GxP-Compliant Calibration Learning from the Warning Letters - - PowerPoint PPT Presentation
GxP-Compliant Calibration Learning from the Warning Letters Vaisala in Brief We serve customers in controlled environments in life science, power transmission, and other targeted industrial applications. Over 80 years of expertise
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power transmission, and other targeted industrial applications.
instrumentation and measurement products and services.
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Our Goal is to Help Customers
adulterated product
GxP regulations and/or guidelines Our Offering Measurement instrumentation, continuous monitoring systems and validation systems for regulated or highly controlled life science environments.
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Chat Manager:
Janice Bennett Vaisala Marketing Manager
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Guest Speaker:
Heather Wade Heather Wade Group Metrology Consultant
Speaker:
Paul Daniel Vaisala
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– Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.
– The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.
– Complete records shall be maintained of the periodic calibration of laboratory instruments, apparatus, gauges, and recording devices required by § 211.160(b)(4).
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– Control of inspection, measuring, and test equipment. Each manufacturer shall ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results. Each manufacturer shall establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained. The procedures shall include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained. These activities shall be documented.
– (b) Calibration procedures shall include specific directions and limits for accuracy and precision. When accuracy and precision limits are not met, there shall be provisions for remedial action to reestablish the limits and to evaluate whether there was any adverse effect on the device’s quality. These activities shall be documented. – (b)(1) Calibration Standards: Calibration standards used for inspection, measuring, and test equipment shall be traceable to national or international standards. If national or international standards are not practical or available, the manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall establish and maintain an in-house standard. – (b)(2) Calibration Records: The equipment identification, calibration dates, the individual performing each calibration, and the next calibration date shall be documented. These records shall be displayed on or near each piece of equipment or shall be readily available to the personnel using such equipment and to the individuals responsible for calibrating the equipment.
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– Calibration
– The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.
– Quality Unit:
– Making sure that effective systems are used for maintaining and calibrating critical equipment;
– Production Activities:
– Making sure that the necessary calibrations are performed and records kept;
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– 5.30: Control, weighing, measuring, monitoring and test equipment that is critical for assuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule. – 5.31: Equipment calibrations should be performed using standards traceable to certified standards… – 5.32: Records of these calibrations should be maintained. – 5.33: The current calibration status of critical equipment should be known and verifiable. – 5.34: Instruments that do not meet calibration criteria should not be used. – 5.35: Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an impact on the quality of the intermediate(s) or API(s) manufactured using this equipment since the last successful calibration.
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– 6.61: Complete records should be maintained for… periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;
– 19.30: During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.
– 19.60: Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification assures API quality during this development phase.
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– 3.41: Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.
– 4.18(b): The Processing Instructions should include… the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing). – 4.29: There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for… equipment assembly and calibration; – 4.31: Logbooks should be kept for major or critical analytical testing, production equipment, and areas where product has been processed. They should be used to record… calibrations, maintenance, cleaning or repair
– 6.7: …the following details should be readily available to the Quality Control Department: procedures for and records of the calibration of instruments and maintenance of equipment.
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– Mutual Recognition Arrangement (MRA) – “Accredited Once, Accepted Everywhere”
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568104211
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– Test instruments were made in-house – Test instruments not calibrated for 5 or 6 years
– Did SOP did not include:
– Limits for precision and accuracy – Remedial actions for calibration failure – Traceable standards
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Each manufacturer shall ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results. Each manufacturer shall establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained. The procedures shall include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are
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– Calibration procedures shall include specific directions and limits for accuracy and
remedial action to reestablish the limits and to evaluate whether there was any adverse effect on the device's quality. These activities shall be documented.
– (1) Calibration standards.
national or international standards. If national or international standards are not practical or available, the manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall establish and maintain an in-house standard. – (2) Calibration records.
next calibration date shall be documented. These records shall be displayed on or near each piece of equipment or shall be readily available to the personnel using such equipment and to the individuals responsible for calibrating the equipment.
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– Only trained individuals should interact with FDA.
– What is the impact of inadequate SOP?
– Inadequate SOP caused instruments to not get calibrated.
– What happens when Instruments are not calibrated for over 5 years?
– Accuracy will decrease, and measurement flaws can cause decrease in product quality.
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– Balance was calibrated by bracketing above 120 mg (e.g., 200 and 500 mg) – Verification weight had not been calibrated in over 10 years.
