Lessons from Pharmaceutical Laboratory related FDA Warning ... · • Incudes statements of non-compliance with GMP and positive GMP certificates • Information includes company

1

Lessons from Pharmaceutical Laboratory

related FDA Warning Letters

Ludwig Huber

[email protected]

The Agilent Pharma Compliance Seminar 2015

© Copyright Ludwig Huber - LabCompliance Slide 2

Overview

• FDA Inspections and reports

• GMP compliance along the sample and data workflow

• Recent FDA warning letters & 483s and recommendations

how to avoid FDA warning letters related to

– Requirements for quality systems

– Requirements applicable for every workflow step

– Requirements applicable for individual workflow steps

• Responding to Warning Letters and 483’s

• Preparing the laboratory for FDA and equivalent

international GMP inspections

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FDA Inspection Documentation

• 483 Form Inspection Observation

– only deviations listed

– written for inspection exit meeting

• Establishment Inspection Report (EIR)

– very detailed (20-40 pages)

– more like an inspection protocol

• Warning letter

– With significant deviations

– Reviewed by FDA centers

For examples, please check: www.fdawarningletter.com


483 Form Inspection Observations

• Written during or after the inspection

• Discussed with and handed out to the user firm in the inspection exit meeting

• May reflects the view of the inspection team

• Major problem: inconsistency

• Available to the public, including to competition, through FOI (Freedom of information)

• Can have negative impact on company’s reputation

• Can have other consequences: withholding product approvals

• Companies are advised to respond within 15 days

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Establishment Inspection Reports (EIR)

• Written when the inspector is back in the office

• Very detailed inspection protocol, e.g., lists

question/answers and positive and negative

findings

• Reviewed by regional headquarter office

• Helpful in preparation for FDA inspections

• Available through FOI and private service providers

(e.g., some are listed on

www.fdawarningletter.com)


Warning Letters

• Issued in case of severe deviations

• Reviewed by higher level FDA officials

• Frequently make reference to 483 inspection observations and to company responses

• Companies are advised to respond within 15 days

• Typically follow inspection scheduled

• The FDA publishes warning letters on two websites– http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/

– http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/default.htm

www.fdawarningletter.com

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/default.htm

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What about Europe

• EMA launched new version of the EudraGMDP

website

• Incudes statements of non-compliance with GMP and

positive GMP certificates

• Information includes company name, location, issue

date, nature of no-compliance and the action taken

by issuing authority in order to protect public health

• Examples for actions taken

– Withdrawal of current valid GMP certificate

number

– Batch recallhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2

013/12/news_detail_001994.jsp&mid=WC0b01ac058004d5c1#press-release


Example from EudraGMDP Website

Nature of non-compliance : It was

not possible to confirm the validity

of stability testing data. Several

falsified and inaccurate results had

been reported in long term stability

and batch testing. Discrepancies

between electronic data and those

results formally reported were

identified.

Issue Date

March 21

2014

Company and location

5

© Copyright Ludwig Huber - LabCompliance

Consequences of Non-Compliance

• 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

Slide 9


Typical Warning Letter Statement

• Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations.

• Include an explanation of each step taken to prevent the recurrence of violations and copies of supporting documentation.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289224.htm

http://www.fiercepharmamanufacturing.com/story/ranbaxy-fda-enter-consent-decree-over-gmp-data-breaches/2012-01-26

http://www.bloomberg.com/news/2012-01-26/ranbaxy-reaches-agreement-with-u-s-over-alleged-violations-at-drug-plants.html

ttp://www.bloomberg.com/news/2012-01-26/ranbaxy-reaches-agreement-with-u-s-over-alleged-violations-at-drug-plants.html

http://www.financialexpress.com/news/ranbaxy-labs-to-pay-up-to-500m-fine-in-settlement-with-us-fda-forecast-cut/890582/

http://www.financialexpress.com/news/ranbaxy-labs-to-pay-up-to-500m-fine-in-settlement-with-us-fda-forecast-cut/890582/

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Responding to Deviation Findings

• During the inspection before the inspection

observation has been drafted

• In response to the 483 inspection

observations

– Not legally required but recommended to

reply within 15 days

• In response to warning letters

– Legally required: 15 days

• Through other communications with the FDA


Missing Roles and Responsibilities

Reference: www.fdawarningletter.com (242)

