Transcript No Slide Title

Process Validation – What the
Future Holds
Presented by: Karen S Ginsbury
PCI Pharmaceutical Consulting Israel Ltd.
For IFF
February 2011
1
Course Objective
Take an in depth look at the regulatory
requirements (EU and FDA) for process
validation
– FDA process validation guidance
– Q10 – Pharmaceutical Quality System
Guidance
• Management Review
• Ongoing product and process performance
monitoring
2
The Objective…
• Gain an overall understanding of the topic of
Process Validation over a product lifecycle tied
in with Product Quality Review in the context
of ongoing verification of process and product
performance
• Tie in with CAPA programs to provide an
enhanced quality system
3
To be discussed…
• The GMP regulations:
- EU on Product Quality Review
and Process Validation
- US on Annual Product Review
and Process Validation
• Q10 – Pharmaceutical Quality System:
Ongoing Process and Product Performance
Monitoring
• FDA Process Validation guidance
4
To be discussed…
• What industry is currently doing
• Critical Process Parameters and their review
• Critical Quality Attributes and their inclusion
in the review
• Data trending (Use of simple statistical tools)
• Validation, deviations and changes
5
To be discussed…
•
•
•
•
•
•
Organizational Structure, escalation policy
SOPs
CAPA and Follow-up
Critical systems, support systems
Management involvement / commitment
Mobilizing resources
6
Purpose of Validation:
•
•
•
•
•
To satisfy the regulators!!
Ensure you got what you intended
In accordance with design / development
Map critical elements / show reproducibility
Allow for:
–
–
–
–
Continuous Improvement / Change management
Ongoing maintenance
Ongoing qualification
CAPA
The future is now
The future is now
•
Your firm failed to provide validation protocols that evaluated the impact of the
increasing batch sizes on product quality. You failed to conduct a study to
demonstrate at what point each batch size is uniformly blended. You have not
conducted any analysis comparing data between your validation batches. Further,
your firm uses a general "Master Validation Plan" for process validation on all
products. Validation must be demonstrated for each product and process. The
critical controls and processing parameters must be known and shown to be in
control, and a demonstration of process reproducibility with objective measures
must be made.1
•
1
Further information on FDA's current thinking on process validation is available in
Food and Drug Administration, Draft Guidance for Industry, Process Validation:
General Principles and Practices November 2008, available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM070336.pdf
The Future is Now
10
The Future is Now
11
Regulatory Basis for Validation
USA / FDA
Sec. 211.68 Automatic, mechanical, and electronic equipment
•
“Automatic, mechanical, or electronic equipment or other types of equipment,
including computers, or related systems that will perform a function satisfactorily,
may be used in the manufacture, processing, packing, and holding of a drug
product
• Such equipment shall be routinely calibrated, inspected, or checked
according to a written program designed to assure proper performance.
Written records of those … inspections shall be maintained”
• Input to and output from the computer or related system of formulas or
other records or data shall be checked for accuracy. The degree and
frequency of input/output verification shall be based on the complexity
and reliability of the computer or related system
Regulatory Basis for Validation – EU
Annex 15 – Qualification and Validation (2001)
• …a GMP requirement that manufacturers identify what
validation work is needed to prove control of critical
aspects of their particular operations
• Significant changes to facilities, equipment and
processes, which may affect the quality of the product,
should be validated
• A risk assessment approach should be used to
determine the scope and extent of validation
Warning Letters
14
Some Concepts
• Uncertainty: The lack of certainty, A state of
having limited knowledge where it is impossible
to exactly describe existing state or future
outcome or there is more than one possible
outcome
• Measurement of Uncertainty: A set of possible
states or outcomes where probabilities are
assigned to each possible state or outcome
• Risk: A state of uncertainty where some possible
outcomes have an undesired effect or significant
loss
Uncertainty
“It is not enough to satisfy the customer…
You MUST delight them”
W. Edwards Deming
Two More that have to be understood
Critical Quality Attribute (CQA):
• A physical, chemical, biological or microbiological
property or characteristic that should be within an
appropriate limit, range, or distribution to ensure the
desired product quality
[= safety, efficacy, performance]
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 the process
produces the desired quality
17
Production Yield (Y) is a CQA affected by the Variable Inputs (X)
