I. Introduction
1 Overview
Benorilate synthesis workshop production equipment are device-specific, dedicated to a single species, the production of the same specifications API, the development of various types of devices are detailed, sound recording and cleaning device cleaning procedure, in the production process and finished mass closely cleaning process comprising: a tank, an esterification reaction tank, centrifuge, plate and frame filter press filtration system decarbonization refining crystallizer, centrifuge clean area, oven, grinder, two-dimensional chlorination reaction mixture washing machines and other equipment. At the same time, cleaning the clean area can be verified to the effect of cleaning the clean room. This validation that is cleaning validation procedures for cleaning and cleaning effect over key links.
Objective 2
By the reaction tank, a centrifuge, a filtration system decarbonization refining crystallizer, centrifuge clean area, inspection and monitoring air drying, jet milling and other equipment cleaning process, cleaning devices have been developed to prove practical procedure, to ensure that drugs can be achieved quality objectives, documentation management in line with the GMP requirements, and provide information and evidence for further modification and improvement of equipment cleaning procedures.
3 Authentication Category
The verification synchronization verification. Two references
This document reference to the following standards and guidelines: 1. People's Republic of China Pharmacopoeia (2010 edition) 2.GMP (2010 revised edition) 3. Drug GMP Guide
4. Verify pharmaceutical production guidelines (2003 version) three verification preparation
1 verification staff and responsibilities
1.1 responsibilities of various departments to verify the quality of the person in charge:
Approved verification plan to verify the report. Person in charge of production:
Audit verification program to verify the report. Production Operations Responsibilities:
Audit verification program to verify the report. Provide public assurance system. Provide equipment maintenance guarantee.
Defining solutions to inconsistencies.
Responsible for verification of measuring instruments and provides calibration certificate. Workshop responsibilities:
Drafting, reviewing verification program to verify the report. Tissue embodiment authentication scheme.
Collect relevant data, related to the preparation of the verification report. Complete the necessary training of personnel involved in verification.
Designated operators, production equipment operation, cleaning and maintenance. Determine the final SOP. Quality Management Department Responsibilities: Responsible for audit verification program.
Oversees strict accordance with the authentication scheme and is based on document provides methods and standards to perform verification. Responsible for deviations and change the evaluation and treatment of the validation process of Hu County. Maintenance of all controlled documents in line with regulations.
Responsible for the development of relevant quality standards, inspection procedures and sampling procedures.
Responsible for the relevant sampling and verification and issue inspection report based on the test results. Audit verification result, the final validation report to ensure that all acceptance criteria are met. After completing the verification of qualified certificate issued verification.
Objective: To make sure that all personnel are trained to participate in verification, to ensure the smooth implementation of the verification.
Procedure: Before beginning the implementation of verification, training of all personnel to participate in verification by the verification program drafters. Acceptance criteria: proven attended were trained authentication scheme.
Confirm record: fill out the "Training confirm" Schedule 1, training attendance sheet attached to the verification report. 3 Verify that the reference confirmation documents
Purpose: To ensure that all documents used to support the program for current and valid documents.
Procedure: Before verification implemented by the verification team members check verification process of the used files, check the file if qualified person drafting, review and approval and the implementation period.
Acceptance Criteria: Verify documents are used in the process qualified person drafting, review and approval and the implementation period. Confirm record: fill out the "Confirm File" in Schedule 2. four verification range
Decarbonization filtration system, purified crystallizer, centrifuge clean area, air drying, jet milling and other cleaning process equipment. The number is not the same name as a device specifications, types, are the same material, the same cleaning method, were taken and therefore a cleaning validation.
3.1 validation group (1) drafting authentication scheme;
(2) verify the drafting of the report, to determine the revalidation cycle, to verify the results of the evaluation, quality management department audit report.
3.2 Quality Management Department
(1) Panel established verification according to the verification objects;
(2) Quality Management Department is responsible for verifying approval scheme; (3) Quality Management Department is responsible for verifying approval of the report; (4) is responsible for issuing a certificate of verification; (5) in charge of revalidation confirm cycle;
(6) Quality Management Department QC laboratories responsible for the process of sampling and analysis, and issue inspection report based on the results.
3.3 Workshop
(1) with the verification team ready verification program, and summary reports;
(2) with the verification team to complete the confirmation, check to verify completion of the project; (3) responsible for equipment cleaning work.
