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Deviation Management in Pharmaceutical Industry

Presentation · August 2020

DOI: 10.13140/RG.2.2.16476.21126

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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. cross-
contamination, 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

.......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,
FDA : 21 CFR part 211 whether or not the batch has already been distributed.
section 160 & 192 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
Equipment Breakdown
In adequate documentation
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
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
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
Specification limits incorrect
MI/PI incorrect
Machine settings outside the recommended parameters
(Specified Parameters are incorrect)
Wrong variable data or not legible (packaging).
 Source of Deviation
Process Error
Facility Breakdown
Yield Reconciliation
Other
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
•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)
•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
•Reconciliation outside Specification Limits
•Additional sampling (e.g. during validation) results in a reduced yield (minor)
• 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
Yes No Yes
Product direct Occurred Possible
Problem fully
or indirect before contaminant
corrected? Critical
contact production loss of control
Usual setup
equipment? startup? uniformity?

No Yes No

Minor
Minor Major

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Classification of Deviation (Critical, Major, Minor)

Yes
Wrong Grade
or amount of Critical
raw materials?

No

Yes Yes
Spillage or No No
Formulation or Mix in wrong Possible loss
potential loss
order, speed of strength or Critical
bulk mixing of active or
time, temp? uniformity
problem excipients

Yes Yes No

Critical Critical
Major

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

Classification of Deviation (Critical, Major, Minor)

Critical Critical

No
Yes

Wrong Grade Wrong Grade

or amount of or amount of
raw materials? raw materials? Yes

No Yes

No
Spillage or No No
Loss of in-process Mix in wrong Possible loss
potential loss
order, speed of strength or Minor
control or interrupt of active or
time, temp? uniformity
to processing excipients

Yes
Yes Yes

Critical Critical
Critical

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Classification of Deviation (Critical, Major, Minor)

Yes
Prior history of
defects related
Critical
to the
incident?

No

No
Important in- No Incorrect No In process test
Document, Record process test records for records show
Minor
& Monitoring changed or critical trends toward
Related Incident omitted process step? failure?

Yes Yes Yes

Critical
Major Major

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Classification of Deviation (Critical, Major, Minor)

Critical

Yes

Lack of No Incorrect
evidence of procedure or
clean/sanitize conditions
Yes Major
contact used for
equipment clean/sanitize

No

No
Equipment or No Visual No Product
Cleaning or product contamination supports the
Minor
sanitization related exceeded max. in equipment growth of
incident hold time on inspection bacteria/mold?

Yes
Yes Yes

Critical Critical
Major

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Classification of Deviation (Critical, Major, Minor)

Critical Major Critical

Yes Product
Yes
Contact

Lack of No Unusual result in

Equipment
evidence that sterilization
No breakdown or
sterilization monitor records repair needed Major
conditions (temp, time, in Grade C, B Non
fully met?
pressure, vac ?)
or A Contact

Personnel No
Equipment or No Any breach of No error or breach
Sterility Assurance product HVAC or clean
in aseptic Major
exceeded max. room
Related Incident hold time controls?
room (C, B or
A)

Yes
Yes Yes

Critical Critical
Critical

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Risk Based Approach

Severity
RA
Type Minor Major Critical
Loss: identity,
strength, purity,
quality
Improbable
(Half 1 2 4
yearly/yearly)
Probability
Remote
Monthly/Quarterly 3 5 7
Frequent
Daily/weekly 6 8 9

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

Impact Analysis Follow-up

Investigation

Lot Disposition Corrective and

Preventive Actions

Root Cause Analysis Conclusions

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Possible route causes: Laboratory

Sample
Wrong preparation
Calculation
procedure error

Procedure not Test Procedure Wrong

followed sample

Transfer of data
Dilution error

Testing conditions
(e.g. Temperature)

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Possible route causes: Laboratory

Cleaning of
equipment Wrong
Wrong programme
equipment file

Equipment
Test
out of SST failed
calibration Equipment

Equipment out of Wrong equipment

maintenance parameters
Equipment
malfunction

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Possible route causes: Production

Wrong filling
process (e.g.
speed) Storage and
Storage and transport of filled
transport of capsules
empty capsules

Defect Packaging operation:

Empty
Capsules • Feeding
capsules
defect • Speed

No automated
removal of defect Packaging
Filling equipment
capsules equipment defect
defect

A.B.M. Mahfuz ul Alam, QAM, ACI Limited

 Possible route causes: Production

Excipients
Storage and contaminated Solvents
transport of contaminated
components

Personnel
API Hygiene
contaminated Black
Particles

HVAC Equipment repair

operations

Equipment defect Equipment

(e.g. sealing) Equipment maintenance
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
cleaning
 Case Study 1: xxx TABLETS

Initial Situation:
• Amber particles were found during packaging in-
process 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:
Excipients
Storage and contaminated Solvents
transport of contaminated
components

Personnel
API
Amber Hygiene
contaminated
Particles

HVAC Equipment repair

operations

Equipment defect Equipment

(e.g. sealings) Equipment maintenance
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
cleaning
 Case Study 1: xxx TABLETS

Workshop Part 2:
Which specific actions should be taken to
investigate this problem?
• Documents to be seen
• Questions to be asked
• Persons to be involved
• Measures to be taken
• Controls to be performed
• Decisions to be made
A.B.M. Mahfuz ul Alam, QAM, ACI Limited
 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 styrene-
butadiene 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