PHARMA DEVILS

QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

PROTOCOL
FOR
RISK ASSESSMENT
& MITIGATION
OF
PROCESS SIMULATION
STUDY

Facility: PLANT
LOCATION:………….......

Document No.
Supersede Document No.
Effective Date
No. of Pages
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

PROTOCOL CONTENTS
S.No. Section Title Page No.
1.0 Protocol Approval 3
2.0 Overview 4
Objective
Purpose & Scope
Risk Assessment Team
Responsibility
3.0 Introduction 5
4.0 Quality Risk Management Process 6
Risk Identification 6
Risk Analysis 6
Risk Evaluation 6
Risk Control 7
Risk Reduction 7
5.0 Risk Assessment for Process Simulation Study 8
Risk Assessment Legend 8
Risk Assessment Tool – Failure Mode Effect Analysis (FMEA) 11
6.0 Acceptance Criteria 13
7.0 Risk Control Strategy 13
8.0 Report Preparation and Approval 13
9.0 References 13
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

1. Protocol Approval
This is a specific protocol for Risk assessment and Mitigation of Process Simulation Study which has to
be carried out in Sterile Plant.

Prepared By:
Name Designation Department Signature Date

Checked By:

Name Designation Department Signature Date

Approved By:

Name Designation Department Signature Date

 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

2.0 Overview

2.1 Objective:
The Objective of this Protocol is to adopt a systematic process for the assessment, control,
communication and review of risk associated with the Process Simulation study which is to be
carried out in the sterile Plant ………….

2.2 Purpose and Scope

The purpose of this Protocol is to outline a scientific and practical approach for decision making
process by applying a suitable tool of risk assessment covering all aspects of risk associated with
Process Simulation study.

2.3 Risk Assessment Team

 Production Executive/Officer/Manager
 Quality control Executive/Officer/Manager
 Projects Engineer/Sr. Engineer/Manager
 Maintenance Executive/Officer/Manager
 Quality Assurance Executive/Officer/Manager

2.4 Responsibility

S.No. Department Designation Responsibility

1. Production Executive Review of Protocol & report
/Officer/ To Provide the all relevant information that are required while
Manager undergoing Risk assessment process i.e. Quantity, Packaging etc.
2. Quality Executive Review of Protocol & report
control /Officer/ To provide information about the availability of Analytical
Manager methods Pharmacopeia reference and finally reviewing the testing
procedures
3. Maintenance Executive Review of Protocol & report
/Officer/ To assist the risk assessment team about the technical queries of
Manager facility & equipments
4. Projects Executive Review of Protocol & report
/Officer/ To assist the risk assessment team about the technical queries of
Manager facility & equipments & also provide provisions for further
reduction of associated risk with facility & operations
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

S.No. Department Designation Responsibility

5. Quality Executive Preparation of Protocol & report
Assurance /Officer / To review all the Procedural controls both in-house and vendor
Manager To conduct audits to assess the quality management system and
manufacturing facility
Final approval of Protocol & report By head quality Assurance
3. Introduction:
Risk analysis for Process Simulation study shall be done by considering the below mentioned
factors

 The Risk Impact on the Process

 The Risk impact on the Process Equipment
 The Risk impact on the Aseptic Environment of the Plant
 The Risk impact on the Product Quality & Sterility
 The Risk impact on the regulatory compliance
 The Risk impact on customer
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

4. Quality Risk Management Process

Risk assessment is a systematic process of organizing information to support a risk decision to be
made within a risk management process. Its consists Identification of hazards and the analysis
and evaluation of risks associated with exposure to those hazards
Quality risk assessment begins with a well defined problem description or risk question.
For risk assessment process three fundamental questions are considered
 What might go wrong?
 What is likely hood (Occurrence) it will go wrong?
 What are the consequences (Severity)?
 Risk Identification
Risk Identification is systematic use of information to identify hazards referring to risk
questions or problem description. Information may include historical data theoretical
analysis, informed opinions and concerns of stakeholders. Risk Identification will be
conducted by reviewing the types of events that might occur in both normal and unusual
situations. This may be done by challenging the normal presumptions, and considering
the possibilities of unanticipated situations. For each risk event, the underlying (root)
cause should be determined that will create the potential risk occurrence.
Risk Identification addresses the “what might go wrong” question including identifying
the possible consequences. This provides the basis for the further steps in quality risk
management process.

