Quality Risk Management Approach

to Ensure

Cold Chain Integrity

Syed Huda

Regional Quality Assurance Manager

Hoffmann-La Roche Ltd., UAE

• What is Risk Management • Why to perform Risk Management • How to perform it and the tools available • Regulatory Requirements • Practical application of risk management

principles and tools on Cold Chain

Agenda

What is Risk Management

Oxford Advanced Learner's Dictionary • Risk is the possibility of something bad happening at some time in the

future; a situation that could be dangerous or have a bad result

ICH Q9 • Risk is defined as the combination of the probability of occurrence of

harm and the severity of that harm.

• Product quality should be maintained throughout the product lifecycle

Failure – What can go wrong

Probability of Occurrence

Severity

• ICH Q9: Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle.

• ISO 14971: Risk management is the systemic application of management policies, procedures, and practices to the task of analyzing, evaluating, controlling and monitoring risk.

What is Risk Management

Benefits of Cold Chain Quality Risk Management

• Reduction of Delays

• Faster Product Release & easy decision making

• Faster Investigation Process in case of deviation

• Less Temp. Deviations

• Reduction of Damages

– Reduction of Claims

Reduced overall cost and better process understanding for more qualified and science based decision making

Regulations / Guidelines / Standards

• WHO TRS no. 937 Annex 5 • 21 CFR part 210, 211, 600 • USP 1079 • Canada Guide 0059

• In March of 2013 the EU

released new guidelines for GDP

• In June of 2013 the Chinese

FDA implemented their new guidelines.

• Risk aversion planning – documented • Environmental controls for cold chain

products, like vaccines and Bio-Logics • Selection of staff and on-going staff training • Warehouse and storage condition

management • Environmental condition management of

products during transportation – “source to patient”

• A fully documented Risk Mitigation plan as part of the Quality Management System

Maintain product quality during storage, handling and distribution of temperature sensitive products.

Renewed Focus on total Supply Chain Risk Aversion and Mitigation Planning

Typical Supply Chain

Raw Material Sources

Raw Material

Warehouse Manufacturing

Finished Product

Warehouse

Patients Hospital s/

Clinics / Pharmacies

Distributor

monitoring of the supply chain from “Source to Patient” – end to end visibility • Monitoring is in many ways reactive. Use of go/no go devices only tells at the end what

happened • Management is having procedures and devices for Real Time Monitoring and a solution

that allows intervention if problems such as temperature excursion are encountered

RISK RISK

Risk Assessment: Matters to Consider • Nature of the products:

– Labelled storage requirements and associated warnings

– Sensitivity of product to extremes of temperature

– Product packaging

• Operations: – Likelihood of exposure to temperatures outside the labelled storage limits

– Max. and min. temperatures that may be experienced by the product

– Exposure to fluctuating temperatures – freeze thaw or high temperatures

– Number / nature of the stages of delivery and number of drop-off points

– Scale of the operation

– Mode of transportation i.e. road, sea or air

– Transit time and in-transit handling

– Number of hand-offs and human elements

Risk Assessment: Matters to Consider

Site or equipment: • Capability: Manufacturing and storage facility, service providers, contract

acceptor, hospital and pharmacy equipped to handle cold chain products

• Cold and Hot spots: During storage in (cold room or refrigerator) and transport (truck or shipping box)

• Temperature monitoring strategy and equipment used – e.g. Chemical indicators, RFID, etc.

• Adequacy of the temperature monitoring system i.e. type used, quantity & positions and the frequency of readings

• Data collection and storage procedures

• Backup systems and procedures

• Stress / emergency conditions: Power failure, equipment failure, open door, recovery time, system settings variation etc.

• Ability to respond to mechanical and other issues and managing excursions and emergency situations

GENERAL QUALITY RISK MANAGEMENT PROCESS

• Initiating a Quality Risk Management Process • Risk Assessment

– Risk identification – Risk analysis – Risk evaluation

• Risk Control – Risk reduction – Risk acceptance

• Risk Communication • Risk Review

Risk Assessment

Process? – Risk Identification

• Identify failure modes – Risk Analysis

• Assign risk scores (severity, occurrence & detectability)

– Risk Evaluation • Classify risks (Low, Med, High) • Document assessment • Escalate Risk as necessary

– Communicate

Participants? – Site Business and Quality Function as

Facilitators – Key stakeholders

Inputs?

– Process Map

– Historical data, and other available information

– Pre-work

Outputs?

– Risk Master Plan

–Initial Cold Chain risk logs

Process?

– Risk Reduction: Evaluate and Identify controls

– Make risk acceptance decision

– Communicate

Participants?

– Site Business and Quality Function as Facilitators

– Key stakeholders from the site (3rd Party)

Inputs?

– The initial risk management tool

Outputs?

– Defined risk control actions

– Risk acceptance decision and rationale

– Risk mitigation plan for implement

– Risk Log

Risk Control

Process?

– Consider new knowledge & experience related to risk and communicate to management

– Monitoring the effectiveness of the risk reduction actions

Participants?

– Site Business and Quality Function as Facilitators

– Key stakeholders

Outputs?

