ICH Q10

Pharmaceutical Quality System (PQS)

© CBE Pty Ltd

This training program is copyright to CBE Pty Ltd and may not be modified, reproduced,
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© CBE – DCVMN 010 V2 Introduc)on   1

 Three Day Program – 1st day
Wednesday Morning
§  Introduction to ICH Q10 – Pharmaceutical Quality System
§  Management of Deviations/Investigations and CAPA

Wednesday Morning
§  Change Management
§  Equipment Qualification

Wednesday Afternoon
§  Practical Exercises (Deviations and CAPA)
§  Practical Exercises (Change Management)
§  Practical Exercises (Equipment Qualification)

© CBE – DCVMN 010 V2 2

 Three Day Program – 2nd Day

Thursday Morning
§  Controlling Cross Contamination – Biologics Facility
§  Risk Management
Thursday Morning
§  Supplier Assurance Programs (Qualifying Suppliers)

Thursday Afternoon
§  Practical Workshop Exercise

© CBE – DCVMN 010 V2 3

 Three Day Program – 3rd Day

Friday Morning
§  Viral Inactivation – Industry requirements
§  Cleaning and Cleaning Validation in a Biologics Facility
§  Microbiological Control

Friday Morning
§  Effective Internal Auditing

Friday Afternoon
§  Practical Workshop Exercise

© CBE – DCVMN 010 V2 4

 PQS - Module Outcomes

On completion of this module the participant should be able

to:
§  Interpret ICH Q10 expectations
§  Develop a Quality Manual (QM) template and Quality
Policies (POL)
§  Design a pharmaceutical quality system using the QM
template
§  Strengthen GMP compliance systems

© CBE – DCVMN 010 V2 Compliance by Design 5

 PQS Module Topics

Basics  of  Quality  and  Compliance  

How  does  a  Pharmaceu9cal    Quality  System  fit  

together  ?  –  ICH  Q  10    

Devia9ons    

CAPA  and  Con9nuous  Improvement  

© CBE – DCVMN 010 V2 Introduc9on  

 Major International Codes of GMP
§  PIC/S Guide to Good Manufacturing Practices - PE 009 - 2014
§  EU Guide to Good Manufacturing Practices (Eudralex Ch 4)
§  World Health Organisation (WHO) c GMPs
§  United States - FDA CFRs Part 21
§  CFR 210/211 for Drugs and Biologics - current GMPs
§  CFR 820 Quality Systems for Medical Devices - current GMPs
§  ICH Q7 GMP for Active Pharmaceutical Ingredients
§  Canadian cGMP (aligned with PICs)
§  ISO 13485 : 2003 - Medical Devices
§  ICH Guidance Documents – Technical Standards

© CBE – DCVMN 010 V2 Regulatory  Agencies  

 Some Useful Reference Documents
§  EU/PICs/TGA cGMPs – Chapter 1 – Quality
Management
§  ICH Q10 - Pharmaceutical Quality System
§  ICH Q8 – Pharmaceutical Product Development
§  ICH Q9 - Risk Management in Pharmaceuticals
§  FDA Quality Systems Approach to Pharmaceutical
CGMP Regulations (9/2006)
§  GHTF - GHTF/SG3/N15R8 - Implementation of risk
management within a Quality Management System

© CBE – DCVMN 010 V2 8

 Significant Changes
40 Year History of Pharmaceutical Quality
Management

1972
Quality Control

Sterile Validation 1975

Quality Assurance 1975

General Validation 1980s

Quality Management 1990s

Risk Management 2004+

PQS – ICH Q8/Q9/
Q10

© CBE – DCVMN 010 V2

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 Quality Control and Sampling

Inward   Unit  Op.  

Supplier  
Goods  QC   #1  

C  of  A  

QA  Release  

Finished   Unit  Op.  

Product  QC   #2  

Sampling  Plan    
Lot  Size  =  1000  
Sample  size  =  20  (2%)  

© CBE – DCVMN 010 V2 10

 Quality and Compliance
§  Quality refers to:
§  Product Quality – meeting agreed specifications
§  Quality Systems – planned and deployed processes
(systems) used to monitor, report and take corrective
actions

§  GMP Compliance refers to:

§  Identification, documentation and deployment of GMP
obligations
§  Ongoing verification that GMP obligations are being
met, or not.

