Rapid Pharma Development GmbH. Impurities in the contexts of CMC Development

Transcription

1 Rapid Pharma Development GmbH Impurities in the contexts of CMC Development

2 The Challenge What is your Goal? What is your path?

3 Plan for Success Define your goal: Target Product Profile Daily dosage Cost of Goods Administration Route Define your path: Project Plan Work backwards: NDA submission, Clinical Studies, IND, Tox Studies,.. Material needs for preclinical and clinical studies

4 Drug Development Summit CTD: Common Technical Document Module 1 Regional Admin Information TOC Introduction Module 2 CMC part Overall Quality Summary non clinical Overview non-clinical Summary clinical Overview Clinical Summary Module 3 Module 4 Module 5 Quality Nonclinical Study Reports Clinical Study Reports

5 Quality Statement drugs should be safe, pure, effective and of consistent quality to ensure that they are fit to be used for their intended purpose

6 Clinical Hold Quality Concerns that cause a Clinical Hold are either e.g. 1. identification of safety concern or 2. insufficient data to evaluate safety toxic impurities (solvents, genotoxics) instability during the course of the clinical trial generating toxic impurities insufficient analytical effort

7 The Guidelines Sources on the net: Q3A(R2) Impurities in New Drug Substances Q3B(R2) Impurities in New Drug Products Q3C(R4) Impurities: Guideline for Residual Solvents

8 Impurities Organic Manufacturing Origin sm, intermediates, reagents, byproducts Storage Origin (Degradants) hydrolysis (acidic, basic), oxidation, thermal >0.05 % have to be reported in phase I rrt >0.1% identified, response factors known Typically HPLC with UV detection to quantify these

9 Special Cases Solvents (Q3C) Inorganics (metals, salts, glass, charcoal) Genotoxics (draft guidance Dec 2008) Enantiomers (considered as known impurity, but qualification of high levels possible) Polymorphs (solid state form has to be controlled, bioavailability is effected)

10 Solvents PDE based Click on to 10 edit g daily Master dosage title style Acetonitrile 4.1 mg/day (410 ppm) daily dosage 500 mg -> up to 0.82 wt% acceptable Class I don t use: Benzene, CCl4 Class II: control THF 7.2 mg/day NMP 5.3 mg/day Class III: 0.5% MTBE, EtOAc, Ethanol, Propanol

11 Genotoxics Terminology PGI potentially genotoxic impurity: Compounds with Structure Alerts Genotoxic Compound: Compounds that cause damage to DNA Mutagenic: DNA impact that is tranferred from cell to cell Genotoxic and Mutagenic: Ames Test and other assays Carcinogenic: long term studies -> genotoxic = potential carcinogen

12 Genotoxic Levels TTC threshold Click toxicological edit Master concern title style 1.5 μg/d ->1 g 1.5 ppm FDA: Draft Guidance Dec 2008 EMA: CPMP/SWP/5199/02 June 2006

13 Decision Tree

14 Structural Alerts

15 Not all Alerts are positive

16 Influence of Chemists Try to avoid Genotoxic Impurities

17 Salt Formation: Mesylates Source: Teasdale et al. Org. Process Res. Dev. 2010, 14,

18 Alkylhalides Generally: The presence of a strong acid together with an alcohol may generates a PGI. E.g. HBr as byproduct in a condensation reaction If early in a synthesis typically these PGI are purged. Late in the synthesis may be a concern In all cases develop suitable analytical methods LS-MS GC-MS are typical work horses Q. Yang et al. Org. Process Res. Dev., 2009, 13, pp

19 Genotoxic as reagents How to avoid dibromoethane! but then what about the Styrene oxide? And how did they make 16? Butters et al. Chem. Rev. 2006, 106,

20 Aromatic Anilines B. Mayes et al. Org. Process Res. Dev., 2010, 14 (5), pp

21 Hidden PGI hydrolysis Byproduct itself may not be detected as PGI, but on stability or during next steps, or drug product manufacturing wet granulation, the PGI may rebuild.

22 Stability Studies S. Raillard et al. Org. Process Res. Dev., 2010, 14 (4), pp

23 Generics Quelle: D.D. Wirth, B.A. Olsen, D.K. Hallenbeck, M.E. Lake, S.M. Gregg und F.M. Perry, Chromatographia, 1997, 46,

24 Excipients Excipient Povidone, crospovidone polysorbates Magnesium stearate, fixed oils, lipids Lactose Benzylalcohol Polyethyleneglycol Microcrystalline Cellulose Starch Talc Dibasic calcium phosphate dihydrate Stearate lubricants Hydroxypropyl methyl/ethyl cellulose Residue (Impurity) Peroxides Antioxidants Aldehydes, reducing sugars Benzaldehyde Aldehydes, peroxides, oeganic acids Lignin, hemicelluloses, water Formaldehyde Heavy metals Alkaline residues Alkaline residues Glyoxal Source: Crowley, P.J.; Martini, L.G.; Drug-Excipient Interactions, Pharmaceutical Technology Oct 2001

25 Conclusion A chemist should aim to avoid PGI as reagents, starting materials, byproducts, synthetic intermediates Generics and Excipients should receive more attention by regulatory agenices Analytical Methods can only find what you are looking for Stability Studies: Degradants may also form PGI Recommended Reading: D. Snodin Org. Process Res. Dev., 2010, 14,

26 Conclusion Drug Master File Chemistry Manufacturing Control Knowledge and Experience Don t build your house without an architect

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28 The architects Dr. Dieter Krimmer Managing Partner at RPD Project Manager at Roche Track Record: Tamiflu, Saquinavir, Tenovovir, Nelfinavir, Viread Dr. Robert Hett Managing Partner at RPD Site Manager at Carbogen Senior Scientist at Sepracor, USA Track Record: Bortezomib, Arformoterol