Excipients:Unknown Unknowns, Unforeseen Failure Modes

& Criticalities

Professor Brian A CarlinDirector Open Innovation FMC BioPolymer

Chair IPEC America Quality by Design Committee

1

Excipient Knowledge Gap

Maker Understanding

User Understanding

SharedUnderstanding

There are known knowns. These are things we know that we know.

There are known unknowns. That is to say, there are things that we know we don't know.

But there are also unknown unknowns. There are things we don't know we don't know.

Donald Rumsfeld FDA

Understanding2

Olympic Design, Titanic Outcome?

• Titanic same “unsinkable” design as Olympic

• Olympic had 3 collisions, retiring after 25yrs

• Why Titanic failure vs Olympic(“Old Reliable”)

Robust Design of RMS Olympic

• 1911: Olympic holed in collision

• Two watertight compartments flooded

• BY DESIGN sailed back for repair

• Validation of CQA, Unsinkable?

Unforeseen Failure Mode sank Titanic (and Costa Concordia)

• Design space: 4 compartment flood

• Minor tangential collision flooded 5

• Titanic stayed afloat long enough to launch lifeboats, but sinking inevitable

Raw Materials/Components in Regulated Sectors

Industry Components Specification Sigma

Airlines Individually engineered

CompositionPerformanceTolerances

6σ

Chemical (solution)

Molecular CompositionPurity

6σ ActivesReagents

Food(semisolid)

Complex variable mixtures

Nominal CompositionPurityPerformance

6σ

Pharma(solid)

Mass produced particulates

Nominal Composition*Purity* *pharmacopoeial

2-3σ Excipients(+ small scale fixed processes)

Can suppliers help identify potential failure modes?

• Challenger supplier refused to sign launch recommendation

• Told NASA not to launch shuttle below 12oC

• Not enough data on O-ring seal at lower temperatures

http://rmc.nasa.gov/archive/rmc_v/presentations/oconnor%20osma%20risk%20is%20part%20of%20nasa%20mission.pdf

Unknown Unknowns

Excipients & ICH Q9 Risk Assessment

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf

Known Knowns

Attributes known to both parties and specified.

e.g.: C of A or Pharmacopoeial attributes

Risk Assessment must involve suppliers

Unknown KnownsUnspecified 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

Yes

No

Excipient interaction with finished product criticality leading to unanticipated modes of failure

Jim Michaels NIPTE/FDA Mtg 13th June 2012

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.

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

Pharma Quality issues too frequent to be Black Swans?

http://www.pharmaevolution.com/messages.asp?piddl_msgthreadid=14162&piddl_msgid=89321#msg_89321

Raw Materials in QbD• Quality of Design

– Good raw materials will not rescue bad design– Good design does not eliminate raw material impact– Excipient risk must be managed

• Control Strategy > Design of Experiments • Do not underestimate complexity and variability

of excipients, nor complexity of finished products

• Pharmacopoeial compliance ≠ fitness for purpose

• Compliance & supply chain security alone are insufficient to manage excipient risk.

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 143-153http://ojs.abo.fi/index.php/jefc/article/view/190/176

Microcrystalline Cellulose

• MCC often miscast as “non-critical” filler to take advantage of wider SUPAC limits

• Direct Compression/Roller Compaction binder• MCC often miscast as filler or (wet) binder in

tablet/capsule granulations (rheology modifier, water manager)

• Wet binder only in Extrusion/Spheronisation• Absence of functional specifications

– Compactability, water interactivity

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Impact on susceptible products

(esp. fixed processes)Variable (so-called) immediate release profiles:-• Formulations (mcc) rate limiting on release• Inadequate disintegrant in direct compression

gives compaction dependent release• Overgranulation in wet granulation can

retard release• Sphere/pellet release (extrusion/spheronisation)

– Direct mcc-dependent release from uncoated spheres– Indirect effect on release from coated spheres if mcc

impacts size distribution & coating thickness

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Can raw materials impact excipient functionality?

• (Wood) pulps for mcc = Unknown Unknowns

• Unknown to users in absence of notification/change control

• Batch-specific pulp usage not routinely reported

• Impact unknown to maker and users• Pulp sourcing and processing is proprietary• How to measure impact of variability of a

raw material unknown unknown? 19

Collaboration on potential new critical material attributes

(Un)Predictability of Excipient Performance?

“About 25% of the time drug product manufacturers test excipient suitability for processing, using experimental (laboratory) scale batches, or pilot scale manufacturing batches. This was higher than expected.”

Greater than 70% of all respondents perform additional functionality or processability testing on excipient from a new supplier (or vendor)

PQRI Excipient Survey Findings

http://www.pqri.org/pdfs/XWG_Survey_Report_FINAL14Sep06.pdf

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Continuously Produced Excipients

• Many Excipients continuously produced on 10,000-100,000 MT scale pa

• “Batches” or “Lots” are time slices which can represent 10-1000 MT quantities

• C of A average or composite data smoothes variability and confounds multivariate analysis

• Need to access higher frequency in-process test data (intra-batch) and understand supplier process capability

22

bv

http://mediaserver.aapspharmaceutica.com/meetings/09AM/Slides/11.12.09_Thu/408%20B/0830/Bruno%20Hancock.pdf

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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!– even if excipient attribute is known and within specification

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

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

Which is more critical: aircraft engine or lavatory pump?

Criticality as Design Element vs System Performance Criticality

Excipient “non-

critical”

Excipient not in DOE

Scale-up

Limited Excipient

experience

No functional Spec

Suboptimal Product or

Failures

Beware “Non-critical” ExcipientsSome more design critical than others

All potentially performance critical

DOEs are only as good as the considered factors Impact of excluded factors will not be evaluated

DOE focus on design critical elements, e.g.:-• Rate controlling membrane• Suspending agent• Solubiliser• Disintegrant level

Control Strategy focus on potential application-specific failure modes associated with ALL excipients in formulation

Use Control Strategy, not Design of Experiments, to manage Excipient

Risk

Excipient in

DOE(or Production)

Redesign Product or

Specify Excipient (CMAs)

ProductNOT

Robust

No Evidenceof Problem

CQA Affected?

is NOT evidence of no

problem!

Yes

No

Using multiple DOEs to prove lack of excipient impact is counting white swansRanging studies useful: criticality often proportional to proximity to margin

Binomial Probability of Excipient Related Quality Issue

Excipient Reliability

Trials = #excipients x #batches x #products

99%99.9%99.99%

Does Design Space need redefining?

• The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. (ICH Q8 R2)

• Multidimensional parametric space within which acceptable quality product is obtained, Includes input material attribute and process parameter ranges. (Chatterjee, AAPS 2012)

• Multidimensional parametric space within which acceptable quality product is predicted and within which applicant proposes to operate without advance regulatory notice?– “Risks from uncertainty can be addressed in implementation

of design space• Performance Monitoring• Risk-based change control performed under firm’s quality

system”(Chatterjee, AAPS 2012)32

Closing the Excipients Knowledge Gap

SupplierKnowledge

Industry, Academic, & RegulatoryKnowledge

SharedUnderstandi

ng

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)

Excipient Risk Management

• Excipient unknowns are more likely to cause product failure than measured knowns

• Quality of Design not predictive of 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