* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Objective Risk Assessment via Asking the Right Question at
Survey
Document related concepts
Neuropsychopharmacology wikipedia , lookup
Environmental persistent pharmaceutical pollutant wikipedia , lookup
Tablet (pharmacy) wikipedia , lookup
Environmental impact of pharmaceuticals and personal care products wikipedia , lookup
Drug design wikipedia , lookup
Compounding wikipedia , lookup
Drug discovery wikipedia , lookup
Adherence (medicine) wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Transcript
Objective risk assessment via asking the right question at the right time: Knowledge based decisions for dosage form design/development/control Ken Morris, Ph.D. University Professor and Director Lachman Institute for Pharmaceutical Analysis Long Island University – Brooklyn Campus Arnold & Marie Schwartz College of Pharmacy and Health Sciences 1 Patient related failure modes as the basis for development, risk assessment and equivalence Examples Patient Failure mode Efficacy Toxicity Side effects Compliance Dosing regime Route of administration Examples of Pharmaceutical Source(s) of variability Stability (phys-chem) Cp vs. time t½ Dissolution Processing changes Company changes From where does the knowledge come? 2 Implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA) Testimony of Janet Woodcock, M.D. Before the Committee on Oversight and Government Reform United States House of Representatives, February 4, 2016 Ongoing Challenges …”Second, there is a need for more research in the generics space. Some drugs lack generic competition because there is no convincing bioequivalence test method available. … Similarly, methods for showing chemical sameness for certain complex drugs are not available…” 3 Pharmaceutical Science for Generic Drugs: The Science of Equivalence Robert Lionberger, Ph.D., 4/30/15 (slide 26) Three for the Future of NIPTE • Ensure modern manufacturing for the 5 out of 6 products that are generics • Advance the science of equivalence: – Prioritize tools and science that make equivalence evaluation clear and development easier – Product design for human use • Engage with GDUFA regulatory science 4 The Science of Equivalence: Therapeutic and Bio-Equivalence are only as good as the Pharmaceutical Equivalence • BE is limited in scope (low variability normal healthy subjects) and relies on a clear definition and understanding of the PE to be of use • Relying on BE in the absence of PE is a no-starter, TE assumes PE/BE/GMP • Hence the need to set meaningful specifications for a product before it goes to the clinic (incl. est. shelf life) • PE must be strong in prod/process understanding and inform SOP design • Pharmaceutical Equivalence needs to move from the 19thcentury classification (tablet, elixir, etc.) to 21st Century Classification – New drugs get the right CQA’s – considering patient needs and related failure modes. Same CQA’s and lot-lot variability for Generics. 5 RQRT #1: Levothyroxine Sodium Pentahydrate 6 • Symptoms vs. problems • Adherence vs. compliance – How do I know what I know? • Critique the methodology 7 Eric Duffy – CDER-FDA 8 • Impact of the Solid State on Chemical Stability: Dehydration (Solid 16.11 State Chemistry of Drugs, Byrn 1999) OXIDATION REACTIONS PRECEDED BY LOSS OF SOLVENT Although not extensively studied, there are several solid-state oxidation reactions that are preceded by and may indeed require prior loss of solvent of crystallization. CO 2– A. Dihydrophenylalanine H + NH3 dihydrophenylalanine CO –2 O2 H + NH3 phenylalanine • Impact of the Solid State: Crystalline Hydrate Classification System (Morris and Rodriguez 1993, Morris and Brittain1998) Dehydration can lead to amorphous material, new crystal structures, dehydrated hydrates which maintain the packing motif of the original structure, or mixed structures 9 Dehydration of l-TH can produce a dehydrated hydrate which maintain the packing motif of the original structure as shown Katrusiak and Katrusiak, 93(12), JPS 2004 10 Does Dehydration Precede Degradation? Control fit to Control RT / 0% O2 fit to RT / 0% O2 Does O2 Cause Degradation? Pharm Dev and Tech Vol. 20(3), pgs.314-319 May 2015 % Levothyroxine Sodium Remaining 105 100 60oC / 0% O2 fit to 60oC / 0% O2 RT / 21% O2 fit to RT / 21% O2 95 90 60oC / 21% O2 fit to RT / 21% O2 85 80 75 70 65 60 0 2 4 6 Time (Days) 8 10 11 12 So a lot was known or discoverable about levo’s properties and issues – NTI (narrow therapeutic index drug) – Very low dose, 25-300ug – Chemically labile • Stable if hydrated but oxidized if dehydrated/disordered • Processing effected stability (ala structure) – Cincinati thesis • Excipient interaction (often via pH)-thesis, Mansoor’s papers – Long PK t½ of approximately 7 days Yet products were developed and approved apparently oblivious of the prior knowledge and/or logical concerns • This illustrates the point that for generic products, the dosage form quality specs need to be developed at the preclinical or pre-biostudy stage (QTPP – Q8 -ala Q6A) • Otherwise, you can’t know what variability is due to the patient variability