• Deviation

Data security protocols are not established that describe the user's

roles and responsibilities in terms of privileges to access, change,

modify, create, and delete projects and data (242)

• Root Cause (assumed)

The company was not aware that user roles and privileges need to be

defined

• Corrective actions

- Develop procedure to define access levels and user rights

- Upgrade the system with suitable software-

- Implement the procedure for the inspected system

• Preventive actions

Implement the procedure on all regulated computer systems

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© Copyright Ludwig Huber - LabComplianceSlide 13

Compliance across the GMP Lab

SamplingSample

handlingTesting Test reports

Record

maintenance

Sampling plan &

representative

sampling, statistics

reserve samples

Sample

identification &

protection of

sample integrity

Monitoring the

quality of test

results, generate

complete records

Test conditions

& test results, data

review, handling

OOS & OOT

Ensure

record

integrity &

security

GMP controls across all workflow steps

• Validation of analytical

methods & procedures

• Equipment calibration

testing & maintenance

• Qualification of material

• Traceability

• Handling Out-of-specification

results

• Qualification of personnel

• Controlled environmental

conditions

• Written procedures

Quality system controls across the laboratory

Documentation control, corrective & preventive actions, complaint handling,

supplier & subcontractor management, internal audits, change management,

management reviews, continuous improvement, product reviews

Slide 13

Trace forwardTrace backward

Slide 13


Poor Quality System • It is apparent that you have not implemented

a robust quality system at your firm.

• Be advised that corporate management is responsible

for ensuring the quality, safety, and integrity of drugs

• FDA strongly recommends that your corporate

management immediately undertake a comprehensive

evaluation of global manufacturing operations to ensure

compliance with CGMP regulations (W-287)

Corporate initiates implementing a global quality system

using ICH Q10 “Pharmaceutical Quality Systems” as a

guidance.

Make sure that the quality system is understood,

implemented and maintained

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Responsibilities not Defined

• 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)

• Failure to have a document, which delineates the responsibilities and procedures applicable to the quality control unit (W-044)

Define written roles and responsibilities for each

person and function in quality assurance, quality

control and for technical management


Inadequate Document Control

• Your firm failed to establish and maintain adequate procedures to control documents and ensure all obsolete documents are promptly removed from use or otherwise prevented from unintended use (W-212)

Describe how written documents are initiated,

authored, reviewed, approved distributed and regularly

reviewed and updated

Describe how staff is trained on new and updated

procedures and how obsolete procedures are removed


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SOPs not Followed

• Failure to establish control procedures designed to assure batch uniformity and the integrity of drug products (W-066)

• Operations and QC personnel failed to follow procedures in the conduct of the last three GC Calibrations (W-240)

Verify through internal audits that written procedures are

Available for all critical routine tasks

Accurate (compliant with GMP)

Understood

Followed


No on-going GMP Training

• Our review of your firm's training program disclosed that

there was no requirement for on-going CGMP training of

employees.

• The firm only had an initial CGMP training and did not

provide regular CGMP training to all employees involved

in the manufacture of drug products.

• There is no reference to CGMP training of supervisors or

directors. (W-219)

Include in the training program a schedule for regular

cGMP training

Make sure everybody working under GMP attends all GMP

trainings, including supervisors and directors, and IT

personnel

Slide 18

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No Supplier Quality Agreement

• Failure to establish and maintain the requirements, including

quality requirements that must be met by suppliers.

• For example, your firm has not specified quality requirements

for suppliers, maintained lists of approved suppliers and

developed written procedures describing how suppliers are

evaluated for quality acceptance requirements (W-048).

Develop an SOP for assessment of material suppliers

Include a list with quality requirements

Develop and maintain a list of approved suppliers

Slide 19


No Qualification of Material

• 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)


Develop a procedure to ensure the quality of incoming

material through

Testing of the incoming material or

Supplier assessment and agreements

A combination of the above

Slide 20

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Contract Laboratories not Qualified• Your firm did not qualify the contract laboratories used for

the testing.

It is FDA's expectation that your firm have a quality

agreement with the contract laboratories in place.

We recommend that this agreement be signed by all parties

involved and that it include, as a minimum, specific details

delineating the roles and responsibilities of each party

And a description of the materials, services,

communication, and all testing expected to be performed

by each party should also be included. (W-219).