– Updated risk assessment

– Communication

Risk Review

Inputs?

– Updated risk log with the risk controls

–Other available information

Principles of Quality Risk Management

1. The evaluation of the risk to quality should be based on scientific knowledge and link to the protection of the patient

2. The level of effort, formality and documentation of the quality risk management process should be of the same level/measure of risk

3. The QRM process is iterative in nature. Overtime new knowledge & experience is acquired that must be evaluated and incorporated into the Risk Management Plan

When to use formal risk assessment

Less Formal More Formal

Relevant historical data available Yes No

Complex issues, process or system No Yes

High level of available process knowledge and experience Yes No

Problem statement is critical to product quality patient safety No Yes

Can answer the critical questions like; What might go wrong? Likelihood (Probability) of it going wrong and consequences (Severity) of it goes wrong

Yes No

Typical considerations to determine what level of formality is required for the risk management

RISK MANAGEMENT METHODOLOGY

1. Basic risk management facilitation methods: – Flowcharts, Check Sheets, Process Mapping

– Cause and Effect Diagrams (Ishikawa / fish bone diagrams)

2. Risk ranking and filtering

3. Failure Mode Effects Analysis (FMEA)

4. Failure Mode, Effects and Criticality Analysis (FMECA)

5. Fault Tree Analysis (FTA)

6. Hazard Analysis and Critical Control Points (HACCP)

7. Hazard Operability Analysis (HAZOP)

8. Preliminary Hazard Analysis (PHA);

9. Supporting statistical tools – Control Charts, Design of Experiments (DOE), Histograms, Pareto Charts,

Process Capability Analysis

What is FMEA?

• Failure Mode and Effects Analysis is intended to:

• Recognize and evaluate potential failures and their effects

• Prioritize potential failures, vital few from trivial many

• Identify actions to reduce/eliminate the chance of failure

• Document results and actions

• Considerations:

• It is an early warning preventive technique

• It is subject to bias, thus need cross-functional team

FMEA Basics Steps 1. Define the Question/System Boundaries

2. Develop a Process Map

3. Risk Identification:

• Identify Potential Failure Modes, Potential Failure Effects and Potential Causes

4. Risk Analysis:

• Determine Severity, Probability of Occurrence and Likelihood of Detection

• Identify Current Controls

5. Risk Evaluation

• Rank and Prioritize risks that require risk reduction actions

6. Risk Control:

• Recommend Risk Reduction Actions, Review and Approve

• Implement Risk Reduction Actions

7. Update the FMEA

8. Risk Review and Risk Re-Assessment

Team Considerations

• For the best results from FMEA:

– Use a team • Ensure there is a process expert on the team

• recommended minimum team

– Site Business Function

– Site Quality Function

– Process Subject Matter Expert (SME)

– Orient and prepare the team • Review the scope

• Build the process map as a team

• Brainstorm Potential Failure Modes as a team

• Evaluate risks as a team

FMEA: Key Definitions

• Failure Mode: The way a failure occurs

• Failure Effect: The consequence of a failure mode [on the operation, function, or status of an item]

• Failure Cause: The reason for the failure

• Severity: The significance of the failure effect

• Probability of Occurrence: The frequency or probability that the failure mode occurs and results in the failure effect

• Likelihood of Detection: Ability of planned tests and inspections to remove defects or detect failure modes

• Risk Priority Number (RPN): a quantitative indicator of criticality

How >

What >

Why >

How Bad >

How Often >

When >

How Urgent >

Supporting Processes Qualification Power

CSV

Pest control

Maintenance Cleaning

Warehouse: Process Map Example: Goods storage & Distribution

Customer order

Processing

Step No. 5

Storage of goods

Step No. 2

Reception of goods

Step No. 1

Redressing and Relabeling (if applicable)

Redressing & Relabeling

Step No. 4

Picking & Transportation to

Redressing & Relabeling

Step No. 3

Process Map Example: Defines where the process starts and where it ends and the sequence of

activities and decision points

Control &

monitoring

Potential Failure Modes & Failure Effects • Failure mode is how a product, process or system can fail to perform as

intended i.e. how something can go wrong

• Failure effect is the immediate effect of the failure mode and answers the question, “then what?” or so what?”

• A failure mode can have multiple failure effects. List all effects and rate their severity

Product packed with wrong components is released to

market

Recall not conducted to GMP requirements

Product eluted at wrong time

MODES

EFFECTS

pH probe not standardized

Packaging Component Specification non updated

No Recall SOP

Failure Modes & Effects: Examples

Item/Step Potential Failure

Mode

Potential Failure

Effect

Cause(s)

Repackaging

and Relabeling

The artwork is

not verified with

health authority

approved

documents

The product packed

with wrong

packaging

components is

released to the

market

- No clear communicated change over time from

superseded to current version.

- Operator error, did not pick up differences between

actual pack and registered artwork.

- Regulatory Affaires not updating current artwork

folder.

Specification for

packaging

component is not

updated

The product packed

with wrong

packaging

components is

released to the

market

- Quality Unit not adequately resourced.

- No process in place to maintain packaging material

specifications.

