FDA/EU Compliance for Quality Control Laboratories Page 1 Ludwig Huber Phone: +49 7902 980582 E-mail: [email protected] Ludwig Huber, Ph.D

FDA/EU Compliance for Quality Control Laboratories

Page 1

Ludwig HuberPhone: +49 7902 980582E-mail: [email protected]

Ludwig Huber, Ph.DChief Advisor, Global FDA Compliance

© Copyright Ludwig Huber - LabCompliance Slide 2

Overview• Planning for GMP compliance• Develop procedure and other documents• Building the right laboratory organization• Qualify personnel and document qualification• Qualify suppliers and materials• Validate analytical methods• Calibrate and qualify equipment and computer

systems• Implement procedures for sampling and sample

analysis• Implement procedures for data review, approval

and archiving

© Copyright Ludwig Huber - LabCompliance

GMP and ISO 17025 Laboratory Compliance

SamplingSample

handling&storage

TestingData review

and approval

Record archiving

Compliance across all workflow steps

• Validation of analytical methods & procedures

• Equipment calibration testing & maintenance

• Qualification of material• Traceability• Control of non-conforming

testing

• Qualification of personnel• Controlled environmental

conditions• Written procedures

RepresentativeSamplingSampling plan

Avoid cross ContaminationEnsure sample integrity

Clear specifications& test protocols

Primary & secondary reviewHandling OOS

Ensure data Integrity @ availability

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Plan for GMP/ISO 17025 Compliance Compliance master plan / Quality Plan

• Guideline for effective and consistent implementation of GMP regulation

• Documents the laboratory’s approach for compliance

• Ensures efficiency AND consistency

• Useful for audits to explain the laboratory’s approach towards compliance

Project Plan

• Outlines steps, tasks, deliverables and owners


Contents of the Master/Quality Plan• Policy• Quality management documentation• Organization and responsibilities• Staffing and people qualification• Selection and validation of analytical methods• Equipment and computers• Sampling and sample handling• Reagents and calibration standards• Testing• Handling non-conformance• Reporting and archiving

or


Develop Procedures and other Documents

High level, strategic documentation(regulations, business, quality)

Process related documentation, approaches(SOPs)

TrainingMaintenance

Validation, Audits

Product test records, batch records, validation results,

training records, chromatograms

Test proceduresOperation manuals,

QC procedures

PolicyMaster Plan

Product/event related documentation(work instructions, also called SOPsor test scripts, protocols)

Compliance Records(batch/event related documentation)

Wri

tten

pro

cedu

res

Use the same set throughout the organization


Build the Right Organizational Structure and Assign Tasks (Example)

Director

Finance & Admin.

Human Resources

Laboratory Mgmt.

Quality Assurance

IT/ISSafety Officer

Lab 1 Lab 2 Lab 3

Avoid Conflicts of Interest


Qualify Personnel

1. Define requirements - what is the assigned task?

2. Identify knowledge3. Determine gaps4. Make a plan to fill the gaps5. Train6. Evaluate training7. Document

1/2 year or yearly reviews

Job description


Documenting Training

Job description

Qualification requirements

Name

Education

Experience

Gaps, Trainings plan

Trainings

Type, content

Supervisor(name, signature)

DateDuration

This documentation should be kept separated from other personnel files, for example performance evaluations


1. Documenting internal and external experience

2. Mail audit with follow up

3. Direct audit

Slide 10

#3. is most time consuming and recommended for high volume and high risk suppliers

Criteria• Product risk• Supplier risk

Qualify Suppliers and Materials


Incoming Quality Control of Material

• Purchase from qualified suppliers• Limited sample testing• Number of tests depend on

– Criticality of reference material– Experience with the supplier– Experience with initial tests

• Retest after specified time period (e.g., after one year)

Slide 11


Preparation of Working Standards

Company Internal Reference Material

Primary Standard

Working Standard

Method Validation

Certified Reference Material

Equipment Calibration

System Performance Check

Secondary Standard


Definition Method Scope

Define Validation Criteria

Test

Define Routine Tests

Validate Analytical Methods

Sample matrix Compounds Equipment, Location

Optimize method parameters Define performance

characteristics Acceptance criteria Develop test cases Preliminary tests Final tests SOPs System Suitability tests Analytical quality control


Method Parameters and Tests

Parameter Tests (examples)

Accuracy Minimum at 3 concentrations, 3 replicates

Precision

RepeatabilityIntermediate

Reproducibility

Minimum of 9 determinations over the specified rangeOver 3 days, 2 operators, 2 instruments,

