REVISED

SCHEDULE M
Session 14:
Investigation and CAPA

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 Revised Schedule M-An overview

• Schedule M prescribes the Good Manufacturing Practices (GMP) for pharmaceutical products and the revised
Schedule M rules ensures that GMP is followed.

• GMP is mandatory standards which builds and brings quality into a product by way of control on materials,
methods, machines, processes, personnel, and facility/environment, etc.

• GMP was first incorporated in Schedule M of the Drugs and Cosmetics Rules 1945 in the year 1988 and the last
amendment was done in 2005.

• With the amendment, the words ‘GMP’ has been replaced with ‘Good Manufacturing Practices and
Requirements of Premises, Plant and Equipment for Pharmaceutical Products’.

• The revised Schedule M includes the introduction of a pharma quality system (PQS), quality risk management
(QRM), product quality review (PQR), and specific guidelines for the qualification and validation of
equipment. It also mandates a computerized storage system for all drug products.
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 Pharmaceutical Quality System

• Manufacturer must assume the responsibility for the quality.

• Senior management has the ultimate responsibility.

• Consistency in the quality

• Product and process knowledge

• Products are designed and developed taking into account GXP

• Production and release as per conditions of license and other applicable regulations

• Notification of changes to the LA, Approval of planned changes from LA where required,

• Continual improvement in the quality

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 Pharmaceutical Quality System (

Contd.)
• Regular review of the quality

• Root cause analysis of defective products

• Periodic management review

• Quality Manual-The product quality system shall be defined and documented.

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 Quality Risk Management (QRM):

• Assessment of risk, Control of risk, Communication of risk, Review of risk

• Product quality review :

• Starting materials, critical in-process control and finished product results.
• Review of all batches that had failed.
• Review of non-conformance related investigation and corrective and preventive action taken.
• Review of complaints and recalls etc.
• Qualification status of equipment such as heating, ventilation and air-conditioning, water and compressed
gases.
• Even for exported products
• Annually
• Technical agreements, up-to-date.

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Revised Schedule M
Requires
Use of structured
Mandates detailed Classification of
tools for RCA like
Investigation and failures based on
Fish Bone,5 Why’s,
documented RCA impact ( Critical,
FMEA
Major, Minor)

•Focuses on
timelines,Responsible
•Periodic reviews of
Person and
effectiveness of CAPA
Documentation for
CAPA implementation

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 Revised Schedule M
•Requires risk based •Mandates Specific
•Integrates QRM prioritization of failures trainings, for personnel
Principles into failure and and actions based on involved in investigations
investigation and CAPA, their potential to impact and RCA. Refresher
Proactive Approach product qualityor patient trainings for understanding
safety of TCA tools

•Requires Systematic
Documentation, Timelines Key Performance
,Risk Assessment Indicators (KPIs)-
Summaries, Trend Monitoring CAPA
Analysis

The Revised Schedule M is more proactive, data-driven, and systematic in handling failure investigations and
CAPA, emphasizing prevention and continuous improvement
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 Failure Investigation

• Failure refers to state or condition of not meeting a

desirable or intended objective or pre-defined
acceptance criteria.
• A planned and documented analysis of events and
circumstances contributing to a problem to
determine the cause of the problem and the most
appropriate corrective and/or preventive action(s).
May involve any combination of experiments,
testing, review of data, statistical analysis,
interviews, expertise, and product inspection.
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 Definitions
Correction: An action to eliminate a detected nonconformity.
• E.g. Remedial action: Repair, rework, or adjustment
•Corrective action: Action to eliminate the causes of an existing (detected) nonconformity or other
undesirable situation. The corrective action should eliminate the recurrence of the root cause(s).
Preventive action: Action to eliminate the causes of a potential nonconformity or other undesirable potential
situation. Preventive action should prevent the occurrence of the potential issue by eliminating the occurrence of
the root cause(s).
Nonconformity: non-fulfilment of a specified requirement. Any material or process that does not meet its required
specifications or documented procedure
CAPA (corrective action and preventive action): A systematic approach that includes actions needed to correct
(correction),avoid recurrence (corrective action), and eliminate the cause of potential nonconforming product and
other quality problems (preventive action). It is critical to the success of the pharmaceutical industry, and is used
to mitigate non-conformances that arise during production or in the field.

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Flow Chart

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 Why we do investigation?

• Primary goal is preventing harm to end-users by ensuring product

consistency, preventing contamination, and maintaining rigorous
quality standards.

• Understand their potential impact on future processes.

• Conduct thorough risk assessments before initiating investigations
to identify and manage potential risks effectively.
• Evaluate proposed Corrective and Preventive Actions (CAPA) to
• Adopt a proactive approach to mitigate risks and ensure the
successful implementation of corrective measures.

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 Why we do investigation?

