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Overview – Internal review

• Presentation title: QRM, It’s not all about the assessment

• Track title: Day 1, Session 2

• Speaker: Seamus Orr

• Date / Time: 10 August 2015, 14.30 – 15.00

• Time allotted: 30 minutes

• Dot point overview (no more than 10 points):

• Definition of Quality Risk Management (QRM)

• Importance of QRM

• Regulatory expectations

• “Reactive” QRM

• “Proactive” QRM

• Practical QbD approaches for QRM

• Conclusions

QRMNot all about the Assessment

Presented by Seamus Orr

10th August 2015


Overview

• Definition of Quality Risk Management (QRM)

• Importance of QRM

• Regulatory expectation

• “Reactive” QRM

• “Proactive” QRM

• Practical QbD approaches for QRM

• Conclusions


Quality Risk Management

PIC/S code of GMP, PE 009-11, March 2014


Benefits of QRM for Manufacturers

Better understanding of processes and controls.

Increased awareness by staff of risk concepts, leading to better compliance with GMP and product safety, quality and efficacy.

Cost savings from reduction in defects and poor quality.

Greater likelihood of passing regulatory GMP inspections.


Using Risk Based Decisions

• Opportunity to scale validation and project activities

• Be prepared to use risk assessments to justify including or omitting any activity

• Number and detail of design reviews

• Need and scope of source code review

• Rigor of supplier assessment

• Level and scope of testing ...Companies should not invest more effort and time into the risk management process than is commensurate with the potential impact on the system or business.”


International Conferenceon Harmonisation

The US FDA influence includes the FDA Process Validation Guidelines

ICH Q8 Pharmaceutical Development

ICH Q9 Quality Risk Management

ICH Q10 Pharmaceutical Quality System

ICH Q11 Development and Manufacture of Drug Substances


Quality Risk Management (QRM) in Part 1 of the PIC/S GMP Guide

Clauses 1.5 and 1.6 of Part 1 of the PIC/S GMP

Guide requires QRM to be an integral part of a manufacturer’s Quality System.

These clauses make QRM mandatory

for manufacturers.

That is, the manufacturer is responsible for assessing

risks to medicinal products and managing these risks to

an acceptable level.


Annex 20

corresponds to ICH Q9

is voluntary but QRM is not;

provides tools for how to comply with the expectation that QRM is applied.

For coherence and completeness, the whole of ICH Q9 has been copied into Annex 20. i.e. they are identical


What is Risk?

Retrospectively:

• Making decisions around product and quality risk

• for deviations/issues/complaints

Pro-actively:

• Facility Design

• Qualification & Validation

• Change Management - Impact assessments

• PM Programs and Calibration

• Audit Frequencies

• Materials Management

• Training Optimisation


Quality Risk Management (QRM)

The QRM process must be systematic with defined policies and procedures

Must operate across the lifecycle

Principles and methodologies should be clear

Criteria and decisions from assessments should be documented



Begin the QRM Process

Risk Identification

Risk Analysis

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Assessment

Risk Control

Output of the QRM Process

Review Events

Risk Review

QRMTools

Risk C

om

mu

nicatio

n

Control Strategy Development

Continual Improvement

Product & Process Development


Initiate the Risk Management Process

• Risk Assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. The steps include risk identification, risk analysis and risk evaluation.

• Risk Control includes decision making to reduce and/or accept risks. The purpose of risk control is to reduce the risk to an acceptable level.

• Risk Communication is the exchange or sharing of information about risk and its management between the decision makers and others.

