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Investigation Tools used in Pharma – SOP

& Guideline
 pharmabeginers -  October 1, 2020 -
 Audit / Calibration / cGMP / Checklist / Checklist / Formats / Doc / GC / Health & Safety
(EHS) / HPLC / Maintenance Sops / Micro Sop / Microbiology / Production / Production Sop /
Protocol / QA Sop / QC Sop / SOPs / Sterile / Stores Sops -
 1 Comment

The investigation related to quality-related events that occur from cGxPs approved speci cations,
and/or procedures including but not limited to Protocols, Master Batch Records (MBR), Batch
Packaging Records (BPR), breakdowns, facilities, storage, distribution, manufacturing, testing,
packaging, warehouse and distribution of drug products.

Guideline on Investigation Tools

1.0 PURPOSE:

This Standard Operating Procedure (SOP) de nes the requirements for reporting,
documenting, investigating, evaluating, managing, resolving, and approving closure of
investigation from cGxPs, approved speci cations, and/or procedures.

2.0 SCOPE:

This SOP/Guideline applies to Investigations related to quality-related events that occur from
cGxPs, approved speci cations, and/or procedures including but not limited to

Protocols,

Master Batch Records (MBR),

Batch Packaging Records (BPR),

Breakdowns,

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 Facilities,

Storage,

Distribution,

Manufacturing,

Testing,

Packaging,

Warehouse and distribution of drug products.

3.0 REFERENCES – GUIDELINE FOR INVESTIGATION:

SOP for Handling of Corrective and Preventive Actions (CAPA)…….<SOP>

US FDA 21 CFR Part 211, 501, 600 and 820

SOP for Quality Risk Management……….<SOP>

European Commission: EudraLex – Volume 4 – Good Manufacturing Practice (GMP)

Guidelines

SOP for Handling of Market Complaints……..<SOP>

ICH Q7 – Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

SOP for Deviations/Incidents

CDER Guidance for Industry: Quality Systems Approach to Pharmaceutical

cGMP Regulations, September 2006

EMEA Guidance: Manufacture of nished dosage forms, April 1996

SOP for Documents Management System

4.0 RESPONSIBILITY – INVESTIGATION TOOLS:

Quality Assurance Head/Designee shall be responsible for-

The oversight and assessment of the investigation.

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 Reviewing and approving the investigation plan, report, and timely resolution of all
investigations.

Assuring timely implementation of corrective actions and ensuring corrective actions are
effective.

Providing assistance in performing investigation.

Reviewing and approving the investigation reports.

Deriving appropriate CAPA and ensure adequate implementation of CAPA.

Disposition of impacted products/batches and/or releases other controls, based upon

investigation conclusions and associated corrections.

Taking necessary action to notify customers or regulatory agencies about the outcomes of
the investigations, wherever applicable.

The overall resolution of all investigations originating from “Critical”/ “Major” events.

Assuring timely implementation of corrective actions and ensuring corrective actions are
effective.

Reviewing and approving investigations impacting multiple sites and or requiring market
action.

Manufacturing head/designee shall be responsible for-

Ensuring all manufacturing deviations/incidents are reported to QA on the day of discovery,

but no later than the end of the next working day.

Ensuring that resources are available to support the investigation closure and assist QA.

Quality control head /designee shall be responsible for-

Ensuring all deviations/incidents, non-conformances, failures, and/or events in the

laboratory are reported to the QA on the day of discovery, but no later than the end of the
next working day.

Ensuring resources are available to support the investigation closure and assisting the QA as
required.

5.0 ABBREVIATIONS – INVESTIGATION TOOLS:

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 BMR: Batch manufacturing record.

CAPA: Corrective and Preventive Action

CCR: Change Control Record

CFT: Cross-Functional Team

EHS: Environmental health safety

SME: Subject Matter Expert

DEFINITION:

Acceptance Criteria:

The product speci cations and acceptance/rejection criteria, such as acceptable quality level
and unacceptable quality level, with an associated sampling plan, that are necessary for
deciding to accept or reject a lot or batch (or any other convenient subgroups of
manufactured units).

The criteria, a system or process must attain to satisfy a test or other requirements.

Assessment: The act or process, of evaluating (e.g. extent, magnitude, position, impact or
compliance level) of a process, system, project, action, or activity.

