The document discusses the integration of Good Manufacturing Practice (GMP) systems as compliance tools in the pharmaceutical industry, highlighting various components such as cleaning validation, investigations, and supplier qualifications. It reviews recent observations from health authorities, emphasizing failures in batch investigations and the management of contamination risks. The content includes a call for better controls and communication among systems to ensure sustainability and compliance.

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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