© CBE – DCVMN 010 V2 11

 Compliance Programs
Execu9ve  Commitment  

Objec)ves  

Iden)fy  Obliga)ons   Gap  Analysis  

Assign  Responsibility  

Competence  &  Compliance  Training  

Compliance  Focused  Behaviours  

Controls  to  Manage  Iden)fied  Obliga)ons  

Performance  Monitored,  Measured,  Reported  

Demonstrate  Compliance  (documents,  records  prac)ces)  

Con)nuous  Improvement  and  Management  Review  

© CBE – DCVMN 010 V2 12

 PQS/Compliance Gap Analysis

§  identify and assess compliance obligations and potential

failures - not just GMP
§  Include external and internal obligations in gap analysis
§  Prioritize gaps using use risk principles
§  Establish a compliance register or database
§  Develop a PQS remediation/ improvement plan
§  Establish a system to monitor external changes in PQS
& compliance obligations e.g Legislation, cGMP updates
…

© CBE – DCVMN 010 V2 13

 Things to look for in the gap analysis
Element What to look for
Deviation, OOS System How effective are the failure investigations
CAPA System Does the CAPA system look at root causes or just
symptoms
Audit Programs Do the audit look at symptoms or root causes – are
issues effectively resolved
Reviews, Trends and Are management reviews and APQRs detailed enough
Reporting and responsive
Training Do training programs address compliance obligations
Management Is compliance a KPI within position descriptions
Responsibility
Prioritisation and Is there a mechanism for resource prioritization e.g..
Resource Allocation risk based
Change Management Does change management include compliance review

© CBE – DCVMN 010 V2 14

 How does a Quality System Fit Together ?

Change   Incidents  &   Quality  

Training   Control   Devia9ons   Control  

Document  
Control   Valida9on   Failure  Inves9gat’n   Lab  OOS  

Produc9on   Management  
CAPA   Review  
Control  
Supplier  
Assurance   Annual  Product  
Monitoring  &   Review  
Trend  Analysis  
External  
Complaints  &  
Internal   Audits   Recall  

Regulatory   Pharmacovigilance  

© CBE – DCVMN 010 V2 15

 “Linkage” of the QMS system
elements
§  Each of the major elements are inter - linked to other
elements
§  Elements either drive or feed others or vice versa
§  Linkage of related elements is critical to quality
management oversight
§  Without strong linkage identification of problem root cause is
difficult
§  With linkages, problems and root causes can be traced through
the linked system

§  Linkage enables “escalation” of significant issues

© CBE – DCVMN 010 V2 16

16
 FDA Six Control Systems – Inspection 7356.002
•  Batch  compounding,  dosage  form  produc)on,    
•  In-­‐process  sampling  and  tes)ng,    
Produc9on  System   • 
• 
Process  valida)on.    
Master  batch  records  and  manufacturing  
procedures.    
•  Change  control,  reprocessing,  
batch  release,    
•  Annual  product  review     •  Control  of  finished  products,  components,  
water,  gases,  containers  and  closures.    
•  Valida)on  protocols,    
•  Product  defect  evalua)ons  
Material  System   •  Valida)on  of  computer  inventory  control      
•  Drug  storage,  distribu)on  controls,    records.  
•  Evalua)on  of  returns.  
 
•  Buildings  and  facili)es  &    maintenance  
Quality   Equipment  /  Facili9es  
• 
• 
Equipment  qualifica)ons  (IQ/OQ);    
Equipment  calibra)on;    
Assurance   • 
• 
Cleaning  and  valida)on  of  cleaning  processes.    
U)li)es  -­‐  HVAC,  gases,  steam  and  water  

•  Packaging  and  labeling  opera)ons  &  controls    

•  Label  examina)on  and  usage,    
Package  /  Label  System   •  Label  storage  and  issuance,  
•  Valida)on  of  these  opera)ons.    