 Risk Analysis
Risk analysis is the estimation of risk associated with the identified hazards.
It is the quantitative or qualitative process of linking the likelihood of occurrence and
severity of harm and sometime the detectability of harm is also consider during
estimation of risk.

 Risk Evaluation
Risk Evaluation compares the identified and analyzed risk against the given risk criteria.
Risk evaluation considers the strength of evidence for all three of fundamental questions.
Risks are ranked by scoring various criteria with appropriate numerical ratings, adding to
scores to determine the overall score of each risk, and sorting the risks into descending
order based on each score. A risk scoring threshold is established, over which risks must
be mitigated using adequate design and/ or process controls that will protect the system.
Those risks that fall below the threshold are either unmitigated or scheduled for later
mitigation. An additional threshold or characteristic of risk can be used to determine the
differentiation of non- mitigation versus postponed mitigation.
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

 Risk Control
Risk control includes decision making to reduce or mitigate risk. The purpose of risk
control is to reduce the risk to the acceptance level
The risk control is done by considering the following question
 Is the risk above an acceptable level?
 What can be done to reduce or eliminate risk?
 What is appropriate balance among benefits, risks and resources?
 Are new risk is introduced as a result identified risk being controlled?
 Risk Reduction
Risk reduction focuses on processes the mitigation or avoidance of quality risk when it
exceeds the acceptable level. Risk reduction includes action taken to mitigate the
severity, occurrence or probability of harm and the processes that improve the
detectability of harm. It is the part of risk control strategy and involves
 Engineering Control
 Procedural Control
 Manual control etc.
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

5.0 Risk Assessment for Process Simulation Study

5.1 Risk Assessment Legend

A. Severity

Ranking Effect Criteria

10 Hazardous Hazardous effect without warning. Safety related. Regulatory non-
compliant.
9 Serious Potential hazardous effect. Able to stop without mishap. Regulatory
compliance in jeopardy.
8 Extreme Item inoperable but safe. Customer very dissatisfied.
7 Major Performance severely affected but functional and safe. Customer
dissatisfied.
6 Significant Performance degraded but operable and safe. Non-vital part
inoperable. Customer experiences discomfort.
5 Moderate Performance moderately affected. Fault on non-vital part requires
repair. Customer experiences some dissatisfaction.
4 Minor Minor effect on performance. Fault does not require repair. Non-vital
fault always noticed. Customer experiences minor nuisance.
3 Slight Slight effect on performance. Non-vital fault notice most of the time.
Customer is slightly annoyed.
2 Very Slight Very slight effect on performance. Non-vital fault may be noticed.
Customer is not annoyed.

1 None No effect.
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

B. Probability or Occurrence

Ranking Possible Failure Rates Probability of Failure

10 > 1 in 2 Almost certain
9 1 in 3 Very high
8 1 in 8 High
7 1 in 20 Moderately high
6 1 in 80 Medium
5 1 in 400 Low
4 1 in 2,000 Slight
3 1 in 15,000 Very slight
2 1 in 150,000 Remote
1 1 in 1,500,000 Almost impossible

C. Detection
Ranking Detection Likelihood of Detection by design control
10 Absolute Uncertainty No design control or design control will not detect potential cause
9 Very Remote Very remote chance design control will detect potential cause.
8 Remote Remote chance design control will detect potential cause.
7 Very Low Very low chance design control will detect potential cause.
6 Low Low chance design control will detect potential cause.
5 Moderate Moderate chance design control will detect potential cause.
4 Moderately High Moderately high chance design control will detect potential cause.
3 High High chance design control will detect potential cause.
2 Very High Very high chance design control will detect potential cause.
1 Almost Certain Almost certain that the design control will detect potential cause.
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

5.2 Risk Assessment Tool – Failure Mode effect Analysis (FMEA)

5.2.1 Risk Identification
Risk assessment team shall identify all possible failure modes of Process simulation Study by
reviewing the various aspects of facility design & operational features, Provisions and Adopted
procedures. The risk identification involves three aspects

1. Identification of Failure Mode of Process simulation study

a. Failure of Equipment
b. Failure of Process
c. Failure of Provisions
d. Failure of Procedures etc.