I Chart
115
UCL=111.55
Individual Value
110
105
_
X=99.63
100
95
90
LCL=87.71
60
62
64
66
68
70
72
Observation
74
76
78
80
People
I Chart
115
UCL=112.65
Inputs to the process
110
Individual Value
105
100
_
X=97.94
95
90
85
LCL=83.23
80
40
42
44
46
48
50
52
Observation
54
56
58
60
Equipment
I
N
P Measurement
U
T Process
S
(X) Materials
I Chart
115
UCL=112.65
110
Individual Value
105
100
_
X=97.94
95
90
85
LCL=83.23
y = ƒ(x)
control variability
of the Output
I Chart
80
42
44
46
48
50
52
Observation
54
56
58
60
I Chart
120
UCL=116.68
Individual Value
115
110
105
_
X=102.37
100
95
115
UCL=114.17
110
y
Individual Value
40
105
_
X=99.95
100
95
90
LCL=88.05
20
22
24
26
28
30
32
Observation
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36
38
40
I Chart
115
LCL=85.72
85
1
11
21
31
41
51
61
Observation
71
81
91
UCL=111.55
110
Individual Value
90
105
_
X=99.63
100
95
90
LCL=87.71
60
62
64
66
68
70
72
Observation
74
76
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OUTPUT
I Chart
UCL=111.17
110
Individual Value
105
_
X=98.76
100
95
90
LCL=86.35
85
80
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84
86
88
90
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Observation
94
96
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Environment
Adapted from slide by 18
Moheb Naser, FDA
From the FDA Guide
• CGMP regulations require that batch samples
represent the batch under analysis e.g. § 211.160(b)(3)
and that the sampling plan result in statistical
confidence § 211.165(c)
• in-process specifications “. . . shall be derived from
previous acceptable process average and process
variability estimates where possible and determined by
the application of suitable statistical procedures where
appropriate”
This requirement, in part, establishes the need for
manufacturers to analyze process performance and
control batch-to-batch variability
From the Guide
• We recommend an integrated team approach
to process validation that includes expertise
from a variety of disciplines, e.g. process
engineering, industrial pharmacy, analytical
chemistry, microbiology, statistics,
manufacturing, and quality assurance
From the Guide
• The approach to PQ should be based on sound
science …
• we strongly recommend firms employ
objective measures (e.g., statistical metrics),
wherever feasible and meaningful to achieve
adequate assurance
From the Guide
• In most cases, PPQ will have a higher level of
sampling, additional testing, and greater
scrutiny of process performance
• The level of monitoring and testing should be
sufficient to confirm uniform product quality
throughout the batch during processing
From the Guide
• The increased level of scrutiny, testing, and sampling
should continue through the process verification stage
as appropriate, to establish levels and frequency of
routine sampling and monitoring for the particular
product and process
• Considerations for the duration of the heightened
sampling and monitoring period could include, but are
not limited to:
–
–
–
–
volume of production
process complexity
level of process understanding
experience with similar products and processes
From the Guide
• The extent to which some materials, such as
column resins or molecular filtration media,
can be re-used without adversely affecting
product quality can be assessed in relevant
laboratory studies
• The usable lifetimes of such materials should
be confirmed by an ongoing PPQ protocol
during commercial manufacture
Life Cycle Approach
Identification
of process
variables
Process
design
Process
monitoring
and
improvement
PROCESS
VALIDATION
Control
strategy
Process
qualification
No more magic #3!
Process Validation – FDA
• Current Process Validation is from 1987
• Guidance is out-dated and no longer reflects
current GMPs
• The new document is closer to ICH Q8, 9 and
10 philosophy of lifecycle approach to product
(risk) management
Process Validation - EU
Process Validation - EU
• The current guideline was developed before ICH Q8/9/10
• Additional means are available to verify the control of the process
by alternative means to the traditional process validation batches
• The main objective is that a process design yields a product meeting
its pre-defined quality criteria
• Q8/9/10 provide a structured way to define CQAs, design space,
manufacturing process and the control strategy
• Continuous process verification can be utilised in process validation
protocols for the initial commercial production and for
manufacturing process changes for the continual improvement
throughout the remainder of the product lifecycle
Surprised?…You Shouldn’t be!
• Q10, section 1.6 Enablers:
– 1.6.1 Knowledge management
“…process validation studies over the product
lifecycle”
• Q10, section 3.1 Lifecycle Stage Goals:
– 3.1.2 Technology Transfer
“This knowledge [from tech transfer] forms the
basis for manufacturing process, control strategy,
process validation approach and ongoing
continual improvement”
Surprised?…You Shouldn’t be!
