According to GMP requirements, at the end of production, to inter-operation of equipment and thoroughly cleaned to avoid contamination and cross-contamination between different batches or different varieties of products, according to the configuration of each apparatus, operating, cleaning and maintenance operations procedures and ingredients for risk analysis of solubility in water, chosen the worst case of products;
In order to verify the reliability and stability of the cleaning method, the selected worst case time for cleaning validation product 3, after the end of each batch of product, with all equipment and containers used in the production process for cleaning, cleaning physical appearance of the equipment, detection of chemical and microbiological residues residues, residues required to be lower than the set limit requirements, to ensure better quality. 2. Verify range:
For solid dosage forms to verify that all clean workshop capsule production line equipment. Related equipment as follows:
3. Responsibilities 3.1 Verification team:
3.1.1 is responsible for verifying program development and implementation of verification activities. 3.1.2 is responsible for verifying the organization and coordination. 3.1.3 is responsible for collecting, sorting cleaning validation data.
3.1.4 is responsible for the preparation of verification reports, data aggregation, analysis, evaluation of the results, draw conclusions verification. 3.2 Quality Assurance:
3.2.1 is responsible for verifying the daily work management. 3.2.2 responsible for drafting validation protocols and reports.
3.2.3 is responsible for organizing and coordinating the verification activities. 3.2.4 is responsible for the verification process of monitoring and sampling. 3.2.5 is responsible for developing test items and validation cycles.
3.2.6 is responsible for collecting, sorting cleaning validation data, preparation of reports and verify the results of the evaluation. 3.2.7 is responsible for issuing verification certificates.
3.2.8 responsible for managing the verification documents and archives. 3.3 Production:
3.3.1 responsible for auditing validation protocols and reports. 3.3.2 is responsible for cleaning validation process equipment. 3.3.3 is responsible for cleaning agents, formulation and use of disinfectants. 3.3.4 assist in the repair and maintenance of equipment. 3.4 Engineering:
3.4.1 is responsible for equipment, instruments, measuring tool calibration. 3.4.2 is responsible for maintenance of equipment maintenance. 3.4.3 audit program is responsible for verification and reporting. 3.5 Quality Control:
3.5.1 is responsible for verifying the detection process the sample and inspection report based on the test results. 3.5.2 audit program is responsible for verification and reporting. 3.5.3 is responsible for maintenance of test equipment.
3.6 Verification Time: date to date 4. Risk assessment:
4.1 Risk-management leadership team personnel to direct contact with materials and pharmaceutical production equipment for the cleaning procedure risk assessment of the quality of the risks of proposed treatment measures, specific see "Verifying master plan"; 4.2 due on a product for the next not evenly distributed contaminated product contact surface of the entire device, choose the worst area of the device, these areas represent the greatest challenge to the cleaning procedures and cleaning residual levels of difficulty, so cleaning validation sampling plan of active ingredient We must first determine the risk analysis, the specific see "verifying master plan." 5, verify the contents:
5.1 cleaning validation check before confirming the project
5.1.1 Confirm verification involves personnel were trained according to regulations, specifically the annex.
5.1.2 Confirm verification involves existing file approval procedures, manage and manipulate files, instructions clear and unambiguous, easily lead to misuse.
5.1.3 sure air purification systems, water purification systems, compressed air systems etc proven capable of normal operation; temperature and humidity between each operation, by pressure and environmental inspection compliance with GMP requirements. 5.2 Clean conditions:
5.2.1 personnel purge: Press the "personnel entering the clean zone purification procedures" to.
5.2.2 Process water (purified water): According to "People's Republic of China Pharmacopoeia" 2015 edition and two "purified water quality standards for internal control" test, should be specified. 5.2.3 Environmental Equipment: D grade. 5.3 Cleaning Operation:
After the device is completed detached detachable portions, rinse with potable water rinse or brush to no residue ----- inner and outer wipe clean surface with potable water wiping apparatus twice with purified water ----- ---- - Finally, 75% ethanol, or 3% hydrogen peroxide disinfection. 5.4 Sampling:
5.4.1 Sampling people: QA staff.
5.4.2 Sampling timing: cleaning effect confirmed: cleaning within half an hour after the completion of
5.4.3 sampling site: the device surface and a surface in contact with the drug may be in direct contact with the drug or the most difficult to clean parts of the surface.