Transportation

and products in

transit

Temperature not

maintained

during transit

Stability/potency

compromised

- Transit time for container exceeded

- Container damaged in transit

Risk Analysis

Step FMEA

1. Score the

Severity

What is the effect of the failure mode to Product Quality/Patient Safety,

Business, and Operations according to the predefined severity criteria

• If this happens, how bad will it be?

2. Score the

Probability

How often will the failure mode result in the failure effect considering the

identified preventive controls

3. Score the

likelihood of

Detection

When will the failure mode, cause of failure or failure effect be detected

considering the identified detection controls

4. The Primary Risk Number (PRN) is the product of severity and probability of occurrence

5. The Risk Priority Number (RPN) is the product of severity, probability of occurrence and

likelihood of detection

Severity

Score Category Quality/Regulatory

10 Catastrophic (includes

Critical Class 1)

Effects may cause a Health Authority to suspend the

Manufacturing/ Marketing Authorization

8 Critical (includes Critical

Class 2 & 3)

Effects may lead to serious/critical regulatory observations

and/or lead to a product recall

6 Major

Effects may lead to major regulatory observations or

nonconformance with internal quality standards, procedures

or regulatory requirements leading to product quality impact

4 Moderate

Effects may lead to only minor observations or

recommendations in regulatory inspections; or minor

nonconformance with internal quality standards, procedures

or regulatory requirements; no product quality impact

2 Minor/ Negligible Effects will not lead to nonconformance with internal quality

standards, procedures or regulatory requirements

Example of scoring Severity

Probability of Occurrence

Score Category Criteria

10 Very

High Certain to occur routinely

8 High Occurs frequently

6 Moderate Occurs occasionally

4 Low Has not occurred often

2 Remote Extremely unlikely to occur

Estimate the probability of occurrence for the cause of each failure mode

Example of scoring Probability of Occurrence

Likelihood of Detection

Score Category Criteria

10 Remote There is no established inspection, testing, or monitoring in place to

detect the failure.

8 Low

There is limited inspection, testing, or monitoring in place. Detection is

delayed and multiple failures may go undetected between consecutive

steps.

6 Moderate

Some inspection, testing, or monitoring is in place. Detection is

delayed and single failure could go undetected between consecutive

steps.

4 High Inspection, testing, or monitoring is in place. There is a high probability

that the failure will be detected within the step.

2 Very High Consistent inspection, testing, or monitoring is in place to immediately

and consistently detect the failure.

Example of scoring Likelihood of Detection

Risk Evaluation

Primary Risk Number (PRN)

Probability of Occurrence

2 4 6 8 10

Severity

10 20 40 60 80 100

8 16 32 48 64 80

6 12 24 36 48 60

4 8 16 24 32 40

2 4 8 12 16 20

High: Require Risk Control Action(s)

Medium: Reduce Risk to As Low as Reasonably Practicable (ALARP)

Low: Acceptable

Risk Evaluation Risk Prioritization Number (RPN)

Probability of Detection

2 4 6 8 10

Primary

Risk

Number

(PRN)

100 200 400 600 800 1000

80 160 320 480 640 800

64 128 256 384 512 640

60 120 240 360 480 600

48 96 192 288 384 480

40 80 160 240 320 400

36 72 144 216 288 360

32 64 128 192 256 320

24 48 96 144 192 240

20 40 80 120 160 200

16 32 64 96 128 160

12 24 48 72 96 120

8 16 32 48 64 80

4 8 16 24 32 40

192–1000 High: Require Risk Control Action(s).

72–160 Medium: Reduce Risk to As Low as Reasonably Practicable (ALARP)

8–64 Low: Acceptable

Risk Evaluation Determine where the risks fall on the appropriate risk

acceptability matrix-Determine Risk Acceptability

• Rank the risks in order of the Primary Risk

Number (PRN) and Risk Priority Number

(RPN)

• Both the PRN and RPN matrices should

be utilized when determining where

recommended actions are required

• Is the risk acceptable? If so, document

Rationale for Acceptance

• What can be done to reduce or eliminate

the risk?

• What is the appropriate balance among

benefits, risks, and resources?

• Are new risks introduced as a result of

the identified risks being controlled?

• Identify recommended action

Accept Risk

Communicate Risk

Improve Detection

Reduce Occurrence

Reduce Severity of Risk

Remove Risk Prevention…

…Detection

Reduction…

…Acceptance

Opportunity for Improvement

• While there is global guidance (ICH Q1A(R2) 2003, WHO TRS 953 Annex 2 2009) on long-term and accelerated stability studies supporting typical storage temperature conditions, there is no industry or regulatory guidance on temperature excursion or temperature cycling stability studies to support outside label claim temperature conditions for a specified duration, such as during shipping.

• This is an opportunity for the industry to define the temperature cycling stability study guidance to support a shipping temperature range that is wider than the storage temperature range.

Summary • There will always be Risk even with the best risk management plan, good

SOP’s and WI’s and properly trained people

• Routinely review risks with the team to include any additional risk

• All Quality Systems and Risk Aversion Plans should have one over-arching goal ! Patient Safety coupled with Drug Efficacy

• Final Point:! Be prepared for the unexpected!!

Questions