This image humorously illustrates how a process can degrade

in quality or coherence as it moves through different stages
of review and approval.
Interpretation:
•The image is a drawing of a horse, but its quality changes from
left to right.
•The leftmost section (representing "Planning") is a well-
detailed, realistic horse.
•As the process moves through "CFT Review" and "Approval,"
the quality and detail decrease.
•By the time it reaches "Regulatory Review," the horse is
poorly drawn, simplified, and even cartoonish.

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 Message:

•It represents how projects (especially in regulated industries like

pharmaceuticals) can start with a solid plan but degrade due to
multiple layers of reviews, approvals, and regulatory constraints.
•Each stage introduces compromises, leading to a final outcome
that does not match the original vision.

•It highlights challenges in cross-functional collaboration and

regulatory-driven modifications.

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Investigation and CAPA sources

Internal Source
• Nonconforming/OOS/Atypical/Deviation reports
• Laboratory failures
• Equipment data (calibration, preventive maintenance, and repair)
• Rework data
• Returned product
• Internal audits
• Stability
External Source
• Complaints
• Field service reports
• Product Recall
• External audits/supplier audits and assessments, customer
feedback, and results from external audits and assessment such as
regulatory agencies, ISO etc

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 INVESTIGATION PROCESSES

• Investigation Framework:
 Establish a clear, systematic investigation process with defined steps.
 Appoint a lead investigator responsible for overseeing the entire investigation.
 Train investigation personnel on compliance regulations and internal ethics.

• Evidence Collection and Analysis

 Conduct thorough evidence gathering of Document reviews, Electronic record examination,
Systematic evidence collection.
 Use a closed-loop quality event management system to track investigations.

 Root Cause Identification

Perform comprehensive clarification of the issue i.e. Customer complaints, Deviations,
Nonconformances, Out-of-specification

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 INVESTIGATION PROCESSES

• Documentation and Reporting

 Maintain detailed investigation records
 Communicate findings to management
 Suggest and implement corrective measures.

• Investigate all unexplained discrepancies immediately. Conduct thorough root cause analysis and
Implement CAPA actions and ensure effective investigation by collecting the data;
 Immediate Identification
 Recognize and flag the discrepancy
 Halt potential further distribution if significant risk exists
 Comprehensive Documentation
 Record all relevant details
 Capture initial observations

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 Investigation and CAPA System
Keep in mind
it is to Correct,
• Clearly define the problem-Clearly /measurable terms – What, Prevent &
Identification
When, where, how often, how much -Identification Improve

• Appraise the magnitude and impact-safety, death, injury, rework,

Evaluation
etc.-Evaluation

Investigation
• Make a plan to research the problem-Investigation
Define 4 W and 1H-
What, Where, When.
RCA
• Perform a thorough assessment- Analysis /Root Cause Who and How

Action Plan
• CAPA -Create a list of required tasks –Action Plans

implementation
• Execute the action plan - Implementation

Follow Up
• Verify the effectiveness –Follow Up

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Investigation Process

Review past history /similar issue

Review records and documents/Trainings

Review process/operations

Review the sit/Evaluate factors like Work load/ environment/

Assess Equipment and System

Genbetsu or Gemba Walk

Collect Evidence/Perform interviews

Document-Location, Date, Time, Who reported, Problem

Statement-Product, Batch #,Equipment etc

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Common Causes of Failures

Human Error

Equipment Failure/ Technical Failure

Procedure is Inadequate or Not Clear

Procedure Not Followed

Training Inadequate

Design Error

Poor Communication

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What are HEs?

A mistake done by a person while working

And What is the reality??

Was it purely a person’s mistake?

Were SOPs clear?

Was training provided in real sense?

Was anything left to person’s understanding/ experience?

Was the process understanding was ensured by an SME before

Reports were adequately designed to record all details?

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 Investigation and CAPA sources
1. The Weed (Symptom of the Problem)
•Represents visible issues, such as batch failures,
deviations, out-of-specification (OOS) results,
contamination, or equipment breakdowns in a
pharmaceutical facility.
•These are the immediate problems noticed on the
surface.

2.The Root (Underlying Causes)

•Represents hidden factors that contribute to the
issue, such as poor process control, inadequate
training, improper equipment calibration,
uncontrolled environmental conditions, human
error, or system failures.
•If these root causes are not addressed, the problem
will recur, just like a weed growing back if only the
top is removed. Visual representation of Root Cause Analysis (RCA)
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 Relevance in GMP and Quality Management:

•CAPA (Corrective and Preventive Action): Identifying and

eliminating root causes rather than just treating symptoms.
•Deviation and Failure Investigations: Ensuring compliance with
ICH Q10 (Pharmaceutical Quality System) to maintain product
quality and patient safety.
•Risk Management (ICH Q9): Proactively addressing risks that
could impact product quality or regulatory compliance.
•Continuous Improvement: Avoiding repeated issues by
eliminating the root cause, leading to more robust processes and
fewer deviations.

