1 5 PQ Inspections

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Good Manufacturing Practices:

WHO Inspections

Tony Gould(Slides provided by Dr Andre van Zyl)


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2 | PQ Workshop, Abu Dhabi | October 2010

To get started:

Risk assessment (SOP)

Scheduling

Preparation

Announce inspection

Provide tentative inspection plan

Inspect, prepare inspection report

Review corrective action

Inspections


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Inspections

Done by teams of inspectors

WHO inspector plus appointed from DRA (PICS member)

Invite local inspector (DRA)

Some cases observers and technical advisors

Technical assistance (independent, no conflict of interest)

Inspections


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Current trends in Inspections

Guide toManufacturer

Risk Classification

RELATIVE RISK CATEGORY

PRODUCT TYPE / ACTIVITY

LOWMEDIUMHIGHCRITICAL

Finished Products:

XSterile finished products

XNon-sterile finished products

APIs:

XSterile APIs

X

Nonsterile APIs where there is a

special risk (e.g. isomerism,

polymorphism, special risk of harmful

impurities, etc)

XOther nonsterile APIs

XQC Laboratories

XCROs
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdlXWhbnqWrpHRsaXlg0KKKaG2g)/pl/defaultgalerie/248/6/1/884434863.jpg


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APIs

Why inspect? Quality

Heparin

Baxter 2008, more than 80 deaths in USA

Investigated FDA (GMP sourcing of starting material, lack of control)

Nelfinavir, Lopinavir /Ritonavir

Roche 2008, global recall of batches

genotoxic substance (GMP, cleaning of tanks)

Morphic forms

European lawFPP manufacturer's responsibility Self, contracted party, DRA

Rationalization, economy Initially mostly in Europenow Asia (India and China)control?
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdmXWhUmqWtp3FkaH9klJyTrVReww)/pl/defaultgalerie/248/6/1/1446610592.jpg


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API

Parameters considered:

Polymorphism

Solubility in water

Route of Synthesis

Solvents used

Impurities Sterile API

Fermentation

Toxicity

Activity/potency

Particle size Other properties to be considered

Site compliance information (WHO/EDQM/Other)
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdmXWhUl6Kqo3dla3lqlJyTrVReww)/pl/defaultgalerie/248/5/1/1113271838.jpg


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VIII. PRODUCTION AND

IN-PROCESSCONTROLS

IX. PACKAGING ANDIDENTIFICATIONLABELING OF APIs ANDINTERMEDIATES

X. STORAGE ANDDISTRIBUTION

XI. LABORATORYCONTROLS

XII. VALIDATION

WHO GMP for APIsICH Q7

II. QUALITYMANAGEMENT

III. PERSONNEL

IV. BUILDINGS ANDFACILITIES

V. PROCESSEQUIPMENT

VI.DOCUMENTATION

AND RECORDS

VII. MATERIALS

MANAGEMENT


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XIII. CHANGE CONTROL

XIV. REJECTION AND RE-USE OF

MATERIALS

XV. COMPLAINTS AND RECALLS

XVI. CONTRACT MANUFACTURERS

XVII. AGENTS, BROKERS, TRADERS,

DISTRIBUTORS,

REPACKERS, AND RELABELLERS

API
http://www.api.polpharma.pl/files/(x6urq7udbXZt2WxVgFSTskWh2rGie51teGaebYyAZF65XZermaFib5yAZaGlXXdmXWhUmaiwpnVra39olJyTrVReww)/pl/defaultgalerie/248/5/1/1379557896.jpg


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WHO GMP and Inspection of API manufacturers

Increasing GMP requirem ents


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APIs

Why inspect?

