The importance of raw material quality risk management in QbD and its impact on the regulated sector

Transcription

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 brian.carlin@fmc.com B Carlin Sindusfarma

2 International Pharmaceutical Excipient Council B Carlin Sindusfarma

3 IPEC: Total Excipient Control D Schoneker Pharma Times 45(3) March 2013 B Carlin Sindusfarma

4 Quality by Design: FDA 21 st 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

5 QbD Distance Learning B Carlin Sindusfarma

6 FDASIA 2012/ANSI 363 Excipient GMP B Carlin Sindusfarma

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

8 A Good Design? 1910: Launched 1911: Rammed & holed by cruiser 1918: Rammed & sank U : Rammed & sank Nantucket lightship 1935: Retired after 257 transatlantic crossings RMS Olympic ( Old Reliable ) B Carlin Sindusfarma

9 Rearranging the deckchairs on Titanic does not impart resistance to icebergs! QbD: Compliance Quality B Carlin Sindusfarma

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

11 Engineered Systems are not perfect B Carlin Sindusfarma

12 Incógnitas Desconhecidas B Carlin Sindusfarma

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

14 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

15 Excipients & ICH Q9 Risk Assessment B Carlin Sindusfarma

16 Unknowns Add to System Complexity Known Variability Inputs System States Parameters Outputs Unknowns??? B Carlin Sindusfarma

17 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) B Carlin Sindusfarma

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

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." B Carlin Sindusfarma

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) B Carlin Sindusfarma

21 Known to User Yes No 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 Excipient interaction with finished. product criticality leading to unanticipated modes of failure e.g.: Attribute not critical in itself but critical if variability impacts finished product sensitivity or weakness e.g.: Unspecified attributes Known Knowns Attributes known to both parties and specified. e.g.: C of A or Pharmacopoeial attributes Yes 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 B Carlin Sindusfarma No

22 Jim Michaels NIPTE/FDA Mtg 13 th June 2012 B Carlin Sindusfarma

23 Beware Non-critical Excipients 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 Scaleup Limited Excipient experience B Carlin Sindusfarma

24 Control Strategy, Not DOE, for Managing Excipient Risk Excipient in DOE (or Production) Redesign Product or Specify Excipient CQA Affected? Yes Product NOT Robust No No Evidence of Problem is NOT evidence of no problem! B Carlin Sindusfarma

25 Binomial Probability of Excipient Related Adverse Event Excipient Reliability 99% 99.9% 99.99% Trials=#excipients x #batches x #products B Carlin Sindusfarma

26 Dr. Laura Birou, Director of North America-IIAPS International Institute For Advanced Purchasing and Supply Xavier University Global Outsourcing Conference 2012 B Carlin Sindusfarma

27 Cost of Poor Quality 5-10% = $4.5-9bn*) *Pavlovic K, Božanic V Int J Qual Res 6(1) Not including regulatory costs! The Tip of the Iceberg J DeFeo Quality Progress May 2001 B Carlin Sindusfarma

28 Closing the Excipients Knowledge Gap Supplier Knowledge Shared Understanding Industry, Academic, & Regulatory Knowledge 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

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

30 Collaboration on new critical material attributes B Carlin Sindusfarma

31 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 13 th June 2012 Jeff Medwid NIPTE/FDA Mtg 13 th June 2012 B Carlin Sindusfarma

32 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 B Carlin Sindusfarma