Process Validation From Design Space to Continuous Improvement

8/25/2014
Process Validation
From Design Space to Continuous Process Improvement
CARLO L. PERETE, M.Sc.
Vice President, ISPE Philippines

Technical Services Lead, GSK Philippines
1
8/25/2014
2
8/25/2014
AGENDA:
DAY 1
• The evolution of Process Validation
• Process Validation Stage 1

• Workshop # 1: Identifying Product Control Strategy
DAY 2

• Workshop # 2: Continuous Process Monitoring
•Challenges in implementing the new PV approach
3
8/25/2014
CREDITS
• ISPE Guide Series: Product Quality LifeCycle Implementation (PQLI) from Concept to Continual
Improvement, Part 1 – Product Realization using Quality by design (QbD): Concepts and Principles.
International Society of Pharmaceutical Engineering (ISPE). First Ed., November 2011. www.ispe.org
• ISPE Guide Series: Product Quality LifeCycle Implementation (PQLI) from Concept to Continual
Improvement, Part 4– Process Perfomance and Product Quality Monitoring System. International Society
of Pharmaceutical Engineering (ISPE). First Ed., 2013. www.ispe.org
• Lepore, J. Expectations / Deliverables from PV Stage 1. ISPE Process Validation Conference, 2012.
Silverspring, MD.
• Johnson, Marc D. Statistically Determined Acceptance Criteria and Sampling Plans for PPQ. ISPE Process
Validation Conference, 2013. New Brunswick, NJ.
• Barrick, J. Process Validation Stage 2: Determining and Justifying the Number of Process PQ Batches .
ISPE Process Validation Conference, 2013. New Brunswick, NJ.
• Barrick, J. Continued Process Verification, PV Stage 3a Decisions. ISPE Process Validation Conference,
2013. New Brunswick, NJ.
• Kiefer, M. Challenges in Implementing the Life for Generic Manufacturing. ISPE Process Validation
Conference, 2013. New Brunswick, NJ.
CREDITS (cont...)
• Wee, C. Learnings for Quality by Design (QbD) from a Total Quality Management Perspective. ISPE
Annual Conference. 2014. Singapore
• Kettlewell. R. et al. Continuous Verification: Providing an Alternative Approach to Process Validation.

Pharmaceutical Engineering; Vol. 31 No. 1: Jan/Feb 2011. www.ispe.org
• Piriou, J. et al. Control Strategy as the Keystone of the Product LifeCycle, from Product/Process
Understanding to Continuous Process Verification and Improvement . Pharmaceutical Engineering; Vol. 32
No. 1: Jan/Feb 2012. www.ispe.org
• Perete, C. Process Optimization of Herbal Tablet Manufacturing using Central Composite Design.
University of the Philippines, 2007. Manila.
4
8/25/2014
The evolution of Process Validation

(OR How Science caught up with documentation)

1987 1999 2004 2005 2009 2011 2012 2013 2015
5
8/25/2014
US FDA Guidance for Industry – May 1987
PROCESS VALIDATION
- establishing documented evidence which

provides a high degree of assurance that a
process will consistently produce a product
meeting its predetermined specifications and
quality attributes

1987 1999 2004 2005 2009 2011 2012 2013 2015
6
8/25/2014
US FDA Guidance for Industry

Pharmaceutical cGMPs for the 21st Century
 Facilitate industry application of modern quality management

techniques, including implementation of quality systems
approaches, to all aspects of pharmaceutical production and
quality assurance
 Encourage implementation of risk-based approaches that focus

both industry and Agency attention on critical areas
 Ensure that regulatory review, compliance, and inspection

policies are based on state-of-the-art pharmaceutical science
US FDA Guidance for Industry

Pharmaceutical cGMPs for the 21st Century
 Pharmaceutical (development and) manufacturing is

evolving from an art form to one that is now science and
engineering based.
 Effectively using this knowledge in regulatory decisions in

establishing specifications and evaluating manufacturing
processes can substantially improve the efficiency of both
manufacturing and regulatory processes.
7
8/25/2014

1987 1999 2004 2005 2009 2011 2012 2013 2015
ICH Q8 – Pharmaceutical Development
Quality Target Product Profile (QTTP)

“A prospective summary of the quality characteristics of a
drug product that ideally will be achieved to ensure the
desired quality, taking into account safety and efficacy of
the drug product”
8
8/25/2014
Critical Process Parameter (CPP)

“A process parameter whose variability has an impact on a
critical quality attribute and therefore should be
monitored or controlled to ensure that the process
produces the desired quality”
Critical Quality Attribute (CQA)

“A physical, chemical, biological or microbiological property
that should be within an appropriate limit, range or
distribution to ensure the desired product quality”
9
8/25/2014
“The information and knowledge gained from

pharmaceutical development studies and
manufacturing experience provide scientific
understanding to support the establishment of
DESIGN SPACE, specifications and
manufacturing controls.”
10
8/25/2014
“Process development studies should provide the

basis for process improvement, process
validation, continuous process verification (where
applicable), and any process control
requirements.”