Corrective and Preventive Action:

A concept with current Good Manufacturing Practice (cGMP) that focuses on the systematic
investigation of root causes of unexpected incidences to prevent their recurrence (corrective
action) or to prevent their occurrence (preventive action).

Corrective Action:

Action is taken to eliminate the causes of an existing nonconformity, defect, or other

undesirable situation, in order to prevent a recurrence.

Preventative Action:

Action is taken to eliminate the cause of a potential nonconformity, defect, or other

undesirable situation, to prevent occurrence.

Cross-Functional Team:

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 Diverse team members (SME) typically comprised of heads from Quality, Manufacturing,
Quali ed Person, Regulatory, Laboratory, or their quali ed designees used to review and
provide a disposition for the proposed deviation.

cGxP:

cGxP is a general term that stands for current Good “x” Practice (x = Clinical, Engineering,
Laboratory, Manufacturing, Documentation, Pharmaceutical, etc.).

The titles of these Good “x” Practice guidelines usually begin with “Good” and end in
“Practice”.

cGxP represents the abbreviations of these titles where “x” a common symbol for a variable,
represents the speci c descriptor.

Correction: Immediate action taken to resolve nding/issue.

Critical Classi cation:

Any departure from established standards that has caused or has a high probability of
causing adverse impact on product safety, quality, identity, potency, or purity.

Major Classi cation:

Any departure from established standards which may have an impact on safety, quality,
identity, potency or purity physical characteristics and ef cacy of the product or process (
e.g. use of the different type of equipment).

Minor Classi cation:

Any departure from established standards which may not have an impact on safety, quality,
identity, potency, or purity physical characteristics and ef cacy of the product or process (
e.g. use of the different size of a ber drum).

Deviation :

Any departure (planned or unplanned) from approved procedures or records, including, but
not limited to

Standard Operating Procedure,

Master Production Record,

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 Batch Production Record,

Standard Testing Procedure or the failure of a batch or any of its components to meet any
of its speci cations shall be documented and explained.

Potential product quality impacting events shall be investigated and the investigation and its
conclusions shall be documented.

Elimination:

Errors Eliminate the possibility of error.

This can be accomplished by eliminating the task.

For example, eliminate mixing errors by purchasing pre-mixed materials.

Eliminate recording errors by directly linking the measurement device to a printer.

Event: Any unforeseen happening or unexpected occurrence.

Incident / Unplanned Deviation– Owner:

An individual responsible for initiating the event/incident investigation determines the root
cause and implements corrections.

Incident/Unplanned Deviation:

An unplanned or uncontrolled/unexpected GMP incident or deviation or an event in the form

of departure from the designed systems or procedures at any stage of material receipt,
manufacturing, packaging, testing, holding, and storage of drug substance and it is
Intermediate/Components due to system failure or equipment breakdown or human
interventions and observed at a later time during execution, audit, etc.

Initiator – Incident/Unplanned Deviation: An individual who initiates an event/incident

record.

Initiator – Temporary Change / Planned Deviation:

Functional Supervisor or the higher-level person who initiates a Temporary Change or a

Planned Deviation record.

Initiator- Investigation: An individual who initiates an investigation record.

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 Investigation: A documented logical and/or scienti c review of data related to all quality
events that lead to the identi cation of the root cause and corrective and preventive action.

Market Action:

An action required to resolve a situation for a marketed product.

General reference embracing a noti cation, potential recall, market withdrawal, or eld
correction.

Nonconforming Material: Material that does not meet speci ed acceptance criteria.

Product Quality Complaint :

Any written, electronic or oral communication reported by Customers, Physicians,

Pharmacists, Hospitals, Regulatory Agencies, Health Authorities, Government Laboratories,
MA Holders, Retailers, Distributors, etc., that alleges de ciencies related to the safety, identity,
strength, quality, purity reliability, and/or ef cacy of a product after it is distributed beyond
the control area quality systems.

Subject Matter Expert: An individual, who is educated, trained, and/or highly experienced in
a particular eld or subject

Task:

Any activity identi ed as a part of executing a ‘Temporary Change’ or ‘Planned Deviation’.

Tasks can be of two types, i.e., pre-requi (to be completed before the execution of the
temporary change or planned deviation) and non-pre-requi (can be completed concurrently
with the execution of the temporary change or planned deviation).

