A comprehensive presentation on GMP systems and integration. This includes validations, vendor qualification, preventative maintenance, audits, CAPA, and utilization of system results.

1. GMP SYSTEMS INTEGRATION –
COMBINE RESULTS AND
UTILIZE AS A COMPLIANCE
TOOL
Betzaida Bigio
Bristol Myers - Squibb
Betzaida Bigio 1

2. We will be Discussing
 GMP systems – no definitions
 How they interact
 Review of recent observations
 How they can be integrated to
establish controls
 Interactive Exercise
Betzaida Bigio 2

3. GMP Systems
 Annual Product Reviews (APR)
 Change Control
 Validations
 Equipment qualifications
 Vendor Qualifications
 Preventive Maintenance (PM’s)
 Audits (Internal & External)
 Suppliers audits
 Stability
 Customer complaints
 Suppliers complaints
 CAPA
 Investigations
8/30/2012 3

4. Integration Between Systems
 Discussion of Recent observations
 Classification of observation
 Integration between systems based
on each observation
8/30/2012 4

5. Recent Health Authorities
Findings
 Discussion of 2011- 2012 Warning letters
 Eighteen (18) Warning letters
 Focused on Pharmaceutical Industries
 cGMP for API (Active Pharmaceutical Ingredient)
 cGMP for Finished Pharmaceutical
 Location of inspected Sites:
 India
 China
 Germany
 Poland
 UK
 Canada
 Mexico
 Switzerland
 Israel
 Japan
 US
8/30/2012 5

6. Recent Observations - “Hot”
Topics
 Cleaning Validation
 Investigations
 Media Fill
 Laboratory Controls
 Test Methods
 Environmental Monitoring
 Microbiology Contamination Prevention
 Disinfectant qualification
 Visual Inspection Qualification
 Supplier Qualification
 Reduce testing
 APR, Record Retention
 Incoming testing of raw materials 8/30/2012 6

7. Cleaning Validation
 Use of two equipment parts for the production of
multiple drug products without validating the process
 Process validation for six (6) products conducted
only with one out of two parts
 Parts identical in construction but different internal
configurations
 Failure to demonstrate are identical
 Not cleaned and maintained equipment at appropriate
intervals – holding time
8/30/2012 7

8. Integration Between Systems per
Observation
Validation/Qualification: Controls
 Use of two equipment parts for the  Equipment qualification
production of multiple drug
products without validating the  Process Validation
process
 Process validation for six (6)  Cleaning validation
products conducted only with
one out of two parts  Holding time
 Parts identical in construction
but different internal  Dirty time
configurations
 Systems:
 Failure to demonstrate are
identical  Change Control
 Not cleaned and maintained  Validation
equipment at appropriate intervals –
holding time
8/30/2012 8

9. Cleaning Validation
 Failure to have in shared manufactured areas, multi-product
equipment:
 Well-designed contamination prevention strategy in place
 Proper segregation
 Or dedicated equipment to a single mfg process
 No documented evidence of cleaning between batches or between
product changeovers occurred on non-dedicated equipment
 Technology transfer to a facility that was previously used to
manufacture without conducting adequate decontamination,
renovation, and activation of the facility
8/30/2012 9

10. Integration Between Systems per
Observation
Validations/Qualifications: Controls
 Failure to have in shared
manufactured areas, multi-product  Equipment qualification
equipment:
 Process Validation
 Well-designed contamination
prevention strategy in place  Cleaning validation
 Proper segregation
 Or dedicated equipment to a  Holding time
single mfg process
 No documented evidence of cleaning  Dirty time
between batches or between product
changeovers occurred on non-  Systems:
dedicated equipment  Change Control
 Technology transfer to a facility that  Validation
was previously used to manufacture
without conducting adequate
decontamination, renovation, and
activation of the facility
8/30/2012 10

11. Investigations
 Not thoroughly investigated the failure of a batch or any
of its components
 Failure to include other batches in investigations
 No investigation raw data for a media fill failure
 Failure to determine root cause on crystals in the vial
 Changes to filling process
 Changes to filling needles
 Vial washers
8/30/2012 11

12. Integration Between Systems per
Observation
Investigations: Controls
 Not thoroughly investigated  Product behavior on APR
the failure of a batch or any of
its components  Stability
 Failure to include other  Predictive maintenance
batches in investigations
 Preventive maintenance
 No investigation raw data for
a media fill failure  Systems:
 Failure to determine root  Investigations
cause on crystals in the vial  CAPA
 Changes to filling process  Supplier
 Changes to filling needles  Change Control
 Vial washers  PM’s
8/30/2012 12

13. Investigations
 Investigations
 Failure to investigate and document contamination
of API
 Root cause not determined and production continued
 No segregation of impacted lots
 Failure to extend investigation to other batches
 Contaminated lot release and shipped, then recalled –
failure to have controls in place to identify material
status
 Inadequate equipment maintenance program
 Firm authorize the use of equipment known to be
defective (10 maintenance requests in one year)
8/30/2012 13

