXX refined peptide

     Test

     Mould vial Dilution* Medicinal butyl rubber stopper

    Sterilization*

     Clean, bake and Filling* sterilize

     Lyophilization Test

     Clean and Capping Packing Plastic-alumin dry um cap

     Storage under -18? Acetic acid XXX finished

     product

4. Technical process

    4.1 The technical process of Synthesis (assume that the initial raw material is XXXmmol resin)

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-08

    Prepared by: Production Dept. Drafted by/date:

    Dept. Review/date: QA Review/date:

    Approved by/date: Date of Effectiveness:

    Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    4.1.1 Synthesis of amino acid resin (Fmoc-Thr(ol)-TA-XXX Resin).

    (Note: TA=XXX)

    4.1.1.1 Put XXXmmol of XXX Resin (Sub=0.XXmmol/g) into the reactor and add about XL of DMF swelling resin.

    4.1.1.2 Fmoc deprotection: add 20% piperidine /DMF solution and keep it in reaction for XX minutes.

    4.1.1.3 Resin washing: wash the resin with DMF for X times (XL each time), and pump out the resin.

    4.1.1.4 Take Fmoc-XXX-OH mmol, HOBt XXmmol and DIPCDI XXmmol respectively, add a small quantity of XXX to dissolve them, and then put the solutions into the above reactor, keep them in reaction under the room temperature for X hours.

    4.1.1.5 Take 20 mg of sample and test the substitutability.

    4.1.2 Synthesis of peptide resin

    4.1.2.1 Synthesize the polypeptide with a peptide synthesizer (room temperature: 26--30?)

    4.1.2.2 Input the target sequence and configure related parameters.

    4.1.2.3 Start synthesis: perform recycled synthesis operations, including deprotection and coupling reaction, etc., according to the synthesis process.

    4.1.2.4 After the synthesis and deprotection of the last amino acid, the reaction is over and the resin is pumped out.

    4.1.3 Oxidation and cyclization

    4.1.3.1 Put X times of XXX solution into the reaction column and keep it for oxidation and cyclization for X hours.

    4.1.3.2 Remove the column, and move the resin from the column into a vacuum dryer for vacuum drying for X hours.

    Get the fully-protected peptide resin.

    4.1.4 Cleavage of peptide resin

    4.1.4.1 Take some peptide resin and place into a special container for cleavage. Add X times of cleavage reagent (XXX: thioanisole: XXX alcohol: XXX=9:5: 30: 2) and keep them in reaction in shade for X hours.

    4.1.4.2 After the reaction is finished, filter and drop the filter liquor into X times of absolute ether, freeze

    Technical Standards of RS Synthesis Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-09

    Prepared by: Production Dept. Drafted by/date:

    Dept. Review/date: QA Review/date:

    Approved by/date: Date of Effectiveness:

    Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    for aging, centrifugalize for separation and collect the sediment.

    4.1.4.3 Wash the sediment with a proper quantity of frozen absolute ether for 3 times.

    4.1.4.4 Dry with a vacuum dryer and get the crude XXX.

    4.2 Technological process of purification

    4.2.1 Process of HPLC purification

    4.2.1.1 Conditions of purification:

     Quantity of sample: Xg/time

    Mobile phase: A: X% tetramethyl XXXX solution: water: acetonitrile /10: 880: 200

     B: X% tetramethyl XXXX solution: water: acetonitrile/10: 300: 300

     The pH values of Phase A and Phase B are adjusted to X with 10% phosphoric acid solution.

    Gradient: time A B

     0 90 10

     5 80 20

     10 70 30

     14 55 45

     18 70 30

     25 90 10

    Chromatographic column: Rampak column packing machine, filler: Vydac-C18

    Test wavelength: XXXmm

    Flow rate: XXX ml/min

    4.2.1.2 Process of purification

    Take some crude peptide and dissolve with XX% acetic acid water solution, the concentration is about XX

    g/L, then filter with 0.45μm filter membrane. Load the samples, separate and purify, collect the main peaks, concentrate with rotary distillation.

    4.2.2 Process of salt conversion

    Technical Standards of RS Synthesis

    Title: XXXXXX Process Procedure

    Doc. No.: P-TS-XXXX-X Substitute Doc. No.: —— Page: 27-010

    Prepared by: Production Dept. Drafted by/date:

    Dept. Review/date: QA Review/date:

    Approved by/date: Date of Effectiveness:

    Distributed to General Manager, Chief Engineer, QA of Quality Control Dept., Production Dept.

    4.2.2.1 Test conditions

    Quantity of sample: X g/time

    Mobile phase: A: HO 2

     B: 2% acetic acid + 48% water + 50% acetonitrile

    Gradient: 100% A balanced chromatographic column

     100% B elution sample

    Instrument: chromatographic system

    4.2.2.2 Test process

    4.2.2.2.1 Balance the chromatographic column with A and load the sample of concentrated HPLC drip onto the chromatographic column, then flush with A for 10 minutes.

    4.2.2.2.2 Elute acetic acid XXX with B, monitor at XXX nm till there is no further peak.

    4.2.2.2.3 Concentration under reduced pressure.

    4.3 Process of refining, baking and packing

    4.3.1 Dilution

    4.3.1.1 Calculate the dilution volume (V) of all fine peptide obtained from the purification according to the weight (?W, mg) and content (C%, g/g). Dissolve with freshly cooled water for injection and finalize the solution with a concentration (c) of XXX mg/ml. The calculation formula for the dilution volume (V) shall be (accurate to 1ml):

    V=?W*C/c (unit: ml)

    4.3.1.2 Filter the diluted liquid with a sterilized 0.45+0.45μm sterilizing filter into a serum bottle which has

    been dry sterilized under XXX? for 2 hours. Seal the bottle. Before sterilization and after use, the sterilizing filter should pass the bubbling point test.

    4.3.2 Split charging

    4.3.2.1 Transfer the semi-finished sterilized liquid, 50ml mould vials which have been dry sterilized under XXX?, medicinal butyl rubber stoppers, disinfectant and other sterilized operation tools (all above sterilized items should be packed), with the external wall of their containers wiped with 75% ethanol or other disinfectant,

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