Slide 21

Assess conformity to the agreement through audits


No Documentation of Chemicals, Reagents, Solutions

• During the laboratory walkthrough, several solutions were

observed inside the refrigerator, with precipitation, that

apparently are uses for system suitability testing with no

indication of preparation date, lot number, and expiry

dates (W-241)

Develop a procedure to document material, e.g.,

chemicals, reagents, solutions and standards indicating the

Preparation date

Expirations date

Lot number

Storage conditions (temperature, humidity, light)

Slide 22

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Method Validation

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

The FDA frequently mentions these four parameters as the

only required validation parameters, They are listed in CFR

211 but not sufficient. You need to do more

Study ICH Q2 and USP 1225 and develop an SOP

accordingly

Start looking at the new FDA Method Validation guidance

from 2014, It has modern elements as Quality by Design,

Design of Experiments, and integrated lifecycle

management


No Forced Degradation for Stability Indicating Methods

• During the inspection your firm could not provide forced degradation data to support suitability of the HPLC test method for stability testing (W-274)

Proof the suitability of the testing method for stability

testing through the use of forced degaradation samples

When transferring stability indication methods between

laboratories proof the suitability of the receiving

laboratory through succesful testing of degradation

products .

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Compendial Methods not Verified

• Method verifications for compendial tests are not performed. Any method, including compendial methods, must be verified as suitable under actual conditions of use (W-274). .

Demonstrate that your laboratory is suitable to run

compendial methods under actual conditions of use

Follow USP general chapter <1226> as a guideline for

verification of compendial methods

Repeat one to three validation experiments

Using the risk based approach select validation studies

that are most difficult to pass.


No Formal Method Transfer• The firm failed to determine the acceptability of ten

methods prior to using them in the QC laboratory through formal method transfer procedures (282)

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

• Demonstrate that the receiving laboratory is suitable to

run the method under actual conditions of use

Follow USP general chapter <1224> as a guideline for

transfer of analytical method

Unless there is any specific reason not to do so, use

the comparative testing approach for the transfer .

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No Equipment Qualification Program

• The calibration procedure for HPLC systems is inadequate in that it did not include the detector’s linearity, injector’s reproducibility, and accuracy of temperature settings for the column heater (W-097)

• Failure to have an adequate qualification (calibration) program for the QC laboratory instruments.(W-246)

Use the USP <1058> approach for analytical

equipment qualification and calibration.

Use the equipment supplier‘s test procedures and/or

qualification services to ensure FDA compliant testing


Equipment Qualification Raw Data Missing

• You were unable to provide raw data or documentation regarding the qualification and calibration of your instruments and data to demonstrate that your quality unit reviewed and approved the work performed by your contractor. (w-246)

Make sure that the qualification records are complete

Develop an SOP that defines what constitutes a

complete record for each qualified instrument.

Examples are (electronic) raw data, supporting material

such as chromatograms and spectra, signatures of the

engineer who performed the qualification and the

signature of a reviewer.

15


Equipment Failures not Investigated

• Deviations pertaining to laboratory equipment failures were not investigated. During the review of the service report log books for HPLC and GC units, the investigator found many instances of servicing due to instrument problems that were not documented as deviations(W-287).

Record and Investigate any equipment malfunction that

may have an impact on quality control testing

Investigation should include an evaluation if the quality

of test results, generated at or before the malfunction,

could have been impacted..


No Failure Investigations for failed Calibrations

• There was no documentation that an investigation was conducted to determine the root cause of the failed calibrations of the Gas Chromatograph.

• In addition, your firm failed to implement adequate corrective action to prevent re-occurrence..(W-240)

In case of failed equipment calibration

identify the root cause why this happened

develop and implement a corrective action plan

develop and implement preventive action plan

verify the corrective and preventive action plans for

effectiveness

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No Measures for Equipment Performance Qualification

• The HPLC performance qualification lacks sample energy (intensity of light source), and lamp use hours determination. (W-246)

Establish a performance qualification program to ensure that

the equipment runs on a day-by-day basis without any

problem

Put controls into the system that measures the performance

of critical parts such as the lamp which has a direct impact

on the limit of detection and limit of quantitation.

