Transcript Investigation and CAPA system

Effective Investigation
and
Corrective And Preventive
Action (CAPA)
Sanjay Kumar Jain
07 Aug 2016
What is Investigation?
Investigation is the process of collecting and analyzing
data to determine the cause of a non-compliance / failure
What is Non-compliance / Failure?
 Failure refers to the state or condition of not meeting a desirable or
intended objective, and may be viewed as the opposite of compliance.
 Failure in other words is a Non-conformity which may include  Product failure (Release testing / In-process testing / stability testing)
 Failure of Utility
 Quality System failure
 Market complaints
 Deviation
Why Investigation ?
 To prevent reoccurrence
 Failures are cost to company / Organization
 Failures can have adverse health impact on the consumers if
go undetected
 Cost of poor Quality can be Fatal
 To perform Impact assessment
 Are more batches affected?
 Are more products affected?
 To identify the cause and take corrective actions
 To identify other similar situations and take CAPAs
 Continuous improvement
 Regulatory requirement
Investigation – Regulatory requirement
 Schedule
M
–
GOOD
MANUFACTURING
REQUIREMENTS OF PREMISES, PLANT AND
PHARMACEUTICAL PRODUCTS.
PRACTICES
EQUIPMENT
AND
FOR
 24.2
An investigation shall be carried out into the cause
necessitating re-processing and appropriate corrective measures
shall be taken for prevention of recurrence.
 28.1 All complaints thereof concerning product quality shall be
carefully reviewed and recorded according to written procedures.
Each complaint shall be investigated /evaluated by the designated
personnel of the company and records of investigation and
remedial action taken thereof shall be maintained.
 8.8. There shall be written microbiological monitoring program for
different types of water. The results shall justify the frequency of
sampling and testing. Investigation shall be carried out and
corrective action taken in case of deviation from prescribed limits.
Investigation – Regulatory requirement
 21 CFR 211 – cGMP for Finished Pharmaceuticals
 Subpart B--Organization and Personnel
 211.22 - Responsibilities of quality control unit in
investigation of errors observed during testing.
 211.125 - Investigation of discrepancies in label reconciliation
 211.170 – Investigation of deterioration observed in Reserve
samples
Investigation – Regulatory requirement
 21 CFR 211 – cGMP for Finished Pharmaceuticals
 Subpart J--Records and Reports
 211.180 General requirements - A review of complaints, recalls,
returned or salvaged drug products, and investigations.
 211.186 Master production and control records – Investigation
of yield deviations;
 211.192 Production record review – Investigation of any
unexplained discrepancy or failure of a batch or any of its
components to meet any of its specifications, whether or not
the batch has already been distributed.
 211.198 Complaint file – Investigation of market complaints
 211.204 Returned drug products - Investigation of returns
Investigation – Regulatory requirement
 EudraLex - Volume 4 Good manufacturing practice (GMP)
Guidelines
 Good Manufacturing Practice for Medicinal Products
(GMP)
 (iv) Documentation and investigation of any significant deviations
in sampling, inspecting and testing;
 (vi) Documentation and investigation of any significant deviations
in the manufacturing;
 (x) Investigation of complaints
 Product Quality Review
 (iii) A review of all batches that failed to meet established
specification (s) and their investigation.
 (iv) A review of all significant deviations or non-conformances,
their related Investigations.
 (viii) A review of all quality-related returns, complaints and recalls
and the investigations performed at the time.
Investigations top MHRA deficiency list
MHRA : Medicines and healthcare products regulatory agency
.