Variations

Change manufacturers and suppliers

Different specifications, route of synthesis, impurity profile

Stability, re-test dates vs expiry dates

Incomplete dossier, DMF, APIMF


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Examples of observations of non-compliance in 2007

Batch records and SOPs

Before steps were processed a complete centrifugation operation before actualoperation;

BMR was not completed, although the step was already in progress... No start

time of the cooling process no records of the temperature for every 30minute as required in the BMR equipment logbook no entry

The SOP cleaning of centrifuge bag was incompleteNo evidence of: dedicated bags

labeling of storage drums

Also for fluid bed bags

Risk of cross contamination

API


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Examples of major non-compliances (2009)

Quality management

Lack of knowledge and experience

Deviations not reported

Change control incomplete

Documentation

Recording of operations, also not reflecting all steps and full of errors Incomplete process validation

Materials management

Sampling (number of samples, release date before manufacturing date)

Storage and use - FIFO

Buildings and facilities Water systems; HVACpoor design and controls

equipment cleaningshow product residue after cleaning, equipmentcleaned in outside environment

API


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Inspection of API manufacturers

0

5

10

15

20

25

30

35

2002 2004 2005 2006 2007 2008 2009

Number of sites

Ave numberobservations


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Inspection ofAPI manufacturers

0

5

10

15

20

25

30

35

40

Ave (total) obs per

site

Ave (Major)

TB

HIV/AIDS

MAL

2007 -2009. Inspec tion s (dis ease areas)and number of observat ions

0

1

2

3

4

56

7

8

9

10

Major deficiencies

MaterialsManagement

SOPs

Cleaning

Batch records

Labeling

Crosscontamination

Areas of n on-compl iance


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Inspection of API manufacturers

Summary of trends

Number of inspections between '05 and '099 to 12. Low numberin 2007

Highest number of inspections in India, followed by China

Observations range between 20 and 28 (low number in 2007)

Lower number of observations in ARV manufacturers, but lowernumber of major non compliances at malaria manufacturers

Observations relating to material management, SOPs anddocuments, cleaning


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To get started (FPP manufacturer): Product dossier submitted

Listed as a manufacturer in a product dossier

Assessment in progress

Risk assessment

Submit a SMF

Announce inspection

Provide tentative inspection plan

Inspect, prepare inspection reportcorrectiveaction

Inspection of FPP manufacturers


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Manufacturers: Normally over 4 days

Covers all aspects of GMP

Quality management, Quality assurance, Premises, Equipment, Documentation,

Validation, Materials, Personnel

Utilities (e.g. HVAC, water) . . .

Also data verification (dossier) including stability data, validation

(process), development batches and bio batches

Quality control laboratoryspecifications, reference standards,

methods of analysis, validation and qualification



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FPP

Findings

Validation and qualification work was often incomplete

Validation Master Plans (VMP) lacked details

Validation policies as defined in the VMPs were not implemented

Process validation was lacking

Validated procedures (e.g. environmental monitoring) were lacking

Incomplete (not detailed) qualification of HVAC, water and

computer systems


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FPP

Findings Insufficient filtration of air to production areas

No prevention of possible cross-contamination and contamination.

"As built" AHUs lacked components reflected in the schematic drawings,including filters

No qualification of sampling areas and reverse unidirectional air flow units

Temperature and RH mapping studies incomplete, or results not applied

HVAC systems not controlled or monitored, start up, shut down

Filters: not planned, classified, tested (including installed filter leakage test), monitored

Pressure differential gauges not controlled, including calibration and zero checks


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PQR Not done annually Not all data reported including starting materials, commitments, variations

Trends not reviewed / discussedresults merely reported

Deviations

Not reported, some are opened, new deviations opened on a deviation Not authorized by production manager or QA prior to implementation

No assessment on impact, not additional testing

Change control procedures not followed No assessment on impact, no routing to responsible persons

No qualification or validation

Wrong materials used (e.g. MOC extension of PW loop)

GMP ...


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In process controls Some less critical ones reported

Wrong results represented

Even though "fail"reported as "pass"

Qualification

Often incomplete

Wrong sequence Unreliable data

"approved" and signed off despite non compliance

with specifications, errors not picked up

Computers, software, excel calculations

Process validation

Lacking

Unreliable results

GMP ...


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OOS

SOP for the reporting and investigation of Out of

Specification (OOS) results not implemented

No record of OOS results

In case of an OOS, re-testing was done, however, the

results were recorded on a loose piece of paper, other

sheets were not appropriately completed e.g. method

number, no of samples, LIMS number

FPP


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Reworking materials / products: GMP allows in exceptional cases - reworks were done on a

routine basis.