– Halted use of the balance – Updated policies to require yearly calibration of reference weights
– Company needed procedure to review calibrations and catch bracketing error. – Company needed to make a plan to deal with distributed product.
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Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.
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– Is it necessary?
– Bracketing is traditionally used when linear response between points can be proven. – The use of bracketing depends on the instrument and the application. – For modern electronic balances, per USP <41>, bracket at 5% and 100% of capacity.
– What happens to a weight if it is not calibrated?
– Weights will drift due to friction from normal use.
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– Densitometer was not calibrated (noted in 483 Observation).
– Densitometer was “For Information Only” – 3rd party testing was used to determine fill volumes.
– FDA found multiple batch records where the densitometer was used to calculate fill volumes.
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Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include: – (4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.
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– What are the dangers of this designation?
– If data from the instrument is reported, the instrument must be calibrated.
– Your responsibility extends to your contractors.
– You must ensure that your contractors can meet your GxP / ISO requirements.
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– The battery calibration procedure has not been validated and determined to be effective
– 21 CFR 820.75 (a)
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Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented.
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– Follow an accepted national or international standard method. – If you use an in-house method, you need to validate to prove it works.
– Product Recall or Evaluation
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– Started Root Cause Investigation to find the reason.
– Discovered autoclave with drifting temperature control sensor. – No further action was taken.
– Company response stated:
– Sensor drift had been known for 2 years, but variation was always within acceptance criteria.
– Company failed to and evaluate the reference standard or calibration process.
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All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any
the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.
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– Why was sensor drifting?
– Evaluating drift within acceptance criteria – Possible sources:
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– Calibration procedures shall include specific directions and limits for accuracy and
remedial action to reestablish the limits and to evaluate whether there was any adverse effect
– (1) Calibration standards.
manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall establish and maintain an in-house standard. – (2) Calibration records.
the next calibration date shall be documented. These records shall be displayed on or near each piece of equipment or shall be readily available to the personnel using such equipment and to the individuals responsible for calibrating the equipment.
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– Not enough information to ensure instrument is calibrated correctly.
– Calibration is Comparison
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– Specific written directions – Defined accuracy – Provisions for remedial action – Documented calibration records – Traceable calibrations, including measurement uncertainty
– “Metrological Traceability”
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BEFORE: Known & Accurate Quantity Unknown Quantity vs. REFERENCE Unit Under Test
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Known & Accurate Quantity Known Quantity vs. BEFORE: AFTER: Known & Accurate Quantity Unknown Quantity vs. REFERENCE Unit Under Test
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Known & Accurate Quantity Known Quantity vs. BEFORE: AFTER: Known & Accurate Quantity Unknown Quantity vs. REFERENCE Unit Under Test
X Uncertainty Y X + Y +
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Known & Accurate Quantity Known Quantity vs. BEFORE: AFTER: Known & Accurate Quantity Unknown Quantity vs. REFERENCE Unit Under Test
X Y X+Y
X Uncertainty Y X + Y +
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– Use a test instrument to measure the thickness of the ceramic material on each tooth.
– The instrument lacked any indication of its calibration status.
– The company calibration procedure requires calibration stickers on test instruments.
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Each manufacturer shall ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results. Each manufacturer shall establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and
equipment, so that its accuracy and fitness for use are maintained. These activities shall be documented.
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– You make it GxP when you put it in SOP.
– Calibration information must be readily available – It must be easy to determine calibration status of instrument
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1. Inadequate Calibration SOP: Custom test instruments not calibrated in 5 years. 2. Inadequate Calibration SOP: Calibration not bracketed, Reference weights uncalibrated. 3. Uncalibrated QC densitometer incorrectly claimed to be “For Reference Only”. 4. Calibration procedure not validated and proven to be effective (for AED batteries). 5. Failure to investigate drifting temperature sensor on autoclave. 6. Inadequate Calibration SOP: No specific directions, limits, or calibration records. 7. Failure to follow Calibration SOP: Calibration stickers were required, but omitted.
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– No procedure – Not following procedure properly – Following inadequate procedure
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Heather Wade Metrology Consultant The Heather Wade Group www.heatherwadegroup.com Email: h.wade@heatherwadegroup.com
Paul Daniel
Vaisala, Inc. Email: paul.daniel@vaisala.com