•  Laboratory  procedures,    
•  Tes)ng,  analy)cal  methods  development    
Laboratory  System   •  Method  valida)on  or  verifica)on,    
•  Stability  program  

© CBE – DCVMN 010 V2

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 An Overview of ICH Q10
Pharmaceutical Quality System

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 ICH Q10 - Pharmaceutical Quality System
§  Based on ISO 9000/ISO13485/CFR 820 systems model
§  Compliments ICH Q8 and ICH Q9
§  Applies across the product life-cycle
§  Consistent with GMPs - not intended to add new
expectations to regulations and compliance
§  Applies to APIs, drug products and biotechnology
§  Strengthens the link between product development and
manufacturing activities

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 Pharmaceutical Quality System, Quality
Assurance, GMP and Quality Control
Pharmaceu9cal  Quality  System  (ICH  Q10)  

Quality  Risk  Management  (ICH  Q9)  

Quality  by  Design  (ICH  Q8)  

 Supply      è        Manufacturing        è        Distribu9on        è        Customers  

© CBE – DCVMN 010 V2 20
 ICH Q10 - Some Important Principles
•  The size and complexity of the company’s activities
should be taken into consideration when developing a new
pharmaceutical quality system or modifying an existing
one.

•  While some aspects of the pharmaceutical quality system

can be company-wide and others site-specific, the
effectiveness of the implementation of the pharmaceutical
quality system is normally demonstrated at the site level.

© CBE – DCVMN 010 V2

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 ICH Q10 - Pharmaceutical Quality System

© CBE – DCVMN 010 V2 22

 A Hierarchy QMS/GMP Documentation
QP  

Objec)ves  
New expectation
Quality  Manual  
(Guidance/Policy)  
Systems  Quality  
Management  SOPs  
Opera)ng  SOPs  
Master  Batch  Records  

Operator  Instruc)ons  

Manufacturing  and  Quality  Records  

Training  Manuals  and  Records  

© CBE – DCVMN 010 V2 23 Compliance  by   23
Design  
 Expectation of Skills and Knowledge
Development of Personnel
 
Quality    
Knowledge  

GMP  Knowledge  

Product  and  Process  

Knowledge  
(Skills  Competency)  

GMP  Behaviour    
(Minimising  Human  Error)  

Training  Manuals,  Records  and  Competency  

Assessments  
© CBE – DCVMN 010 V2 24 Compliance  by   24
Design  
 Integration of PQS and GMP Elements in the
Quality System

PQS   GMP  
•  Knowledge  Management,  Training   •  Quality  Management/Quality  
and  Educa9on   Assurance  System.    
•  Monitoring  Systems   •  Facili9es  and  Equipment  System.    
•  Change  Management  
•  Materials  System.    
•  CAPA  &  Improvement  
•  Produc9on  System  
•  Management  Review  and  
Responsibility   •  Packaging  and  Labeling  System  
•  Quality  Planning    &  Resources   •  Laboratory  Control  System  
•  Process  Performance  and  Product  
Quality  Monitoring  System  

© CBE – DCVMN 010 V2 25

 PQS Enablers
Quality Risk Management (QRM)

§  Quality risk management, in

line with ICH Q9, provides an
essential component of the
Quality System.
§  QRM enables both effective and
efficient practices.
§  Application of QRM ensures the
quality system is efficient.
§  Provides a systematic approach
to escalating and prioritising
significant events
© CBE – DCVMN 010 V2 26
 Risk Management Maturity
A Guide to Supply Chain Risk Management for Suppliers to the Pharmaceutical, Medical
Device and Allied Industries

Table 2 – Risk Management Maturity

Risk Maturity Risk Processes Attitude Behaviour Skills &

Level knowledge
Risk No Formal Risk Fear of Blame Unconscious
Scepticism Processes Avoidance Culture Incompetence
Awareness Ad hoc use of Suspended Reactive, Fire Conscious
Stand Alone Belief fighting Incompetence
Processes
Understanding & Tick Box Passive Compliance, Conscious
Application Approach Acceptance reliance on Competence
registers
Embedding & Risk Active Risk-based Unconscious
Integration Management Engagement decision making Competence
embedded in
Business
Robust Risk Regular review & Champion Innovation, Expert
Management Improvement Confident Risk
taking

© CBE – DCVMN 010 V2 Compliance by Design 27

 PQS Enablers - Knowledge Management

§  Knowledge management means the

systematic accumulation of information
concerning products so that this knowledge
can be leveraged in the future.