Only required if testing is done in different laboratories

Specificity Prove with specific methods: HPLC, DAD, MS, dif. columns

Limit of detection Visual approach, S/N >= 3

Limit of Quantitation S/N >= 10, Standard deviation of response

Linearity Min 5 concentrations: visual, correlation coefficient (r)

Range 80 to 120% of test concentration, from linearity tests

Well Characterized Biological Products


Intermediate Precision ExampleSample Day Operator Instrument

100% conc. (3x) 1 1 1

100% conc. (3x) 1 2 2

100% conc. (3x) 1 3 3

100% conc. (3x) 2 1 2

100% conc. (3x) 2 2 3

100% conc. (3x) 2 3 1

100% conc. (3x) 3 1 3

100% conc. (3x) 3 2 1

100% conc. (3x) 3 3 2

• Minimum: 2 days, 2 operators, 2 instruments, • Calculate overall RSD


Examples for Acceptance Criteria

Parameter Test

Accuracy 90 – 110%, 80 – 120% at specifications limit

Precision

RepeatabilityIntermediate

Reproducibility

<1.5 % RSD (up to 15% at LOQ)<2.0 % RSD (higher at LOQ)< 3% RSD (higher at LOQ)

SpecificityPeak resolution >1.5 (related substances)

or >2 (main peak)Peak purity check with UV DAD or MS

Limit of Detection N/A

Limit of Quantitation 0.05%

Linearity visual inspection of linearity curve, r>0.9900

Range o.k. if accuracy, precision, linearity criteria are met

Quantitative Impurities in Finished Drugs


Example: Report Summary TableValidation Parameter

Measure Acceptance criteria Results

Accuracy

Recovery – Conc1

Recovery – Conc2

Recovery – Conc3

97 – 103 %

97 – 103 %

97 – 103 %

99%

100%

100%Method

PrecisionRSD ≤ 1.5 % 0.4%

Intermediate Precision

RSD ≤ 2.0 % 0.8%

Specificity Peak Resolution Factor R R for all peaks >1.5 All peaks >2.0

LinearityCorrelation Coefficient

Visual inspection of plot

≥ 0.9900

Linear response plot

0.9900

Shows linearity

Range

Correlation Coefficient

Precision at 3 concentrations

Recovery at 3 Conc.

≥ 0.9900

≤ 1.5 %

97 – 103%

0.9900

<1%

99.6%

Robustness

Column Temp. ±2 C

Mobile Phase ±2 %

Sample extraction time -20 %

Compound stability 6 days

R for all peaks >1.5


Recovery in spec.

<3% degradation


R for all l peaks >2.0

Recovery in spec

<2% degradation


Maintain, Calibrate and Qualify Equipment and Computers

• Develop procedures for equipment purchasing, qualification, calibration and maintenance

• Qualify the equipment

• Identify defect or non-qualified equipment

• Develop and implement maintenance and qualification schedule

• Keep equipment under change control and re-qualify, if necessary

• Record changes


Design Qualification

Installation Qualification

Operational Qualification

Performance Qualification

Equipment Qualification - 4Q Model User requirement specifications Functional specifications Operational specifications Vendor qualification

Check arrival as purchased Check proper installation of

hardware and software

Test of operational functions Performance testing Test of security functions

Test for specified application Preventive maintenance On-going performance tests


OQ Test - Example

Date Weight 1Weight 2 Test engineerName Signature

Weight 3 o.k.

yes9999.8 999.9 100.0 Hughes2/3/06

Instrument BestBalance

Serial number 55236A

Maximal weight 11 g

Control weight 1 10,000 mg Limit +-10 mg

Control weight 2 1,000 mg Limit: +-1 mg

Control weight 3 100 mg Limit: +- 0.1 mg


Why Companies in EU/US Choose Manufacturers Operational Qualification ServicesTools•Some tests require traceable test tools•The tools typically need to be calibrated yearlyQualification•Test engineers must be formally qualified•Training must be regularly updated and thoroughly documented•Manufacturer engineer bring qualification certificates along•Manufacturer engineers can fix problems if OQ does not passDocumentation•Vendors provide inspection ready documentation Compliance•There are many FDA warning letters based on user’s OQ•I am not aware of a vendor’s OQ based warning letter