Investigations top MHRA deficiency list
MHRA : Medicines and healthcare products regulatory agency
USFDA - FY 2013 Inspectional Observation Summaries
Number of 483s issued from the System
Center Name
Drugs
483’s issued
690
Ref No
Frequency
Short Description
21 CFR 211.22(d)
155
Procedures not in writing, fully followed
21 CFR 211.192
131 (19%)
Investigations of discrepancies, failures
21 CFR 211.100(a)
106
Absence of Written Procedures
21 CFR 211.160(b)
99
Scientifically sound laboratory controls
21 CFR 211.67(b)
77
Written procedures not established/followed
21 CFR 211.113(b)
76
Procedures for sterile drug products
21 CFR 211.67(a)
71
Cleaning / Sanitizing / Maintenance
21 CFR 211.165(a)
66
Testing and release for distribution
21 CFR 211.110(a)
65
Control procedures to monitor and validate
performance
21 CFR 211.166(a)
62
Lack of written stability program
USFDA: United states Food and Drug administration
WARNING LETTER – 2012 to 2013
Total Observations = 266
Documentation
2
Water System
3
Vendor…
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4
Training
6
Computer System
6
Microbiology Lab
12
Stability
14
Quality Assurance
15
Investigation
42
Laboratory…
75
Process Control
87
0
20
40
60
80
100
Process Control = 87 (33%)
Laboratory Control=75(28%)
Investigation=42(16%)
Quality Assurance=15 (6%)
Stability=14(5%)
Microbiology=12(5%)
Computer System=06(2%)
Training=06(2%)
Vendor Management=04(2%)
Water System=03(1%)
Documentation=02(1%)
Investigation report – Typical content
 Quality issue definition
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What is the observation (give the reference of standard) ,
Who observed
When observed
Where it happened
How it happened
 Objective
 Scope
 Investigation Team
 Hypothesis
 Documents to be reviewed
 Investigation tools
 Investigation findings
 Impact assessment
 Root cause(s)
 Correction
 CAPA(s)
 Batch disposition
 Conclusion
Objective and Scope
 Objective shall spell out clearly following –
 To identify the root cause / most probable root cause
 To perform the impact assessment
 To recommend CAPA
 Scope
 How many finished product batches
 How many products
 How many API batches
Investigation team
 Investigation team shall be cross functional team
comprising of –
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Initiating department
Quality Assurance
Quality control / ADL
FnD
Engineering
One person shall lead the team
Assemble for Brainstorming and Discuss the hypothesis
List down the documents to be reviewed
Distribute the work
Team to Re-assemble and share the findings
Document all the finding with supporting documents
Verify / Check the hypothesis
Hypothesis
 A hypothesis is an educated guess about how things work.
 A hypothesis is a specific, testable prediction about what you expect to
happen in your study.
 Most of the time a hypothesis is written like this: "If _____[I do this]
_____, then _____[this]_____ will happen." (Fill in the blanks with the
appropriate information from your own experiment.)
Review of documents
 Team shall list down all the documents which shall
be reviewed as part of the investigation
 Batch manufacturing record
 Batch packing record
 Analytical records / results
 Annual product review trends
 Previous OOS / deviation reports
 GMP documents related to the batch
 Stability data (exhibit & commercial batches)
 Method validation & transfer data
Investigation tools
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Failure Mode effect analysis
Fish Bone Diagram
Why – Why analysis
Fault tree diagram
Fish Bone Diagram
 Agree on a problem statement (effect). Write it at the centre right of the
flipchart or whiteboard. Draw a box around it and draw a horizontal arrow
running to it.
 Brainstorm the major categories of causes of the problem. If this is difficult
use generic headings:
 Methods
 Machines (equipment)
 People (manpower)
 Materials
 Measurement
 Environment
 Write the categories of causes as branches from the main arrow.
 Brainstorm all the possible causes of the problem. Ask: “Why does this
happen
 Again ask “why does this happen?” about each cause. Write sub–causes
branching off the causes. Continue to ask “Why?” and generate deeper levels
of causes. Layers of branches indicate causal relationships.
Fish Bone Diagram
Why-Why analysis
Problem – Low BU result for one of the sample location
Why Low BU result
for one location?
There was weighing error
Why weighing
error?
Analyst missed to consider the paraffin film
weight while deriving the net weight
Why paraffin film is
used?
To wrap around the rubber stopper of the vial
containing sample
Why vial with
rubber stopper? Do
we have alternative?
Use vial with screw cap
Investigation findings
 Investigation Team shall –
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Re-assemble to discuss the work done and record all the findings.
Discuss the observations and make the inferences
Discuss the out come of the experiment planned based on hypothesis
Draw conclusion
Plan further course of action
Give references of guidance for protocol bound study
 Ensure following while writing investigation  Stick to facts - write things which might be true, but which you cannot
prove
 Avoid personal comment - Do not put in your personal opinions.
 Keep your language simple - Keep sentences short and language simple
and concise.
 Avoid vague words - Avoid using vague words, such as “usually" or
“mostly".
Impact assessment
 Impact means “a marked effect or influence.”
 Assessment means “the action of assessing someone or
something”
 Impact assessment is important component of failure
investigation to assess the impact of failure on finished
product quality
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For same products involving multiple batches
For other products
For other API batches
For other areas
Root cause / Most probable root cause
 The most basic cause (or causes) that can reasonably be
identified that management has control to fix and, when
fixed, will prevent (or significantly reduce the likelihood
of) the problem’s recurrence.
Batch disposition
 Final decision for the batch / batches / products shall be
clearly written down
 Released or
 Rejected
CAPA - Definition
 CORRECTION
 Immediate action taken to correct the existing non
conformity to avoid further damage
 CORRECTIVE ACTION
 Action to eliminate the cause of a detected non‐ conformity
or other undesirable situation
 Corrective action is taken to avoid recurrence of
non‐conformity
 PREVENTIVE ACTION
 Action to eliminate the cause of a potential non‐ conformity
or other undesirable potential situation.
 Preventive action is taken to avoid occurrence of potential
non‐conformity
In the race for Quality, there is no
finish line………………………………………
………………………………………………………
Any Questions ??