7.0 PROCEDURE – INVESTIGATION TOOLS:

An investigation may be required to determine root cause(s) for any of the following
situations, but not limited to:

Deviations/ Incidents/ Non-conformances/Failures/ Events.

Product Quality Complaints

Product Recalls, recovery, withdrawal, or return of goods.

Internal/external audit or inspection ndings.

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 Periodic Product Quality Reviews.

Ineffective Corrective and Preventive Actions (CAPA).

Any other product quality or patient safety-related issues or review ndings.

Initiation of investigations:

An investigation record may be initiated by a Responsible Person from any department

(referred to as “Initiator” hereafter) intending to investigate an identi ed quality issue.

QA shall assign the investigation report number and make the necessary entry in the
investigation number allocation log as per Annexure3.

QA shall assign the investigation number as given below,

The Investigation number shall be alphanumeric i.e. IR/XX/YY/ZZZ.

Where,

IR: Investigation Report

XX: Department Code (Refer in Table -1)

YY: Stand for the year. The last 2 digits of the year shall be 20 for 2020,

ZZZ: Stand for serial no. of investigation which runs continuously irrespective of the
change in department code.

Every year 3 digit serial number shall start from 001.

e.g. First Investigation report of 2020 in the Production department shall be numbered as
IR/PR/20/001,

Second Investigation report of 2020 in the QC department shall be numbered as

IR/QC/20/002.

Table- 1

Department Code

Quality Assurance QA

Quality Control QC

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Warehouse WH

Production PR

Maintenance MN

Personnel & Administration PA

Information Technology IT

Environment, health, and safety EHS

Formulation Development Department FDD

Packaging Development Department PDD

The Initiator shall initiate an investigation record and log the investigation number.

The investigation record shall be submitted to the Responsible Person for further execution.

Investigation plan:

The Responsible Person shall acknowledge and complete the hypotheses, investigation plan
and approach, and obtain required resources (Materials, Equipment, Facilities, and
Personnel) and required data (existing) and intended analytical techniques.

If applicable, The Responsible Person shall attach supporting documents,

The Responsible Person shall identify the cross-functional investigation team comprised of
individuals from affected or other sites, resources external to the company, or Subject Matter
Expert(s) in the area(s) relevant to the investigation

The Responsible Person shall submit the investigation plan for approval to QA.

QA may ask for additional information and/or request changes to the investigation plan.

On a satisfactory review of the investigation plan, QA and Quality head shall approve the
investigation plan.

The cross-functional investigation team shall propose a hypothesis to identify the root
cause(s) and consider the following elements during hypothesis development-

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 Environmental monitoring excursions,

Raw material non- conformance appropriateness,

Process deviations – effectiveness,

Equipment-instrument failure,

Material or product mishandling,

Storage condition excursion,

Calibration excursions and non-conformances,

Test method failure,

cGxP non-compliances,

Signi cant changes in historical frequency/trending of similar issues and prior actions
are taken.

The investigation team / CFT shall use appropriate investigative techniques to determine the
root cause(s) as a part of the investigative approach.

A list of potential techniques along with their applicability is provided in Table 1.

This list is not meant to be exhaustive. See Annexure-1 for additional details for these tools.

Table 1: Investigation Technique

Objective of Possible Analysis Primary Use/Applicability

Analysis Methods/Tools

Issue Af nity Diagram A means to creatively generate a large number of

Analysis ideas/issues and then organize and summarize
them into natural groupings in order to understand
the essence of a problem and breakthrough
solutions.

Brainstorming To creatively and ef ciently generate a high

volume of ideas on any topic.

Prioritization To narrow down options through a systematic

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 Matrices approach of comparing choices by selecting,
weighting, and applying criteria.

Trend Check Sheet To systematically record and compile data from

Analysis historical sources, or observations as they occur so
that patterns and trends can be clearly detected
and shown.

Control Charts To monitor, control, and improve process

performance over time by studying variation and
its source.

Process Capability To determine if a process, given its natural

variation is capable of meeting established
customer requirements or speci cations.

Run Chart To study observed performance data for trends or

patterns over a speci ed period of time.

Pattern Check Sheet To systematically record and compile data from

Analysis historical sources, or observations as they occur so
that patterns and trends can be clearly detected
and shown.