4 cleaning supplies
Cleaning agent: toluene, 5% aqueous acid solution, 5% aqueous alkaline solution, water, purified water, recovering the ethanol, 75% ethanol. Washing tool: the cleaning cloth, the fibers do not fall off cleaning cloth, the cleaning basin, the python, stainless steel spatula, long-handled nylon brush.
5 Training
Verify program implementers should be a corresponding post induction proof, participated in the relevant SOP and training necessary production technology, equipment operation and examination by. After the implementation of the program approval, first organize relevant personnel training. Training of personnel by the cleaner main embodiment drafter authentication scheme, the respective group leaders of the verification operator intervention team training. (Cleaning validation device attached Benorilate training records)
6 cleaning validation of risk analysis:
6.1 The characteristics of the production process and production phases, three phases of the device for cleaning validation: ① chlorination reaction of the first stage; ② the second stage esterification;
③ material from entering the clean zone of the third stage to the finished.
6.2 verification requirements
Since the device is a dedicated synthesis workshop equipment, thus:
① According to the FDA cleaning validation guidelines, the basic requirement is visually clean and free of visible material, no visible residue. Chemical synthesis stage visual equipment clean.
② need to assess whether the cleaning agent and washing conditions can cause decomposition of the residue. If you break down, it would constitute impurities. If the constitution impurities, whether the next batch will be affected. ③ need to assess the validity clean.
④ While special equipment, but in order to ensure the integrity of the batch, the residual number of finished products to the next batch should not exceed 0.1% of the finished product (for the intermediate, this is not required).
6.3 equipment cleaning procedures at all stages of description and risk analysis, risk analysis specific device, see part cleaning validation: risk analysis prior to cleaning validation.
The first stage cleaning device: The first stage device comprises a general production zone of the reactor tank, a first stage of the cleaning agent is toluene and the toluene wash liquid (recycled) evolution, heating tank to the backup tank to dry. Due to volatile toluene, it may not remain. After daily cleaning, the cleaning effect of the visual acceptance criteria no residual effectiveness, thus: ① After the completion of the first phase daily cleaning device, cleaning visual inspection.
② cleaning plan defined period of 7 days, a large number of strong acid used in the reaction, and therefore does not constitute a microbial process contamination risk. Therefore, the detection of microorganisms without the need for cleaning validation level.
The second stage cleaning device: the device comprises a second stage esterification reaction tank, centrifuge, plate and frame filter device are the final step in the synthesis reaction Benorilate synthesis process, because the second step is a strong base, so the first Usually two-stage cleaning apparatus using a cleaning agent 5% of acidic water, drinking water and purified water.
① After the completion of the second phase of daily cleaning device, clean visual inspection.
② For general region centrifuge, plate and frame filter press, due to the general frame filter centrifuge production area dedicated to centrifugation, press filtration process intermediates according to FDA guidelines cleaning validation, for the intermediate, does not require batch the integrity of the times, so you can visually clean.
Centrifuge bag and frame filter cloth can not be microbiological sampling, and there is no microbial contamination, and so does the centrifuge frame filter cloth bag for detecting the level of microorganisms.
Clean validity ③ plans defined for seven days. A large amount of alkali used in the reaction, so microbial contamination of the process does not constitute a risk, so no need to monitor the cleaning validation microorganisms.
④ As the former general cleaning needs to be performed thoroughly cleaned, so if general cleaning validation results meet the requirements, then no need for a thorough cleaning validation.
The third stage cleaning equipment: Equipment for the third stage of the clean area device comprising purified crystallizer, centrifuge clean region, the clean region oven, clean area mill, a two-dimensional mixer clean area. Devices are used in the production process Benorilate purified by centrifugation, dried, pulverized, mixed positions. Yin Beinuo ester is insoluble in water, purification solvent is ethanol, the ethanol cleaning agent is recovered. The solvent ethanol as solvent three, and the product has never been benorilate residual solvent exceedances. Effective cleaning effect as the visual acceptance criteria no residue remaining amount benorilate not exceed 0.1% of the batch volume. Therefore, ① after the completion of the third phase of daily cleaning equipment, clean visual inspection.
② from the third stage heated until dissolved bleaching cleaning starts, specific operations, see cleaning procedures.
③ the cleaning apparatus on the tank hardest part of the purified crystals and stirred at an upper portion of the can end; purified crystals thus packet tank monitoring points should
Comprising an upper lids and stirring was repeated three times.