14. Integration Between Systems per
Observation
Investigations: Controls
 Failure to investigate and
 Product behavior on APR
document contamination of API  Stability
 Root cause not determined and  Materials segregation
production continued
 No segregation of impacted lots  Supplier’s audit
 Failure to extend investigation to  Preventive & Predictive
other batches
maintenance
 Contaminated lot release and
shipped, then recalled – failure to  Systems:
have controls in place to identify  Investigations
material status
 CAPA
 Inadequate equipment maintenance
program  Supplier
 Firm authorize the use of  Change Control
equipment known to be defective  Materials
(10 maintenance requests in one
year)  PM’s
8/30/2012 14

15. Media Fill
 Media fill insufficient to establish that the
aseptic process is in control
 Inadequate reconciliation of filled vials
 Filled vials not match with incubated vials
 Employee who perform critical duties in your aseptic
process did not participate in the simulation process
qualification
8/30/2012 15

16. Integration Between Systems per
Observation
Media Fill: Controls
 Media fill insufficient to  Manufacturing simulation
establish that the aseptic  QC – Microbiology
process is in control  Training – Job description, job
 Inadequate reconciliation of
duties, SOP’s, employee
filled vials
qualifications, and
 Filled vials not match with
incubated vials certifications aligned
 Employee who perform  Systems:
critical duties in your aseptic  Manufacturing
process did not participate in
 Training
the simulation process
qualification  QC - Microbiology
8/30/2012 16

17. Laboratory Controls
 Test Methods
 Not established scientifically sound and appropriate
specifications, standards, sampling plans, and test procedures
design to assure that components, in-process materials, and
DP conforms with standards
 Validation data for laboratory methods incomplete or not
available
 Validation method approved without the complete data in
place
 Equipment qualification – all instruments whether newly
purchased or already in use , be qualified prior to being release
for use
8/30/2012 17

18. Integration Between Systems per
Observation
Laboratory Controls: Controls
 Test Methods  Change Control should establish
 Not established scientifically sound specific requirements
and appropriate specifications,  Appropriate equipment
standards, sampling plans, and test
procedures design to assure that qualification
components, in-process materials,  Documentation approval
and DP conforms with standards
 Validation data for laboratory  Employee training
methods incomplete or not
available  Systems:
 Validation method approved  Quality Assurance
without the complete data in  Quality Control
place
 Change Control
 Equipment qualification – all instruments
 Validations/Qualification
whether newly purchased or already in
use , be qualified prior to being release  Training
for use
8/30/2012 18

19. Suppliers Qualification
 Reduce testing
 Inadequate sampling process if no evidence of vendor
sampling, shipping, and transit process
 Incoming testing of raw materials
 Not conducted at least one specific identification test
 Lack of appropriate validation of the supplier test result
 Accept CoA of a stopper supplier without conducting
adequate vendor qualification
 No evidence of how your vendor conducts the sampling
(composite, segregation…)
8/30/2012 19

20. Integration Between Systems per
Observation
Supplier’s Qualification: Controls
 Reduce testing  Material qualification
 Inadequate sampling process if  Supplier audit
no evidence of vendor sampling,  Quality agreement
shipping, and transit process
 Testing of components &
 Incoming testing of raw materials
material
 Not conducted at least one
specific identification test  Comparison between CoA and
 Lack of appropriate validation of test results
the supplier test result
 Systems:
 Accept CoA of a stopper supplier
without conducting adequate  Quality Assurance
vendor qualification  Quality Control
 No evidence of how your vendor
conducts the sampling
(composite, segregation…)
8/30/2012 20

21. Shutdown/Start-up
 Inadequate aseptic and support area sanitization
following maintenance shutdown
 Assure to complete:
 Media fill
 Smoke studies
 QA authorization to resume activities
 NO failure on Media fill results (this was the case in the warning
letter, two contaminated units, not adequate investigated root
cause)
8/30/2012 21

22. Integration Between Systems per
Observation
Shutdown/Start-up: Controls
 Cleaning
 Inadequate aseptic and  Change Control should establish
specific requirements
support area sanitization  Asceptic Techniques
following maintenance  Assure to complete:
shutdown  Media fill
 Smoke studies
 NO failure on Media fill
 QA authorization to
results (this was the case resume activities
in the warning letter, two  Systems:
contaminated units, not  Quality Assurance
adequate investigated  Quality Control
 Manufacturing
root cause)
8/30/2012 22

23. Microbiology Contamination
Prevention
 Disinfectant qualification
 Not establish a schedule for the cleaning with agent
design to kills spores – mold found
 Disinfectant rotation – efficacy studies not
completed for three of the disinfectant
 Failed to demonstrate that is suitable and effective
to remove microorganism from different surfaces
 Failure to challenge with multiple organisms
8/30/2012 23

24. Integration Between Systems per
Observation
Microbiology Contamination
Prevention: Controls
 Disinfectant qualification  Quality Control – Micro
 Not establish a schedule for the  Robust Qualification of
cleaning with agent design to disinfectant
kills spores – mold found
 Disinfectant rotation – efficacy  Systems:
studies not completed for three  Quality Assurance
of the disinfectant
 Quality Control
 Failed to demonstrate that is
suitable and effective to  Qualification
remove microorganism from
different surfaces
 Failure to challenge with
multiple organisms
8/30/2012 24

