4. System for Quality
What is tested is not sold
What is sold is not tested
So,
Quality is not testing of product.
It should to be built in each stage
of process/operation.
5. Principle of GMP
Quality, Safety, and
Effectiveness must be designed
and built into the product;
Quality cannot be tested into
the product;
Product Quality depends on:
Each step in a manufacturing process must be
controlled to maximize the probability that
the finished product will meet all its quality
and design specifications.
6. GMP Guidance/ Reference
ICH- Q7
FDA- CFR-210 &211
Schedule – M
WHO GMP : Technical Report series - 937
EU GMP guidelines, Part I annex 15
EU GMP Part II chapter 13
PIC/S Recommendations PI 006-3
8. ICH: Q7 Contents (Chapters)
1.0. Introduction
3.0 Personnel
2.0 Quality Management
5.0 Process equipment
4.0 Building and premises
7.0 Materials Management
6.0Documentation & Records
9.0 Packaging and labelling
8.0 Production & in-process
Controls
11.0 Laboratory Control
13.0 Change control
10.0 Storage & Distribution
15.0 Complaints and recalls
14.0 Rejection and re-use
of materials
12.0 Validation
16.0 Contract manufacturing
9. Deviations
• Associated with limits vs. specifications
• GMP mistakes or errors
– Reprocessing or Rework
– Unapproved changes
– Performing an activity without proper training
– Outside of operating parameters or in-process
control limits
– Failure to follow written SOPs or approved batch
record instructions
10. Definition
Deviation
• Departure from an approved instruction
or established standard.
• Deviation is a departure from approved
procedure or established standard or
specification
11. Deviation – GMP requirement
From ICH
• 2.16 Any deviation from established procedures should
be documented and explained. Critical deviations
should be investigated, and the investigation and its
conclusions should be documented.
• 2.53 Written procedures should be established and
followed for investigating critical deviations or the
failure of a batch of intermediate or API to meet
specifications. The investigation should extend to other
batches that may have been associated with the
specific failure or deviation.
12. Deviation – GMP requirement
• 8.15 Any deviation should be documented and
explained. Any critical deviation should be
investigated.
• Deviations in yield associated with critical process
steps should be investigated to determine their
impact or potential impact on the resulting quality
of affected batches.
• Any deviations from this should be evaluated to
ensure that there are no detrimental effects upon
the fitness for purpose of the material.
13. Deviation – GMP requirement
• 5.35 Deviations from approved standards of calibration
on critical instruments should be investigated to
determine if these could have had an impact on the
quality of the intermediate(s) or API(s) manufactured
using this equipment since the last successful calibration.
• 6.72 All deviation, investigation, and OOS reports should
be reviewed as part of the batch record review before the
batch is released.
• 12.22 A validation report that cross-references the
validation protocol should be prepared, summarizing the
results obtained, commenting on any deviations
observed, and drawing the appropriate conclusions,
including recommending changes to correct deficiencies.
14. Types of deviations
A deviation is an activity performed
differently and/or modified than that
specified in an approved document.
There are two types of deviations
1) Planned Deviation.
2) Unplanned Deviation.
15. Planned Deviation
• Planned deviations, which are described, and pre-approved
deviation from the current operational document/system,
covering a specified period of time or number of batches.
• Planned deviation shall be approved before execution
• Planned deviations should be handled through the QA approved
change control procedures.
• All changes should be evaluated for product impact, significance
– The need for requalification or revalidation
– Changes ultimately approved or rejected by QA.
• QA should insist that planned deviations not be used; all
deviations should be unintentional, unplanned, or unexpected.
16. Unplanned Deviation
• Unplanned deviations also called as
incident.
• Incident can be defined as unplanned or
uncontrolled event in the form of non-
compliance from the designed systems or
procedures at any stage of manufacturing,
packaging, testing, holding and storage of
drug product due to system
17. Classification
Critical/major/minor
Quality Impacting Incident:–
• Quality impacting incidents are errors or occurrences
during execution of an activity which will affect the
Quality, Purity, Strength of the drug product.
Quality Non-impacting Incident:-
• Quality Non-impacting incidents are errors or
occurrences during execution of an activity which may
have no impact on the quality, purity and strength of a
drug product
18. Documentation
• Deviation reported in real time
– Timely notification of QA (within 24 hours)
• Thorough root cause investigation
• Timely investigation (within 30 days)
• Corrective actions proposed and initiated or
completed
• Investigation closed
• Implicated batch(es) released or rejected
• Preventive actions initiated and closed
19. Documentation
• The guidelines require that ANY deviation to the defined
processing steps in the production records should be
documented. It may be useful to have an additional page in
the production record to allow easy recording of unexpected
occurrence or deviation to the standard instructions.
• It is then the responsibility of the persons reviewing the
completed production records (Production) to decide which
deviations could be considered critical and require
investigation.
• The Quality Unit should check the deviation records (not the
full production/batch records!)