• Q10, section 3.2 Quality System Elements:
– 3.2.1 Process Performance and Product Monitoring
System
“…provide knowledge to enhance process
understanding, enrich the design space (where
established), and enable innovative approaches to
process validation”
Definition: 1987 Guide
• Process validation is establishing documented
evidence which provides a high degree of
assurance that a specific process will
consistently produce a product meeting its
pre-determined specifications and quality
characteristics
Current Definition: January 2011
Proposed definition:
process validation is defined as 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
Preapproved Protocols?
Completion of Optimization?
Revised Process Validation Guide
•
Three phases to the validation:
1. Process Design
2. Process Qualification
3. Continued Process Verification
•
•
•
Lifecycle Approach
No more magic “three”
Can use data from lab scale / pilot batches to
support process qualification
FDA Process Validation Guide
Stage
Purpose
Activities
Process Design
Define commercial process based on
knowledge gained through
development and scale up activities
Outcome: design a process for routine
manufacture that will consistently
deliver product meeting its critical
quality attributes
Confirm process design as capable of
reproducible commercial manufacturing



Integrated product and process design
Product development activities
DOE combined with Risk Assessment
to explore process parameters,
variability, effect on quality attributes
and process controls




Provide ongoing assurance that the
process remains in a state of control
during routine production through
quality procedures and continuous
improvement initiatives








Facility design
Equipment & utilities qualification
Performance qualification
Emphasis on use of statistically based
sampling plans, statistically valid
acceptance criteria and statistical
analysis of process data to understand
process consistency and performance
Organized data collection every batch
Data trending and statistical analysis
Product review
Equipment and facility maintenance
Calibration
Management review and production
Employee feedback
Continuous improvement
Process
Qualification
Continued
Process
Verification
Worst Case
• A condition or set of conditions encompassing
upper and lower processing limits and
circumstances, within standard operating
procedures, which pose the greatest chance
of product or process failure when compared
to ideal conditions
• Such conditions do not necessarily induce
product or process failure
- Annex 15 glossary
FDA Guide
• Each step of a manufacturing process is
controlled to ensure that the finished product
meets all design characteristics and quality
attributes including specifications
• Each step of a manufacturing process is
controlled (Product Control Strategy) to assure
that the finished product meets its Critical Quality
Attributes and Performance Characteristics as
defined in the Quality Target Product Profile
Stages of Validation - Process Design
Stage 1 – Process Design:
The commercial process is defined during this
stage based on knowledge gained through
development and scale-up activities
This is a pre-requisite for process validation
Process Qualification
• During the process qualification the process
design is confirmed as being capable of
reproducible commercial manufacture. This
stage has two elements:
1.Design of facility and qualification of
equipment and utilities
2.Process Performance qualification (PQ)
Continued Process Verification
• Ongoing assurance is gained during routine
production that the process remains in a state
of control
40
Continued Process Verification
Ongoing Verification / Reports / CAPA
•
•
•
•
•
•
•
Complaints
Annual Product Review
Critical Systems Review
Environmental Monitoring
OOS / Out of trend results
Deviations (planned / not)
Rejected Batches
• Change Control
• Validation / Calibration
Status
• Maintenances
• Batch Records (statistics)
• Audits
• Stability
Demonstrating Ongoing Control
• A 10 year old car will not
perform in the same manner
as a brand new one
• BUT
if you can demonstrate, by
ongoing process monitoring
that product performance
is unchanged (within the
limits of the specification)
then the old car is still validated
Demonstrating Ongoing Control
• Which means looking after the equipment:
– Maintenance records:
preventive and breakdown
– Cleaning records
– Use logs
– Calibration logs
• And periodically performing
review of the logs looking for:
–
–
–
–
Increased frequency / severity of breakdown
Failed calibrations
Failed or non-conforming batches of product
Borderline product – close to specification
What about Grandfather Products
• Grandfather products shouldn’t be a concern:
Product Quality Review and vast knowledge
accumulated over years should provide an
excellent basis for ongoing process validation
– if you don’t have it already…you should have
(more or less)
But – new products, IMPs…when will
regulators expect to first hear the term
Process Validation and see data?
Quality Review - GMP
Requirements
• USA
– 21 cfr part 211.180 General Requirement
section (e)
– EU Guide
– Chapter 1 to the EU Guide to Good Manufacturing
Practice (October 2005)
[since updated to include Quality Risk Management]
46
21 cfr 211.180 (e)
Written records required by this part shall
be maintained so that data therein can be
used for evaluating at least annually, the
quality standards of each drug product to
determine the need for changes in drug
product specifications or manufacturing or
control procedures. Written procedures
shall be established and followed for such
evaluations and shall include provisions for:
47
21 cfr 211.180 (e) cont/
(1) A review of a representative number of
batches, whether approved or rejected,
and where applicable, records associated
with the batch.
