GxP-Compliant Calibration - Vaisala · – (b)(1) Calibration Standards: Calibration standards used for inspection, measuring, and test equipment shall be traceable to national or

GxP-Compliant Calibration

Learning from the Warning Letters

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Vaisala in Brief We serve customers in controlled environments in life science,

power transmission, and other targeted industrial applications.

Over 80 years of expertise providing a range of innovative instrumentation and measurement products and services.

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Vaisala in Life Sciences

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Our Goal is to Help Customers• Reduce their risk of lost or

adulterated product • Reduce their risk of failing to meet

GxP regulations and/or guidelines

Our OfferingMeasurement instrumentation, continuous monitoringsystems and validation systems for regulated or highly controlled life science environments.

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Webinar Team

Chat Manager:

Janice BennettVaisalaMarketing Manager

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Guest Speaker:

Heather WadeHeather Wade GroupMetrology Consultant

Speaker:

Paul DanielVaisalaSr. GxP Regulatory Expert

GxP-Compliant Calibration

Learning from the Warning Letters

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Agenda

Brief Review of GxP Calibration Regulations

Basic Regulatory Process

Real FDA Warning Letters issued for Calibration failures

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What are GxP “Life Science” Industries?

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Usually described by the products: Pharmaceuticals

Medical Devices

Biologics

Tissue (Blood and Organs)

Nutraceuticals

Cosmetics

Veterinary Products

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What are our GxP “Life Science” Regulations?

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USA 21 CFR Part 211: cGMP for Finished Pharmaceuticals 21 CFR Part 820: Quality System Regulation (Devices)

Multiple Countries (USA, Canada, Japan, Europe) ICH Topic Q7: Guidance on GMP for APIs

International (over 50 countries) PIC/s: Guide to GMP for Medicinal Products - Part I

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cGMP for Finished Pharmaceuticals 211.68(a): Automatic, mechanical, and electronic equipment

– 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 calibrationchecks and inspections shall be maintained.

211.160 (b)(4): Laboratory Controls – General Requirements– 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.

211.194 (d): Laboratory Records– Complete records shall be maintained of the periodic calibration of laboratory instruments, apparatus, gauges,

and recording devices required by § 211.160(b)(4).

Regulations: FDA – 21 CFR Part 211

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Quality System Regulation (Devices) 820.72(a): Control of Inspection, Measuring, and Test Equipment

– Control of inspection, measuring, and test equipment. Each manufacturer shall ensure that all inspection, measuring, and testequipment, 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.

820.72(b): Calibration– (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.

Regulations: FDA – 21 CFR Part 820

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Guidance on GMP for APIs Definitions:

– 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.

Chapter 2: Quality Management Responsibilities– 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;

Regulations: ICH Topic Q7

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Guidance on GMP for APIs Chapter 5.3: Calibration

– 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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Guidance on GMP for APIs Chapter 6.6: Laboratory Control Records

– 6.61: Complete records should be maintained for… periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;

Chapter 19.3 - Equipment and Facilities– 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.

Chapter 19.6 – Validation– 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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Guide to GMP for Medicinal Products Part I Chapter 3: Premises - Equipment

– 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.

Chapter 4 - Manufacturing Formula and Processing Instructions– 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 operations, including the dates and identity of people who carried these operations out.

Chapter 6 - Quality Control - Documentation– 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.

Regulations: International

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ISO/IEC 17025:2017General requirements for the competenceof testing and calibration laboratories

Applicable worldwide

Top laboratory management standard

Accreditation = www.ilac.org– Mutual Recognition Arrangement (MRA)– “Accredited Once, Accepted Everywhere”

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Equipment Calibration Requirements: Shall be accessible Shall have procedure(s) for handling, transport, storage, use, and planned maintenance

Shall verify equipment before placing into use Shall be accurate for its applications Shall be calibrated when: The accuracy or uncertainty affects validity of data Establishing metrological traceability of the reported results Shall be recalibrated to maintain confidence

ISO/IEC 17025:2017

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Equipment Calibration Requirements (continued): Shall be identified with its calibration status Shall be taken out of service if damaged or suspect readings Lab shall evaluate effect of defect/deviation Lab shall initiate non-conforming work investigation Shall perform intermediate checks following a procedure Shall prevent unintended equipment adjustments Shall have records Shall be metrologically traceable (measurement uncertainty)