2. Identification of Potential cause

a. Operator Error
b. Equipment Malfunctioning
c. Instrument malfunctioning
d. Non availability or Non rational Procedures
e. Inefficient Provisions for operations etc.

3. The consequences i.e. End results of failure mode

The failure Mode may leads to
a. Poor process Performance
b. Poor Product Quality
c. Deterioration of Aseptic conditions required for sterile manufacturing
d. Regulatory non compliance
e. Unsafe operating conditions
f. Unsafe environmental conditions etc.

4. Justification
The identification done for the risk shall have scientific rational and must be justified for its
validity. The below mentioned table shall be used for Risk Identification process.

S.No. Failure Mode Potential cause of What are the Justification

{What can go wrong} Failure Consequences
Risk Identification
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

5.2.2 Risk Analysis

Risk Analysis is the second step of risk identification Process. It involves the assessment of the
1. Severity of the Consequence of failure Mode
2. The Probability or Occurrence of Failure mode by reviewing effectiveness of the existing
Design control
3. The its detectability under the existing design control

Base upon the analysis Risk priority number will be assigned to the particular failure Mode
as per the formula

RPN = Severity X Occurrence X Detection

Each index ranges from 1 (lowest risk) to 10 (highest risk). The overall risk of each failure is called
Risk Priority Number (RPN) and the product of Severity (S), Occurrence (O), and Detection (D)
rankings: RPN = S × O × D. The RPN (ranging from 1 to 1000) is used to prioritize all potential
failures to decide upon actions leading to reduce the risk, usually by reducing likelihood of
occurrence and improving controls for detecting the failure

The below mentioned table shall be used for Risk Analysis process.

S.No. Failure Potential cause of What are the Risk Priority Existing
Probability
Severity

Detection

Mode Failure Consequences Number Design

{What can Control
go wrong}

(S) (P) (D) RPN=S x P x D

Risk Analysis Risk valuation
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

5.2.3 Risk Reduction or Mitigation

The Risk Reduction or Mitigation is the Third step of Risk assessment process. if the Existing
design control cannot lead the risk priority number to the acceptable level then additional design
control shall be worked by providing
1. New or Improved Provisions or Procedures
2. Modification in the existing facility design
3. Additional resources
4. Improved control strategy etc.
The additional design control shall be appropriately worked out to reduce the risk to its
acceptable level. The below mentioned table shall be used for the Risk Reduction or
Mitigation process

S.No. Failure Potential

Probability

Probability
Detection

Detection

Number
Severity

Severity

Priority
Mode cause of Existing Additional

Number

Risk
{What can Failure Design Priority Design
Risk

go wrong} Control Control

(S) (P) (D) (RPN) (S) (P) (D) (RPN)

Risk Mitigation
RPN=S x P x D

RPN=S x P x D
 PHARMA DEVILS
QUALITY ASSURANCE DEPARTMENT

PROTOCOL FOR RISK ASSESSMENT OF PROCESS SIMULATION STUDY

5. Acceptance Criteria:
The Risk Priority Number shall be within the range 0<RPN<100

6. Risk Control Strategy:

S.No. Risk Priority Risk Decision Risk control strategy
Number
1 0<RPN<100 Risk Acceptable No control is required
2 100<RPN<500 Risk Reduction Additional Procedural Control
Manual Control
Documentary Evidence
3 500<RPN<1000 Risk Reduction Rugged Procedural control
Additional Manual Control
Auditing
Engineering controls (if Possible)

7. Report Preparation and Approval

The report shall be prepared by evaluating all possible risks and finally shall be approved by
Quality Assurance head

8. References:
1. Risk Management Master Plan
2. ICH Q9