1. Excipients: Unknown Unknowns, Unforeseen Failure Modes & Criticalities
Professor Brian A Carlin
Director Open Innovation FMC BioPolymer
Chair IPEC America
Quality by Design Committee

2. Excipient Knowledge Gap
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
Maker
Understanding
User
Shared
FDA
Understanding

3. Olympic Design, Titanic Outcome?
Titanic same “unsinkable” design as Olympic
Olympic had 3 collisions, retiring after 25yrs
Why Titanic failure vs Olympic (“Old Reliable”)

4. Robust Design of RMS Olympic
1911: Olympic holed in collision
Two watertight compartments flooded
BY DESIGN sailed back for repair
Validation of CQA, Unsinkable?

5. 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

6. Raw Materials/Components in Regulated Sectors
Industry
Components
Specification
Sigma
Airlines
Individually engineered
Composition
Performance
Tolerances 6σ
Chemical
(solution)
Molecular
Purity
Actives
Reagents
Food
(semisolid)
Complex variable mixtures
Nominal Composition
Pharma
(solid)
Mass produced particulates
Nominal Composition*
Purity* *pharmacopoeial
2-3σ
Excipients
(+ small scale fixed processes)

7. 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

8. Unknown Unknowns

9. Excipients & ICH Q9 Risk Assessment

10. Risk Assessment must involve suppliers
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
Excipient interaction with finished product criticality leading to unanticipated modes of failure
Known to User
Yes No
Known Knowns
Attributes known to both parties
and specified.
e.g.: C of A or Pharmacopoeial 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)
Yes No
Known to Supplier

11. Jim Michaels NIPTE/FDA Mtg 13th June 2012

12. 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.

13. 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

14. Pharma Quality issues too frequent to be Black Swans?

15. 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.

16. 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)

17. 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

18. 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

19. 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?

20. Collaboration on potential new critical material attributes

21. (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

22. Continuously Produced Excipients
Many Excipients continuously produced on 10, ,000 MT scale pa
“Batches” or “Lots” are time slices which can represent 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

23. bv

24. 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

25. Explosive Percolation
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."
The probability Ppath that there is a path between opposite sites of a L×L square lattice.

26. 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)

27. Which is more critical: aircraft engine or lavatory pump?

28. Criticality as Design Element vs System Performance Criticality

29. Suboptimal Product or Failures
Beware “Non-critical” Excipients Some more design critical than others All potentially performance critical
Excipient “non-critical”
Excipient not in DOE
Scale-up
Limited Excipient experience
No functional Spec
Suboptimal Product or Failures
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

30. is NOT evidence of no problem!
Use Control Strategy, not Design of Experiments, to manage Excipient Risk
Excipient in
DOE
(or Production)
Redesign
Product or
Specify Excipient
(CMAs)
Product
NOT
Robust
No Evidence
of Problem
CQA
Affected?
is NOT evidence of no problem!
Yes No
Using multiple DOEs to prove lack of excipient impact is counting white swans
Ranging studies useful: criticality often proportional to proximity to margin

31. Binomial Probability of Excipient Related Quality Issue
Excipient Reliability
99%
99.9%
99.99%
Trials = #excipients x #batches x #products

32. 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)

33. Closing the Excipients Knowledge Gap
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)
Supplier
Knowledge
Industry, Academic, & Regulatory
Shared
Understanding

34. 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