B Carlin Sindusfarma 2013 1
The importance of raw material quality risk
management in QbD and its impact on the
regulated sector
A importância do gerenciamento se risco de
qualidade de materias primas no QbD e seus
impactos no setor regulado
Professor Brian A Carlin
Director Open Innovation FMC BioPolymer
Chair IPEC Americas QbD Committee
Chair IPEC Americas Excipient Composition Committee
Member USP Excipient Committee
B Carlin Sindusfarma 2013 2
International Pharmaceutical
Excipient Council
B Carlin Sindusfarma 2013 3
IPEC: Total Excipient Control
D Schoneker Pharma Times 45(3) 54-56 March 2013
B Carlin Sindusfarma 2013 4
Quality by Design: FDA 21st century cGMP
• Desired state
•A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight. Janet Woodcock, M.D. Director CDER
• From Quality by Inspection to QbD
•2σ to 6σ
• New Manufacturing Technologies
• Batch to continuous manufacturing
•Eliminate scale-up
B Carlin Sindusfarma 2013 5
QbD Distance Learning
www.qbd-dmu.co.uk
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FDASIA 2012/ANSI 363 Excipient GMP
B Carlin Sindusfarma 2013 7
Raw Materials in QbD
• Quality of Design
•Good raw materials will not rescue a bad design
•Good design minimises but cannot eliminate raw material impact
•Excipient risk must be managed
• Raw materials & components in other regulated sectors
•Do not underestimate complexity of Pharma excipients
•Do not underestimate complexity of Pharma finished products
•Do not underestimate variability of Pharma excipients
• Specification of raw materials
•Pharmacopoeial compliance is not fitness for purpose
• Design of Experiments vs Control Strategy
• Compliance & supply chain security alone are insufficient to manage excipient risk.
B Carlin Sindusfarma 2013 8
A Good Design?
• 1910: Launched
• 1911: Rammed & holed by cruiser
• 1918: Rammed & sank U-103
• 1934: Rammed & sank Nantucket lightship
• 1935: Retired after 257 transatlantic crossings
• RMS Olympic (“Old Reliable”)
B Carlin Sindusfarma 2013 9
Rearranging the deckchairs on Titanic does
not impart resistance to icebergs!
QbD: Compliance ≠ Quality
B Carlin Sindusfarma 2013 10
Raw Materials/Components
in Regulated Sectors
Industry Components Specification Sigma
Airlines Individually
engineered
Composition
Performance
Tolerances
6σ
Chemical
(solution)
Molecular Composition
Purity
6σ
Actives
Reagents
Food
(semisolid)
Complex
variable
mixtures
Nominal Composition
Purity
Performance
6σ
Pharma
(solid)
Mass
produced
particulates
Nominal Composition*
Purity*
*pharmacopoeial
2-3σ
Excipients
(+ small scale
fixed processes)
B Carlin Sindusfarma 2013 11
Engineered Systems are not perfect
B Carlin Sindusfarma 2013 12 http://rmc.nasa.gov/archive/rmc_v/presentations/oconnor%20osma%20risk%20is%20part%20of%20nasa%20mission.pdf
Incógnitas Desconhecidas
B Carlin Sindusfarma 2013 13
Black Swan Theory….
the extreme impact of certain
kinds of rare and unpredictable
events (outliers) and humans'
tendency to find simplistic
explanations for these events
retrospectively, after the fact.
B Carlin Sindusfarma 2013 14
http://mastermindmaps.wordpress.com/2010/11/22/black-swans/
Nassim Nicholas Taleb "The Black Swan:
The Impact of the Highly Improbable.” 2nd Ed. Random House Trade Paperbacks (May 2010)
C of A
Not on C of A
B Carlin Sindusfarma 2013 15
Excipients & ICH Q9 Risk Assessment
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf
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Unknowns Add to System Complexity
System
•States
•Parameters
Inputs Outputs
Known
Variability
Unknowns
???
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Excipient Unknown Unknowns
• Composition
• Functionality/Performance
• Relevance of Pharmacopoeial Attributes
•Fitness for purpose?
• Unspecified excipient attributes
•Controlled? Notified?
• True variability of specified attributes
• Criticalities in the Finished product
Carlin B, J Excipients & Food Chem 3 (4) 2012 143-153
http://ojs.abo.fi/index.php/jefc/article/view/190/176
B Carlin Sindusfarma 2013 18
Application Criticalities
• Criticality = Point of transition from one state to another:- not in ICH definition
• Excipients may unexpectedly affect CQAs if there is a criticality in the application
• Criticalities not built in by design •Unanticipated, interactions •Not always intrinsic to an excipient •Variable (scale-dependent?) •Non-linearities, discontinuities, tipping points
• Disproportionate impact if minor excipient variability interacts with a criticality!
B Carlin Sindusfarma 2013 19
Explosive Percolation
The probability
Ppath that there is
a path between
opposite sites of a
L L square lattice.