• Risk Review requires the output/results of the risk management process be reviewed to take into account new knowledge and experience, i.e. not a once only event

• QRM processes subject to periodic and triggered review

Initiate Risk Management Process

Risk Assessment

Risk Control

Risk Review

Risk Communication

acceptable

unacceptable

13

The ICH Q9 Risk Management Model




Risk Identification

Risk Analysis

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Assessment

Risk Control


Review Events

Risk Review

QRMTools

Risk C

om

mu

nicatio

n

Product & Process Development

ICH Q9

QRM critical at several

stages of Process

Development




Risk Identification

Risk Analysis

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Assessment

Risk Control


Review Events

Risk Review

QRMTools

Risk C

om

mu

nicatio

n

Control Strategy

Development

ICH Q9




Risk Identification

Risk Analysis

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Assessment

Risk Control


Review Events

Risk Review

QRMTools

Risk C

om

mu

nicatio

n

Continual Improvement


Risk Management Methodology

• Supporting statistical tools

• Acceptance Control Charts (see ISO 7966)

• Control Charts (for example)

Control Charts with Arithmetic Average and Warning Limits (see ISO 7873)

Cumulative Sum Charts; “CuSum” (see ISO 7871)

Control Charts (see ISO 8258)

Weighted Moving Average

• Design of Experiments (DOE)

Pareto Charts

• Process Capability Analysis

• Histograms

• Use others that you are familiar with….


QbD – a systematic approach

TO

OLS

Ishikawa

Capability

FMEA

Pareto

DOE


QbD – a systematic approach

• Target the product profile

• Determine Critical Quality Attributes (CQAs)

• Link input material attributes and process parameters to CQAs and perform risk assessment

• Develop a design space

• Design and implement a control strategy

• Manage product lifecycle, including continual improvement


• 2.3 Linking Material Attributes and Process Parameters to CQAs – Risk Assessment

• Risk assessment is a valuable science-based process used in quality risk management (see ICH Q9) that can aid in identifying which material attributes and process parameters have an effect on product CQAs. While the risk assessment is typically performed early in the pharmaceutical development, it can be helpful to repeat the risk assessment as information and greater knowledge become available.

Q8(R1) Pharmaceutical Development Revision 1 – from the Guidelines


Q8(R1) Pharmaceutical Development Revision 1 – from the Guidelines• 2.3 Linking Material Attributes and Process

Parameters to CQAs – Risk Assessment continued • Risk assessment tools can be used to identify and rank parameters

(e.g., operational, equipment, input material) with potential to have an impact on product quality based on prior knowledge and initial experimental data. For an illustrative example, see Appendix 2. The initial list of potential parameters can be quite extensive, but is likely to be narrowed as process understanding is increased. The list can be refined further through experimentation to determine the significance of individual variables and potential interactions. Once the significant parameters are identified, they can be further studied (e.g., through a combination of design of experiments, mathematical models, or studies that lead to mechanistic understanding) to achieve a higher level of process understanding.


Q8(R1) Pharmaceutical Development Revision 1 – from the Guidelines• 2.4 Design Space

• The linkage between the process inputs (input variables and process parameters) and the critical quality attributes can be described in the design space.

• Is Key for claiming Process Understanding

• Process understanding is Key for Quality Risk Management

• QRM is the base for any Control Strategy


Q8(R1) Pharmaceutical Development Revision 1 – from the Guidelines• 2.4.1 Selection of variables.

• The risk assessment and process development experiments can not only lead to an understanding of the linkage and effect of process inputs on product CQAs, but also help identify the variables and their ranges within which consistent quality can be achieved.

• An explanation should be provided in the application to describe what variables were considered, how they affect the process and product quality, and which parameters were included or excluded in the design space. An input variable or process parameter need not be included in the design space if it has no effect on delivering CQAs when the input variable or parameter is varied over the full potential range of operation. The control of these variables would be under good manufacturing practices (GMP). However, the knowledge gained from studies should be described in the submission.


Water

Content

Drying

Granulation

Raw

Materials

Compressing

Plant

Factors

Operator

Temp/RH

Precompressing

Main Compressing

Feeder Speed

Press Speed

Punch Penetration

Depth

Temp

RH

Air Flow

Shock Cycle

Drug

Substance

P.S.Process Conditions

LOD

Diluents

P.S.LOD

Other

Lubricant

Disintegrant

Binder

Water

Binder

Temp

Spray Rate

Spray Pattern

P.S.