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 Symptoms, causal factors, and root causes

Symptoms Causal factors Root cause

Fever Infected wound Poor hygiene

Equipment broken Not adequate maintenance or no Procedure does not specify the
maintenance at all maintenance or not include it
Product not homogeneous Operator did not follow the mixing The procedure is ambiguous and it
procedure does not include sufficient details (for
example, mix for a few seconds)

Incorrect information entered into the Operator did not follow the procedure Operator not properly trained because
manufacturing record of training environment
Mathematical calculation mistakes Human error Operators were not properly trained
(for example, rounding errors) on rounding numbers
Incorrect product label Operators failed to detect the Excessive load of work and an all-
incorrect expiration date printed on manual inspection activity
the labels

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 𝗜𝗻𝘃𝗲𝘀𝘁𝗶𝗴𝗮𝘁𝗶𝗼𝗻 Tools

• WHY-WHY Analysis

• Fish-Bone Analysis / Cause and Effect/ Ishikawa

• Brain Storming

• Fault Tree Analysis

• Failure Mode and Effects Analysis (FMEA)

• Process Mapping

• Pareto Analysis

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 5-Why Technique

• It is a root cause analysis tool used to identify the underlying cause of a problem
by asking "Why?" five times (or as many as needed).
• State the problem clearly.

• Ask "Why?" repeatedly to uncover the root cause.

• Stop when the true root cause is identified.

• Implement corrective actions based on the root cause.

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 5-Why Technique

• Whys technique is a simpler form of fault tree analysis for investigations, especially
investigations of specific accidents as opposed to chronic problems.
• It is a brainstorming technique that identifies root causes of accidents by asking why
events occurred or conditions existed
• The 5 Whys process involves selecting one event associated with an accident and
asking why this event occurred. This produces the most direct cause of the event
• Drill down further indicating if their were any sub-causes of the event, and ask why
they occurred.
• Repeat the process for the other events associated with the accident

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5-Why Technique

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Brainstorming
Why is it useful?
• Brainstorming is useful because it can help a group of people
utilize its collective brainpower to generate many ideas in a
short period of time.
• It stimulates creativity and promotes involvement and
participation.
When is it used?
• It is used to help clarify mutual expectations and devise
ground rules related to a team’s way of operating.
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Brainstorming
How is it done?
Identify a
topic, Each person When all
problem, or presents one All ideas are ideas are
issue, and idea going in recorded on a exhausted, Keep the idea
make sure sequence flip chart.
there is Focus is on take a break. generation
(round robin). There is no When you separate from
mutual If a person quantity of
does not have
evaluation or ideas, not the come back, the evaluation
understanding discussion
an idea, pass quality. people may or analysis of
of the task during the
and move on to have more ideas.
and objective. session.
the next ideas to add
Write the
person. to the list.
topic on a flip
chart.

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 Brainstorming guidelines
Evaluate Ideas
• Generate as many ideas as possible.
and refine prior
to action
• Encourage free-wheeling.

• No criticism is allowed, either positive or negative.

• Enable an equal opportunity to participate.

• Record all ideas .

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Fishbone Diagram
What is it?
• The fishbone diagram (also known as the cause-and-effect
diagram.It is a technique to graphically identify and organize
many possible causes of a problem (effect).
Why is it useful?
• Fishbone diagrams help identify the most likely root causes of a
problem. Also help to teach a team to reach a common
understanding of the problem. This tool can help focus problem
solving and reduce subjective decision-making.

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Fishbone Diagram
When is it used?
• It is used when the need exists to display and explore many
possible causes of a specific problem or condition.
• It can also help with the identification of root causes.

What does it look like?

• Allow team members to specify where ideas fit into the diagram
• Clarify the meaning of each idea using the group to refine the
• ideas.

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Fishbone Diagram

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 Fault Tree Analysis
• Fault Tree Analysis (FTA) is a systematic, top-down, deductive method used to
analyze the root causes of a specific undesirable event (called a "top event"). It
is widely used to identify and mitigate risks. Top Down Approach. It has 2
Primary components, Events and Logic Gates
Key Features of FTA:
• Focus: Identifies the root causes leading to a failure or undesirable event.
• Structure: Represented as a tree-like diagram with the top event at the top and
contributing causes branching below.
• Logical Approach: Uses logical gates (AND, OR) to connect causes and model
complex systems.
• Visualization: Provides a clear, visual representation of failure pathways.