In the limit of infinite L,
Ppath becomes a step
function, jumping from 0 to
1 at pc. Such a situation
where one goes from the
impossible (Ppath=0) to the
inevitable (Ppath=1),
without ever visiting the
improbable, is called a "0-1
law" in mathematics. In
physics, this phenomenon
is called a "phase
transition."
http://www2.imperial.ac.uk/~mgastner/percolation/percolation.html
B Carlin Sindusfarma 2013 20
Examples of Criticalities
• Percolation thresholds
•Disintegrant in insoluble/hydrophobic matrix
•No wicking without contiguous network
•Non-linear tablet hardness-force profile
•Contiguous high density regions within compact
• Conflicting technological objectives
•Overgranulation
•Lubrication vs Compaction vs Dissolution
• Unidentified Critical Material Attributes
•especially with “non-critical” excipients in ‘”simple” formulations (what can go wrong?)
Percolation theory - a novel approach to solid dosage form design
Leuenberger H et al Int J P’ceutics 38 (1987) 109-115
B Carlin Sindusfarma 2013 21
Known Knowns
Attributes known to both parties
and specified.
e.g.: C of A or Pharmacopoeial
attributes
Unknowns Compromise Risk Assessment
Unknown Knowns
Unspecified Attributes which can
impact finished product
performance including CQAs.
e.g.: Variability of high volume continuously
manufactured excipients not reflected
in C of A data
e.g.: Unspecified attributes
Unknown Unknowns
.
e.g.: Attribute not critical in itself but critical
if variability impacts finished product
sensitivity or weakness
e.g.: Unspecified attributes
Known Unknowns
Undisclosed raw material
impacts, not fed back to supplier
for control or improvement of
excipient fitness
e.g.: Failure to specify fitness for purpose
requirements
(composition/functionality)
Known to Supplier
Kn
ow
n t
o U
ser
Yes No
Ye
s
No
Excipient interaction with finished
product criticality leading to
unanticipated modes of failure
B Carlin Sindusfarma 2013 22
Jim Michaels NIPTE/FDA Mtg 13th June 2012
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Excipient “non-
critical”
Excipient not in DOE
Scale-up
Limited Excipient
experience
No functional
Spec
Suboptimal Product or
Failures
Beware “Non-critical” Excipients
DOEs are only as good
as the considered
factors
Impact of excluded
factors will not be
evaluated
B Carlin Sindusfarma 2013 24
Control Strategy, Not DOE,
for Managing Excipient Risk
Excipient in
DOE (or Production)
Redesign
Product or
Specify
Excipient
Product
NOT
Robust
No Evidence
of Problem
CQA
Affected?
is NOT
evidence of
no problem!
Yes
No
B Carlin Sindusfarma 2013 25
Binomial Probability of Excipient Related Adverse Event
Excipient Reliability
Trials=#excipients x #batches x #products
99%
99.9%
99.99%
B Carlin Sindusfarma 2013 26
Dr. Laura Birou, Director of North America-IIAPS
International Institute For Advanced Purchasing and Supply
[email protected] 239-405-2800
Xavier University Global Outsourcing Conference – 2012
B Carlin Sindusfarma 2013 27
Cost of Poor Quality
($90bn @ 5-10% = $4.5-9bn*)
The Tip of the Iceberg
J DeFeo
Quality Progress 29-37 May 2001
*Pavlovic K, Božanic V
Int J Qual Res 6(1) 23-28 2012
Not including
regulatory costs!
B Carlin Sindusfarma 2013 28
Closing the Excipients Knowledge Gap
Supplier
Knowledge
Industry,
Academic, &
Regulatory
Knowledge
Shared
Understanding
Collaboration crucial
to identify:
impact of variability from
previously unspecified raw material
attributes both in new product
development and commercial
manufacturing
AND
existence of criticalities in
commercial formulations and their
susceptibility to both known and
unknown raw material attributes
(elimination of failures)
B Carlin Sindusfarma 2013 29
The Central Role of the Supply Chain in
Developing Process Understanding
Why ….. What does the supplier have to contribute ??
• Knowledge of the product itself
• Knowledge of how the product was created
• Knowledge of the how the product will behave in unexpected circumstances
• Knowledge of the how the product can be changed or improved
• Knowledge of how to specify the product
• Knowledge of the risks associated with the product
G Mahboubian-Jones FDA-Xavier Conference 2012
B Carlin Sindusfarma 2013 30
Collaboration on new critical material attributes
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Benefits of Excipient Understanding
• Adequate specification of excipients reflecting shared understanding and fitness for purpose in application.
• Regulatory recognition of supplier-user partnerships jointly reducing excipient-related risks through mutual due diligence.
Brian Carlin NIPTE/FDA Mtg 13th June 2012
Jeff Medwid NIPTE/FDA Mtg 13th June 2012
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Excipient Risk Management
• Excipient Unknowns more likely to cause product failure
• Pharmaceutically aligned excipient suppliers can identify potential failure modes related to their excipients IF they know what you are doing
• User-supplier joint due-diligence provides lowest risk basis for approval