Deviation Handling

R Raghunandanan, Mumbai
Director ISPE India
26th February 2011

Agenda

Introduction
What, how and who in deviations
Types of deviations
Regulatory perspective
SOP for deviation handling
Process steps

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Introduction (1)
Medicines are different from any other
consumer products
End user of our products are patients, invalid,
infants, aged
They can not perceive quality, they accept
what you make and provide
They may be dealing with life and death
situation
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Introduction (2)
Thats why GMP standards are developed
GMP requires all processes / procedures to be
controlled
Any change from GMP must be justified,
approved and documented
Deviations are unplanned changes
Management of deviations is mandated by
GMP
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What are deviations

A deviation is an unplanned departure from
SOPs, methods, specifications, protocols,
instructions, processes, batch records or other
official documentation
Unintentional / unplanned changes which
occur during manufacturing / packing are
termed as Process Deviations.
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What are not covered in the topic

OOS / OOT results
Stability failures
Customer Complaints
Adverse Events
Recalls
(Separate control systems must be in place
dealing with all these situations)
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How deviations occur (1)

Deviations happen or sometimes deliberately
caused
Activity not carried out in accordance with
standard accepted procedure
Erroneous and out of date documents in use
Faulty systems and condition of facilities
Labelling errors
Improper segregation
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How deviations occur (2)

Equipment failures

Material not meeting requirements

Human error
Inadvertent
Lack of training
Lack of knowledge
Callous attitude
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How deviations occur (3)

Manufacturing processes, procedures, people
QC documentation, labelling, segregation,
equipment failures, reagents
Engineering Procedure deviations,
unsatisfactory conditions of plant and facility
Warehouse documentation, segregation,
building condition, environmental conditions
Procurement deliveries, documents,
transportation not up to standard
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Why deviations reporting (1)

Quality is not static
Quality is not a stationary goal
The goal posts keep changing
Both globally and locally
Documentation of what happens during mfr
and testing is mandatory

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Why deviations reporting (2)

In spite of robustness the unplanned events
may happen in any operations
Need to have an approved and common
procedure for dealing with these happenings
Need to provide a mechanism to alert the
senior management

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Why deviations reporting (3)

Need to provide a mechanism for assessment
of potential impact on
Quality
Regulatory compliance
Need to have timely CAPA
Reporting is also a regulatory/cGMP
requirements
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Type of deviations Critical

A critical GMP deviation/exception could
endanger product safety and/or efficacy and
adversely impact the patient due to the use of
an inadequate process or controls.
Failure of detection would lead to a product
recall / withdrawal /serious complaint.

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Type of deviations Major

A major GMP deviation/exception does not
directly influence product safety and efficacy
but may require remedial action before
approval is granted to manufacture or
continue to manufacture. This could lead to:
Serious regulatory compliance implications
Major cost to business
Adverse comments from inspectors
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Type of deviations Minor

A minor GMP deviation/exception does not
directly influence product safety and efficacy
but may have an impact on cosmetic quality.
E.g.:
Cosmetic complaint on secondary packs
Minor document irregularities

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Regulatory Perspective US FDA

21CFR Part 211.100 (b)
(b) Written production and process control
procedures shall be followed in the execution
of the various production and process control
functions and shall be documented at the
time of performance. Any deviation from the
written procedures shall be recorded and
justified
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Regulatory Perspective US FDA

21CFR Part 211.111 Time Limitations on
Production
Deviation from established time limits may be
acceptable if such deviation does not
compromise the quality of the drug product.
Such deviation shall be justified and
documented.

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Regulatory Perspective US FDA

21CFR Part 211.192 Production Record Review

Any unexplained discrepancy (including a percentage of

theoretical yield exceeding the maximum or minimum
percentages established in master production and control
records) or the failure of a batch or any of its components to
meet any of its specifications shall 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 drug products that may
have been associated with the specific failure or
discrepancy. A written record of the investigation shall be
made and shall include the conclusions and follow up.

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Regulatory Perspective Schedule M

Section 21.3. During processing, the following information
shall be recorded at the time each action is taken and the
record shall be dated and signed by the person responsible
for the processing operations:
( i ) comments or explanations for significant deviations
from the expected yield limits shall be given,
( j ) notes on special problems including details, with signed
authorization, for any deviation from the master formula
Section 8.8. Water system - Investigation shall be carried out
and corrective action taken in case of deviation from
prescribed limits
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EU Guidelines to GMP Part 1

Chapter 1
Section 1.2 (vi) GMP Any significant
deviations are fully recorded and investigated
Section 1.3(iv) Quality Control Any
deviations are fully recorded and investigated
Section 1.3(vi) Quality Control - Product
assessment includes a review and evaluation
of relevant production documentation and an
assessment of deviations from specified
procedures
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EU Guidelines to GMP Part 1