Documentation of On-going PQ Testing

Example: HPLC System

Test # Date Time T10 T11 T12 T13 T14 Comment

Bl noise

Tailingfactor

Peak resol

Precis.#1

Precis.#2

mm/day

a=amp=pm

AcceptLimit<1x10-4

Accept Limit<1.3

Accept Limit>2.0

Accept Limit<1%

Accept Limit<1%

Passed/failed

Test #

Date Time T10 T11 T12 T13 T14 Comment

001 08/04 06.20 p 4.5x10-5 1.1 2.3 0.61 0.50 passed

002

003

004

System Suitability Testing. Day-by-Day


Configuration

Installation Qualification

Operational Qualification

Performance Qualification

Computer System Validation Phases

Configuration design Configuration implementation

Check arrival as purchased Check proper installation of

hardware and software

Test of configuration specifications Test of functional specifications Test of security functions Test for user requirement

specifications Preventive maintenance

Design Qualification User requirement specifications Functional/config. specifications Vendor qualification


Implement Procedures for Sample Analysis

• Sampling• Sample handling• Testing• Data review and approval

SamplingSample

handling&storage

TestingData review

and approval


Sampling • Sampling process well planned, executed according

to the plan and documented in the sampling protocol

• Clean equipment to avoidcross contamination

• Representative

• Sample location well defined

• Sampling should not change properties

• Should protect people taking the sample

SamplingSample

handling&storage

TestingData review

and approval


Reserve Samples (GMP only)

• Samples used for retesting of the original sample if the initial test results is non-conforming (out of specifications) in the event of customer complaints

• Typical amount: 1.5 x sample amount• Should be visually inspected for deterioration

at least once a year


Sample Testing• Develop test program for APIs, finished drugs,

raw material

• Develop clear specifications

• Document acceptance criteria and actual results

• Document test procedures and test equipment

• Formally review and approve test results

– Analysts

– Second person (technical & independent reviewer)

• Document test conditions with test results

SamplingSample

handling&storage

TestingData review

and approval


Review and Approval of Test Results

• Develop and follow procedure for review

of test results • Review by the analyst: what to look

at, how to document • Review and approval by a second person • Release of test results

SamplingSample

handling&storage

TestingData review

and approval


Handling Failure Investigations / Out-of-Specification Test Results• Investigation required if a test result is out of specification

• Required to identify the root cause of a problem

• Should follow documented procedure

• Failure can be caused by individual testing, process error, or product problem

• Maintain a list of all OOS test results

• Corrective and Preventive Action Plans, Root Cause Analysis

Follow FDA Guide: Investigating out of Specifications Test Results for Pharmaceutical Production


Tasks and Responsibilities of the Analyst• Perform test correctly

- be aware of potential problems- follow SOPs- follow good science

• Stop testing in case of OOS results• Inform supervisor about OOS results• Retain test preparations

- until data is reviewed and investigation is finished

• Conducts and documents OOS, each step of laboratory failure investigations and investigation results


(e)-Records Maintenance and Archiving• Study regulations: which records are required, for how long should

they be archived?

• Define raw data

• Ensure track-ability of final results to raw data

• Maintain integrity of data

• When using electronic records, follow Part 11

• Ensure that electronic audit trail is available, activated and reviewed

• Develop a strategy and procedures for backup, archiving and retrieval of data

SamplingSample

handling&storage

TestingData review

and approval

Record archiving


Conduct Internal Laboratory Audits

• Should be part of any good quality system

• Develop audit plan and schedule

• Develop and implement a corrective and preventive action plan

• Plan for follow up inspections

• Conduct audit like FDA inspections

• Develop table of contents for each audit report


Audit Documents for Internal and External Inspections

• Organization charts• Standard Operating Procedures• Study protocol• Data storage worksheets

• Notebooks: paper and/or electronic• Analytical raw data• Instrument qualification, calibration and maintenance protocols• Records on personnel qualification


Prepare Your Organization for FDA and other Inspections

• Develop SOP for FDA inspections• Develop Checklist • Train management and staff• Conduct ‘FDA inspection like’ internal

audits• Establish an audit response team• Review previous inspections and corrective

actions• Reserve and prepare meeting rooms

Slide 34


Raw Data (1996)

• Operating parameters were maintained with the relevant xxx. However, electronic raw data was not saved (W-167).

21 CFR Part 211: (e) Complete records shall be maintained of all stability testing performed in accordance with Sec. 211.194 (e).

Study regulation and check if the print-out has all records

Slide 35


FDA Enforcement: Mio$ 500 Fine

• FDA Press release on Jan 25, 2012• Prevents temporary import for products from two sites in India• Causes pay cut for company executives and directors• Ranbaxy to hire consultant with expertise in data integrity• Possible delay of generic versions of blockbuster drugs (e.g.

Lipitor) with uncalculatabled costs

30 products were banned from the US market•GMP violations•Inadequate testing•Falsified data•Data integrity issues


Raw Data (May 2013)• During an audit of the data submitted in support of

the xxx tablets, our investigator requested to review the electronic analytical raw data to compare the values for (b)(4) assay and degradation products. However, your firm provided only the printed copies of the raw data because your firm did not have the software program available to view the electronic raw data.