or PD issues instead of the variability in the dosage form? 12 What are some of the right question(s) at the right time: during development and ANDA review for levothyroxine sodium pentahydrate? • • • • • • • Development What are the patient failure modes used in product design What does the literature say about the science and API What are the CQAs Is the API chemically stable What is the solid form of the API and is it physically stable over the shelf life Does the process compromise API stability Specs and Risk Assessment • • • • • • Review Is the DH complete (including problems observed) What is the API characterization process Are the analytical methods really targeting CQAs Are the specifications relevant Are the process controls sufficient to insure integrity of the API Is the dosage form PE to the RLD 13 NTI quality classification: knowledge base development (generating “new” prior knowledge) Drug Oral Dose (mg) Stability Cp t1/2 (hr) Solubility (mg/mL) Product Recall Basis (2012 - 2016) Mol. Wt (g/mol) Prazosin 1 Light Sensitive 2.5 0.5 (HCl salt) - 383.4 Warfarin 1 Temperature sensitive 40 0.017 Super potetnt, CU, Stability 308.33 Clonidine 0.1 + 14 50 - 230.09 Valproic Acid 125 Light and Temperature Sensitive 12.5 50 Failed Dissolution 144.21 Digoxin 0.05 Light Sensitive 42 0.0648 - 580.94 Levothyroxine 0.025 168 0.000105 0.15 (salt) Subpotent, stability, (45) 776.87 Phenytoin 30 17 0.032 Failed dissolution 252.27 Isoetharine Mesylate 0.35 3.18 - 335.42 Disopyramide 100 0.0449 Failed dissolution 339.47 Light Sensitive, Oxidation Temperature sensitive Temperature sensitive + 6.7 Many more descriptors are relatively straight forward to obtain or generate 14 RQRT #2: Methylphenidate • [11-13-2014] FDA concerns about therapeutic equivalence with two generic versions of Concerta tablets (methylphenidate hydrochloride extendedrelease)Based on an analysis of data, FDA has concerns about whether or not two approved generic versions of Concerta tablets (methylphenidate hydrochloride extended-release tablets), used to treat attention-deficit hyperactivity disorder in adults and children, are therapeutically equivalent tothe brand-name drug. • In some individuals, the Mallinckrodt and Kudco products may deliver drug in the body at a slower rate during the 7- to 12-hour range. The diminished release rate may result in patients not having the desired effect. • As a result, the FDA has changed the therapeutic equivalence (TE) rating for the Mallinckrodt and Kudco products from AB to BX. This means the Mallinckrodt and Kudco products are still approved and can be prescribed, but are no longer recommended as automatically substitutable at the pharmacy (or by a pharmacist) for Concerta. 15 Methylphenidate (Clinical Therapeutics, 34(5), p1170, 2012) Therapeutically equivalent? Not always Pharmaceutically equivalent? Not really 16 What are some of the right question(s) at the right time: during development and ANDA review for methylphenidate? Development • What are the patient failure modes used in product design • What does the literature say about the API/dosage forms • What is the mechanism of modifying the release profile • What are the controls for the consistency of the modified release coating • What constitutes adherence to PE principles • What are the specs and risk assessment • • • • • Review Is the DH complete Were the patient failure modes used appropriate What’s the BE vs. the target demographic Does the level of PE cover all marketed dosage forms What is the appropriate RLD and has PE been established for it 17 RQRT #3: Mesalamine, RLD variable, generics? Asacol—Average dissolution curves for three different lots measured at (a) pH 6.5, (b) pH 6.8 (c) pH 7.2, JPS, 97(4), 4/08 Mean dissolution time as a function of the overall mean tablet coating thickness measured by terahertz pulsed imaging 18 Draft Guidance on Mesalamine It’s known that the dissolution is dependent on coating thickness, what good is BE w/o PE? 19 What are some of the right question(s) at the right time: during development and NDA or ANDA review for mesalamine? • • • • • Development What are the patient failure modes used in product design What does the literature say about the API/dosage forms What is the mechanism of modifying the release profile What are the CQAs and the controls for consistency of the modified release coating (deign space) What is the risk assessment • • • • • Review Is the DH complete What is the scale-up strategy Is the CQA monitoring technology sufficient to assess process capability Is the use test (dissolution) sufficiently powered to detect variability at the appropriate level Should a bio-waiver be possible for the RLD and/or a generic 20 RQRT #4: Fosinopril Sodium: NCE • ACE inhibitor NCE successfully developed in the 80’s • NDAs are more complicated and there’s less prior knowledge • However, using scientific principles and experience several challenges (all public) were addressed • A Chemical stability and excipient interaction illustrates RQRT principles 21 Fosinopril Sodium (JPS 88(7), 1999, p696) Hypothesized reaction pathway(s) and excipient (MgSt) interaction