怎样做好GMP的验证.doc

Risk AnalysisMixer-granulation- dry-mixing time- granulation liquid; amount, temperature, time- mixing intensity- wet mixing time- granulation end-point- drying temperature- drying timeTablets - compressing speed- compressing force- load level of blend feeding- feeding - hardness- friability- weight uniformity- content uniformity- disintegration time- dissolution rateCapsules- flow behavior of granules-compaction pressure- filling speed- load level of blend feeding- powder bed level- weight uniformity- content uniformity- dissolution rateOral liquid manufacture- stirring time- type of stirrer, speed- standing time up to filling- temperature of vessel jacket for heating- filter (type, retention rate, etc.)- weight/volume of content- accuracy of filling- filling speed- temperature- pH- viscosity- refractive indexAccuracy- this means the closeness between the analyzed value and the actual value. This test should be done in at least three concentrations, each repeated at least three times. Recovery rate should be 95% - 105%.Precision- this means the closeness between all the analyzed values. Each analyzed value should be repeated 6 times. RSD for chemical and instrumental analysis should be not greater than 1.5% & 2.0% respectively.Specificity- this means the capability of the method to accurately analyze the intended component and not be interfered by the presence of other componentsAnalysis limit - this means that the method needs not report the quantitative result. It only needs to report higher than or lower than certain value.Detection limit- this means the lowest value at which the method could analyze or detect.Linearity- this means that the relationship between the reported values by the analytical methods, and the actual parameters of the material (e.g. concentration of component A or solubility of product B etc), is linear. Range- this means the values between the highest and lowest levels. Cleaning validationPrinciples and objectivesCleaning method and procedureWhich is the molecule to represent residue?Which part of equipment is to represent cleanliness? selection of the sampling pointMethods of measuring remaining residue selection of the sampling methodDetermining allowable level of residueCleaning method and procedureGenerally, by rinsing, wiping or combination of bothWhatever method, the cleaning procedure could be summarized into the following steps:1) The needed dismantling before cleaning and re-assembly after cleaning2) Type, concentration, volume and preparation method of cleaning agent (water, solvent, detergent?)3) The manner, temperature, speed and time under which the cleaning agent comes into contact with surfaces to be cleaned4) Cleaning requirement and expectation (steps and results)5) Defining the longest duration after the start of production and before the start of cleaning.6) Defining the longest period of continuous production without cleaning7) Defining the longest duration after the end of cleaning and the start of next production8) Defining and meeting the microbial standards 9) The procedure of drying and storage of cleaned equipmentWhich is the molecule to represent the residue?Generally, the molecule, which is most difficult to be cleaned by the selected cleaning agent (e.g. water or solvent), is used to represent the residue. This selection should be also based on the potency, as well as the allowable residual level.Which part of equipment is to represent cleanliness?Generally, it is the most inaccessible (reached manually by wiping or reached by solvent in in-situ washing/rinsing) part of the equipment.The following shows some examples:Inlet and outlet HEPA filters around the seals and supporting frame Point extract systems - falls of soot contamination. Sampling devices and scoops - hidden contamination Ventilation, vacuum and utilities (e.g. nitrogen lines, air) lines (back diffuse by powder and vapor)Equipment internals, overheads and connecting nozzles and bellows of the transfer lines (corners, hidden parts)Pumps, valves, different type of transfer lines and in-line filters (dismantle and manually clean if possible).Method of measuring chemical residue inspection and testing (allowable level of chemical residue for cleaning validation acceptance criteria)Analysis of rinse samplesAssume G ml of solvent was circulated through the equipment (in-situ rinsing). At the end of re-circulation, a sample of the rinsing solvent is taken and analyzed for residue (by HPLC, UV or equivalent).The allowable residue in the sample must be less than the following, as calculated by:(A/B) x (C/G) x F where:A =the smallest NOEL (Non-observable effect level) in the group of product manufactured by that equipment (ug)B =the largest daily dosage (ml/day or mg/day) in the group of product manufactured by that equipmentC =the smallest batch size in the group of product manufactured by that equipment (kg or L)F =the efficiency of sampling (i.e. how much of the actual residue is measured? In %)G =the quantity of solvent used for in-situ cleaning (ml)For lower potency product, A = the smallest active ingredient concentration x 0.001For higher potency product, A = the smallest NOELAfter in-situ cleaning by circulation of solvent, the