The lamp usage time is one possibility but measurement of the

on-going lamp energy or the HPLC baseline noise is more

meaningful.


No Computer Validation at the Users Site

• During the inspection, I asked if the computer software has been

validation to assure that it performs for it's intended use.

• I was told that the software was validated by the manufacturer.

The managing director provided me a copy of the letter the

received from (the vendor).

• The letter indicated that the software was validated. She also

gave me a copy of validation information that was obtained from

(the vendor) during the inspection. (W-191)

I told the managing director I still need to see what

they have done to validate the system since the

computer was making a decision to accept or reject

potential donors

Slide 32

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Excel Spreadsheets not Validated and Controlled

• The calculation for residual solvent uses an Excel

spreadsheet that has not been qualified. We are concerned

about the data generated by your QC laboratory from non-

qualified and uncontrolled spreadsheets

• The use of the Excel® spreadsheets in analytical calculations

are neither controlled nor protected from modifications or

deletion (W-286)

Develop an SOP: “Validation and Control of Spreadsheet

Application with recommendations for

Validation using the lifecycle approach (DQ/IQ/OQ/PQ)

Control focusing on security and integrity of records

and spreadsheets

Slide 33


No Statistical Rational for Representative Sampling

• Your rationale for inspection of reserve samples is not based

on acceptable statistical sound assessment (W- 266)

• Failure to collect a sufficient number of samples based on a

validated statistical plan. (W-186)

• Samples taken of drug products are not representative and

properly identified. (W-266)

• Please provide scientific rationale for your current sampling

procedure and any revised SOPs with supportive documents.

(W-245)

Develop valid statistical controls, e.g., for

Sampling plans for drug products and for

Visual inspections of reserve samples

Slide 34

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Inadequate System Suitability Testing

• Methods do not include system suitability tests to ensure that

the system is operating properly (W-162)

• No System Suitability performance before running testing (132)

• The SOP requirement for the assay analysis of xxx was not

followed in that the HPLC system suitability test was only

performed weekly per firm SOP, instead of the actual time of

testing (W-133)

Develop a procedure for system suitability testing

What needs to be tested – check USP chapter 621

When should the test be done – what frequency

Make sure the SOP is followed

Slide 35


Trial Sample Injections not Recorded

• Our investigators identified your practice of performing trial

sample injections for HPLC analyses.

• For example, trial injections of stability samples were

acquired in the “Test” folder prior to official testing.

Immediately after the trial injections were completed, the

official samples were analyzed.

• The trial injection raw data, captured in the back-up files,

were deleted from the test folder. (W-295)

Develop a procedure to determine instrument readiness

Equilibrate the complete system without sample

injections, but under real HPLC conditions

Run system suitability test runs

Store all data in a sample folder and review the data

Slide 36

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Selective System Suitability Test Results discarded

• Your analyst selectively invalidated data during related

substance testing. For example, for (b)(4), batch (b)(4) on May

15, 2013; you did not retain data from all six injections used

for the initial system suitability. Your analyst discarded one of

the six injections performed with no justification. (W-294)

Develop a procedure for system suitability testing

Follow USP 621 for conducting the tests

Ensure that all SST runs are recorded

Investigate failed runs

Stop sample analysis after failed runs

Slide 37


No Procedure for Chromatographic Peak Integration and Re-integration• The inspector documented that HPLC processing methods

(including integration parameters) and re-integrations are

executed without a pre-defined, scientifically valid procedure

• A QC operator interviewed during the inspection stated that

integrations are performed and re-performed until the

chromatographic peaks are “good”, but was unable to

provide an explanation for the manner in which integration is

performed.. (W-287)

Optimize chromatography to avoid re-integration

Develop a prodecure for integration and re-integration

Define when special authorization is required

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No SOP and Inadequate Handling of Out-of-Trend Results

• There is no standard operating procedure in

place that describes the steps to be followed during

an Out-of-Trend (OOT) Investigation

• Besides, the "OOT Investigation"

performed was inadequate. (W-241)

1. Study requirements for handling OOT results

2. Develop an SOP for FDA compliant handling OOT

results


Incomplete Laboratory Test Records • 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)

Make sure that the laboratory test records are complete

Develop an SOP that defines what constitutes a complete

test record, check 21 CFR 211.194(a)

Examples are (electronic) raw data, supporting material

such as chromatograms and spectra, signatures of the

analyst who performed the test and the signature of a

reviewer.