Study regulation and check if the print-out has all records

Slide 37


Resources• Agilent Primers

– Analytical Instrument Qualification and System Validation)– Validation of Analytical Methods– Good Laboratory Practice and Good Manufacturing Practice– Understanding and Implementing ISO/IEC 17025– Compliance for BioPharmaceutical Laboratories– Qualification and Validation for Supercritical Fluid Chromatography– Elemental Impurity Analysis in Regulated Pharmaceutical Laboratories – Genotoxic impurities in pharmaceutical products

• Free tutorials (method validation, computer validation, GLP)www.labcompliance.com/tutorial

• Seminar reference material, e.g., ppt presentations

www.labcompliance.com/agilent (available until July 15, 2015

Slide 38


Thank your very much for your attention.

Page 39


Thank YouI would like to thank • All attendees for your attention• Agilent Technologies for invitation and organization

Check topics and details of 100+ audio/video seminarsAudio: www.labcompliance.com/seminars/audioVideo: www.labcompliance.com/seminars/video

Give feedback and choose any two from over 150 documents(value: $138) for free: SOPS and/or Validation examples.GOTO: www.labcompliance.com/misc/conferences/feedback.aspxoffer expires on July 15, 2013

Slide 40Ludwig Huber


Appendix

Slide 41

Examples for FDA Warning Letters related to

Laboratories and how to avoid them

Reference: www.fdawarningletter.de


Training

Ref: www.fdawarningletter.com (W-228)

• Failure to adequately establish procedures for identifying training needs and ensure all personnel are trained to adequately perform their assigned responsibilities and the training is documented (228)

• Your firm fails to document on the job training.(228)

• Your firm failed to list second shift quality personnel, their positions, and to whom they report within the corporate quality structure.(228)

1. Develop a training plan for each employee with identification of training needs

2. Document all training activities including on the job training and training of shift workers

Slide 42


Supplier and Material Qualification

• There is no assurance that your firm establishes the reliability of the supplier's analyses through appropriate validation of the supplier’s test results at appropriate intervals (W-245)

• There are no incoming component specifications for acceptance and no supplier quality agreements (W-254)

Ref: www.fdawarningletter.com (W-228)

1. Develop and implement a supplier assessment program2. Regularly test incoming material

Slide 43


Method Validation

• The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented (W-187)

• Failure of your quality control unit/laboratory to ensure your analytical methods used to evaluate the stability of your APIs are validated to be stability indicating. (W-243)

1. Develop procedure for validation of analytical methods2. Follow ICH Q2 for selecting test parameters and

conditions

Slide 44


Method Changes• Failure to maintain complete records of any modification of an

established method employed in testing [21 CFR § 211.194(b)] (W-171)

• Specifically, the records of laboratory methods stored in the xxx computer system do not include the identity of the person initiating method changes. (W-171)

• Appropriate controls are not exercised over computers or related systems to assure that changes in analytical methods or other control records are instituted only by authorized personnel. (W-171)

Develop SOP on how to authorize and document changes to analytical methods

Slide 45

© Copyright Ludwig Huber - LabComplianceSlide 46

Method Transfer

• The analytical method have not been transferred between the issued laboratory and the two chemists currently working in the QC laboratory. (W-241)

• The methods have been transferred before the two chemists were hired.

• There are no records which document training in the two procedures. (W-241)

• Methods that were validated at one facility and transferred to xxx site are being used without a methods transfer or revalidation protocol. (W-186)

Develop SOP for analytical method transfer. Follow USP <1224>, Train analysts in the receiving lab


Verification of Compendial Methods

Method verifications for compendial tests are not performed. Any method, including compendial methods, must be verified as suitable under actual conditions of use. This has not been done for any method provided by your clients. (W-247)

Develop procedures for verification of compendial methods following USP <1226>


FDA Warning Letter/483/EIR• Your firm failed to conduct injector and detector performance

testing for the HPLC system (221)

• For example, no HPLC injector and detector testing for linearity, accuracy, and precision were conducted, such as: 1) various injection volumes and standard concentration testing; 2) evaluation of detector for noise/drift; and 3) carryover testing to evaluate response at low levels to determine the detection of possible interferences that may affect peaks of interest (221)

Test HPLC for all parameters as specified

Slide 48


Equipment• Lacks documentation of installation and operation qualification of equipment (160)

• The Validation Master Plan does not contain an operational qualification for xxx (164)

• There is no requirement for a Performance Qualification protocol (164)