• The Quality Unit should check the deviations to see the
procedure was followed and CRITICAL deviation records for
impact on API quality and ensure that critical deviations were
investigated (reference 2.22 and 6.72 ICH Q7).
20. Documentation
• A critical deviation is defined as a variation to previously
established critical parameters or a significant variation to
standard operations which COULD affect the quality of the
API or intermediate. Critical deviations should always be
investigated and corrective actions identified.
• investigation and its conclusions should be documented. Q7A
allows the company to determine the extent of the
investigation or explanation.
• Where deviations recur on a regular basis the need for
example to re-qualify equipment, retrain operators, redefine
the process parameters or to implement other appropriate
actions should be considered.
21. Examples of deviations
Examples of deviations are:
• Incorrect charging of raw materials
• Temperature, pressure, vacuum parameters outside defined
limits.
• Operating instructions not correctly followed.
• Breakdown of process equipment or failure of utilities.
• Equipment out of calibration.
• Production records not adequately completed.
• Temporary alteration to defined production instructions
• In Process Control Limits not achieved.
• Alternative production equipment used at short notice.
• Extraneous contamination of API and intermediates
• Any other unplanned event.
22. Observation
• General FDA 483 Observation
• Corrective actions do not ‘match’ or
support definitive or potential root causes.
23. Deviation investigations
• Deviation investigations must not be biased from
the start
– From an FDA or cGMP perspective, the purpose of
conducting a deviation investigation is not to “release
the batch.”
– The true purpose of a deviation investigation is to
• determine the root cause for the “deviation”
• implement appropriate and meaningful corrective
actions, and
• evaluate the implicated system (e.g., the training
program) once a pattern of repeating deviations is
noted.
24. Investigation steps
1. Discovery of the Deviation
2. Documentation of the Events
3. Immediate Corrective Action
4. Investigation of the Root Cause
5. Causal Analysis
6. Corrective Action
7. Effectiveness Evaluation
25. Investigation
• What was discovered?
• Who was involved?
• When did the event occur?
• Where did the deviation occur?
• How was the deviation discovered?
• How frequently does the process occur?
THERE IS A BIG DIFFERENCE BETWEEN WHAT HAPPENED
VS. WHY OR HOW SOMETHING HAPPENED
26. Investigation
• Are there environmental problems?
• Are the work conditions suitable?
• Are there process flow problems?
• Are there facilities problems?
• Are there any equipment or materials problems?
• Are instructions for use clear?
• Are there problems with staff communication or staff training?
• Is there adequate supervision?
• Are there problems with the methods, SOPs, forms, or task
analysis?
• Do the steps performed match the operating procedures?
• Has a process recently changed?
27. Investigation
• Understanding of how or why the deviation occurred.
• Understanding of the circumstances at the time of the
deviation
• Determination of other products, processes, or
individuals were involved
• Gathering of data to aid in the accurate future
determination of a root cause and development of
corrective action.
Data Collection
Interview: Staff, Customers, Suppliers
Review: Policies, Procedures, Forms
Record Review: verify the relevant records
28. Corrective and Preventive Action
• CAPA (Corrective and Preventive Action) is
a deviation management program that
focuses on the systematic investigation of
discrepancies, adverse events, or failures.
• If used properly, the CAPA system will
provide a means to prevent the deviation
from recurring.
• systematic investigation of the deviation.
29. Corrective action:
• An action taken to eliminate the root
cause and symptom of an existing
deviation or nonconformity to prevent
recurrence
• This is a REACTIVE action that eliminates
problems identified in products, services,
or processes and takes care of the
immediate problem
30. Preventive action:
• This is an action taken to eliminate the
potential causes of a nonconformity,
defect, or other undesirable situation in
order to prevent occurrence.
• This is a PROACTIVE action which avoids
deviations through planned activities. It
also eliminates or reduces the recurrence
of the problem.
31. Immediate action
• Examples of Immediate Corrections
• Products
– Quarantined
– Isolated
– Discarded
• Equipment
– Removed from Service
– Replaced
• Processes
– Manufacturing Suspended
– Test Results Withheld
– Recovery Procedure Halted
32. Developing the Corrective Action
• SOPs
• Process changes
• Training or Retraining
• Implementation of automation or new equipment
•
• •Decide on the implementation timeframe
• •Determine the method of CA communication
• •Determine staff involved in carrying out the CA
33. Effectiveness Evaluation
• The Corrective action was completed and implemented as
planned
• The corrective action was effective in the reduction or halt of
recurring deviations.
• Verify that corrective action was properly implemented
• Determine data source for Effectiveness Evaluation
• Determine when to perform Effectiveness Evaluation
• Determine evaluation period
• Consider impact of learning curve
• Determine success criteriaDepending on the organizational
SOP, the evaluation for
• effectiveness should begin within 60 days of the
• corrective action plan implementation date.
34. Importance of documentation
• If it isn’t documented, it didn’t happen
• If it isn’t documented, it doesn’t exist.
• Precise, economical word usage