Inappropriate authorization for the reworks including no priorauthorization by QA, authorization by production supervisors up to

7 weeks after the rework was initiated.

A rework was even initiated prior to the conclusion of the OOSinvestigation.

Reworked batches were not subjected to additional testing

including stability studies

Only one of all the reworked batches was subjected to stabilitytesting according to the stability plan.

FPP


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Inspections by country

0

5

10

15

20

25

China Egypt India Morocco South Africa

Country

Numberofsites

2008

2009

Co-inspectors by country

0

2

4

6

8

10

12

14

Austr CH Es Fr Hu UK WHO SA DEN

Country

Numberofsites

2008

2009

Total


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Observations 2008 and 2009

0

20

40

60

80

100

120

1 3 5 7 9 11 13 15 17 19 21 23 25

Number of sites

Numberofobservations

2008 Total

2009 Total

2008 Major

2009 Major

Non compliant sites

0

2

4

6

8

10

R H T M INJ OSD

Disease group

Number 2008

2009

Total


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Inspections of Contract Research Organizations

(CROs)

New York Times 2007

Clinical sites: Normally over 2 days

Started 2004 -Covers all aspects ofGCP and GLP

Ethical considerations, Protocol,Volunteers etc

Data verificationidentified

misrepresentation of data

Clinical part

Clinic, Pharmacy and relatedareas, data verification

Bio-analytical part

Laboratory and data verification

Statistical analysis


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I ti f C t t R h


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Also:

Guidance for Indus try

B io-analyt ical Method Validat ion

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Veterinary Medicine (CVM)

May 2001

Inspections of Contract Research

Organizations (CROs)

f


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Inspections of

Contract Research Organizations (CROs)

Clinical Part of the study

Protocol, Ethics committee

Volunteers

Informed consent

Source data and CRFs

B io-analyt ical part of the study

Sample management

Method val idat ion and samp le analys is

I ti f


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Inspections of


Main problems in some CROs:

Many haven't done studies for "regulated market" submissions

Lack of GCP and GLP regulations, requirements, enforcement and

compliance

IEC not independentset up by sponsors

Manipulation of data

No source data / records available (CRO and Sponsor)

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Inspections of


Examples of observations

Half of the CRFs "missing"

Source data destroyed accidently by fire or "monsoon"

Sponsor claims the data were kept by the CRO, and the CROclaims the data were kept by the sponsor

All data and retention samples destroyed as the product "expired"

even though the submission is still under evaluation

I ti f C t t R h


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Inspections of Contract Research

Organizations (CROs)

Examples Half of the CRFs "missing" (at

sponsor / CRO?), source data

destroyed accidently by fire or

"monsoon", destroyed as the product

"expired"

Out of 95 ECGs copied by the

inspectors, 43 appear to have been

recorded from the same and single

subject during a single session

Manual integration and results notreal

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Inspections of


Example: Numerous improper manual integrations were notedby the inspectors for QC samples.

Such integrations were found both for the method validation and forthe trial phase. These integrations were corrected during theinspection by one staff member under control of one inspector.

The status of the results of several QC samples was affected bythese improper manual integrations

Taking these corrected results into consideration the results ofsubjects No. 5 and 20 should be rejected:

subject No. 5: results were only obtained for 4 of the 6 QC samples and the results of2 of these 4 samples fall out of acceptance limits;

subject No. 20: the results of both LQC samples fall out of acceptance limits..


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Example discrepancies


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Recent observations included unreliable data such as:

Discrepancies between electronic raw data files and data submittedin study reports for assessment;

Improper manual integration of chromatograms observed duringinspections even as "no manual integration" was reported;

Differences in chromatogram peak areas between the electronicraw data files and the printouts submitted to the WHO;

Batches that fail when data is calculated from raw data files duringinspections (e.g. for QC samples) even as these batches were

presented as "passing" with values different from those actuallyobtained during subject sample analysis;

Inappropriate bio analytical method validation.

Inspections of



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Number of inspections

0

10

20

30

40

50

60

2005 2006 2007 2008 2009

FPP

APICRO

QCL

total


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1 5 PQ Inspections