Published on May 15, 2010
Design & Control of Pharmaceutical Products & Processes: FDA’s PAT Guidance Ajaz S. Hussain., Ph.D. Previously a champion at FDA (2000-2004) for the FDA Initiatives on Process Analytical Technology and Pharmaceutical Quality for the 21st Century Currently; Vice President Biological Systems Research Philip Morris International, R&D, Neuchatel, Switzerland May 11, 2010. Bethesda , Maryland
Outline Background Motivation for the FDA’s PAT Initiative What has been achieved? Challenges that remain Key questions Is bio-processing, and the regulatory approach for biologics, more conducive for PAT/QbD? How does appropriate comparability assessment of biologics provides a means to avoid the Popperian trap? Has the FDA’s PAT Guidance outlived its utility? A way forward Ensure applications of new technologies in drug development and manufactruing are not automatically placed on a regulatory critical path
Background Motivation for the FDA’s “PAT Initiative” What has been achieved? Challenges that remain
FDA’s PAT Initiative: Vision 2020 One piece of the puzzle – a “door opener” Pharmaceutical Quality for the 21st Century Critical Path Initiative “Risk” based decisions based on mechanistic knowledge Collaborative vocabulary Design focused (QbD) Mechanistic understanding Knowledge a basis for regulatory flexibility Design space Enhance collaboration between CMC Review & CGMP Inspection functions http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt#288,28,A Perspective on PAT: One piece of the puzzle
Motivation For The FDA‘s PAT Initiative
What Has Been Achieved? Consensus on the “desired state” of Pharmaceutical Quality in the 21st Century ICH Guidelines: Q8, Q9, Q10 An active and growing global technical community Increasing number of publications; rapid growth in biopharmaceutical sector Wide recognition of the available opportunities http://graphics.eiu.com/files/ad_pdfs/eiu_ORACLE_ PHARMA_WP.pdf
Manufacturers Slowly Embracing PAT/QbD A 2008 Survey “In four years since 29% no plans to start either PAT/QbD the ICH outlined the 15% doing PAT as part of a broader QbD effort concept of design 16% who say they have focused on PAT efforts space in its Q8 first and are now doing QbD, and guideline, 15% who plan to launch PAT but not QbD pharmaceutical companies – despite depending on 31% do not use process capability analysis. innovation for their Who use SPC are mainly using univariate livelihood – have methods - pharmaceutical manufacturing is been slow to adopt inherently multivariate Quality by Design (QbD)” Paperless recordkeeping is still a ways off at Ronald D. Snee, February most drug manufacturing facilities. 2009 | Pharmaceutical Processing http://www.futurepharmaus.com/Default.aspx?mc=Manufacturers- slowly&page=fpt-viewarticle
What Challenges Remain? Regulatory approaches have not evolved adequately - high regulatory uncertainty: PAT Vs. QbD Specification set after completing the clinical trials & based on compendial standards The concept of “design” and “design space” have not been clearly understood Limited utility of prior knowledge in regulator decisions
Key questions Is bio-processing, and the regulatory approach for biologics, more conducive for PAT/QbD? How does appropriate comparability assessment of biologics provide a means to avoid the Popperian trap*? Has the FDA’s PAT Guidance outlived its utility? *Reference Manual on Scientific Evidence. Federal Judicial Center 2000 http://bulk.resource.org/courts.gov/fjc/sciman00.pdf
Is bio-processing, and the regulatory approach for biologics, more conducive for PAT/QbD? Intrinsically systems based – Systems Biology an opportunity Appropriate comparability assessment avoids procrustean standards and illustrates a way to avoid the Popperian trap Team approach to CMC review and CGMP inspections
Systems Biology: An opportunity for PAT based bioprocess development Osmolarity pH Temperature A Gene > mRNA > Protein B Nutrition Genome Sequences Antibiotics Shear stress Pressure Transcriptome Genetic Network “Environome” Protoeome Metabolic Network Metabolome Fluxome Target Exp. Cell Physiology Bioprocess & Metabolic. Engg. Kinetics Bioproducts Environome Eng. Life. Sci. 6: 455-469 (2006) Engineering
Appropriate Comparability Assessment: A Means to Avoid the ‘Popperian Trap’? “Simply put, the Agency adopts an empirical approach to the fundamental regulatory questions of safety and effectiveness” “Theories about mechanism of action of a drug or disease mechanisms play important parts…but they are entirely subsidiary….” “These conclusions cannot, in the typical case, be predicted, nor can they be arrived at by an “understanding” of the underlying events, an understanding that must always remain incomplete (and, importantly, incomplete in ways that are unknown to us).” R. Katz. The American Society for Experimental NeuroTherapeutics. Vol. 1, 307–316, July 2004