equipment could be cleaned by purified water (using in-situ circulation). Purified sample could then be taken for comparison with standard purified water and including analysis of residue solvent.Direct surface (swab) testingAssume E cm2 of the equipment surface has been cleaned (by in-situ rinsing or by wiping). At the end of cleaning, a swab sample of the cleaned surface (swab area of 25 cm2 or 100 cm2) is taken and analyzed for residue (by HPLC, UV or equivalent).The allowable residue in the sample must be less than the following, as calculated by:(A/B) x (C/E) x D x F where:A =the smallest NOEL (Non-observable effect level) in the group of product manufactured by that equipment (ug)B =the largest daily dosage (ml/day or mg/day) in the group of product manufactured by that equipmentC =the smallest batch size in the group of product manufactured by that equipment (kg or L)D =the area of swab cloth (usually 25 cm2)E =the area of internal surface which the following batch of material comes into contact with (cm2)F =the efficiency of sampling and analysis (i.e. how much of the actual residue is measured? In %)Validating swabbing technique & establishing swab recoveryClean stainless steel plate (7.6 cm x 7.6 cm)Standard chemical solution, syringe, swab clothAllow solution to evaporate, swab, extract swab cloth and analyzeCalculate swab recovery and compare with amount of chemical on plate.Calculate swab and analysis efficiencyProcedures to establish visual detection limit of residual stain of compoundsSimilar to above;clean stainless steel polished plate (7.6xm x 7.6cm)Standard chemical solution and syringe, torch light, mirror and swab clothAllow solution to evaporate, swab, extract swab cloth and analyzeCompare the swab extent with visual observationCalculate swab recovery and compare with amount of chemical on plate.Calculate swab and analysis efficiencyMethod of measuring microbial inspection and testing(Determining allowable level of microbial for cleaning validation acceptance criteria)Using the same method as in the chemical residue sampling, take the microbial samples from the cleaned equipment surface prior to taking chemical residue samples.The criteria should be:Less than 50 CFU/swab cloth, orLess than 25 CFU/ml in the final rinse.Sampling plan for the multi-product manufacturing equipment (example)ProductSolubilityNOELBatch sizeDaily dosage(1)0.0016060090(2)0.30.2100015(3)0.00080.032003(4)120.67505(5)0.0001350060(6)0.11.55005(7)2.50.00140010Therefore the worst condition parameters selected for the calculation in(A/B) x (C/E) x D x FisA =0.001B =90C =200D =25 cm2E =44206 cm2F =assume 50% or according to swab validation resultUsing product No. (5) as the reference since it has lowest solubility.Control and documentation of cleaningCleaning logLabelsControl of accessComputer validationObjectiveValidation of computerized systems provides the documented evidence that the computerized systems performed the required tasks reliably. Here, the term computerized systems covers the functional unit comprising computer hardware, computer software and any further peripheral and non-computer components such as sensors and machines (automated systems).Different computer systemsa) Designing a new computerized systemb) Using a commercially available computerized systemc) Using existing computerized systemComputerized system validation planning & DQAnalogous to the validation of equipment, the validation of new computerized systems starts with the Master Validation Plan (VMP). This qualification exercise includes testing of the central processing unit, of the memory systems, of the displays, of the data acquisition/storage units, of the networks and of the printers. Often, the qualification involves both software and hardware. The Life Cycle approach of validating new software is quite commonly used. The following list outlines general categories of hardware components:Controllers, Peripheral Devices, Input &Output Modules, Network Modules and Cabling, Redundant Components, Power Requirements, Enclosures.The software normally can be divided into three categories: (i.e. System or Operating, Configurable and Application Specific).Application specific modules: Program structure and file hierarchy Modes of operation Safety interlocks Error handling and failure modes Alarm priorities and logging Proportional-Integral-Derivative (PID) and other controls Graphical display screens Recipe management Report generation Security system Data archivingIQOnce the system has been installed, all instrument calibrations identified by the metrology program should be initiated. The IQ protocol contains instructions for verifying the installation of hardware and software components and implementing change control. The software portion includes the verification of the file download operation, during which application specific software programs are installed and checked. It is important to document the name, version, and location of the source code for the operating and configurable software with the corresponding controllers identification. OQIndividual units of the system should perform as intended throughout anticipated operating ranges. Execution of the formal OQ involves conducting