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Biotechnology & GMP Raw material, Process & Process Validation and its Regulatory Aspects
References:
GMP for pharmaceutical products: main principles; WHO TRS No. 908,2003 GMP for biological products; WHO TRS No.822,1992 A WHO guide to GMP requirements, part 2:validation; WHO,1997
GMP
The good practices outlined are to be considered general guides and they may be adapted to meet individual needs.
GMP
-are aimed primarily at diminishing the risks inherent in any pharmaceutical production
Principle: production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality.
GMP
Media/Cell culture
Excipients Validation - process - method Stability studies
Final lot
Final bulk
receipt cleaning quarantine sampling storage labelling dispensing processing packaging distribution
If deviations occur: should be done in accordance with an approved procedure approved in writing by a designated person
Checks on yields and reconciliation of quantities to ensure that there are no discrepancies outside acceptable limits.
Operation on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mixup or cross-contamination.
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all materials bulk containers major items of equipment rooms packaging lines
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Access to production premises should be restricted to authorized personnel. Non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.
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The performance should not have any negative effect on the quality of the product or another product.
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When dry materials and products are used in production, special precaution should be taken to prevent the generation and dissemination of dust.
proper air control e.g. supply and extraction of air of suitable quality
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uncontrolled release of dust, gases, particles, vapours. sprays or organisms from materials and products in process residues on equipment intruding insects operators clothing, skin, etc. living organisms, hormones, cytotoxic substances, and others
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carrying out production in dedicated and self-contained areas conducting campaign production followed by appropriate cleaning in accordance with a validated cleaning procedure providing appropriately designed airlocks, pressure differentials and air supply and extraction systems
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minimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air wearing protective clothing using cleaning and decontamination procedures of known effectiveness using a closed system in production testing for residues using cleanliness status labels on equipment
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Measures to prevent cross-contamination and their effectiveness should be checked periodically according to SOP Production areas periodic environmental monitoring
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clean and free from any starting materials, products, product residues, labels or documents not required for the current operation
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Any necessary in-process controls and environmental controls should be carried out and recorded Indicate the failures of equipment or services (e.g. water, gas) to equipment
cleaned without delay, stored under clean and dry conditions in separate area
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Time limits for storage of EQ after cleaning and before use Containers for filling should be cleaned before filling Any significant deviation from the expected yield
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Checks
sanitized and stored according to written procedures (action limits for microbiological contamination and measures
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EQ and instruments
serviced and calibrated at prespecified interval records maintained checked daily or prior to use clearly indicated the date of calibration and servicing, recalibration (label attached to instrument) not present any hazard to the quality of the products
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SOP for manufacturing operations: available, up date Starting material: source, origin, method of manufacture, QC Media and culture shall be added to fermenter and other vessels under carefully controlled conditions, avoid contamination
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Media should be sterilized in situ. In line sterilizing filters for routine addition of gases, media, acids, alkalis, deforming agents, etc. to fermenter should be used where possible. Validation of sterilization. Inactivation process: measures should be taken to avoid risk of cross-contamination between treated and untreated products.
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should be dedicated to purification of one product should be sterilized or sanitized between batches define the life span of columns and the sterilization method
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In-process controls play a specially important role in ensuring the consistent quality of biological products because certain deficiencies may not be revealed by testing the finished product.
Tests that are crucial for quality control but that cannot be carried out on the finished product shall be performed at an appropriate stage of production.
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Samples of intermediate and final products shall be retained in sufficient amount and under appropriate storage conditions to allow the repetition or confirmation of a batch control. Certain operations require the continuous monitoring of data during a production process e.g.monitoring and recording of physical parameters during fermentation.
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Validation: Definition
Validation is the documented act of proving that any procedure, process, equipment, material,activity or system actually leads to the expected result.
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Validation studies
analytical test equipment facility systems (air, water, steam, process; manufacturing processes, cleaning, sterilization, sterile filling, lyophilization)
Separate validation for
lyophilizer/ lyophilization process cleaning of glassware/ cleaning of facility sterilization process/ sterility test
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Validation studies
verify the system under test under the extremes expected during the process to prove that the system remains in control. Critical equipment and processes are routinely revalidated at appropriate intervals to demonstrate that the process remains in control.