Flow Charts To identify the actual ow or sequence of events in

a process and to show the complexity, problem
areas, redundancy, unnecessary loops, and places
where simpli cation /standardization is possible

Histograms To summarize process data that has been

collected over a period of time and to graphically

present its frequency distribution in bar form.

Matrix Diagram To systematically identify, analyze, and rate the

presence and strength of relationships between
two or more sets of data.

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 Normal Test Plots To investigate whether process data exhibit the
standard normal “bell curve” or Gaussian
distribution. (Also, known as Normal Probability
Plots, Normal Quartile Plots.)

Pareto Charts To focus efforts on the problems that offer the

greatest potential for improvement by showing
their relative frequency or size in a descending bar
graph.

Radar Chart To visually show in one graphic the size of gaps

among a number of both current organization
performance areas and ideal performance areas.

Cause/Effect Activity Network To nd both the most ef cient path and a realistic
or Diagram schedule for the completion of any project.

Linkage
Cause & To identify, explore, and graphically display, in
Analysis
Effect/Fishbone increasing detail, all of the possible causes related
Diagram to a problem and to discover its root cause(s).

Cause/Effect Fault Tree Analysis or To analyze the effects of operating conditions on

or Failure Mode Effect design reliability and safety.
Analysis
Linkage
Analysis
Flow Charts To identify the actual ow or sequence of events in
a process and to show the complexity, problem
areas, redundancy, unnecessary loops, and places
where simpli cation/standardization is possible.

Force Field Analysis To identify the forces and factors in place that
support or work against the solution of a problem,
so that the positives can be reinforced and/or the
negatives eliminated or reduced.

Relations Diagram (or To systematically identify, analyze, and classify the

Interrelationship cause and effect relationships that exist among all
Digraph) critical issues, so that key drivers or outcomes can
become the center of an effective solution

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 Scatter Diagram To study and identify the possible relationships
between the changes observed in two different sets
of variables.

Tree Diagram To graphically representation and implement by

taking a broad goal and breaking it into increasing
levels of detailed actions that must be done to
achieve the stated goals.

5-Why’s To quickly separate symptoms from causes and

identify the root cause of a problem.

Note: Refer to Annexure 1 on “Tools for Root Cause Analysis” for more details.

The following program management-related activities shall be used during the

investigation:

Drive the investigation to the timeline in the plan; update the plan, as required, and maintain
communication with functional management and other stakeholders on progress and
issues.

Identify and obtain resources from respective functional heads, as needed, to complete
thorough and effective investigation.

Escalate issues and roadblocks to management, as needed, when:

Technical obstacles result in revisions to approach or timeline.

Resources are not available to execute the plan.

Functional alignment is not achieved on priorities.

Investigation Execution:

The investigation team/CFT shall collect, organize, and document the data needed to
perform a root-cause analysis.

Data may come from a variety of sources, including, but not limited to the following, as given
in Table 2:

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 Table 2: Possible Data Sources

Potential Source of Issue Possible Data Sources

General sources Historical trends, including previously associated

investigations, if applicable Interview of associated
personnel Annual Product Quality Reviews
Recalls/return goods

Environmental monitoring Microbiological test data Temperature and Humidity

excursions Monitorial data

Raw material Raw material receiving logs and records Raw material
nonconformance/appropriateness test procedure Raw material test reports

Process deviations/ effectiveness Validation records Batch process records of affected

batches and previously manufactured batches using the
same equipment/room Change control history and log
Stability data Process Package, Development Report On-
line, at-line process monitoring/recording Systems
Online cameras

Equipment/instrument failure Preventive Maintenance and breakdown record

Equipment/Instrument usage log Equipment
/Instrument data printouts

Material/product mishandling Packaging record(s) Shipping record(s)

Storage condition excursion Storage facility/chamber monitoring record

Calibration excursions and non- Calibration records

conformance

Test method failure Analytical test data Analytical method

validation/veri cation report

GMP non-compliances Personnel training records Deviation record

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 Conduct any additional experiments or tests, as required by the investigation plan to
supplement data collected from existing sources.

If the investigation is for any ndings of contaminant, physical, biological, or chemical in

nature, it shall be con rmed by analysis for its nature and the extent of impact shall be
determined with a detailed investigation.

The suspected causes or hypotheses shall be veri ed with adequate experiments, simulation
processes, or backed up with strong, supporting scienti c rationale to assign as the root
cause.

