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Deviation Management in Pharmaceutical Industry
Presentation · August 2020
DOI: 10.13140/RG.2.2.16476.21126
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Abm Mahfuz Ul Alam
ACI HealthCare Limited, Narayangonj, Bangladesh
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Workshop on
Deviation Management
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
What we expect from you
• Raise awareness for the impact of deviations on the business
• Improve understanding of the relevance of adequate
deviation handling
• Improve documentation
• Improve risk analysis for decision making (critical/non-critical)
• Include all relevant colleagues/spread awareness
• Establish better rationales for effective CAPA’s
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
What is deviation ????
Deviation:
An unexpected incident that occur during or after the
manufacture, processing, packaging, storage, transport or
testing of pharmaceutical dosage forms.
A deviation may be a planned one as part of temporary change
(HPLC column, prolongation of calibration time etc) or not
planned but result by an incident or error during or after the
process.
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Deviations - what are they?
•
Exceptions or excursions from written, approved procedures (i.e. SOPs,
Master batch records, etc.)
– Exceed pre-established manufacturing or analytical criteria
• time
• temperature
– Use of “wrong” equipment or material (other than specified)
– Use of equipment or material wrong
– Use of wrong procedure
– Use of procedure wrong
– Accidental (unplanned) versus intentional (planned)
– An unexpected, unpredictable occurrence
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Type of Deviation
Minor Deviation:
Failure that would not be expected to result in any loss of
therapeutic effect to the patient or invoke a product complaint.
Major Deviation:
Failure that indicate use of product directly affect the patients, so
that failure could result in adverse reaction, partial loss of
therapeutic effect or would likely result in a product complaint.
Critical Deviation:
Failure that indicate use of product directly have highly affect the
patients which could result in death or injury, adverse reaction,
loss of therapeutic effect or would likely result in a product
recall.
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
What DO You Do When the Deviation Happens?
•
•
•
•
•
•
•
•
•
•
Ignore it
Pretend it never happened
Don’t worry, it’s a “one in a million”
Walk away
Tell your coworker
Tell your supervisor
Fix it
Investigate it
Investigate and then fix it
Investigate, document and then fix it
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Why?? Deviation need to investigate, document and fixed?
•
Quality, Safety, efficacy or customer acceptance of the pharmaceutical
product may be affected (Quality Relevance)
•
Deviation may cause a violation of registered file
•
Deviation has an impact on validation
•
Deviation is a severe non-adherence to GMP standards, e.g. crosscontamination, mix-up, violation of SOPs or procedures
•
Deviation implies further actions or follow up activities
•
Deviation which questions further continuation of production process
•
Deviation which affect other already release lots such that the release decision
is no longer be maintained and action may need to be taken (e.g. Recall)
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
•
Regulatory Requirements
FDA : 21 CFR part 211
section 160 & 192
.......any unexplained discrepancy.......or the failure of a
batch or any of its components to meet any of its
specifications shall be be thoroughly investigated,
whether or not the batch has already been distributed.
The investigation shall extend to other batches of the
same drug product and other rug products that may
have been associated with the specific failure or
discrepancy.
FDA: Guide to Inspection of
Pharmaceutical Quality Control
Laboratories; chapter 6-8
.........all failure investigations should be performed
within 20 business days of the problem‘s occurence
and recorded and written into a failure or
investigation report
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
•
Regulatory Requirements
EU: The Rules Governing medicinal products in the
European Union Volume 4: Good Manufacturing
Practice, chapter 1.3 vi; 1.4 iv & vi
…….any significant deviations are fully
recorded and investigated.
ICH Q7A chapter 2.16 and 2.50
Any deviations from established procedures should
be explained. ….includes a review of all critical
deviations and related investigations.
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Source of Deviation
Operator Error
MI/ PI / Validation Protocols not followed
Incorrect DOM entered into BPR
Check weigher printout missing from batch documents
Materials used while in Q status
Equipment used before being cleaned
Use of wrong equipment
The blending is executed on an other blender of the same type, but the process has
not been validated on this blender
Equipment Breakdown
Pinched Blisters
Dirty punches causing sticking tablets
Detection Camera fails to reject
Sensors fail to reject
Carton Printer not working
Capsule Detector not working
Trip Module not working
Due to damage of the compression tools the compression must be interrupted
In adequate documentation
Specification limits incorrect
MI/PI incorrect
Machine settings outside the recommended parameters
(Specified Parameters are incorrect)
Wrong variable data or not legible (packaging).