(2) A review of complaints, recalls, returned
or salvaged drug products, and
investigations conducted under 211.192 for
each drug product.
48
Chapter 1 – (1.4) Product Quality Review
• Regular periodic or rolling quality reviews
of all licensed medicinal products,
• including export only products
• Such reviews should normally be conducted
and documented annually, taking into
account previous reviews
49
(1.4) PQR Objective
Verify
• The consistency of the existing process
• The appropriateness of current specifications
for:
– starting materials
and
– finished product
to highlight any trends and to identify product and
process improvements
50
Include at least…
(i) A review of starting materials including packaging
materials used in the product, especially those from
new sources
(ii) A review of critical in-process controls and finished
product results
(iii) A review of all batches that failed to meet established
specification(s) and their investigation.
(iv) A review of all significant deviations or nonconformances, their related investigations, and the
effectiveness of resultant corrective and preventative
actions taken.
51
Include at least…
(v) A review of all changes carried out to the
processes or analytical methods
(vi) A review of Marketing Authorisation variations
submitted/granted/refused, including those for
third country (export only) dossiers
(vii) A review of the results of the stability
monitoring programme and any adverse trends
(viii) A review of all quality-related returns,
complaints and recalls and the investigations
performed at the time
52
Include at least…
(ix) A review of adequacy of any other previous
product process or equipment corrective
actions
(x) For new marketing authorisations and
variations to marketing authorisations, a
review of post-marketing commitments
53
Include at least…
(xi) The qualification status of relevant
equipment and utilities, e.g. HVAC, water,
compressed gases, etc.
(xii) A review of any contractual arrangements as
defined in Chapter 7 to ensure that they are
up to date
54
Chapter 1 continued…
• The manufacturer and marketing
authorisation holder should evaluate the
results of this review, where different, and an
assessment made of whether corrective and
preventative action or any revalidation should
be undertaken
55
Chapter 1 continued…
• Reasons for such corrective actions should be
documented
• Agreed corrective and preventative actions
should be completed in a timely and effective
manner
• There should be management procedures for
the ongoing management and review of these
actions and the effectiveness of these
procedures verified during self inspection
56
What parameters should be included
•
•
•
•
•
•
Number of batches manufactured
Number of batches released
Number of batches rejected
Number of batches in quarantine / hold
More / less than previous year? Why?
Comments
57
What parameters should be included 2
• Raw Materials specifications
• Raw Materials manufacturers (changes at
least)
• Raw Materials: batch numbers used for:
– API
– Key excipients?
• Product specifications
• Review of batch records
58
What parameters should be included 3
• Review of manufacturing data:
– were there changes in:
•
•
•
•
•
•
facility
raw material suppliers?
equipment
manufacturing instructions?
product specs
test methods?
– If yes, when exactly did the change happen
59
What parameters should be included 4
• Review of manufacturing data:
set up charts of data or collect on line
– batch yields: theoretical, actual, reconciliation
can the reconciled yield be improved
was it improved / worse than previous year
where are the most losses? Why?
E.g. visual inspection
60
What parameters should be included 5
• Review of manufacturing data / laboratory
results:
– in-process pH, conductivity
– in-process assays: before / after filtration
– in-process assays: before / after mixing
– physical parameters: particle size distribution
other?
– Tablet weight, thickness, hardness, friability etc.
– Fill volume / uniformity of content
61
What parameters should be included 6
• Review of finished product data:
– LOD
– assay
– Uniformity of content
– pH
– impurities?
– OVIs?
– other
62
What parameters should be included
•
•
•
•
•
Review related SOPs?
Reserve samples ?
Stability data: to what level of detail?
What are you looking for
Why do you need to do it?
– If the batches are in limits they are released
– If not rejected
63
Data Trending
•
•
•
•
•
Easiest to assess as line graphs
Average
Standard Deviation
Upper and lower control limits (2 or 3 SDs)
Compared to Upper and lower specification
limits
• Can all be done on Excel (what about
validation????)
• cf with previous years / similar products
64
Deviations
•
•
•
•
•
Don’t list all deviations
Give an overview
Categorize and look at root causes
Compare with previous years
Up or down e.g. equipment deviations,
maintenance - indicative of aging equipment,
consider re-validation? Replacement?