1987 1999 2004 2005 2009 2011 2012 2013 2015
11
8/25/2014
Quality Risk Management (ICH Q9)
Quality Risk Management – a systematic process for

the assessment, control, communication and review of
risks to the quality of the drug product across the
product lifecycle

PRINCIPLES of Quality Risk Management
•the evaluation to the risk to quality should be based on

scientific knowledge and ultimately link to the protection
of the patient
•the level of effort, formality and documentation of the

QRM should be commensurate with the level of risk
12
8/25/2014

TOOLS of Quality Risk Management
• Basic risk management facilitation methods (flowcharts,

Ishikawa diagram, process maps, etc)
• Failure Mode Effects Analysis (FMEA)
• Failure Mode Effects Criticality Analysis (FMECA)
• Fault Tree Analysis (FTA)
• Hazard Analysis & Critical Control Points (HACCP)
• Hazard Operability Analysis (HAZOP)
13
8/25/2014

1987 1999 2004 2005 2009 2011 2012 2013 2015
PRODUCT Life Cycle – ICH Q10
Product
Discontinuation
14
8/25/2014
15
8/25/2014
GMP, ICH Q8, Q9, Q10 and PROCESS VALIDATION
Quality Risk
Management
Statistics
Process QTTP, CQA,
CPP, Design
Validation Space
Quality
Management
System
1987 1999 2004 2005 2009 2011 2012 2013 2015
16
8/25/2014
US FDA Guidance for Industry – Jan. 2011
PROCESS VALIDATION
- the collection and evaluation of data, from the

process design stage through commercial
production, which establishes scientific evidence
that a process is capable of consistently delivering
quality product.

1987 1999 2004 2005 2009 2011 2012 2013 2015
17
8/25/2014
PIC/S – Guide to GMP of Medicinal Products

• The system of quality assurance appropriate for
the manufacture of medicinal products should
ensure that . . . all necessary controls on
intermediate products, and any other in-process
controls and validations are carried out

 Validation studies should reinforce GMP, and be
conducted in accordance with defined procedures
 Significant amendments to the manufacturing
process, including any change in equipment or
materials, which may affect product quality or the
reproducibility of the process should be validated
 Processes and procedures should undergo periodic
critical revalidation to ensure that they remain
capable of achieving the intended results
18
8/25/2014

 All the critical steps in the different
manufacturing processes should be subjected to
validation
 In theory, the number of process runs carried
out and observations made should be sufficient
to allow the normal extent of variation and trends
to be established and to provide sufficient data
for evaluation
19
8/25/2014
Process Validation: the new concept
20
8/25/2014
Process Validation:
from documentation to science . . .
US FDA 1987 PV Guideline US FDA 2011 PV Guideline
Documented evidence Scientific evidence
IQ, OQ, PQ prior to commercialization Covers process design , tech transfer and
commercial manufacture (product lifecycle)
3 batches From One to many batches
21
8/25/2014
Process Validation Lifecycle Overview
22
8/25/2014
23
8/25/2014
24
8/25/2014
25
8/25/2014
26
8/25/2014
27
8/25/2014
28
8/25/2014
29
8/25/2014
30
8/25/2014
Quality Risk Management:

Examples of Severity Scales
RANK SEVERITY CRITERIA
No impact of this process variable / operating parameter

1 Not Severe
on product quality
Large deviation from this process variable / operating
4 Slightly Severe parameter, in conjunction with other factors, have a
significant impact on quality
Large deviation from this process variable / operating
Moderately
7 parameter have a significant impact on quality
Severe
Extremely Small to moderate deviation from this process variable /

10
Severe operating parameter have a significant impact on quality

Examples of Criteria to Assess Probability
Probability
RANK Occurrence Description Failure Rate
of Failure
5 Very High Failure is almost inevitable ≥ 1 in 2
4 High Failure commonly occurs 1 in 20
3 Moderate Occasional Failures only 1 in 100
2 Low Failure is unlikely – isolated incidents only 1 in 10,000
1 Very Low Failure is extremely unlikely ≤ 1 in 1,000,000
31
8/25/2014

