Keeping Pace with Aseptic Fill Finish Operations
in an Evolving Regulatory Environment
September 30, 2010
Presented By: Roshni Dutton, PhD PEng PMP
SNC-LAVALIN Pharma
Central Canada Chapter
Aseptic Filling
September 30, 2010
Keeping Pace with Aseptic Fill Finish Operations
in an Evolving Regulatory Environment
OUTLINE
Aseptic liquid filling line guidelines: EMA, FDA, HC
QbD and PAT: ICH 7, 8, 9, 10
QbD/PAT Examples
Check Weigh
Vision System
Dosing System
Central Canada Chapter
Aseptic Filling
September 30, 2010
1
Aseptic Processing Guidelines
Regulations set forth WHAT must be complied with
Guidelines set forth suggestions of HOW to comply
“Unless specific regulatory or statutory requirements are
cited”, Guidelines do not comprise REQUIREMENTS. They are
not PRESCRIPTIVE.
Nevertheless, Guidelines are the output of Expert Working
Groups, and offer sound advise based on their interpretation of
the regulations and the technology state of the art at the time
of writing.
Compliance Inspections are generally conducted against
Guidelines.
Innovations that improve compliance with regulations are
encouraged over adherence to guidelines.
Central Canada Chapter
Aseptic Filling
September 30, 2010
2
Aseptic Processing Guidelines
FDA Guidance for Industry: Sterile Drug Products
Produced by Aseptic Processing – Current Good
Manufacturing Practice 2004
EU Guidelines to Good Manufacturing Practice
Medicinal Products for Human and Veterinary Use:
Annex 1 – Manufacture of Sterile Medicinal Products
(corrected version) 2008
HC Good Manufacturing Practices (GMP) Guidelines –
2009 Edition: Part 5.0 Sterile Products C.02.029
These documents primarily address aseptic filling lines
Central Canada Chapter
Aseptic Filling
September 30, 2010
3
Aseptic Processing Guidelines: FDA
FDA: Critical Area such as aseptic processing line should meet
Class 100 (ISO 5) standards
FDA: area immediately adjacent to the Critical Area should meet, at
a minimum, Class 10,000 (ISO 7) standards under dynamic
conditions.
FDA: (where isolators are used), a Class 100,000 (ISO 8)
background is commonly used.
FDA: An aseptic processing isolator should not be located in an
unclassified room
FDA: Class 100,000 (ISO 8) is appropriate for less critical activities
such as equipment cleaning
FDA: “The use of the word should in Agency guidances means that
something is suggested or recommended, but not required.”
Central Canada Chapter
Aseptic Filling
September 30, 2010
4
Aseptic Processing Guidelines: EMA
EMA: Aseptic preparation and filling Grade A (ISO 5)
EMA: Background environment should be controlled and for aseptic
processing at least Grade D (ISO 9)
EMA: Partially stoppered freeze drying vials should be maintained
under Grade A at all times
EMA: Vials should be maintained in Grade A environment until cap
has been crimped.
Capping equipment should be located at a separate station equipped
with adequate air extraction, which may not be able to meet Grade
A conditions for non-viable particles in the “in operation” condition
but should meet the microbiological requirements.
Central Canada Chapter
Aseptic Filling
September 30, 2010
5
International Committee on Harmonization
ICH includes representatives of:
Regulatory Bodies
Pharmacopeias
Drug Industry Members
From:
USA, Canada
Europe
Japan
Central Canada Chapter
Aseptic Filling
September 30, 2010
6
ICH Q7, Q8, Q9, Q10: The New Paradigm
“risk-based”
concepts and
principles
Central Canada Chapter
Aseptic Filling
September 30, 2010
7
ICH Q7, Q8, Q9, Q10: A Vision of the Future
Old Approach
Broad Concept
Quality
Systems
Regulatory
New Approach
Remarks
Quality decisions divorced
from science and risk
evaluation.
Adherence to filing
commitments.
Quality decisions and filing
commitments based on
Process Understanding
and Risk Management.
Quality by Design.
Design Space concept
introduced to integrate
process knowledge with
regulatory evaluation.
Post-factum sampling and
quality testing.
Process Validation.
Management of variability
Process control
focused on critical
attributes.
Continuous Quality
Verification.
Quality by Design definition
applied. Measure critical
process parameters to
control output product
quality.
Systems designed to inhibit
changes & minimize
business risks.
Discourages improvement
& innovation.
Changes managed within
company's quality
system.
Real time batch release
feasible.
Regulators and industry
place higher reliance /
trust / understanding on
systems.
Multidisciplinary
evaluation and decision
making.
Compliance focus.
Changes require prior
approval.
Regulatory scrutiny
adjusted to level of
Process Understanding.
Continuous improvement
allowed within Design
Space.
Requires mechanisms to
communicate Process
Understanding data
("inspectable rather than
reviewable").
Central Canada Chapter
Aseptic Filling
September 30, 2010
8
ICH Q8: A Vision of the Future
Design Space:
The multidimensional combination and
interaction of input variables (e.g.,
material attributes) and process
parameters that have been demonstrated
to provide assurance of quality.
Central Canada Chapter
Aseptic Filling
September 30, 2010
9
ICH Q8: A Vision of the Future
Quality:
The suitability of either a drug substance
or drug product for its intended use. This
term includes such attributes as the
identity, strength, purity.
