Beware the non-critical excipient

Transcription

1 Beware the non-critical excipient Dr Brian A Carlin Director Open Innovation, Chair IPEC QbD Committee brian.carlin@fmc.com ExcipientFest

2 Understand your raw materials ExcipientFest

3 Managing the impact of raw material variability on CQAs Formulation & process design must accommodate raw material variability (robustness) Design space should demonstrate acceptability of raw material impact on CQAs Design Space (optional) > Experience Space Balance impact of raw material variability between DOE, risk management & control strategy ExcipientFest

4 Balancing assessment of raw material variability on CQAs What do you do experimentally in Development? DOE What do you NOT do in Development? Insignificant, improbable, detectable risks acceptable (initially) Contingencies Control Strategy o Foreseeable events - Scale-up - Expansion of raw material experience space - Change control o Unforeseen events - Continual Monitoring ExcipientFest

5 Any questions? Please contact your local FMC* representative for more details * or FMC distributor Additional global contacts: Dr. BRIAN CARLIN Director of Open Innovation brian.carlin@fmc.com Tel.: (609) (USA) BRUNO LECLERCQ Global Appl. Dev. Manager bruno.leclercq@fmc.com Tel. (32) (BEL) DHARM VAHALIA Global Brand Manager dharm.vahalia@fmc.com Tel.: (267) (USA) ExcipientFest

6 QRM continues through Product Lifecycle & formulation & monitoring ExcipientFest

7 Excipients & ICH Q9 Risk Assessment ExcipientFest

8 Excipients as Knowledge Gap Supplier Knowledge Shared Understanding Industry Knowledge Collaboration is 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) Samples Data Expertise aims to bridge the knowledge gap ExcipientFest

9 Understanding impact of raw material variability on CQAs Good design minimizes impact of known material attributes Design around known attributes Appropriate excipient sourcing and grade selection Unknown unknowns Unspecified attributes (beyond CofA/Pharmacopoeiae) Raw material attribute interacting with unknown criticality in design (formula and/or process) ExcipientFest

10 ICH Criticality = Importance/Relevance Korea_Sep_07/Day_1/Industry_perspective_-_Thomas_Schultz.pdf ExcipientFest

11 MIL-STD-1629a Definition ExcipientFest

12 Assumption of non-criticality Suboptimal Product or Failures Excipient noncritical Excipient not in DOE DOEs are only as good as the considered factors Impact of excluded factors will not be evaluated No functional Spec Limited Excipient experience Scale-up ExcipientFest

13 Critical(ity) Definitions 3(of a situation or problem) having the potential to become disastrous; at a point of crisis: having a decisive or crucial importance in the success or failure of something: 4 Mathematics & Physics relating to or denoting a point of transition from one state to another Derivatives Criticality o Noun (sense 3), (sense 4). ExcipientFest

14 Application criticalities? Excipients may unexpectedly affect CQAs if there is a criticality in the application Criticalities not built in by design Unanticipated, interactions, scale-up Not always intrinsic to an excipient Variable (scale-dependent?) Non-linearities, discontinuties, tipping points Disproportionate impact if minor excipient variability interacts with a criticality! No evidence of problem in DOE is NOT evidence of no problem ExcipientFest

15 Critical Micelle Concentration ExcipientFest

16 Categorisation of Excipients is no substitute for Critical Thinking Non-critical vs critical excipients Pharmacopoeial compliance fitness for purpose Functional categorisation Intrinsic material attributes impact on specific formulation Process-activated vs attribute-dependent functionalities All models are wrong, some are useful Unknowns vs Knowns ExcipientFest

17 Leverage Supplier Expertise Samples Data Expertise Samples Data Expertise Representing FMC s operating space Physical and functional attributes On-time, every time! Formulation science OSDF process technology Process control Regulatory implications ExcipientFest