Examples of Criteria to Assess Detectability
RANK SEVERITY CRITERIA
Control Systems exist which and will almost certainly detect
1 Almost Certain a potential cause/mechanism and subsequent failure mode in a
preventative manner
Control systems exists with a high chance that it will detect a
4 Highly Likely potential cause / mechanism and subsequent failure mode in a
preventative manner
Control systems exists with a moderate chance that it will
detect a potential cause / mechanism and subsequent failure
7 Moderate
mode in a preventative manner
No control systems exists OR a control systems exists that

will not detect a potential cause / mechanism and subsequent
10 Impossible
failure mode in a preventative manner
DESIGN SPACE in the Flow of Development
Product /
Target Product Process Continual
Prior Control
Product /Process Design Improvement
Knowledge Strategy
Profile Dev Space
Definition of Summary of Overview of Summary of Definition of Proposal of

Product prior scientific Quality by scientific control regulatory
Intended Use knowledge (drug Design key understanding strategy based flexibility based
and pre-defintion substance, actions and of product and on Design on product and
of Quality target excipient, similar decisions taken process. Space leading process scientific
(wrt clinical formulations, and to develop Justification and to Control of knowledge and
relevance, processes). New scientific description of Quality and Quality Risk
efficacy, and knowledge multi- Quality Risk Management
safety) Initial Risk (e.g. DoE, PAT, dimensional Management (materials, site,
Assessment Risk space that (Process scale, etc).
Assessment & assures Quality Robustness)
Risk Control) (inter-
relationships &
boundaries) of
clinical
relevance)
32
8/25/2014
A Framework for the DESIGN SPACE Concept

(REF: Perete, C.L. 2007. Process Optimization of Herbal Tablet Manufacturing using Central Composite Design. Manila: Univ. Of the Philippines)
Granulation Bulk
solution (% Density
w/v) – X2
Particle
Size
Mixing
time (mins) Wet Distribution
– X1
Granulation Tablet
Weight –
Y3
Moisture
Content – Tablet Tablet
X3 Compression Friability–
Y2
Raw Disintegrati
material on Time –
QC Y1
DESIGN SPACE – the multidimensional combination of input variables and process parameters that
have been demonstrated to provide assurance of product quality. Mathematically expressed as
Y = f (aX1) + (bX2) + (cX3) + ...
33
8/25/2014
DESIGN SPACE: An Example

(REF: Perete, C.L. 2007. Process Optimization of Herbal Tablet Manufacturing using Central Composite Design. Manila: Univ. Of the Philippines)
Y (Tablet Hardness) = 4.63 – 0.05 X1 – 0.15X12 – 0.07 X2 + 0.13 X22 + 0.05 X3 + 0.05 X32+
0.06 X1X2 – 0.35X1X3 + 0.15 X2X3
Where: X1= Mixing Time, X2= Moisture Content, X3= % Granulating Solution
34
8/25/2014
35
8/25/2014
36
8/25/2014
37
8/25/2014
38
8/25/2014
39
8/25/2014
A FINAL WORD on Process Validation STAGE 1 . . .
40
8/25/2014
WORKSHOP No. 1:
Identifying CQAs, CPPs and

Product Control Strategy
WORKSHOP No. 1 MECHANICS

INSTRUCTIONS TIMINGS
1. You will be divided into 3 groups 3 mins.
2. Your group will be assigned to work on a particular dosage form, and you will 2 mins.
be issued with a corresponding QTTP
3. Develop a process flow diagram for your assigned product 10 mins.
4. Conduct a process FMEA using the severity, probability and detectability 40 mins.
scales discussed in the lecture
5. Identify the CRITICAL QUALITY ATTRIBUTES (CQA) 10 mins.
6. Identify the CRITICAL PROCESS PARAMETERS (CPP) 10 mins.
7. Develop your PRODUCT CONTROL STRATEGY 15 mins.
8. Assign personnel who will report the FMEA, CQA, CPP and Product Control 20 mins.
Strategy to the PLENARY
41
8/25/2014
42
8/25/2014
43
8/25/2014
44
8/25/2014
45
8/25/2014
46
8/25/2014
47
8/25/2014
48
8/25/2014
49
8/25/2014
50
8/25/2014
51
8/25/2014
52
8/25/2014
53
8/25/2014
54
8/25/2014
Stage 3 - Continuous Process Verification: a new concept
55
8/25/2014
56
8/25/2014
57
8/25/2014
58
8/25/2014
59
8/25/2014
60
8/25/2014
61
8/25/2014
62
8/25/2014
63
8/25/2014
64
8/25/2014
65
8/25/2014
66
8/25/2014
67
8/25/2014
68
8/25/2014
69
8/25/2014
70
8/25/2014
WORKSHOP No. 2:
Continuous Process Monitoring
71
8/25/2014
WORKSHOP No. 2 MECHANICS

