INVESTIGATION FOR

NON-CONFORMITIES

-Arijit Dasgupta
 TYPE OF NON-CONFORMITIES
• 1) Laboratory Incidents
• 2) Deviation
• 3) OOS/ OOT/ OOE
• 4) Market Complaints
• 5) Product Recalls
• 6) Audit Observations
 ROOT CAUSE & TYPES OF ROOT CAUSE
• 1) Root Cause-
• Condition that produces an effect
• Eliminating a cause will eliminate the effect
• 2) Obvious Error-
• An error resulting in an abnormal result which is detectable by direct
evidences
 ROOT CAUSE & TYPES OF ROOT CAUSE
• 3) Assignable Cause-
• A Scientifically justified explanation of the reason for an out-of-
specification test result identified
• 4) Atypical Root Cause-
• An unexpected or unplanned event outside the control of laboratory.
• 5) Contributing Factor-
• Condition that influences the effect by increasing its likelihood
 ROOT CAUSE ANALYSIS (RCA)
• RCA is a process of analysis to define the problem, understand the causal
mechanism underlying transition from desirable to undesirable condition, and to
identify the root cause of the problem in order to keep the problem from recurring
by using a structured procedure

• The purpose of any Root Cause Analysis (RCA) is to find effective solutions to
problems such that they do not reoccur
 ROOT CAUSE ANALYSIS (RCA)
RCA process include following criteria:
• 1. Clearly defines the problem(s)
• 2. Clearly establishes causal relationships between the root cause(s) and the
defined problem
• 3. Clearly describes the known dynamics among those causal relationships on
how they combined to cause the problem
• 4. Clearly presents the evidence used to support the existence of identified
causes
 ROOT CAUSE ANALYSIS (RCA)
For Example; Problem- Blockage of Column Frit/ Damage of Column Frit

Cause- Deposition of Undissolved particles

Root Cause-STP does not mention about Mobile Phase

Filtration

Contributing Factor-Lack of awareness for Analyst due to

incomplete information in the STP & Inadequate Review of STP
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES
• 1) Concerned Department shall issue related form from Q. A department within
defined time period as per Site Specific SOP & Retain all glassware used for
standard & test solution preparations

• 2) Q.A shall assign Identification No. to each respective Form as per Site Specific
SOP
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 3) DESCRIPTION/DETAILS OF INCIDENT –
• Write what is happened exactly (an unexpected event) and not the cause for incident
(reference of acceptance criteria against obtained results shall be written if
applicable)
• For example: RT Shift in Chromatogram/ %RSD Failure/ Instrument stopped
was found during analysis of name of test for name of product dated _______in
instrument name/ ID
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 4) Scope shall be define cautiously
• 5) Investigation Team shall be formed-
• Investigation shall be carried out by the Initiating Department where the Non-Conformity has occurred
• When required, a Cross-Functional team shall be identified by the respective Department Head and Q.A Head to
carry out the detailed investigation
• By preference, the team members shall be those who are relevant subject matter experts on process, equipment or
system under evaluation
• Support of an external agency and subject matter experts may be taken for supporting the investigation if needed
• Investigations shall be done by section-in-charge and root cause and conclusion shall be made by respective HOD
only and not by same section-in-charge who has done investigations
• The Respective Department Head and Q.A Head shall ensure that the investigation is completed within a pre-defined
time line
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 6) IMMEDIATE ACTIONS-
• Informed to HOD/ Supervisor and Immediately stopped ongoing analysis and/ or
related immediate correction
• Quarantine the Solutions; Verify the Table Top solutions against Protocol/ STP
• Review of data for correctness of procedure used w.r.t related Protocol/ STP
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 7) PRELIMINARY INVESTIGATIONS- Shall be done by Initiating Department Section
In-Charge/ Group Leader

• As per checklist of SOP which include thorough Raw Data Verification, Calculation
Verification, Instrument Status (Calibration/ Preventive Maintenance Due Date),
Chemical Verification, Correct Protocol/ STP used or not etc.

• Chromatograms/Measurements/Calculation/Weighing details/Dilution details/

Actual use of glassware’s against Protocol/ Quarantine of solutions etc.
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 8) OUTCOME OF PRELIMINARY INVESTIGATIONS- Write whether any obvious error is
observed/found during the preliminary investigations. Attach the available proofs of error
identified

• 9) ANALYST INTERVIEW – Training, Qualification Record shall be verified

• Ask the questions like -whether he has followed correct steps in procedure mentioned in
related PROTOCOL/STP, If any doubt of any step of analysis, etc.
• NOTE: No conclusion about root cause shall be made in analyst interview without
confirmation study
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 10) INVESTIGATIVE TESTING – This should be done to rule out Instrument Error or Sample/Standard
Preparation/Dilution error etc.
• A) RE-INJECTION from Same Vial – To rule out the Instrument Error,
• B) RE-VIALING From Final Solution – To rule out Wrong Vial Filling or Position/Vial contamination, etc,
• C) RE-DILUTION From Stock Solution – To rule out Dilution Error/Incorrect Glassware used for second
dilution by analyst,
• D) RE-SONICATION, RE-FILTRATION etc. as applicable- To rule out error due to insufficient
sonication/mixing/filter saturation etc.
• NOTE INVESTIGATIVE TESTING ARE CASE SPECIFIC AND MAY NOT BE REQUIRED IN CERTAIN
DEVIATIONS/MARKET COMPLAINTS/ TESTING WHERE STD./SAMPLE SOLUTION CANNOT BE
QUARANTINED E.G. TEST LIKE KF TITRATION
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 11) Results of Investigative Testing Study shall be reported against Initial Results
and Its Conclusion