EMEA Guidelines: Prior Knowledge in the Development of a Biosimilar Erythropoietin EMEA Guideline on Similar Biological Medicinal Products. http://www.emea.europa.eu/pdfs/human/bi osimilar/043704en.pdf (Accessed 29 November 2009) Guidance on Similar Medicinal Products Containing Recombinant Erythropoietin http://www.ema.europa.eu/pdfs/human/bio similar/9452605en.pdf (Accessed 29 November 2009) EPAR Binocrit® http://www.ema.europa.eu/humandocs/PD http://www.sandoz.com/assets/content/en/product_range/biosimilar_pr Fs/EPAR/binocrit/H-725-en6.pdf esenation/Pioneering_Global_Development_of_Biosimilars_BIO_2008 (Accessed 29 November 2009) _FNa_FINAL.pdf
EMEA Guidelines: Prior knowledge in the development of a biosimilar erythropoietin Prior knowledge ⇒ Regulatory & Other Recommendations Process design for a comparable active ingredient, adequate control of process • Human erythropoietin structural & and related impurities, viral clearance, (per ICH guidelines) role. Product design – special attention to formulation and delivery device • Physico-chemical and biological methods are available Clinical Efficacy Reference product, • Expression system – mammalian cells • Efficacy and safety in renal anemia may Analytical Characterization & allow extrapolation to other Design specifications • All epoetins in clinic- similar amino acid indications. seq. endogenous but differ in the • Comparable efficacy in at least two Plan for an integrated & adequately powered, double blind iterative development & glycosylation pattern. randomized, parallel group trials. comparability assessment • Glycosylation influences PK and may affect efficacy and safety • Both routes: IV & SC Design to be comparable!! • Current therapeutic indications • Trials should include “correction phase” • Same mechanism of action • Non-clinical Wide therapeutic window Clinical Safety Pharmacodynamics • Route of administration & different dose • Comparative safety data from efficacy trials Comparative bioassays considerations • 12-months comparative immunogenicity • Usually well tolerated provided data pre-authorization Toxicological studies stimulation of bone marrow is controlled • Sensitive and validated method for anti- • Variability in the rate of hemoglobin At least one repeat dose toxicity epoetin antibodies increase and know factors & local tolerance Pharmacovigilance Plan Clinical PK • Exaggerated PD –complications • Routine & additional pharmacovigilance Comparative -Single dose (IV • Anti-body induces PRCA in renal anemia • Risk minimization activities and Sc). Equivalence margins patients – SC route. Incidence rate very • For example: PRCA, Tumor growth Clinical PD low to be detected pre-approval potential, Thrombotic vascular events, and Part of PK, consider dose- • Possible angiogenic & tumor promoting Potential off-label use response curve Italics – additional recommendations (author)
Has the FDA’s PAT Guidance Outlived its Utility? No, the PAT Guidance outlines regulatory principles which are not optimally incorporated into ICH Q8; for example: “In the absence of process knowledge, when proposing a new process analyzer, the test-to-test comparison between an on- line process analyzer and a conventional test method on collected samples may be the only available validation option.” “In some cases, this approach may be too burdensome and may discourage the use of some new technologies” “A focus on process understanding can reduce the burden for validating systems by providing more options for justifying and qualifying systems …..” http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf
Without the PAT Guidance Document … New knowledge can be paralyzing The ability to measure brings with it the responsibility to explain In a complex organizational setting it is often difficult to find a champion who will take on this challenge in an uncertain regulatory environment The PAT Guidance provided a regulatory solution to such a challenge
Critical Path Initiative: Biomarker Qualification Janet Woodcock, M.D. Deputy Commissioner/Chief Medical Officer January 28, 2007 http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/default.htm
Mechanistic Understanding of Safety http://iccvam.niehs.nih.gov/meetings/10thAnnivSymp/Woodcock.pdf
Biomarker Qualification: Contributing Role of Mechanistic Understanding? Utility of mechanistic understanding within the FDA can get stuck in the ‘Popperian trap’ http://iccvam.niehs.nih.gov/meetings/10thAnnivSymp/Woodcock.pdf
A Way Forward…… Ensure applications of new technologies in drug development and manufacturing are not automatically placed on a regulatory critical path Reduce regulatory uncertainty Avoid “PAT Vs. QbD” perceptions, team effort, training,.. Leverage the comparability approach & the US biosimilar pathway as an opportunity to illustrate how to avoid the ‘Popperian trap’ Consider summarizing accepted prior-knowledge for regulatory decision-making
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