Scrape Down

Chopper Speed

Mixer Speed

Endpoint

PowerTime

Age

Tooling

Operator

Training

Analytical

Method

Sampling

Feed

Frame

Cause and Effect Process


QRM Tools:Failure Mode Effects Analysis (FMEA)

Risk Assessment

Sub-StepEvent

(Failure mode)Effect

Severi

ty (

S)

[1<

2<

3]

Pro

bab

ilit

y (

P)

[1<

2<

3<

4]

Dete

cta

bil

ity (

D)

[1<

2<

3]

Ris

k f

acto

r

(S*P

*D)

Granulation Drying water contentnot meet specification of

degradation2 3 1 6

Risk Reduction

Actions:

Risk reduction strategy

Se

ve

rity

(S

)

[1<

2<

3]

Pro

ba

bilit

y (

P)

[1<

2<

3<

4]

Dete

cta

bil

ity (

D)

[1<

2<

3]

Ris

k f

ac

tor

(S*P

*D)

Ris

k r

ed

uc

tio

n

Comments

introduce online NIR 2 1 1 2 4 indirect measurment

introduce IPC analytic 2 2 1 4 2direct measurement; time

consuming

Mass Spectrometry of exhaust gases2 1 2 4 3

indirect measurment;

unspecific


Summary and PIC/s GMP Regulatory expectations?

A documented procedure/plan for Quality Risk Management.

Application of QRM to all relevant areas, including key QA activities and manufacturing steps.

Integration of QRM into normal business systems.

Use of systematic approach, relevant scientific knowledge and expertise in risk assessment, evaluation and mitigation.

Documenting QRM processes.

Reviewed on a periodic basis.

1

2

5

6

4

3


Regulators and risk management

• Identify and clarify the events considered ‘undesirable’

What can go wrong?

• Qualify or quantify the likelihood and consequence of the riskWhy?

• Evaluate each risk and decide if they are acceptable or require action

What can be done?


Regulators and risk management

Risk Management is the overall and continuing process of risk minimisation through a product’s lifecycle to optimise the benefit/risk balance... risk information continuously emerges.


QRM and regulators

•A documented procedure/plan for Quality Risk Management.

•Application of QRM to all relevant areas, including key QA activities and manufacturing steps.

• Integration of QRM into normal business systems.

•Use of systematic approach, relevant scientific knowledge and expertise in risk assessment, evaluation and mitigation.

•Documenting QRM processes.

•Reviewed on a periodic basis.

What do PIC/s regulators expect regarding QRM?


QRM & other Regulators

(from GMP Frequently Asked Questions, MHRA, UK, June 2010)

(from Pre-approval Inspections Guidance Manual, US FDA, Dec 2010)

(from WHO GMP for pharmaceutical products, main principles, 2011)

“All manufacturing authorisation holders ... must have a system for QRM. Inspectors will review the QRM system as part of the Quality System section of the inspection”.

“It is critical that a robust quality system incorporate a scientific and risk based approach ... “.

“The concept of QA, GMP, QC & QRM are interrelated aspects of quality management & should be the responsibility of all personnel”.


Some Typical Inspection Observations related to QRM

“There were no formal SOP for QRM and impact assessment”.

“The SOP relating to QRM did not provide specific information about how QRM was to be performed and implemented”.

“The SOP for QRM did not include coverage of supplier qualification, deviation management, complaints and defects”.

“There was no risk register to facilitate the management, monitoring and review of formal risk assessments”.


Key messages

• Reduce subjectivity of implementing QRM by making sure the right people are at the table (SME and accountable personnel)

• Use QRM methods appropriately and present the conclusions and justifications clearly

• Use QRM proactively for increasing the knowledge of your product and processes

• Risks to Data Integrity also expected to be reviewed regularly


Thank you for your time.Questions?

Seamus Orr

[email protected]

Senior Consultant

www.pharmout.net

overview internal review - pharmout.net · •2.4 design space •the linkage between the process...

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