• 12) Hypothesis Study- If no Conclusion Obtained; then proceed for Hypothesis Study
• Objective of Hypothesis study Protocol should be clearly mentioned
Which error to be ruled out through this protocol should be part of objective
• NOTE INVESTIGATIVE TESTING ARE CASE SPECIFIC AND MAY NOT BE REQUIRED IN CERTAIN
DEVIATIONS
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 13) Outcome of Hypothesis Study-
• Details of results against original results and conclusion against objective shall be
made whether root cause is identified or not
• Recommendation about next hypothesis if any
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• A) Brainstorming Session
• B) 5-Why Technique
• C) Ishikawa/ Fishbone/ Cause & Effect Diagram/ 6-M Tool
• D) Fault Tree Analysis
• E) Failure Mode & Effect Analysis (FMEA)
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• A) Brainstorming Session:

• A group of professionals (SMEs) from different concerned department shall sit

together & discuss/ challenge decisions so as to find out root cause of problem
• It can be recorded as MOM with signatories of attendees & can be attached with
Investigation Report
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• B) 5-Why Technique:
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• B) 5-Why Technique:
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• B) 5-Why Technique:
• Questions should be recorded in the form of Question & Answer. However, the person
getting Interrogated should not write the answers
• There should be a separate person known as Scribe, continuously recording question &
answers independently
• After that, all persons should sign on the
Form
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• C) Ishikawa/ Fishbone/ Cause & Effect Diagram/ 6-M Tool: Typically Include:

• MAN: Any person/s involved with the process

• METHOD: How the process is performed and the specific requirements for carrying out the process, such as
policies, procedures etc.
• MACHINE: Any Equipment Capability, Computer Accuracy, Instrument Parameters, Qualification/
Calibration/ Preventive Maintenance status etc. required to accomplish the activity
• MATERIAL: Raw Materials, Standard/ Sample, Chemicals & Reagents used to produce the final product
• MEASUREMENTS: Data generated from the process that are used to evaluate its quality
• MOTHER ENVIRONMENT: Conditions such as location, time, temperature, and culture in which the process
operate
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• D) Fault Tree Analysis
• Typically Include:
a. Defining the undesired event to study
b. Obtaining an understanding of the system
c. Constructing the Fault tree
d. Evaluating the Fault tree
e. Controlling the identified causes
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 14) INVESTIGATION TOOLS-
• E) Failure Mode & Effects Analysis (FMEA): Performed as per ICH Q9 Guideline
• Typically Include:
a. Analyses each step w.r.t what failures can occur
b. Analyse Severity, Detectability & Likelihood of Occurrence/ Probability & assign
Score as per Identified Risks
c. Calculate Risk Priority Number (RPN)
d. Evaluate & Mitigate the Risks as appropriate
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)
• 15) Conclusion about Root Cause:
• If root cause is not identified, then most probable cause(s) shall be written

• 16) Impact of Incident:

• Invalidations of results/data of current parameter and or any other parameter, etc.
• Impact of failure on related existing system e.g. Instrument, documentation, facility,
product, process, procedure etc.
• About reoccurrence- whether there was any same type of lab incident/ deviation
happened earlier, whether any other/earlier data is impacted.
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)

• 17) CAPA:
A) Corrective Action:
• Action taken to eliminate cause behind detected Non-conformity
• Its always reactive & Stops Re-Occurrence
B) Preventive Action:
• Action taken to eliminate cause behind potential Non-conformity
• Its always Pro-active & Stops Occurrence
 REQUIREMENTS FOR INVESTIGATION OF
NON-CONFORMITIES (CONTINUED…)

• 18) Closure of NC Report-

• Done by Q.A Head after Classification of NC as Major/ Minor along with decision on
Batch Approval/ Rejection if NC Report found satisfactory
 ROOT CAUSE ANALYSIS (RCA)
For Example; Problem & Root Cause- Damage of Column Frit due to unfiltered mobile phase

Corrective Action- Mobile Phase Filtration, Availability of Filtration assembly with Filter Papers
Discard all columns whose frit get damaged

Preventive Action- STP shall be revised to include Mobile Phase Filtration

Few 483 W.L related to Inadequate
Root Cause Analysis
1) On 11/10/2020, an analysis was aborted for improper peak shape & recorded analytical
interruptions repot no. xxx/yyy. This improper was observed during dissolution test of
Product A. Your Investigation reported poor column as root cause for improper peak.
Based on this; retested new sample on a different column & initial analysis was invalidated.
However, review of Aborted Sample Set reveal that peak shape for SST solution was proper.
Suggesting that improper peak shape was not due to Column.
Review of Retest analysis Sample Set suggest that there is an unknown peak eluting at RT XY
minutes closely to the Main Peak. These unknown peak was not seen in Its Method Validation
study.
2) Firm failed to investigate 25 Equipment Failure/ Error Message “ Cannot Operate because of
Failure in Acquisition_________” observed on 21/02/2021 in Lab Solutions Version 1.108. UV
Visible Spectrophotometer (ID-XXX/YYY) is utilized for Qualitative & Quantitative analysis of
Drug Products & Drug Substances.
Since 01/02/2019, its utilized in the analysis of following listed products & batches for U.S
Market.
THANK YOU