5.4.4 Cleaning Validation Tools required:
5.4.5 sampling location and method:
5.5.1 inspection and sampling sequence:
After the end of the solid preparation workshop three batches of products, the device according to the relevant corresponding SOP cleaning, disinfection. The inside surface of the device to be visually inspected by the equipment QA After drying, the residue should be no visual evidence. After passing visual inspection in order to position the sample on microbiological sampling, then sampling chemical residues, chemical residues left and microbiological sampling of the sampling position can not be repeated, wherein the microorganism sampling area is 25cm2, chemical residues
Sampling area is 25cm2. 5.5.2 Physical appearance inspection
⑴ inspection method: After the cleaning apparatus for cleaning procedures, visual inspection by a person QA. ⑵ Acceptance criteria: an inner wall visual equipment, and difficult to clean the outer surface should be no visible residue position, no residual odor, no stains, after wiping cloth should be no visible stains. 5.5.3 drugs, disinfectant residual quantity limits, microbial limit test reference products selected 5.5.3.1:
I produced a variety of capsules 55, which according to their dissolution in water of the active ingredient, we determined Ganmaoling capsules containing acetaminophen, the worst, the cleaning water is relatively hard water solubility, was chosen as a reference product Ganmaoling capsule capsule production equipment cleaning validation. Capsule continuous production Ganmaoling three batches, batch number:,, 5.5.3.2 drugs and disinfectant residual amount detection: 5.5.3.2.1 specimen sampling (swab method):
QA personnel to bring the sampling clean disposable gloves, silica gel first sampled at a sampling position against the template, the one has been wetted with purified water and squeeze excess solution by swab sample the sampling position, so that little force curved, smooth and gently wipe the surface of the sample, while moving forward to move from side to side, the inverted swab completed, so that the other surface by wiping with a cotton swab method in the direction perpendicular to the moving direction of the previous wiping. The swab was wiped ground-stoppered Erlenmeyer flask, closed with a ground stopper Erlenmeyer flask stopper. (Note: swab sampling process to cover all surfaces of the entire sample on silica gel template) Note: Before sterilization microbiological sampling swab wetted with sterile saline, the same sampling process, the sampling sterilized stopper into the mill with mouth Erlenmeyer flask.
5.5.3.2.2 Sample preparation:
5.5.3.2.2.1 chemical sample prepared: swab after wiping the four opposing cut 20ml (0.4% sodium hydroxide solution) was sonicated for 5min, filtered to obtain.
5.5.3.2.2.2 microbial samples prepared: swab after wiping four cut, filled with 50ml of sterile saline solution into the Erlenmeyer flask, the flask rapidly shaken for several minutes to obtain the test solution. 5.5.3.3 Detection:
5.5.3.3.1 Drug Residues: take each sample solution according to the UV - visible spectrophotometry (General 0401) at a wavelength of 257nm, the measured absorbance. 5.5.3.3.2 disinfectant residual amount detection:
① The principle: strong oxidizing hydrogen peroxide, a redox reaction of iodine with potassium iodide, iodine ions to iodine: H2O2 + KI → test solution and the indicator I2 + H2O (I2 case of starch was blue) ② used :
Potassium iodide (analytically pure) test solution: potassium iodide 16.5g, add water to dissolve into a 100ml, that is, too. Starch indicator: Take soluble starch 0.5g, 5ml add water, stir, slowly into 100ml boiling water, with the added with stirring and continue to boil for 2 minutes, allowed to cool, to obtain.
③ detection process: The sample solution with purified water 10ml each set clean cuvette, each of the potassium iodide solution was added 1ml, shake well, each of three drops of starch indicator was added, shaken and the two tubes were placed in a white background color the observed color.
5.5.3.3.2 microbial limit test: A sample of 1ml by microbial limit test membrane filtration method (2015 edition of "Chinese Pharmacopoeia" 1105 General four) counts the inspection results recorded. 5.5.3.4 drugs and disinfectant residual amount of the acceptability criteria: Drug Residues 5.5.3.4.1 Acceptance Criteria:
Wipe allow residues of ≤ 50% × 10ppm × minimum volume (kg) × 25 (cm2)
Process equipment in direct contact with the inner surface of the total area of the drug (cm2)
23
50% × 10mg / kg × 40kg × 25 (cm) × 10 = 8.3 ug / Cotton 2
602450（cm）
By measuring indicators as: Cotton law allows Residues: 8.3 ug / Cotton
Control solution formulation concentration: 8.3 ug × 4 = 1.66 ug / ml
20ml
Which absorbance: 0.466, the absorbance of each sample solution was measured at a wavelength of 257nm, the absorbance is less than the reference solution, i.e., meet the requirements.
5.5.3.4.2 disinfectant residual amount of the acceptance criteria: each sample solution color than the color of the purified water pipe can not be darker than the cuvette.
5.5.3.4.3 microbial limits acceptability criteria: Total aerobes: ≤50cfu / 25cm2 6, the exceptional condition handler:
The verification process, should be strictly determined in accordance with detection methods developed in the authentication scheme. Data discrepancies appear
When combined standard (or acceptable) range, should be reported to verification team, investigation and analysis, proven team Upon identification of opinion, for processing. After treatment, should be re-verified. 7. Verify that the evaluation of results and conclusions:
Verification team responsible for verifying the results of a comprehensive analysis and make conclusions and evaluate verification, validation by the Leading Group for approval to verify the report. Evaluation of the results of verification should include:
7.1 verify whether projects are missing? Verification records is complete?
7.2 verification process validation scheme without modification? Modify reason, and based on whether or not approved? 7.3 The test results verify compliance with standards? Description of the deviation and the deviation is reasonable? Whether further additional testing?
7.4 Production process is stable, press this process to produce the availability of uniform quality, stable product? 7.5 whether the need to improve the equipment, production conditions, the steps? 7.6 whether the need to increase the production process of detection, control project? 8. Verify cycle and conditions:
8.1 Quality Assurance Department is responsible for cleaning validation according to the situation, the development of the verification cycle, the leading group audit verification report. 8.2 if one of the following circumstances shall be verified: 8.2.1 change disinfectant or cleaning procedures change apparatus; 8.2.2 relatively more difficult to increase the production of clean product;
8.2.3 production process has undergone major changes, will lead to the introduction of new impurities; 8.2.4 Cleaning procedures should be changed revalidation. 9. Verify credentials: see table, "verification certificate."
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