was tested when observed in later development Kinetics/risk analyses showed the effect was not significant to selflife 22 What are some of the right question(s) at the right time: for stability issues during development and NDA review for fosinopril sodium? • • • • • Development What are the patient failure modes used in product design What does the literature and paper chemistry say about the API What excipient interactions might be expected What applicable ICH Q6A tenets apply What are the specs and risk assessment • • • • • Review Is the DH complete Were the risks identified sufficiently explored Were the observed problems explained and supported by data/models Were corrective actions required Does the risk analysis and monitoring support the decision(s) 23 Right Question at the Right Time – Sponsors in practice • The development history/report should be a log of the rationale and, therefore, the internal science and risk assessment questions are asked at the time • Documenting unexpected or out of spec/trend results is essential in supporting decisions made and addressing related questions and “information requests” • Every development history becomes part of the institutional knowledge base and an integral part of risk assessment, reduction and/or mitigation • Adherence to the precepts of QbD and not just simple compliance with regulations and quidances is the most efficient method for quality product development • Right question at the right time should lead to “Right the First Time” approvable applications on the first cycle 24 Right Question at the Right Time - FDA in practice • FDA’s asking the right question – at the right time – critically contributes to effective and efficient development of pharmaceutical products and incorporates science and risk assessment • To ask the right question at the right time FDA needs portions of development report available for review by reviewers with the necessary ‘peer’ expertise, the earlier the better and reviewed with a mind willing to understand • Even with ICH Q8 – effective/congruent review of new drug development reports is yet to be achieved across the ICH regions, so the time is right to encourage this in the U.S. • With the formation of OPQ and the efforts to align new and generic (including biotech) CMC review processes, the QbD-QbR approach holds promise but is in need of significant attention to ensure it is really using the knowledge gained to assess risk and incorporate the principles QbD 25 From where does the knowledge come? Knowledge Bases and Knowledge Management • A Development History captured in the Development Report is the key to both guiding development and being ready for review. • Essential aspects of the development history (DH) include: – The rationale for all phases of development • Fundamental principles, prior knowledge, heuristics • Adherence (not just compliance!) to Q8 and Q6 tenets are implicit in DH – The knowledge base created and effectively curated • Makes the DH an electronic living document capturing all changes • Usage of new and prior knowledge to make decisions • Capturing of failure modes (patient/product) and sharing of knowledge between FDA review and inspection 26 What can you do with a knowledge base? Manufacturing Science in the 21st Century Pharmaceutical: A Case Study on Quality by Design 27 What can you do with a knowledge base? “Ontological informatics infrastructure for pharmaceutical product development and manufacturing” Venkatasubramanian et al., Computers and Chemical Engineering 30 (2006) 1482 An ontology is a formal, explicit specification of a shared conceptualization • Conceptualization refers to an abstract model of some phenomenon in the world by having identified the relevant concepts of that phenomenon. • Explicit means that the type of concepts used, and the constraints on their use are explicitly defined. • Formal refers to the fact that the ontology should be machine-readable. • Shared reflects the notion that an ontology captures consensual knowledge i.e. it is not private to an individual, but accepted by a group Formalizes asking the right question at the right time! 28 Summary: Needs and NIPTE/FDA Approaches • EPISTOMOLOGY – Understanding of patient failure modes • Epistemology – Objective risk assessment • Ontology – what is the “nature” of pharmaceutical knowledge and information • Methodology – How are data generated and analyzed to create new knowledge • Determination of modes attributable to pharmaceutical properties/behavior • Establishment of CQAs for design – Science of Equivalence – PE to TE, generics • Basic research in materials DF design • Establish PE for known CQAs • Specifications and controls before clinicals • ONTOLOGY – Knowledge curation and management • Curation center for scientific and prior knowledge management – generalizable, reusable • Bayesian – generate “new” prior knowledge • Tipping point analysis and opportunities – Synthesis • RQRT – Educational Initiatives • METHODOLOGY – 21st century analytical methodology and new technology – Science and Risk-based cGMPs and SOPs • Adherence directed compliance 29