ISO/IEC 17025:2017

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Equipment (production or lab) must be: Fit for use Capable of producing valid results Routinely calibrated to traceable standards Removed from use if out-of-spec

Summary of Calibration Regulations and Requirements

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Documented calibration program: Calibration Directions Calibration Schedules Limits for accuracy and precision Provisions for remedial action if out-of-spec


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Complete calibration records: Equipment identification Calibration dates (including date due) Individual(s) performing calibration Displayed nearby or available


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Basic Regulatory Process Facility must be Registered or Certified Product must be Approved Proven safe and effective through research and clinical testing

Audits and Inspections Agency Actions (based on FDA) Inspections / Audits Observations Warning Letters (EMA does “Non-Compliance Reports”) Facility Shutdown

Agency Actions are Public Record Affects Company Reputation and Stock Price

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FDA Inspections, Form 483, and Warning Letters FDA Visits Site or Reviews Product Approx. 5000 inspections per year.

Observations are recorded on Form 483 Almost 5000 individual observations per year Manufacturer has 15 days to respond If response inadequate, upgrade to Warning Letter

Warning Letters issued for serious problems 400 to 500 warning letters per year Does not require site inspection Manufacturer has 15 days to respond If response inadequate, further action is taken

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Warning Letter #1

Dimensional test instruments used to verify product meets quality criteria– Test instruments were made in-house– Test instruments not calibrated for 5 or 6 years

Calibration SOP was inadequate and did not include instruments made in-house– Did SOP did not include:

– Limits for precision and accuracy– Remedial actions for calibration failure– Traceable standards

CEO: No calibration needed because instruments are “accurate enough”

Applicable Regulations - 21 CFR 820.72 (a) and (b)

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Product: Surgical Device Where: Europe When: 2017

Case: MARCS-CMS 518581

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21 CFR 820.72 (a) 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.

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Letter #1 - Regulation

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21 CFR 820.72 (b) Calibration.

– 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.

– (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.

– (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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CEO comment – Only trained individuals should interact with FDA.

Inadequate procedure– What is the impact of inadequate SOP?

– Inadequate SOP caused instruments to not get calibrated.

Instruments not 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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Letter #1 – What can we learn?

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Warning Letter #2

Balance used to weigh out small amounts of API – 120 mg– Balance was calibrated by bracketing above 120 mg (e.g., 200 and 500 mg)– Verification weight had not been calibrated in over 10 years.

Initial response from Company– Halted use of the balance– Updated policies to require yearly calibration of reference weights

FDA: Response “inadequate”– Company needed procedure to review calibrations and catch bracketing error.– Company needed to make a plan to deal with distributed product.

Applicable Regulations: 21 CFR 820.68 (a)

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Product: Drugs Where: USA When: 2019


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21 CFR 211.68 (a) Automatic, mechanical, and electronic equipment.

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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Calibration Bracketing – 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.

Un-calibrated Verification Weights– What happens to a weight if it is not calibrated?

– Weights will drift due to friction from normal use.

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Why is using uncalibrated verification weights such a bad practice? The use of references can change their measurement values. Regular calibration can detect and correct out-of-tolerances and reduce risk for the company.

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Case: MARCS-CMS 575542Letter #2 - Discussion

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Why is using uncalibrated verification weights such a bad practice? The use of references can change their measurement values. Regular calibration can detect and correct out-of-tolerances and reduce risk for the company.

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Case: MARCS-CMS 575542Letter #2 - Discussion

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Warning Letter #3

Densitometer used to determine fill volumes when viscous product has bubbles.– Densitometer was not calibrated (noted in 483 Observation).

In response, company claimed:– Densitometer was “For Information Only” – 3rd party testing was used to determine fill volumes.

483 Upgraded to Warning Letter:– FDA found multiple batch records where the densitometer was used to calculate fill volumes.


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Product: Contract Filler (Drugs) Where: Canada When: 2018


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Letter #3: Regulations

21 CFR 211.160 (b) Laboratory Controls – General Requirements

Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure thatcomponents, 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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For Information Only– What are the dangers of this designation?