The reviewer checks if all ‚required records‘ are available

Slide 40

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Incomplete Raw Data

• Your Quality Unit failed to provide all spectra and raw data associated to the reports. (W-248)

• The laboratory records do not include raw data to support the evidence of sample preparation, standards preparation and did not include a statement of the weight or measure of the samples used for each test (W-248)

Make sure that the laboratory raw data are complete

either in paper or in electronic form

Develop an SOP that defines what constitute complete

raw data, check 21 CFR 211.194(a)

For examples see above


Electronic Raw Data not Saved

• Operating parameters of the spectroscopy system were

maintained with the relevant test records. However,

electronic raw data was not saved (W-167).

21 CFR Part 211: (e) requires that complete records shall be

maintained of all stability testing performed in accordance

with Sec. 211.194 (e)..

Develop a policy and procedure that for HPLC data

electronic records must be saved and available for

inspectors

Slide 42

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Missing Audit Trail

• Data stored on the computer can be deleted, removed,

transferred, renamed or altered (W-209)

• There is no audit trail or log of data changes that are

made to the information in the database. (W-224)

Develop procedural and technical controls to ensure

electronic audit trail

Include audit trail in the URS

Make sure that the audit trail function can not be

switched off by the operator

Validate audit trail function


Electronic Audit Trail not Reviewed

• 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 a procedure for reviewing electronic audit trail

Inform you laboratory staff that audit trails are

reviewed

Include audit trail review as checklist item in regular

data review and approval

Ask software suppliers to handle creation and review

of audit trail tables more user friendly

Slide 44

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Manipulation of Printed Raw Data

• Your firm's laboratory analyst had modified printed raw

data related to the IR Spectra test

• Your quality control unit failed to detect that IR spectra

were being substituted by a laboratory employee and detect

the manipulation or alteration of laboratory documents

Use internal or external data integrity specialists

to review and aprove critical records

The specialists should also look at historical data

Slide 45

We highly recommend that you hire a third party

auditor, with experience in detecting data integrity

problems (W-230)


Summary GMP Issues Related to Laboratories• Written procedures (SOPs)

• Supplier assessment

• Material qualification

• OOS/failure investigations

• Equipment qualification

• Method validation

• System suitability testing

• Review of data

• Archiving of data

• Data integrity and security

• Personnel – Training


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Responding to Inspection Deviations

• Fully understand the content of each deviation in the exit meeting

• Respond in time (15 days for FDA Warning Letters and 483s)

• Address each item separately in the response

• Start with a statement that you understand and accept the deviation

• If some deviations are already fixed, provide documented evidence

• For others write how you will correct the deviation: Who, how, when

• Attach preliminary documentation for the corrections, if available

• Commit to train all affected personnel

• Write how you will prevent the same of similar problem re-occurring

(preventive action)

• Write how to evaliate and follow-up on past shipments (historical

data)


Global Response to the same and similar deficiencies

• Although your corrective actions may adequately

address the protection of the (b)(4) computer

from non-traceable changes, your firm has not

taken a global approach to this deficiency. It is

our expectation that your other manufacturing

and laboratory computerized systems will be

reviewed to ensure similar deficiencies do

not exist (FDA WL-253).

25


‘Inspection’ Like Internal Audits

• Opening meeting with management• Review last audit and corrective actions• Review organizational structure, tasks and

responsibilities• High level documentation, e.g., quality plan• Review selected procedures• Review selected records• Walk through the operation• Observe and interview people at work• Exit meeting with management• Follow-up activities


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

– Compliance by Design“ for Quality Control Laboratories:

Learning from FDA Warning Letters

Other Resources

– Tutorials (method validation, computer validation, GLP)

– References to FDA Warning letters and 483s

– Free Labcompliance Newsletter

www.labcompliance.com/agilent

(available until September 30, 2015)

Slide 50

http://www.labcompliance.com/agilent

26


Thank You

I would like to thank

• All attendees for your attention

• Agilent Technologies for invitation and organization

Slide

51

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Documents

Lessons from Pharmaceutical Laboratory related FDA Warning ... · • Incudes statements of non-compliance with GMP and positive GMP certificates • Information includes company