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Source of Deviation
Process Error
•Reblending required
•Variable assay results
•Foreign tablets
•White blemish found on PVC pocket
•Permanent deviation from IPC parameters during compression which can’t be corrected by
adjustment. (Critical)
•During compression occasionally the IPC parameters are not fulfilled. However after adjustment
of the compression parameters the process can be continued under good control and within
specifications (minor)
• Filling weight outside T1 but within T2. (minor)
•Deviation from process parameter which was identified as critical during process validation
(Critical)
Facility Breakdown
•Air Conditioning Unit failed
•Water Purifier failed
•Power Failure
•During dispensing of starting materials the specified humidity and temperature specifications
have not been met
•The filter integrity test before sterile filling has failed
Yield Reconciliation
•Reconciliation outside Specification Limits
•Additional sampling (e.g. during validation) results in a reduced yield (minor)
Other
•
•
•
•
•
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Batch to be packed before testing completed
Batch released before testing completed
Status changed to C prior to completion of testing
Batch stopped due to shortage of labels
Different cleaning agent used for short term, as none of the specified cleaning agent is available
Classification of Deviation (Critical, Major, Minor)
Facility or
equipment problem
No
Yes
Product direct
or indirect
contact
equipment?
No
Minor
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Occurred
before
production
startup?
Yes
No
Problem fully
corrected?
Usual setup
Yes
Minor
Possible
contaminant
loss of control
uniformity?
No
Major
Yes
Critical
Classification of Deviation (Critical, Major, Minor)
Yes
Wrong Grade
or amount of
raw materials?
Critical
No
Formulation or
bulk mixing
problem
Yes
Spillage or
potential loss
of active or
excipients
Yes
Critical
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
No
Mix in wrong
order, speed
time, temp?
Yes
Critical
No
Yes
Possible loss
of strength or
uniformity
No
Major
Critical
Classification of Deviation (Critical, Major, Minor)
Critical
Critical
No
Yes
Wrong Grade
or amount of
raw materials?
Wrong Grade
or amount of
raw materials?
Yes
No
Loss of in-process
control or interrupt
to processing
Spillage or
potential loss
of active or
excipients
Yes
Critical
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Yes
No
Mix in wrong
order, speed
time, temp?
Yes
Critical
No
No
Possible loss
of strength or
uniformity
Yes
Critical
Minor
Classification of Deviation (Critical, Major, Minor)
Prior history of
defects related
to the
incident?
Yes
Critical
No
Document, Record
& Monitoring
Related Incident
Important inprocess test
changed or
omitted
Yes
Major
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
No
Incorrect
records for
critical
process step?
Yes
Critical
No
In process test
records show
trends toward
failure?
Yes
Major
No
Minor
Classification of Deviation (Critical, Major, Minor)
Critical
Yes
Lack of
evidence of
clean/sanitize
contact
equipment
No
Incorrect
procedure or
conditions
used for
clean/sanitize
Yes
Major
No
Cleaning or
sanitization related
incident
Equipment or
product
exceeded max.
hold time
Yes
Major
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
No
Visual
contamination
in equipment
on inspection
Yes
Critical
No
Product
supports the
growth of
bacteria/mold?
Yes
Critical
No
Minor
Classification of Deviation (Critical, Major, Minor)
Major
Critical
Sterility Assurance
Related Incident
Equipment or
product
exceeded max.
hold time
Yes
Critical
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Product
Contact
Yes
Yes
Lack of
evidence that
sterilization
conditions
fully met?
Critical
No
No
Unusual result in
sterilization
monitor records
(temp, time,
pressure, vac ?)
Any breach of
HVAC or clean
room
controls?