Quality by Design (QbD):
Quality is achieved through controlling
operation within the Design Space
Central Canada Chapter
Aseptic Filling
September 30, 2010
10
ICH Q7 & Q8: A Vision of the Future
Validation:
A documented program that provides a high degree of
assurance that a specific process, method, or system
will consistently produce a result meeting predetermined acceptance criteria.
Continuous Process Verification:
An alternative approach to process validation in which
manufacturing process performance is continuously
monitored and evaluated.
Central Canada Chapter
Aseptic Filling
September 30, 2010
11
ICH Q8: A Vision of the Future
Process Analytical
Analytical Technology
Technology
Process
(PAT):
(PAT):
A system
system for
for designing,
designing, analyzing,
analyzing, and
and
A
controlling manufacturing
manufacturing through
through timely
timely
controlling
measurements (i.e.,
(i.e., during
during processing)
processing) of
of
measurements
critical quality
and
performance
attributes
of
Critical
Process
Parameters
(CPP)
that affect
raw andQuality
in-process
materials
andofprocesses
Critical
Attributes
(CQA)
the product.
with the goal of ensuring final product quality.
Central Canada Chapter
Aseptic Filling
September 30, 2010
12
ICH Q9: Quality Risk Management Process
Optional
but can benefit
from its use!
Central Canada Chapter
Aseptic Filling
September 30, 2010
13
ICH Q10: Pharmaceutical Quality System
Central Canada Chapter
Aseptic Filling
September 30, 2010
14
ICH Q9: Quality Risk Classification
(based on SUPAC and GAMP-4)
Impact on Quality
Quality by design +
Systems approach
High
Medium
Low
Risk Likelihood
Level 3
High
Level 2
Medium
Low
Central Canada Chapter
Aseptic Filling
Level 1
September 30, 2010
15
ICH Q9: Quality Risk Priority
(based on SUPAC and GAMP-4)
Risk Classification
High
Medium
Probability of Detection
Low
Quality by design +
Systems approach
High
3
Medium
2
1
Central Canada Chapter
Aseptic Filling
Low
September 30, 2010
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ICH Q7, Q8, Q9 Q10 Inter-relationship
Opportunities to impact
risk using quality risk
management Q9
Design
Process
Materials
Facilities
Manufacturing
Distribution
Patient
Q8
Q7
Central Canada Chapter
Aseptic Filling
Q10
September 30, 2010
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Low
t
m
pr
ov
em
en
ua
li
tin
co
n
High
Q10 Pharm.. Quality Systems
Risk from Manufacturing site
How Q9 interacts with Q8 and Q10
Q8 Pharmaceutical Development
Low
Using Q9
Quality Risk
Management
principles
High
Product / Process Risk
Central Canada Chapter
Aseptic Filling
September 30, 2010
18
QbD/PAT Example One: Check Weighing
Check Weighing, a well developed filling
line In Process Control (IPC), is an
example of QbD/PAT that is already in
practice.
Data capture, evaluation, and response:
Real time in-line measurement
Statistical interpolation and
extrapolation
Incorporation of continuous real time
adjustment of fill volume
Continuous verification
A component of potential for real time
release
Central Canada Chapter
Aseptic Filling
September 30, 2010
29
QbD/PAT Example Two: Vision Systems
Visual Inspection is a well
established QC testing component
of CQAs.
Potential for Visual Inspection to be
linked to CPPs, which for example
might include:
Stoppering pressure
Lyo residual humidity
etc
Potential for Visual Inspection to be
tied to real time adjustment
Potential for Visual Inspection as a
component of QbD/PAT
Central Canada Chapter
Aseptic Filling
September 30, 2010
30
QbD/PAT Example Three: Dosing System
The CPP of each
unit operation
within the
process can
affect the CQA
The CPP of the
Dosing System
can affect CQA
of protein
products
(Source: A-Mab A Case Study in Bioprocess Development 2009)
Central Canada Chapter
Aseptic Filling
September 30, 2010
31
QbD/PAT Example Three: Dosing System
(Source: A-Mab A Case Study in Bioprocess Development 2009)
Central Canada Chapter
Aseptic Filling
September 30, 2010
32
QbD/PAT Example Three: Dosing System
(Source: A-Mab A Case Study in Bioprocess Development 2009)
Central Canada Chapter
Aseptic Filling
September 30, 2010
33
QbD/PAT Example Three: Dosing System
Following investigative
studies a Design Space
for the Dosing System is
specified in terms of CPP
The CPP are measured
and controlled in real time
to maintain the operation
within the Control Space
Dark circles represent magnitude of protein aggregatation
(Source: A-Mab A Case Study in Bioprocess Development 2009)
Central Canada Chapter
Aseptic Filling
September 30, 2010
34
Developing a QbD/PAT System
Identify CQAs
Identify CPPs
Define the Design Space
Define the Control Space within the Design Space
Continuous Verification: Continuously verify operation
within the Control Space
Continuous Improvement: Continuously refine the
Control Space
Central Canada Chapter
Aseptic Filling
September 30, 2010
34
Keeping Pace with Aseptic Fill Finish Operations
in an Evolving Regulatory Environment
CONCLUSION
The evolving regulatory environment coupled with
advancements in technology provide a unique
opportunity in aseptic fill finish operations
Central Canada Chapter
Aseptic Filling
September 30, 2010
35
Keeping Pace with Aseptic Fill Finish Operations
in an Evolving Regulatory Environment
Thank-You
Central Canada Chapter
Aseptic Filling
September 30, 2010
36