Chapter 1
Section 1.4(iv) Product Quality Review A
review of all significant deviations or nonconformances, their related investigations,
and the effectiveness of resultant corrective
and preventative actions taken

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ICH Q7 GMP for APIs

Section 2.16 Quality Management Any
deviation from established procedures should
be documented and explained. Critical
deviations should be investigated, and the
investigation and its conclusions should be
documented.
Section 2.22 Responsibilities of Quality Unit
Making sure that critical deviations are
investigated and resolved
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ICH Q7 GMP for APIs

Section 2.3.4 Responsibilities for Production
activities Making sure that all production
deviations are reported and evaluated and
that critical deviations are investigated and
the conclusions are recorded

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SOP for handling deviations

SOP should define
Objective
Scope
Responsibilities
Definitions
Process steps
Documentation
Review process
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Process Step 1
The person who observes the incident / event
to notify the dept manager immediately
The incident / event recorded with adequate
traceability
Involve QA and decide if the event / incident
is a deviation or not
Evaluate the immediate impact or potential
impact on product quality, GMP and
compliance
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Process Step 2 (1)

Document the deviation with typically the following
A unique reference number
Date of observation
Observer who noted and recorded the deviation
Impacted batches
Impacted process, equipment, system etc.
Description of the deviation
Initial remedial actions taken
Signature of the observer and dept manager
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Process Step 2 (2)

Dept manager to ensure that data is collected
to do an impact assessment
Impact assessment to include
Implicated batch and its details
Any other batches or processes that could
be involved
Current status of these batches / processes

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Process Step 2 (3)

If the impact assessment reveals a serious
quality, patient safety or compliance issue
then treat the deviation as a critical one
Initiate immediate remedial actions involving
all stake holders
If the impact is not serious the process may be
allowed to continue with remedial actions in
place
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Process Step 3
The Dept Manager along with the QA
Manager to decide on the extent of Root
Cause Analysis required
Root Cause Analysis required if the impacts
are serious e.g. threat to patient safety,
severe product quality issues, major
regulatory non-compliance etc.
Root Cause Analysis required if deviation
happens recurrently
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Process Step 4
Establish team for doing Root Cause Analysis

Carry out Root Cause Analysis

Use one or more Root Cause Analysis tools
Identify actual root cause or most probable cause
If actual Root Cause Analysis is not identified carry
out a risk assessment
Document findings

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Process Step 5
Establish CAPA to eliminate the root cause
identified
Define actions and timescales
Follow up CAPA
Complete CAPA documentation
Close deviation

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Process Step 6
QA to periodically review the Deviation
Handling process
Carry out trending of deviations for the year
Process related
Equipment related
Procedure related
Summary findings discussed in Management
Review meetings
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Reprocessing & Reworking

If the deviations or incidents results in
reprocessing or reworking, it should be done
only under advice from QA
This must be followed using a change control
procedure.

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Batch release
QA must approve each deviation and confirm
that all remedial actions have been
appropriately identified, agreed and
completed prior to batch release.

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Archival of deviation reports

All deviation reports must be included as part
of the batch document. A copy of all deviation
reports must be maintained separately for
ready reference.

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Review during PQR

All deviations must be reviewed and
evaluated during the Product Quality Review
process to assess any trends that may require
additional corrective / preventive action to be
taken so as to prevent recurrence.

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Engineering involvement
If it is concluded that the deviation is due to
equipment / machinery failure then the Head
of Engineering should also be consulted for
taking any corrective or preventive actions

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Supplier involvement
If the deviation is attributed to a material
defect then this should be taken up with the
manufacturer (through Procurement) for
initiating any corrective actions as appropriate

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Responsibilities Observer
The Observer is the person who observed or
caused the incident / deviation
To record the incident accurately and
promptly
To take any immediate action to control the
incident
To notify the dept manager of the incident
observed
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Responsibilities Dept Manager

Decide along with QA, if the incident or event
is a deviation
Ensure information on the deviation is
recorded correctly
Perform an impact assessment
Carry out root cause analysis
Take remedial action
Conduct periodic follow up of deviations,
investigations and associated CAPAs
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Responsibilities QA
Decide along with the manager if the incident
or event is a deviation
Evaluate and approve the impact assessment
of the deviation
Assess the remedial action already taken
Classify the deviation after the results of the
investigation are known
Assess to what extent Root Cause Analysis is
required
Approve the investigation report and the CAPA
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Regulators comments
on deviation handling
Deviations handling is a hot topic for regulators
Some of the typical observations include
Deviations not documented as they occur
Reasons for deviations always human failure
No root cause identification for deviations
Investigation too scanty (no relevant details)
Deviations not included in batch records

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Questions

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