25. Microbiology Contamination
Prevention
 Smoke studies
 No evidence of smoke studies
 Failure to demonstrate that appropriate design &
controls are in place to prevent turbulence and
stagnant air in critical areas
8/30/2012 25

26. Integration Between Systems per
Observation
Microbiology Contamination
Prevention: Controls
 Robust Smoke studies
 Smoke studies  Air velocities/pressure & air
 No evidence of smoke changes data
studies  Multidisciplinary team to
 Failure to demonstrate evaluate smoke studies
that appropriate design  Systems:
 Quality Assurance
& controls are in place
 Quality Control
to prevent turbulence  Engineering
and stagnant air in
critical areas
8/30/2012 26

27. Microbiology Contamination
Prevention
 Environmental Monitoring (EM)
 Poor routine examination of facilities (mold in class 100 production
 Poor condition of walls
 Poor aseptic techniques
 Personnel sampling areas (hands, chest, gowning, hood, goggles, sleeves)
 Gowned employee not monitored by a second qualified person
 EM performed at the end of the shift
 Operators sanitizing his hands immediately prior to conducting his own
personnel monitoring sampling
 Operator spraying his hands directly over the air viable microbial plate. Results
may not reflect microbiology environment of the class 100 room.
8/30/2012 27

28. Integration Between Systems per
Observation
Microbiology Contamination
Prevention: Controls
 Environmental Monitoring (EM)
 Aseptic techniques
 Poor routine examination of facilities  Personnel training and
(mold in class 100 production qualification
 Poor condition of walls
 Poor aseptic techniques  Engineering controls
 Personnel sampling areas (hands,  Facilities walk tru
chest, gowning, hood, goggles,
sleeves)  Internal audits
 Gowned employee not monitored by a
second qualified person  Preventive maintenance
 EM performed at the end of the shift  Systems:
 Operators sanitizing his hands  Quality Assurance
immediately prior to conducting his
own personnel monitoring sampling  Quality Control
 Operator spraying his hands directly  Engineering
over the air viable microbial plate.  Internal audits
Results may not reflect microbiology
environment of the class 100 room.  Training
8/30/2012 28

29. Microbiology Contamination
Prevention
 Environmental Monitoring (EM)
 EM trends not analyzed – failure to address
increased adverse trends observed
 Not establish a schedule for the cleaning with agent design
to kill spores although mold was detected in class 10,000
area
8/30/2012 29

30. Integration Between Systems per
Observation
Microbiology Contamination
Prevention: Controls
 Aseptic techniques
 Environmental
Monitoring (EM)  Personnel training and
qualification
 EM trends not analyzed
– failure to address  APR
increased adverse  Systems:
trends observed  Quality Assurance
 Not establish a schedule  Quality Control
for the cleaning with  Training
agent design to kill spores
although mold was
detected in class 10,000
area
8/30/2012 30

31. Visual Inspection
Qualification
 Defect in include visual inspection program
 Inspectors qualification failure
 Visual inspection certification program does not adequately
challenge the technician performing the inspection
 SOP should include all possible defects- inspector should be
capable to detect all possible critical defects, challenge vial
selected, and rotated to ensure that each inspector is
challenged to detect each critical defect
8/30/2012 31

32. Integration Between Systems per
Observation
Visual Inspection Qualification: Controls
 Defect in include visual inspection  Visual Inspection Certification
program Program
 Inspectors qualification failure
 Personnel training and
 Visual inspection certification
program does not adequately qualification
challenge the technician
performing the inspection
 SOP should include all possible  Systems:
defects- inspector should be
capable to detect all possible  Quality Assurance
critical defects, challenge vial  Qualification
selected, and rotated to ensure
 Training
that each inspector is challenged
to detect each critical defect  Manufacturing
8/30/2012 32

33. APR & Record Retention
 APR
 Quality Unit does not perform an annual evaluation
of the process
 This is the process to assure that changes were
effective and the process remains in a validated state
 Record Retention
 Records destroyed
 No evidence of qualification and validation records
resulted in a not validated process, and/or not
qualified equipment
8/30/2012 33

34. Integration Between Systems per
Observation
APR/Record Retention: Controls
 APR program in place
 APR
 Quality Unit does not perform  Record Retention based on
an annual evaluation of the criticality and risk
process  Change controls,
 This is the process to assure that Qualifications/validations -
changes were effective and the never are destroyed
process remains in a validated
state
 Record Retention  Systems:
 Records destroyed  Quality Assurance
 No evidence of qualification  APR
and validation records resulted  Validation
in a not validated process,  Record Management
and/or not qualified equipment
8/30/2012 34

35. Interactive Exercise
8/30/2012 35

36. Instructions
 Evaluate recent Observations to different systems
and relate each of different GPM Systems
 Identify your opportunities
 Identify controls that should be in place in each
system to avoid the out of compliance situation and
establish communication among them
 Assure that your control address post
implementation sustainability
 Identify & avoid Road blocks to maintain
compliance
8/30/2012 36

37. 3
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38. 3
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