④ investigate whether the denuded zone only centrifuge bag remaining on the weight of the material exceeds the allowable amount. (Defined as a residual limit of residues
The material left on the bag weighing no more than 0.1% next batch volume). According to experience, translated at 60% moisture. Clean valid ⑤ plan defined for seven days, disinfect the clean area of frequency of every half disinfect the equipment, and therefore micro
Of biological processes does not constitute a risk of contamination. Unable to sample the centrifuge bag, and the bag has never been observed mildew phenomenon. So do not clean centrifuge valid for verification. For oven cleaning wipe sampling. The residue limits should meet the standard requirements; micro mill for monitoring dust particles, to achieve the required cleanliness and D is qualified; two dimensional mixer with ethanol cleaning liquid to clean the pickup test, compliance. 7. The cleaning validation procedures
7.1 7.1.1 key parts need to verify the reactor:
Reactor is critical to the production plant equipment, reactor agitator consists of three parts, and a reducer composed Fanyingguo body, see figure parts are difficult to clean:
Key schematic view of two frame filter cleaning
Figure IV, oven cleaning schematic key
7.1.5 two-dimensional micro-grinder and mixer shown below: Figure V
7.2 Acceptance Criteria 7.2.1 no visible residues
7.2.2 chemical residues acceptable limits: 0.1% (this is not required for the first stage of chemical space device) produced the smallest quantities of 158kg, the maximum allowable residues: 1/1000 × 158kg = 0.158g 7.2.2.1 sampling wipe method residues limits:
According to the results, the maximum allowable residues 0.158g, each surface area within a certain product, the product according to the average surface assigned to each device, which is MRL:
To 158g, the total area of the material in the production of the contact device is 66.2876m2, 158g residual product by the average surface assigned to each device, which is MRL:
Wipe Test: In the wiping area of 10 cm × 10 cm area of the meter
158g×1000
MRL 100㎝2 A = --------- × × 10% (safety factor) × 70% (sample back
2
Yield) 66.2876m × 10000 = 1.69㎎ / cm 2
The residue limits as: 1.69㎎ / cm 2 / 25ml = 0.0676mg / ml according to HPLC eluate swab testing, residual concentrations calculated.
6.2.2.2 Cleaning Fluid: After cleaning, about 1500L in ethanol was added to the crystallizer was heated with stirring to reflux for 10 minutes, ethanol is pressed into the heated cooling water can often kettle, stirred for 10 minutes pressed into brine tank cooled, stirred 10 minutes into the press centrifuge centrifuge rinsed, and finally flows into the underground tank of ethanol; this was washed successively twice with 75% ethanol and finally rinsed again. Sample detection limit at the exit of the device, its residue limits are:
158×1000
Concentration Limits B = ------- × 10% (safety factor) = 0.0105㎎ / ml 1500L × 1000
For cleaning fluid sampling, as detected by HPLC method for calculating the residual concentration. Residual condensation of the same tank, decarburization filtration system with limited crystallizer. Selecting cleaning agent 7.3
Cleaning procedures require the use of cleaning solvents in drinking water. Used in the refining process made of stainless steel, and therefore, the wiping recovery method is used to verify the mold 10 cm × 10cm stainless steel sheet. Sampling means sampling bottle ordinary 500ml, ordinary swab 15cm, stoppered test tube 25 ml. Sampling method comprising wiping a swab method, the washing water sampling.
7.4 cleaning program
7.4.1 the first and second phases of the cleaning device authentication program.
7.4.1.1 cleaning procedure according to the first and second stages of the device apparatus in the first stage and second stage of the cleaning, including chlorination reaction tank, an esterification reaction tank, centrifuge, plate and frame filter press, two times and cans. Fill in the appropriate equipment cleaning validation records.
After checking 7.4.1.2 completed by cleaning device cleaning the operator positions recorded by a visual inspection of the equipment and trained personnel, and fill in "Visual inspection and sampling record", checked by QA personnel, check the contents comprising:
a. Cleaning is strictly according to a predetermined cleaning procedures for cleaning, inspection and cleaning of its record. b. Is there a "cleaned" status flag after equipment cleaning.
C. and Outer surface is visually inspected visually without residue, in particular, difficult to clean the site check. After the check is complete, the QA staff sign off on a visual inspection and sampling records.