65
Q10 – Pharmaceutical Quality System
June 2008
• model for an effective quality management
system for the pharmaceutical industry
• that can be implemented throughout the
different stages of a product lifecycle
• Product Quality Review is concerned with the
PRODUCT LIFECYCLE – ongoing control
66
Q10 Management Responsibility
• Ensure a timely and effective communication
and escalation process exists to raise quality
issues to the appropriate levels of
management
• Conduct management reviews of process
performance and product quality and of the
pharmaceutical quality system;
• Advocate continual improvement;
• Commit / mobilize appropriate resources
67
Q10 Management Responsibility
• Management should assess the conclusions of
periodic reviews of process performance and
product quality and of the pharmaceutical
quality system
68
Continual Improvement of Process
Performance and Product Quality
• Section 3 of Q10 = PQR
• 3.1.3 Commercial Manufacturing
• The goals of manufacturing activities include
…establishing and maintaining a state of control and
facilitating continual improvement
• The pharmaceutical quality system should assure that:
–
–
–
–
–
the desired product quality is routinely met
suitable process performance is achieved
the set of controls are appropriate
improvement opportunities are identified and evaluated
the body of knowledge is continually expanded
69
3.2.1 Process Performance and Product
Quality Monitoring System
• plan and execute a system for the monitoring
of process performance and product quality to
ensure a state of control is maintained
• An effective monitoring system provides
assurance of the continued capability of
processes and controls to produce a product
of desired quality and to identify areas for
continual improvement
70
3.2.1 Process Performance and Product
Quality Monitoring System
• Use risk management to establish product control strategy
• Provide tools for measurement and analysis of parameters and attributes
identified in the control strategy (e.g., data management and statistical tools)
• Analyse parameters and attributes identified in the control strategy to verify
continued operation within a state of control
• Identify sources of variation affecting process performance and product quality
for potential continual improvement activities to reduce or control variation
• Include feedback on product quality from internal and external sources, e.g.,
complaints, product rejections, non-conformances, recalls, deviations, audits
and regulatory inspections and findings
• Provide knowledge to enhance process understanding, enrich the design space
(where established), and enable innovative approaches to process validation
71
Change Control
• Need ongoing change control
• Need change control for changes resulting
from the annual review
• Do not assume that because it was written in
the conclusions it can be implemented
straight out in production
72
Organizational Structure
• Who does the review?
• Get as much as possible from computers
• Get production / ops involved - they are the
owners of the process
• Make sure that Process Development signs off
on the report - they will need to troubleshoot
73
SOP
•
•
•
•
•
•
Purpose
Responsibility
Procedure
Limits and Limitations
Corrective Actions
Documentation
74
Follow-up
• Part of CAPA program
• Won’t happen on its own
• Requires troubleshooting, which means
process development and change control and
maybe process validation / revalidation
• Documentation
• Approvals
75
Critical Systems Review
•
•
•
•
•
•
•
•
WFI
Purified Water
HVAC system
Clean Steam
Autoclave?
Oven?
Media Fill
(Aseptic Process)
•
•
•
•
•
•
Validation Program
Audit Program
Training Program
Stability Program?
SOPs
Reserve Samples?
76
Management Involvement
• 21 cfr 211.180 (f) (directly after annual review)
• “Procedures shall be established to assure that the
responsible officials of the firm, if they are not personally
involved in or immediately aware of such actions are
notified in writing of any investigations conducted under
211.198 (complaints), 211.204 (returns), 211.208
(salvaging), any recalls, reports of inspectional
observations or any regulatory actions relating to GMP…..
• Management needs to be informed of
outcome of annual review
77
Management Involvement
• Management needs to provide the resources
to implement corrective actions
• Means:
– people
– equipment
– time
– production down time
78
FDA - Risk based Approach to
cGMP
79
Ongoing
•
•
•
•
Critical parameters must be understood
Critical process parameters must be defined
Critical process parameters must have ranges
Trends need to be followed, understood and
acted upon
• Change control may need to follow trends
80
Conclusion
Process Validation is a continuum not a one time event
It should encompass the product lifecycle
It can be tied in with product and process quality reviews
to demonstrate maintenance of an ongoing state of
control
– a MANAGEMENT tool
– an opportunity to correct a process before the process
gets out of hand
– a money saving tool if used properly
– to be used in investigation of deviations
– to be used in estimating effects of changes to the process
81
Thank you for your attention
Questions?
82