Identify other investigations that were similar in nature and review the investigation
approach and results of those investigations as a rationale to assign root cause.

Perform an impact assessment and extend the investigation to other batches and other
products of all the markets, which could have been possibly affected.

The investigation may include additional testing of the involved batches of components.

Analysis and conclusion:

The investigation team/CFT shall assess the data collected during the investigation and
document the root cause(s).

An appropriate investigative technique, as listed in Table 1, may be used for analysis, if

needed.

The evaluation shall be performed as indicated below.

Note: that the steps listed below are indicative of the types of questions to ask; these do not
constitute a comprehensive list. Attach the supporting data, if any.

Evaluation of GMP Compliance:

Con rm processes were followed (i.e., no operator error was found).

Con rm process expectations were understood (i.e., no subjectivity exists as part of the
process; operator understands what to do at each stage of the process).

Review completed documentation, Batch records, logbooks, etc., to con rm appropriate data
was captured/analyzed by the operator.

Evaluation of Equipment and Facilities.

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 Determine how equipment usage may have contributed to the issue.

Review quali ed parameters to determine if running at process extremes may have

contributed to the issue.

Con rm set-up, shut-down, and cleaning processes were followed.

Review maintenance records to determine if recent maintenance may have contributed to

the issue.

Check the calibration requirements and record to con rm the machine are currently
calibrated.

Review spare parts / interchangeable parts to determine if parts failure may have
contributed to the issue.

Consult with machine vendors/equipment manufacturers/technical experts, as appropriate.

Evaluation of Process:

Determine if the process was properly validated.

Determine whether the process is fully and clearly documented to facilitate unambiguous
understanding and interpretation by the intended user.

Assess the possibility of any weakness (lack of robustness) or errors in the process.

Ensure that process documentation forms, including batch process records are correct and
complete.

Evaluation of Analytical/Microbiological Method:

Determine if the method was properly validated/veri ed.

Verify that the method is fully and clearly documented to facilitate unambiguous
understanding and interpretation by the intended user.

Assess the possibility of any weaknesses (lack of robustness) or errors in the method.

Assess the possibility of ambiguity or error in data analysis associated with the method.

Evaluation of Storage/Handling:

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 Determine whether documented storage and handling requirements are appropriate and
have been met.

Assess whether other batches were subjected to the same storage and handling conditions
and whether adverse effects were identi ed on other batches also.

Evaluation of Material:

Review incoming material test data; con rm raw material speci cations have been met.

Identify if material lot/batch was used on other products, identify if adverse effects were
identi ed on other product batches.

Con rm material identi cation.

Consult with vendor/material manufacturer, as appropriate.

Others:

Determine if abnormal manufacturing variations or deviations or incidents occurred on the

line, such as (but not limited to) power spikes or outages; extreme environmental
conditions, accidents, spills, or safety

The investigation team/CFT shall conclude the investigation based on the data analysis and
categorize the root cause(s) into one of the categories in Table 3:

Table 3: Root-Cause Categories

No. Root Cause category

1. Lab Instrument Inadequacy

2. Lab Instrument Malfunctioning

3. Lab Instrument Maintenance

4. Lab Instrument Software

5. Lab Testing Method

6. Equipment Malfunctioning

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7. Facility/Utility Malfunctioning

8. Equipment Inadequacy

9. Facility/Utility Inadequacy

10. Facility/Utility Software

11. Equipment Software

12. Equipment Maintenance

13. Facility Maintenance

14. Utility Maintenance

15. Inadequate Document Control

16. Product Development

17. Packaging Development

18. Labeling

19. Manufacturing Process Validation

20. Raw Material

21. Procedural Inadequacy

22. Packaging Material

23. Procedural Non-Compliance

24. Storage

25. Speci cation/Standard Test Procedure (STP) Inadequacy

26. Transportation & Handling

27. Planning

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28. Ineffective Training Program

29. Sampling

30. Sample Handling

31. Others – specify in the “Root Cause Summary”

Upon completion of the investigation, if the root cause(s) cannot be identi ed, then the most
probable cause(s) shall be provided by the investigation team/CFT.

Details of the investigation and the analysis performed shall be documented.

All raw data and supporting investigation les shall be archived, as per applicable procedure
in accordance with the current version of the respective SOP.