Yes
Critical
No
No
Equipment
breakdown or
repair needed
in Grade C, B
or A
Personnel
error or breach
in aseptic
room (C, B or
A)
Yes
Critical
Non
Contact
Major
No
Major
Risk Based Approach
Severity
RA
Type
Minor
Major
Critical
Loss: identity,
strength, purity,
quality
Improbable
(Half
yearly/yearly)
1
2
4
Remote
Monthly/Quarterly
3
5
7
Frequent
Daily/weekly
6
8
9
Probability
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Responsibilities
– Operating Departments
• Informing Quality of Deviations in Timely Manner
• Identifying/Documenting Deviations
• Help QA in Conducting Investigations
• Implement Corrective & Preventive Actions
– Quality Assurance
• Overall Compliance Responsibility
• Oversee Investigation Activities
• Approval of Investigation Reports/Disposition Decisions
• Instituting Appropriate Actions
• Batch Rejection, etc
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Cornerstones of deviation handling
Deviation
Follow-up
Impact Analysis
Investigation
Lot Disposition
Root Cause Analysis
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Corrective and
Preventive Actions
Conclusions
Possible route causes: Laboratory
Wrong
procedure
Procedure not
followed
Sample
preparation
Test Procedure
Transfer of data
Wrong
sample
Dilution error
Testing conditions
(e.g. Temperature)
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Calculation
error
Possible route causes: Laboratory
Wrong
equipment
Equipment
out of
calibration
Equipment out of
maintenance
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Cleaning of
equipment
Test
Equipment
Equipment
malfunction
Wrong
programme
file
SST failed
Wrong equipment
parameters
Possible route causes: Production
Wrong filling
process (e.g.
speed)
Storage and
transport of
empty capsules
Empty
capsules
defect
No automated
removal of defect
capsules
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Defect
Capsules
Filling
equipment
defect
Storage and
transport of filled
capsules
Packaging operation:
• Feeding
• Speed
Packaging
equipment
defect
Possible route causes: Production
Storage and
transport of
components
API
contaminated
Excipients
contaminated
Black
Particles
HVAC
Equipment defect
(e.g. sealing)
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Solvents
contaminated
Personnel
Hygiene
Equipment repair
operations
Equipment
cleaning
Equipment
maintenance
Case Study 1: xxx TABLETS
Initial Situation:
• Amber particles were found during packaging inprocess check in several tablets
• Product: xxx 250 mg Tablets
• The foreign material was amber , rubbery, and
approx. 1 mm x 1 mm x 2 mm in size
Packaging was stopped: Confirmed deviation
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Dispensing
Mixer
Manufacturing process
V-blender
Granulator
Storage steel totes
Korsch tablet press
Packaging line
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Workshop Part 1:
List possible root causes
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Possible route causes:
Storage and
transport of
components
API
contaminated
Excipients
contaminated
Amber
Particles
HVAC
Equipment defect
(e.g. sealings)
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Solvents
contaminated
Personnel
Hygiene
Equipment repair
operations
Equipment
cleaning
Equipment
maintenance
Case Study 1: xxx TABLETS
Workshop Part 2:
Which specific actions should be taken to
investigate this problem?
•
•
•
•
•
•
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Documents to be seen
Questions to be asked
Persons to be involved
Measures to be taken
Controls to be performed
Decisions to be made
Case Study 1: xxx TABLETS
Results of Workshop - Immediate actions:
1. This batch “on hold”
2. Initiate analytical identification of particles
3. Initiate visual inspection of the concerned batch (AQL
or 100%)
4. Initiate visual inspection of starting materials
5. Contact suppliers
6. Review batch record (concerned batch)
7. Review log books and cleaning records
8. Review deviation records
9. Notify other units and initiate additional controls
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Further Results:
1. QC analysis of amber particles identifies the material
as:
Styrene Butadiene Rubber
(Synthetic non-toxic rubber)
2. Review of manufacturing batch record gives no
further information
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Workshop Part 3:
Which specific steps should be taken
in this situation?
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Further Results:
1. None of the sealant samples from the
manufacturing equipment used in the xxx
process was styrene-butadiene rubber.
2. Sampling equipment for raw materials are all
stainless steel.
3. None of the excipients contained styrenebutadiene rubber
4. The contamination was found in the API
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Further Results (ctd.):
5. Contamination could be limited to those batches
which contained the API from the concerned site.
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Workshop Part 4:
1. Can batches at all be released?
2. Which information and/or documentation is required
for batch release?
3. Which steps are to be taken in order to prevent
further occurrence (root cause identified)?
4. Which steps are to be taken in order to prevent
further occurrence (root cause not identified)?
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
Case Study 1: xxx TABLETS
Learning:
1. Simple defects may only be found
by extensive investigation
2. Thorough investigations avoid
future effort and problems
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
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THANK YOU
A.B.M. Mahfuz ul Alam, QAM, ACI Limited