§  Knowledge can be stored in systems such

as:
§  Quality Records, including testing, stability studies
and reports
§  Registration Dossiers
§  Contracts and Technical Agreements
§  Validation Protocol and Reports
§  Marketplace Events (Complaints, Recalls, Adverse
Events etc.)
§  Annual Product Quality Reviews (PQRs)
§  Process control, significant deviations and changes.

© CBE – DCVMN 010 V2 28

 ICH Q10 – Pharmaceutical Quality Manual

•  A Quality Manual or equivalent documentation approach

should be established and should contain the description of the
pharmaceutical quality system.

•  The description should include:

i) The quality policy
ii) The scope of the pharmaceutical quality system.
iii) Identification of the processes within the pharmaceutical
quality system, as well as their sequences, linkages and
inter-dependencies.
•  Process maps and flow charts can be useful tools to facilitate
depicting these in a visual manner.

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 Example Chapters of a Quality Manual
§  MANAGEMENT REVIEW AND RESPONSIBILITY
§  DESCRIPTION OF THE QUALITY SYSTEM
§  QUALITY PLANNING AND RESOURCE
MANAGEMENT
§  TRAINING AND EDUCATION
§  PRODUCT DEVELOPMENT AND PRODUCT
REGISTRATION
§  QUALITY ASSURANCE AND COMPLIANCE
PROGRAMS
§  MONITORING PROGRAMS
§  CAPA / QUALITY AUDITS / PRODUCT QUALITY
REVIEWS
§  MARKETPLACE MONITORING: COMPLAINTS AND
PHARMACOVIGILANCE PROGRAMS

§  QUALITY RISK MANAGEMENT

§  KNOWLEDGE MANAGEMENT
© CBE – DCVMN 010 V2 30
 Example Chapters of a Quality Manual
§  MATERIAL CONTROL SYSTEM:
§  SUPPLY CHAIN INTEGRITY AND SUPPLIER ASSURANCE

§  PRODUCTION SYSTEM

§  PRODUCT DEVELOPMENT, TECHNOLOGY TRANSFER AND
MASTER INSTRUCTIONS
§  PROCESS PERFORMANCE AND PRODUCT QUALITY
MONITORING SYSTEM
§  PROCESS VALIDATION
§  PACKAGING AND LABELLING
§  DEVIATIONS, INVESTIGATIONS AND NON-CONFORMING
PRODUCT

§  LABORATORY CONTROL SYSTEM

§  CHANGE MANAGEMENT / VALIDATION

§  FACILITIES AND EQUIPMENT SYSTEM / CLEANING/

CONTAMINATION CONTROL AND COMPUTERISED
SYSTEMS
© CBE – DCVMN 010 V2 31
 PQS Objectives
§  Set objectives and clear performance metrics;
§  Objectives are reviewed annually
§  Metrics are measured, time-related and indicate the level of
performance required;
§  Metrics are reviewed regularly;
§  Define how compliance obligations are embedded in
operational practices and procedures.
§  Address processes for identifying, reporting and
responding to compliance failures.

© CBE – DCVMN 010 V2 32

 FDA View on Quality Metrics
Indicator Metric
Lot Acceptance Rate Number of lots rejected in a year / number of lots produced
Right First Time Rate Number of deviations / lot
Complaint Rate Number valid complaints/number of lots released per year
Invalidated (OOS) Rate Number of OOS test results invalidated /tests performed
Annual Product Review Number of APRs generated within 30 days of annual due date
(APR) on Time Rate
Management Most senior manager that signed each annual product review
Engagement
Process capability or Whether performed for each critical quality attribute as part of
performance index that product’s APR.
Corrective and Number of CAPAs that were initiated due to an APR, divided by
Preventative Action the total number of APRs generated.
(CAPA) Rate

© CBE – DCVMN 010 V2 Reviewing    Metrics   33

 ICH Q10 – 4.1 Management Review
•  Senior management should be responsible for
pharmaceutical quality system governance through
management review to ensure its continuing suitability and
effectiveness.