Investigation reports shall have the following content, but not limited to:

Cover Page:

The cover page shall include

Title,

Location,

Unique Investigation Number,

Page number, and Company Logo.

This information shall be re ected on all the pages of the investigation report.

Table of Contents Page:

The table of contents page shall include the content of the investigation with the respective
page numbers.

Approval Page:

The approval page shall include “prepared by”, “reviewed by” and “approved by” signatory
columns.

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 The report shall be prepared by the Investigation Owner in coordination with a cross-
functional team of investigation.

The report shall be reviewed by the cross-functional team or QA and nally approved by
Head QA/designee and Quality Head.

Objective:

The objective shall include the reason for the investigation, assessment of impact/risk, and
explore the CAPA to mitigate the risk.

Background:

The background shall constitute short summary concerning initiating the investigation
based on the master document.

Scope:

The scope shall include the reference to the product name and reference number of the
Deviation/Incident/Market compliant/Product recall of the respective product.

Responsibility:

The Responsibility shall cover the name of the individual(s) involved in the cross-functional
investigation team/CFT and their responsibility during the investigation.

Investigation Results and Discussion:

Summary observations, data ranges, defects, deviations, or incidents shall be included in

this section, and all investigation results shall be summarized.

Additional Experimental Data:

The data of additional experiments conducted shall be included and a conclusion

documented.

Root Cause/Most Probable Root Cause:

List the root cause by providing the reference documents’ numbers which support sound
scienti c List the most probable root-cause when an investigation is not conclusive.

Describe the speci c basis for ruling out possible root causes along with reference numbers
to supporting documents.

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 Impact Assessment:

List all the batches/products/ systems/ procedures impacted by the failure(s).

Impact Assessment shall be assessed with respect to patient safety, product quality, other
batches/product, regulatory commitments, and business.

Risk Assessment: List the risk identi ed and proposal for reduction or elimination of the
risk.

CAPA: Provide CAPA details.

Conclusion:

List the conclusion.

The conclusion shall be supported by documented evidence based on sound scienti c

principles, logic, experimental data, and all other relevant factors.

List of Annexure:

Provide the annexure number for each of the supporting documents referred to as a part of
the investigation.

Investigation closure:

Complete the investigation summary:

Recommended CAPAs; potential controls to assess, mitigate, and reduce the risk of
recurrence.

Include potential risks identi ed as an outcome of the investigation.

Provide the process for communicating risk to impacted areas.

Include the proposed plan for monitoring risk moving forward.

Ensure any open commitments that cannot be completed before the investigation is closed
are being regularly tracked to ensure they are completed by their respective deadline(s).

Investigations shall be completed within thirty (30) calendar days from the time that the
quality event is rst discovered.

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 If an investigation cannot be completed within the required time frames, the Responsible
person shall request an extension from QA with the proposed new timeline and justi cation
for the extension request.

The request for extension shall also include an impact assessment to evaluate the effect on
activities still to be completed through the completion of the investigation.

This assessment shall determine if additional controls are needed to avoid issues during the
interim.

This justi cation for the extension of timelines shall be reviewed and approved by QA prior
to implementation.

If an investigation cannot be completed within the required time frames,

The Responsible Person must submit an interim report at least every 30 days for
the same.

The investigation record shall be submitted to the QA and as applicable, to determine

adequacy, completeness, and approval of remedial actions required.

QA as applicable may ask for additional information and/or ask to perform additional work
as a part of the investigation.

On satisfactory completion of the investigation record, QA shall complete a risk classi cation
(Critical, Major, and Minor) along with documentation of the issue that led to the
investigation and nally close the record.

Each investigation report shall be approved by the Head QA/designee.

Types of Investigations that may require escalation to the Management in accordance with
the written procedures as per the current version of the respective SOP.

Investigations “OPEN” for more than 30 calendar days.

In which Investigations there is no assignable root cause but only a most probable root
cause.

Investigations concluding into product stoppage/manufacturing hold,

Investigation concluding into product/batch recall

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 QA shall disposition impacted products/batches and/or releases other controls, based upon
investigation conclusions and associated corrections.

After the closure of the investigation, if further investigation is required (e.g. due to request
by QA, discovery of new information/data, internal/external audit observations, or
management review), closed investigations shall be re-opened by the Quality Head/designee
or Responsible Person to perform and document the further investigation.

The implementation and effectiveness of CAPA shall be monitored as per written

procedures.