– If data from the instrument is reported, the instrument must be calibrated.

Contract Organization – Your responsibility extends to your contractors.

– You must ensure that your contractors can meet your GxP / ISO requirements.

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Warning Letter #4

AED Manufacturer tests and calibrates batteries for the device.– The battery calibration procedure has not been validated and determined to be effective

Applicable Regulations: – 21 CFR 820.75 (a)

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Product: Medical Devices Where: USA When: 2019


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Letter #4: Regulations

21 CFR 820.75 (a) Process Validation

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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How do you know your calibration procedure is effective?– Follow an accepted national or international standard method.– If you use an in-house method, you need to validate to prove it works.

Very Basic Calibration Failure in a critical component.– Product Recall or Evaluation

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Warning Letter #5

Company noted a failure to achieve sterility in one batch of product.– Started Root Cause Investigation to find the reason.

– Discovered autoclave with drifting temperature control sensor.– No further action was taken.

Investigation included in 483 Observation– Company response stated:

– Sensor drift had been known for 2 years, but variation was always within acceptance criteria.

Upgraded to Warning Letter– Company failed to and evaluate the reference standard or calibration process.

Applicable Regulations: 21 CFR 211.192

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Product: Drugs Where: India When: 2019


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21 CFR 211.192 Records and Reports – Production Record Review

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 of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of 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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Calibration problems not always reported as calibration issues.

Investigations must be thorough.– Why was sensor drifting?

Calibration Issues– Evaluating drift within acceptance criteria

– Possible sources: Faulty sensor, problem with reference standard, or calibration process changed?

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Warning Letter #6

Company manufactures therapeutic lasers. Instruments for release testing had no calibration records.

Calibration procedure was inadequate: No specific directions No limits for accuracy and precision

Applicable Regulations: 21 CFR 820.72 (b)

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Product: Medical Device Where: UK When: 2016

Case: Not disclosed

No provisions for remedial action No records maintained

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21 CFR 820.72 (b) Calibration.

– 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.

– (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.

– (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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Case: Not disclosed

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Inadequate Calibration SOP– Not enough information to ensure instrument is calibrated correctly.

Calibration Definition– Calibration is Comparison

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Case: Not disclosed

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ISO/IEC 17025:2017 – Equipment “Shall”:

– Specific written directions

– Defined accuracy

– Provisions for remedial action

– Documented calibration records

– Traceable calibrations, including measurement uncertainty

– “Metrological Traceability”

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Case: Not disclosed

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Metrological Traceability

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Calibration = Comparison

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BEFORE:Known &

Accurate Quantity Unknown Quantityvs.

REFERENCE Unit Under Test

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Known & Accurate Quantity Known Quantityvs.

BEFORE:

AFTER:

Known & Accurate Quantity Unknown Quantityvs.


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BEFORE:

AFTER:



XUncertainty Y X + Y+

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BEFORE:

AFTER:



XY

X+Y

XUncertainty Y X + Y+

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Warning Letter #7

Company makes dental implants.– 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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Product: Medical Device Where: China When: 2016


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21 CFR 820.72 (a) 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.

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You must do what SOP says you will do, even if not required by GxP– You make it GxP when you put it in SOP.

Calibration Stickers– Calibration information must be readily available– It must be easy to determine calibration status of instrument

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7 Warning Letters1. 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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Overall Summary Reviewed calibration regulations worldwide. Reviewed the regulatory process leading to inspections. Looked at the results of 7 inspections: Warning Letters Each letter was an example of a calibration failure Every failure was related to documentation

– No procedure– Not following procedure properly– Following inadequate procedure

Documentation is the basis for compliance in everything, including calibration.

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Heather WadeMetrology ConsultantThe Heather Wade Groupwww.heatherwadegroup.com

Email: [email protected]

Thanks for Attending!

Paul DanielSr. GxP Regulatory ExpertVaisala, Inc.

Email: [email protected]

Documents

GxP-Compliant Calibration - Vaisala · – (b)(1) Calibration Standards: Calibration standards used for inspection, measuring, and test equipment shall be traceable to national or