Repeat three times to verify. The same type of apparatus wherein a randomly selected for verification, but take the same as the first device when the second and third authentication.
The first stage device to visually acceptable standards for the cleaning device cleaning, no visible residue. 7.4.2 third stage cleaning equipment verification.
7.4.2.1 apparatus for cleaning apparatus according to a third stage cleaning procedures, including condensation decarbonization tank and filtration system.
7.4.2.2 Cleaning Evaluation: (1) no visual residue.
(2) The final test concentration of the swab sample ≤0.0676mg / ml taken. (3) concentration of the washing water ≤0.0105mg / ml 7.4.2.3 Check
After cleaning be completed by the operator equipment clean record, then by trained personnel check whether the cleaning requirements and fill out the "visual inspection and sampling record" full-time quality management personnel responsible for the inspection, including:
① cleaning is strictly in accordance with the cleaning program for cleaning, inspection records clean. ② After cleaning equipment had been "cleaned" status flags.
③ Check no residue visible inner and outer surfaces apparatus, especially for cleaning key points to be checked. ④ Upon completion of inspection signed by the QA staff recognition.
⑤ sampling in accordance with the sampling rules table by the trained plant operators, be marked. 7.4.2.4 Sampling Location:
Plate filter discharge port, an end of crystallization jars, two jars crystal substrate, centrifuges, mixer-dimensional spout washing with ethanol, taken eluent sampling method, repeated three times. Select one isoform apparatus to verify, second and third verification device and the first device is the same device. Three consecutive validation batches.
8.1 Sampling Methods
8.1.1 Sampling Tool: Normal sampling bottle 500ml, ordinary swab 15cm, stoppered test tube 25 ml. 8.1.2 Sampling method comprising wiping a swab, rinsed sampling method.
Swab wipe method: sampling area: 10cm × 10cm (made of stainless steel sheet having an inner diameter of 10cm × 10cm sample of the mold). The mold affixed to the inner surface of the cleaning of the critical points in the above-described apparatus illustrated in (3 foot centrifuges, stainless steel trays, dust catcher, a two-dimensional mixer), after completion of production of the cleaning is finished, on its inner wall with a moistened with a solution of swab wiping smooth and slow, while moving forward, move from side to side. Flip swab, so that also the other side of the swab wiping, wiping the vertical direction with the previous movement, the wiping process should cover the entire surface (FIG wiping schematic below). 4 wipe swabs were 100cm2. After wiping, the sample solution on the four 25ml eluate eluted swab, and promptly labeled, indicating date of sampling. Sampling schematic wipe method
Sampling elution method: The characteristic features of the device itself and sampling methods, and the like of the reactor is not easy to use method of using the wiping apparatus leaching sampling method, after completion of the cleaning device, taking the internal device 500L leaching solution, leaching focus backwash said key verification site. At the lower end of the device, then rinse water sample into a vial. Promptly labeled, indicating the sampling and the sampling date. Sampling end, with purified rinse water to the interior equipment.
8.2. Detection method
8.2.1 Visual inspection: After cleaning in accordance with cleaning procedures, immediately visually review, within the device, the outer surface should be no visible residue. 8.2.2 Chemical Residues,
Leaching assay: take wash water spray was placed in a cuvette, as the test solution, the precise take eluent 100ml, filter, take 10μl high performance liquid chromatography, by HPLC assay.
Detection by wiping method: the dissolution liquid medicine opposite sign cuvette, the precise leaching solution taken wash 100ml, filter, take 10μl high performance liquid chromatography, by HPLC assay. 9. Conclusions and deviation record verification
After the verification is complete, analyze and verify data validated conclusions.
9.1 revalidation: the occurrence of the following conditions need to be re-verified
1. The major equipment changes its cleaning methods were changed. 2. Production of other products, a change varieties cleaning validation. 10. Remarks
Clean validity verification
The actual production situation, benorilate drug production line for the continuous production, storage device before cleaning time is not more than 24 hours, under normal circumstances, after cleaning storage time is not longer than one day, the cleaning of the cleaning general definition SOPs valid for seven days, a longer period of time due to the cleaning verification required, and the actual production, there have been no cases of microbial growth, so this does not validate the cleaning period, the cleaning will be verified during the validity period of the 2014 overhaul. Monitoring results see Table:
Annex 2
Results
Schedule 3
Deviation table
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