Requirements:

Each employee is responsible for the identi cation of deviation/incident/non-

conformance/failures/events at the time it occurs and reporting to the supervisor
immediately.

Establish and maintain a system to assure the investigation is conducted by a Responsible

Person (RP) in conjunction with QA Head or designee and other involved functions, as
required.

The investigation shall include the following information:

The description shall include an objective, factual description based on the science of
what happened and when.

Immediate action is taken, the decisions made about the process and product affected
shall be documented.

The scope shall include an assessment concerning when the process, equipment, facility,
utility, or other source was the last working properly.

All known concerns, not limited to the following, shall be included in the report:

Patient or worker safety.

Out-of-Speci cation and Out-of-Trend observations.

Compliance with cGxPs, compliance with registration, deviation/incident from process

validation.

Impact on product safety or ef cacy.

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 Product stability impact.

Effectiveness of previous root cause corrective actions.

Noti cation requirements.

The gravity of the concern(s) shall be determined by assessing how signi cant
the impact is.

Any additional concern(s) identi ed during the course of the investigation shall be
documented.

The resolution of each concern shall be described, and any unresolved concerns shall be
clearly identi ed.

The impact on the status of the lot shall be described.

The monitoring mechanism for investigations by the CFT shall be developed, refer to
Annexure -2 for a schematic diagram.

Root cause investigation:

The most probable cause of the deviation/ incident/ non-conformance/failure/ event and
what was done to con rm the true cause shall be described.

The investigation shall include the causes that were speci cally eliminated as the root cause
and supporting rationale for that judgment shall be documented.

The basis of the cause shall be described.

Corrective actions taken to address the issue shall be described.

Corrective and Preventive Actions (CAPA) taken and planned shall be described and tracked
through completion.

Lot Corrective Action: A description of the corrective action for the lot (e.g. reprocessing,
rework, downstream processing, inspection, culling, destruction, restriction) and similar
incident history shall be provided, if applicable.

8.0 ANNEXURES:

Annexure 1: Investigation Report Template

INVESTIGATION REPORT OF (Title)

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Date of deviation/Incidents:

Reference Deviation/Incident No.:

Category of Deviation/Incident:

Discrepancy details

Product/Material/ System Name:

Batch No./ Document No./Equipment ID No.:

Targeted completion date

Revised Target date:

Date of Closing

Closing Status

TABLE OF CONTENT

Sr. No. Content Page No.

1.0 Table of Content

2.0 Approval Page

3.0 Objective

4.0 Background

5.0 Scope

6.0 Responsibility

7.0 Investigation Results and Discussion

8.0 Additional Experimental Data

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9.0 Root Cause/Most Probable Root Cause

10.0 Impact Assessment

11.0 Risk Assessment

12.0 CAPA

13.0 Conclusion

14.0 List of Annexures

15.0 Closure of Investigation

Annexure 2: Monitoring Mechanism for Investigation CFT

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 Annexure 3: Investigation Initiation

Discrepancy Discovered on:

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 Reported By:

Discrepancy Details

Prepared by Checked by Dept. Head

Sign & date Sign & date

Annexure 4: Investigation Log

Sr. Investigation Product / Doc. No. / B. Investigation Ref. Target Date

No. material / No. / description Event of
No. equipment / Equipment Report Completion
instrument / No./ No.
system Instrument
name No.

Extension Date of Responsible Status CAPA Remark Sign

investigation person No.
(open
/closed).

Annexure 5: Tool for Root Cause Analysis

Click to download Tool for Root Cause Analysis

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 Annexure 6: Investigation Extension Request

Investigation No. Date of

Initiation

Reference No.

Details for
investigation

Initial Target Date Proposed Target

Date

Justi cation of Extension/Delay: (Attach the objective evidence, if any)

Prepared By Comments Sign & Date

HOD

QA Head

Plant Head

Annexure 7: Work Flow for Investigation

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 **********************************************END**********************************************

TAGS: CAUSE/EFFECT ANALYSIS, INVESTIGATION PLAN, INVESTIGATION TOOLS, ISSUE ANALYSIS, LINKAGE ANALYSIS, PATTERN
ANALYSIS, TREND ANALYSIS

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 Pharmabeginers
Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma
Beginners, an ultimate pharmaceutical blogging platform. Email:
[email protected]

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