•  Management should assess the conclusions of periodic

reviews of process performance and product quality and of
the pharmaceutical quality system.

© CBE – DCVMN 010 V2

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 Commitment to Quality by Management

§  Governing Body and CEO are engaged

§  The Quality Policy is aligned with business objectives
§  Compliance and Quality obligations are embedded in
position responsibilities
§  Resources are allocated to Quality / Compliance
§  Top level engagement in compliance/quality metrics and
reviews

© CBE – DCVMN 010 V2 35

 PQS, Compliance and Quality Organisation

§  Assign compliance and quality responsibilities to

individual managers – set out in position descriptions
§  Ensure all management “walk the talk”
§  Appoint a senior Compliance/ Quality executive:
§  direct access to the Board/CEO
§  Access to expert advice (internal and external)
§  Establish compliance/quality objectives and KPIs
§  Ensure compliance/quality function has the authority to
act

© CBE – DCVMN 010 V2 36

 ICH Q10 - Management Reviews – should include

§  A timely and effective escalation process to senior

management;
§  Measures of customer satisfaction - complaints and
recalls;
§  Conclusions of process performance and product quality
monitoring;
§  The effectiveness of process and product changes
including those arising from CAPA;
§  Any follow-up actions from previous reviews;

© CBE – DCVMN 010 V2

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 Management Reviews, Trend Analysis
and Feedback

Risk Assessment

SOPs & PQRs Conducted

Reports
Management Report KPIs and Quality
Reviews Metrics
Periodic
Meetings Verification of PQS
Effectiveness

Trend Analysis and

Feedback

© CBE – DCVMN 010 V2

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 ICH Q10 Quality System
Section 3 - Continual Improvement of Process
Performance & Product Quality

§  Process performance and product quality monitoring system:

§  Well defined systems
§  Process control
§  Identification of improvement areas
§  Corrective action and preventive action (CAPA) system
§  In place and effectiveness evaluated
§  Focus on Continuous Improvement
§  Change management system:
§  QA oversight
§  Utilizes science and risk-based assessment
§  Management review of process performance and product
quality
§  Periodic reviews of performance against metrics
§  Supports continual improvement
© CBE – DCVMN 010 V2
 ICH Q10 Quality System:
Section 4 - Continual Improvement of the QS

§  Management Review of the Pharmaceutical Quality System

§  Measurement of achievement of QS objectives
§  Assessment of Metrics

§  Monitoring of Internal and External Factors impacting the

QS
§  Emerging regulations, guidance and quality issues
§  Innovations
§  Changes in business strategies and objectives.

§  Outcomes of Management Review and Monitoring

§  (Re)allocation of resources and/or personnel training
§  Timely and effective communication of the results

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 Compliance and Improvement
Element   Compliance   Regula9on   Improved   Integrated   Compe99ve  
is  a  cost  $   Driven   Compliance   Compliance   Advantage  

Quality  Focus   Tes)ng  (QC)   GMPs   Processes  and   ICH  Q8,  9,  10   ICH  Q8,9,10  
Systems   Started   Embedded  

CAPA   Correc)on   Correc)ve   Prevent.   Management   Drive  down  

(Reac)ve)   Ac)on   Ac)on  (RCA)   Reviews   COQ  

Con9nuous   Absent   Event  Driven   QA  Focus   Opera)ons   Company  

Improvement   (Reac)ve)   (Predic)ve)   Focus   Wide  -­‐  Part  of  
Culture  
Compliance   QA/QCs  role   Compliance  /   PQS  Systems   Prepare  for   Welcome  
-­‐  minimal   GMP  Audits   driven  audits   Regulatory   External  
Audits     Audits   Feedback  
Knowledge  &   Basic    GMP   Knowledge  is   Systema)c   Knowledge  is   Knowledge  is  
Training   Training   anecdotal   Training   Documented   Leveraged  
Evaluated   &  Organised    
 
© CBE – DCVMN 010 V2 41