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 Fault Tree Analysis
Steps in Conducting FTA: Example from Pharmaceuticals:
1.Define the Top Event: Clearly state the failure or problem to
be analyzed (e.g., microbial contamination in a sterile product).
2.Identify Immediate Causes: Determine what directly Top Event: Sterile injectable fails sterility testing.
contributes to the top event. •Immediate Cause 1: Contaminated raw material (OR gate).
3.Break Down Further: Drill down into the root causes of each
immediate cause. •Sub-cause: Supplier issue.
4.Use Logical Gates: •Sub-cause: Poor material handling.
•AND Gate: Requires all contributing events to occur for the
top event to happen. •Immediate Cause 2: Improper cleanroom conditions (AND
•OR Gate: Requires at least one contributing event to occur gate).
for the top event to happen. •Sub-cause: HVAC malfunction.
5.Analyze Data: Use historical data, risk assessments, and expert •Sub-cause: Untrained personnel.
knowledge to determine probabilities of events.
6.Identify Root Causes: Pinpoint actionable causes to focus •Immediate Cause 3: Equipment failure (OR gate).
corrective actions. •Sub-cause: Defective autoclave.
7.Mitigation: Develop and implement solutions to reduce risks. •Sub-cause: Improper sterilization cycle.

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Fault Tree Analysis

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 Pareto Analysis
A Pareto Analysis (also known as the 80/20 rule) is a useful tool in the pharmaceutical
industry for identifying the most significant factors contributing to a problem. It follows
the 80/20 rule, where approximately 80% of the complaints originate from 20% of the
causes.
 Failure Mode and Effect Analysis
FMEA is a qualitative and systematic tool, usually created within a spreadsheet, to
help practitioners anticipate what might go wrong with a product or process. In
addition to identifying how a product or process might fail and the effects of that
failure, FMEA also helps find the possible causes of failures and the likelihood of
failures being detected before occurrence.
Criteria for FMEA Analysis
An FMEA uses three criteria to assess a problem:
1The severity of the effect on the customer,
2How frequently the problem is likely to occur
3How easily the problem can be detected.
•High RPN values indicate a need for action to reduce failure risk.
•Controls & Recommendations help mitigate the risk by improving process parameters,
equipment maintenance, and real-time monitoring.
𝗪𝗵𝗮𝘁 𝗶𝘀 𝗖𝗔𝗣𝗔 𝗶𝗻 𝘁𝗵𝗲 𝗣𝗵𝗮𝗿𝗺𝗮𝗰𝗲𝘂𝘁𝗶𝗰𝗮𝗹 𝗜𝗻𝗱𝘂𝘀𝘁𝗿𝘆?
• CAPA stands for Corrective and Preventive Action, and is a
quality management system that involves identifying,
analyzing, correcting, and preventing issues. It's an important

CAPA part of a pharmaceutical company's quality management

system, and helps to prevent problems from recurring.

• It is critical to the success of the pharmaceutical industry, and

is used to mitigate non-conformances that arise during

CAPA production or in the field.

• CAPA systems must be implemented for handling Complaints,

Product rejections, Non conformances, and Recalls.
CAPA

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Do we always need CA and PA?

It should be based on Risk Assessment Criteria

Does it have the potential for a patient or user safety issue?

Type or classification of the product – Sterile/Oral/OTC

Does it affect the reliability, effectiveness or usability of the

product? Note: consider the worst case

Does the frequency of the occurrence of the issue changed? –

Improving /Worsened

Does it represent a regulatory risk (can this product be

considered as adulterated or misbranded?)

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Why is CAPA Essential?

Reduces operational downtime and costs.

Improves process efficiency and reliability.

Ensures compliance with industry standards.

Promotes a proactive risk management culture.

Enhances customer satisfaction by delivering high-quality

products.

Prevention is always better than correction! Ensuring robust

CAPA processes helps organizations build resilience and stay
ahead of potential challenges.

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CAPA Effectiveness

Monitor and Measure Effectiveness: Regularly assess the

success of CAPA actions using KPIs and follow-up audits.

Promote a Quality-Driven Culture

Establish CAPA as a central pillar of a company-wide

commitment to continuous improvement, emphasizing its role
in achieving long-term success

Promotes a proactive risk management culture.

A compliant and effective CAPA system is indispensable for

ensuring quality, safety, and operational excellence in the life
science industry.

By implementing a structured approach to CAPA, companies

can reduce risks, improve efficiency, and build a strong
foundation for sustainable growth and innovation in it.

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SMART CAPA

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 Key Takeaways
Foster a culture
• Investigations and CAPA are critical for GMP compliance of Quality and
Continuous
Improvement
• Robust RCA ensures effective resolution

• Proper documentation show audit readiness

• Challenges-Delays in investigations, Inadequate RCA, Ineffective CAPA,

Insufficient Documentation

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 THANK YOU.

PULSE
( Pharma Upgradation & Learning
Organizers: Knowledge Partner:

Series for Excellence)