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Type of validation
Prospective
pre-planned protocol base on data collected during actual performance of a process already implemented in a manufacturing facility suit manufacturers of long standing, have well-controlled manufacturing process for production for a long time, but has not been validated according to a prospective protocol and concurrent validation is not realistic option is not generally accepted
Concurrent
Retrospective
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Type of validation
removal of impurities by individual purification steps in process - not acceptable to bring unacceptable impurities (endotoxin, unwanted protein, contaminating bacteria and virus) spike into process
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Design qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ)
necessary when planning and choosing EQ or systems to ensure that components selected will have adequate capacity to function for the intended purpose, and will adequately serve the operations or functions of another piece of EQ or operation.
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written for critical processing EQ and systems list all the identification information, location, utility requirements, and any safety features of EQ verify that the item matches the purchase specifications
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outlines the information required to provide evidence that all component of a system or of a piece of EQ operate as specified. should provide a listing of SOPs for operation, maintenance and calibration define the specification and acceptance criteria include information on EQ or system calibration, pre-operational activities, routine operations and their acceptance criteria
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performed after both IQ and OQ have been completed, reviewed and approved describes the procedures for demonstrating that a system or piece of EQ can consistently perform and meet required specification under routine operation and, where appropriate, under worst case situations include description of preliminary procedures required, detailed performance tests to be done, acceptance criteria other supporting EQ used during qualification have been validated.
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system: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQ EQ: autoclave, oven, lyophilizer, continuous flow centrifuge; IQ, OQ, PQ
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Process validation
A process is a series of interrelated functions and activities using a variety of specified actions and EQ which is designed to produce a defined result.
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examine a process under normal operating conditions to prove that the process is in control re-validation
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Process validation
full defined process is carried out using validated EQ at least 3 times, under established procedure process must successfully and consistently meet all acceptance criteria at all steps throughout the procedure at least 3 times consecutively
Validated process Worst case: to ensure that process is acceptable in the extreme case
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Process validation
Example cleaning sanitization fumigation depyrogenation sterilization sterile filling fermentation bulk production purification inactivation filling, capping, sealing lyophilization
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Process validation
all EQ; identity, code number, construction, operation capacity, actual operating range processing parameter; sufficiently detailed to permit complete reproducibility (time period, pH, volume, temp.etc.) specification at each step
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Process validation
Very important
specifications for a process undergoing validation be pre-determined all critical processing parameters for which specifications have been set, there must be equipment to measure all of those parameters during the validation study
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collecting liquid and swab samples for testing of residual product residual protein endotoxin tests microbial tests (bioburden) chemical tests (chlorine and phosphoric acid) residual cleaning agents conductivity tests pH
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Sterilization
microbial challenge
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Sterile filling
test filling process perform filling process with nutrient media run at full scale for at least one fill size worst case; large volume and number of vials filled vials incubated, observed and test for contamination by validated sterility test must be sterile for 3 consecutive runs media fill performed twice a year size of run must be large enough to detect low levels of contamination e.g. contamination rate of 1/1000, 3000 units are needed to provide 95% confidence
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Mock fermentation
to validate the parts of process involving connections, sampling, and additions of nutrients etc. fermentor prepared and operated in simulated process with uninoculated nutrient media process follow the full fermentation process 3 consecutive runs at each stage
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run according to approved Master formula including all raw material, personnel, equipment, and facility preparations, in-process tests, processing, through to final testing of the batch lot. all facility systems must be monitored 3 consecutive lots must be produced and all facility, EQ, support systems, product spec, and process being validated must pass at all steps
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Validation master plan (VMP) Validation protocol (VP) Validation reports (VR) Standard operating procedures (SOPs)
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is a document pertaining to the whole facility that describes which EQ, systems, methods and processes will be validated and when they will be validated. provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation)
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indicate what information is to be contained within each document indicate why and when revalidations will be performed who will decide what validations will be performed order in which each part of the facility is validated
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indicate how to deal with any deviations state the time interval permitted between each validation
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Validation: VMP
Enables overview of entire validation project List items to be validated with planning schedule as its heart like a map
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Validation policy Organizational structure Summary of facilities, systems, equipment, processes to be validated Documentation format for protocols and reports Planning and scheduling Change control Training requirements
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Validation: Protocol
Objectives of the validation and qualification study Site of the study Responsible personnel Description of the equipment SOPs Standards Criteria for the relevant products and processes
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Validation: Report
Title objective of the study Refer to the protocol Details of material Equipment Programmes and cycles use Details of procedures and test methods
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Software changes; controllers Site changes; operational changes Change of source of material Change in the process Significant equipment changes Production area changes Support system changes
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