Ref: www.fdawarningletter.com

Perform IQ/OQ/PQ for Equipment

Slide 49


FDA Warning Letters - Equipment• Failure to have a complete calibration program for

the HPLCs in that the gradient accuracy and detector linearity is not being verified (W-110)

• The equipment xxxx used to analyze the Caffeine product was not calibrated prior to use. (W-019)

1. Learn about details of equipment qualification2. Develop, implement and enforce procedures

for equipment calibration and qualification

Slide 50


FDA Warning Letter/483/EIR• There was no documentation that an investigation was

conducted to determine the root cause of the failed calibrations of the Gas Chromatograph (GC)

• In addition, your firm failed to implement adequate corrective action to prevent recurrence.“ (WL-240)

1. Investigate and document the root cause for failed calibration and qualification

2. Develop a corrective action plan

Slide 51


FDA Warning Letter/483/EIR• The quality control unit failed to adequately train personnel to

perform their duties for Operation of the Gas Chromatograph, and failed to follow procedures in the conduct of GC Calibrations.

1. Train operators when conducting instrument qualification and document the training

2. Request training certificate when done by equipment suppliers

Slide 52


FDA Warning Letter/483/EIR• The calibration program for your stability chambers is

deficient ill that it does not include specific directions and schedules.

• You do not perform re-qualification of the stability chambers.

1. Develop a program for equipment calibration and calibration. Include a schedule

2. Conduct regular requalification of equipment

Slide 53


FDA Warning Letter/483/EIR

• No IQ, OQ or PQ has been performed throughout the life of the system. No validation reports have been generated historically (for the legacy system).

• The (system) has not been maintained under established procedures for change control. This is true throughout the life of this software application. (W-190)

Develop a procedure for validation and change control of legacy system.

Slide 54


FDA Warning Letter/483/EIR• The validation results do not meet the pre-determined

acceptance criteria, and there was no documentation why the results were acceptable. The validation reports do not contain an evaluation of the validation data and activities. Nor does it contain validation analyses and conclusion (W-204)

1. Develop a test plan. Part of it should be to define test cases acceptance criteria a procedure in case the criteria are not met.

2. During the review procedure, check if tests results meet acceptance criteria

Slide 55



Reference: www.fdawarningletter.com

• Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel (W-198).

• There were no written protocols to assign levels of responsibilities for the system (W-209)

Authorize users for specific functionsDefine user rights per procedure

Slide 56


Sampling, Sample Handling

• Failure to retain reserve samples of each batch of each API (W-173)

• Representative samples are not taken of each shipment of each lot of components for testing or examination (W-245)

• Certain elements of sample integrity are addressed in other SOPs, but none of the procedures explicitly call for maintaining sample integrity throughout the testing of the sample. (W-247)

Develop sampling plan and SOP for samplingEnsure representative sampling



• "System suitability conducted for Dissolution Assay per laboratory test methods evaluates only five replicate injections for Relative Standard Deviation (RSD). For NMT 3%. USP requires six replicate injections for instrument precision and accuracy“

1. Study USP requirements for System Suitability Testing2. Develop , implement and audit tests

Slide 58


Data Review • Laboratory records do not include the initials or signature

of a second person showing that the original records have been reviewed for accuracy, completeness and compliance with established standards. (W-241)

• In addition, your firm's review of laboratory data does not include a review of an audit trail or revision history to determine if unapproved changes have been made.. (W-229)

Develop SOP for data review by analyst and independent second personInclude review of electronic audit trail


Data Manipulation• Our investigators also found many instances with extensive

manipulation of data with no explanation regarding why the manipulation was conducted.

• This manipulation would include changing integration parameters or re-labeling peaks such that previously resolved peaks would not be integrated and included in the calculation for impurities (W-203)

Justify and document any data modification

Slide 60


FDA Warning Letter/483/EIR• Data stored on the computer can be deleted, removed, transferred,

renamed or altered (W-209)

• There should be a record of any data change made, the previous entry, who made the change, and when the change was made. (W-209)

• No software changes in the study data could be detected as there was no audit trail capability (W-185)

Record any changes to data in an audit trail

Reference: www.fdawarningletter.com

Slide 61



• There are no procedures for backing-up data files and no levels of security access established“ (W-138)

• You had not established an electronic data back-up procedure (W-185)

Procedures and technical controls for secure back-up

Slide 62


Data Archiving

• Records are issued from the record storage room without any written checkout procedures, and instead upon verbal direction by the QA manager. (W-247)

• The document control SOP lists “quality manager” and “technical manager” under“ Responsibility” for document control, but does not clarify the individual roles of each. (W-247)

Develop procedure with responsibilities and technical controls for data archiving

Slide 63