INSTRUCTIONS TIMINGS
1. You will be divided into 3 groups 3 mins.
2. Your group will be assigned to work on a particular dosage form, and you will be 2 mins.
issued with product in-process control data
3. Construct an X bar S chart 20 mins.
4. Construct a process capability chart 20 mins.
5. Analyze your charts for any out of control (OOC) and out of trend (OOT) data 10 mins.
7. Re-visit your FMEA (from Workshop No. 1) and assess impact on the product 15 mins.
control strategy
8. Assign personnel who will report back to the PLENARY 20 mins.
Process Validation: challenges in

implementation for legacy products
72
8/25/2014
73
8/25/2014
74
8/25/2014
75
8/25/2014
76
8/25/2014
77
8/25/2014
78
8/25/2014
79
8/25/2014
A FINAL WORD Folks . . .
Old Process Validation =

documented common sense
New process validation = science

and risk based, but please don’t
forget common sense!
80
8/25/2014
Thank you!
81

Process Validation From Design Space to Continuous Improvement

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Process Validation From Design Space to Continuous Improvement

Uploaded by

Copyright:

Available Formats

8/25/2014

CARLO L. PERETE, M.Sc.

Vice President, ISPE Philippines

• The evolution of Process Validation

• Process Validation Stage 1

• Process Validation Stage 2

• Process Validation Stage 3

•Challenges in implementing the new PV approach

• Kettlewell. R. et al. Continuous Verification: Providing an Alternative Approach to Process Validation.

The evolution of Process Validation

The evolution of Process Validation

1987 1999 2004 2005 2009 2011 2012 2013 2015

US FDA Guidance for Industry – May 1987

- establishing documented evidence which

The evolution of Process Validation

1987 1999 2004 2005 2009 2011 2012 2013 2015

US FDA Guidance for Industry

 Facilitate industry application of modern quality management

 Encourage implementation of risk-based approaches that focus

 Ensure that regulatory review, compliance, and inspection

US FDA Guidance for Industry

 Pharmaceutical (development and) manufacturing is

 Effectively using this knowledge in regulatory decisions in

The evolution of Process Validation

1987 1999 2004 2005 2009 2011 2012 2013 2015

ICH Q8 – Pharmaceutical Development

Quality Target Product Profile (QTTP)

ICH Q8 – Pharmaceutical Development

Critical Process Parameter (CPP)

ICH Q8 – Pharmaceutical Development

Critical Quality Attribute (CQA)

ICH Q8 – Pharmaceutical Development

“The information and knowledge gained from

ICH Q8 – Pharmaceutical Development

“Process development studies should provide the

The evolution of Process Validation

1987 1999 2004 2005 2009 2011 2012 2013 2015

Quality Risk Management (ICH Q9)

Quality Risk Management – a systematic process for

Quality Risk Management (ICH Q9)

•the evaluation to the risk to quality should be based on

•the level of effort, formality and documentation of the

Quality Risk Management (ICH Q9)

Quality Risk Management (ICH Q9)

• Basic risk management facilitation methods (flowcharts,

The evolution of Process Validation

1987 1999 2004 2005 2009 2011 2012 2013 2015

PRODUCT Life Cycle – ICH Q10

GMP, ICH Q8, Q9, Q10 and PROCESS VALIDATION

1987 1999 2004 2005 2009 2011 2012 2013 2015

US FDA Guidance for Industry – Jan. 2011

- the collection and evaluation of data, from the

The evolution of Process Validation

1987 1999 2004 2005 2009 2011 2012 2013 2015

PIC/S – Guide to GMP of Medicinal Products

PIC/S – Guide to GMP of Medicinal Products

PIC/S – Guide to GMP of Medicinal Products

Process Validation: the new concept

Documented evidence Scientific evidence

3 batches From One to many batches

Process Validation Lifecycle Overview

Quality Risk Management:

No impact of this process variable / operating parameter