4. This presentation discusses Regulatory Science,
nothing more & nothing less
Reference: US-FDA Documents / Scientific Articles/
Real time hands on experience of Compliance & Enforcement
Personal point of view & nothing to disclose
Disclaimer
11. Absolute Fact
Product quality depends on each step in
manufacturing process must be controlled to
maximize the probability and enhance certainty
that the FPP will meet its quality, design
specifications, perform well & uphold promise
13. Deviation
GMP
Mistakes
or Error
Reprocessing or Rework
Unapproved changes
Performing an activity without proper training
Outside of operating parameter or in-process control limit
Failure to follow SOP or approved batch record instructions
16. Departure from an
approved instruction
or established
standard
Departure from
approved procedure
or established
specifications
e.g. Soaking
17. Departure from an
approved instruction
or established
standard
Departure from
approved procedure
or established
specifications
e.g. Soaking
e.g. Water bath
18. Obligation
ANY deviation from established procedure should be documented
and explained. Critical deviations should be investigated, and the
investigation and its conclusion should be documented
[ICH]
20. Obligation
Written procedure should be established & followed for
investigating critical deviations or the failure of a batch … the
investigation should extend to other batches that may have been
associated with the specific failure or deviation
[ICH]
22. Obligation
Deviation in yield associated with critical
process should be investigated to determine
their impact or potential impact on the resulting
quality of affected batches
23. Obligation
Any deviation should be evaluated to ensure that there
is no detrimental effect upon the fitness for the purpose
of material (intermediate, API, etc.)
24. Obligation
Deviation from approved standard of calibration on critical
instrument should be investigated to determine if these could have
had an impact on quality of …. Manufactured using this
equipment since last successful calibration
27. Obligation
Evaluation report that cross refers the validation protocol should
be prepared, summarizing the results obtained,
commenting on any deviation observed
& drawing the appropriate conclusion, including recommending
changes to correct deficiencies
32. Planned Deviation
Pre-described, Pre-approved for specified
period for specific number of batches
Feb 2016
Annual Maintenance
60 Batches .. One batch
per day
Jan 2016
Mfg ..
Schedule 5 to 10 Feb
33. Planned Deviation
Pre-described, Pre-approved for specified
period for specific number of batches
Approved well before execution
Handled through approved change control procedure
Changes should be evaluated for product impact significance
49. Investigation
Remember, there is a big difference b/w
What happened & Why happened -OR- What happened & How happened
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
97. … A multiple injection manufacturing facility
Injection X 500 mg / 10 ml always found with yield 103 to 104%
Assay trend moves in between 101 to 103%
Process loss of 3 to 6% for other injection products
Lets think what is going on …
?
105. 1 Write up the investigation in detail
2 Explain what happened & why
3 Identify & document root cause(s)
4 Detail corrections & corrective actions
106. 5 Ensure CAPA are raised
6 Reviewed by Quality Assurance
7 Final closure by Quality Assurance
8 Record closure & maintain register
107. Take Home Message
Make sure that policy,
procedures, forms, process
flow are well understood &
aligned to walk and talk
together
108. Take Home Message
Appropriate training &
trained staff for investigations
is inevitable to reach logical
decisions that satisfy
regulatory expectations
109. Take Home Message
Be simple
Don’t make the process
unreasonably complicated or
over complicated
112. 1 Poor investigation
2 Not addressing facts/ignoring evidence
3 Only considering one root cause
4 Poor scientific basis
113. 5 Making & stucking on assumptions
6 Not raising CAPA
7 Repeat deviations
8 Leave assessment of impact on other batches
114. … Tablet 400 mg instead of 200 mg
Same product of two different strengths … Proportionality in
granulation was same … Batch was compressed for 400 mg tablet
Packaging jar was labeled for 200 mg … All documents were
prepared for 200 mg except compression …
Lets think what can be done …
?
115. … Evaluation of supplier competence
Glass bottles
We have to monitor and review the performance as per QMS
Lets think what can be done …
?
116. Remember
Deviation is not allowed if not justified in
Quality System
Document to ensure that history of the product can be traced back with regard to
concerning personnel, equipment, materials, process etc.
117. Remember
Handling of non-conformance or deviations
are key component of Quality System
Document investigation, conclusion and follow up to ensure that product confirms
to the required expectations. It is inevitable to measure
process & product attributes
118. Remember
Investigation of discrepancy is critical esp.
when affect product quality
It may be detected at any stage of manufacturing & testing process, it should be
handled appropriately, sometime it may not have an impact on product
119. Remember
Responsive deviation & investigation system
is a front burner attribute of Quality System
Implementation of Quality System facilitates compliance
and assures consistent production for safe, effective product under a sustainable
and productive environment
120. Remember
Deviation may be acceptable if
Does not compromise the quality of drug product, it is justified, documented &
comes under microscope for review on regular basis
122. Remember
Sufficient Rigorous Scientific Evidence &
Statistical Measures
Product and process deviation can be explained scientifically with identifiable root
cause to keep aligned goal of process validation
123. A closer look at
inspection (MHRA)
Deviations were not
fully recorded and
investigated
124. A closer look at
inspection (MHRA)
Deviation
investigations did not
include an appropriate
level of investigations
and did not capture all
relevant information
125. A closer look at
inspection (MHRA)
Quality impact of
deviations and CAPAs
implemented were not
appropriately assessed
126. A B
Approved for particular
purpose
NOT Approved for
particular purpose
127. A B
Weighed on B,
but not recorded
Approved for particular
purpose
NOT Approved for
particular purpose
128. A B
Approved for particular
purpose
NOT Approved for
particular purpose
Weighed on B,
but not recorded
Impact?
130. If B goes out of calibration
& investigated for all the
weighing done on it, the
particular batch will escape
from investigation due to
non-recording
If A goes out of calibration
& investigated for all the
weighing done on it, the
particular batch will be
added for no reason in the
investigation
133. Lets imagine a product/ process/ procedure and think of an instance where
a minimum deviation can greatly impact the product quality
Processing
Parameter
Equipment
Testing
Procedure