a series of static and dynamic tests, which verify and document the correct operation of all the continuous, sequential control parameters and graphical display elements. Challenges on stress (what happens if signal input exceeds maximum visualized practice?), volume (can handle the amount of data specified), response time, throughput rate, accuracy and consistency should be conducted.Sequential control configurations must be tested during the OQ. However, each sequence should be tested as an individual unit. A sequence consists of steps and decision points (i.e. transitions) between steps. PQThe PQ is executed to challenge the computer system as a fully integrated unit. It ensures that the system meets its design and process specifications. Computer control parameters specified in the Batch Processing (or Production) Record are tested under actual process conditions. Acceptance criteria for each test also are established in the PQ. All sequences are integrated, combined with continuous control elements and graphical displays, and tested as one unit. The possibility of switching over to manual operation should be checked. Generally a minimum of 3 consecutive and successful runs is required to demonstrate system performance. Success is measured by examining results from the above testing. Observations and raw data collected by the operators are recorded in the PQ report. Operator change logs, trend graphs, and alarm logs are forms of reports generated by the computer system. Software and data managementData should only be entered or amended by persons authorized to do so. Entries and changes should be tracked and recorded. There should be a defined procedure for the issue, cancellation, and alteration of authorization to enter and amend data, including the changing of personal passwords. When critical data are being entered manually (for example the weight and batch number of an ingredient during dispensing), there should be an additional check on the accuracy of the record which is made. This check may be done by a second operator or by validated electronic means.Security and failure recoveryFor quality auditing purposes, it shall be possible to obtain meaningful printed copies of electronically stored data. Data should be secured by physical or electronic means against wilful or accidental damage. Stored data should be checked for accessibility, durability and accuracy. If changes are proposed to the computer equipment or its programs, the above mentioned checks should be performed at a frequency appropriate to the storage medium being used.Data should be protected by backing-up at regular intervals. Back-up data should be stored as long as necessary at a separate and secure location. If a manual system is being replaced, the two should be run in parallel for a time, as part of this testing and validation.There should be available adequate alternative arrangements for systems, which need to be operated in the event of a breakdown. The time required to bring the alternative arrangements into use should be related to the possible urgency of the need to use them. For example, information, which is required to effect a recall, must be available at short notice.When the release of batches for sale or supply is carried out using a computerized system, the system should recognize that only an Authorized Person can release the batches and it should clearly identify and record the person releasing the batches.COMPUTER SYSTEM DEVELOPMENT LIFE CYCLE APPROACHNew computer systemExisting computer systemDefine System Function StructureDefine System Function StructureQualify SystemDefine softwareDesign/SpecifyHardwareReview Operating ExperienceDevelopSoftwareInstallHardwareConduct System Testing(if needed)VerifySoftwareQualifyHardwareDataTestIndividualModule(ComputerSystem)Data AnalysisIntegrateComputerizedSystemAcceptanceOngoing System EvaluationTest Integrated Modules(Computerized System)Demonstrate Total SystemOperation(Computerized System)ChangeValidation flowchart Complete defining the SystemDocument the reasons why not impactedImpact on GMP?NOYESNew System?Use existing SystemNOYESComplete FDS requirement definitionIs the supplier qualified?System developed internally?NO NOYESYES Document why not qualifiedNew System to be developed internallyValidated by supplierUse existing SystemUse existing SystemImplement retrospective validationHas the System been validated?NODraft, review, approve and implement validation protocols YESEvaluate changeDefine SystemsApprove changeImplement changeVerify operating experienceImplement re-validationComplete System testing (if necessary)Analyze resultsReview validation resultsSystem compliance?Verify and document deviationsEvaluate next stepNOYESValidation completedNew System to be developed internallyNew System to be developed internallyFully complete the FDS detail descriptionDesign System digital-logicDesign softwareDesign complete digital systemDevelop softwareNew hardware?Complete/compile basic designNew SystemNOHardware compliance?YESDesign and install hardware NOQualify hardwareQualify hardwareQualify softwareYESTests verified and accepted by usersReview validation resultsSystem in compliance?System successfully validatedVerify an