Rapid Pharma Development GmbH
Impurities in the
contexts of CMC
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The Challenge
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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, ..
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Drug Development Summit
Module 1 Regional Admin
Information
Module 3 Module 4 Module 5
TOC Introduction CMC part Overall Quality Summary non clinical Overview non-clinical Summary Quality Nonclinical Study Reports Clinical Study Reports Module 2
CTD: Common Technical Document
clinical Overview
Clinical Summary
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Quality Statement
drugs should be safe, pure,
effective and of consistent quality to
ensure that they are fit to be used
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Clinical Hold
Quality Concerns that cause a Clinical Hold
are either
1. identification of safety concern or 2. insufficient data to evaluate safety
e.g.
• toxic impurities (solvents, genotoxics)
• instability during the course of the
clinical trial generating toxic impurities
• insufficient analytical effort
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The Guidelines
Sources on the net: www.ich.org
• Q3A(R2)
•
Impurities in New Drug Substances
• Q3B(R2)
•
Impurities in New Drug Products
• Q3C(R4)
•
Impurities: Guideline for Residual
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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
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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• Inorganics (metals, salts, glass, charcoal) • Genotoxics (draft guidance Dec 2008)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)
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Solvents
• PDE based on 10 g daily dosage
– 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
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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
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Genotoxic Levels
TTC threshold toxicological concern
1.5
μ
g/d ->1 g 1.5 ppm
FDA: Draft Guidance Dec 2008
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Decision Tree
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Structural Alerts
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Not all Alerts are positive
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Influence of Chemists
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Salt Formation: Mesylates
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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
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Genotoxic as reagents
How to avoid dibromoethane!
but then what about the Styrene oxide?
And how did they make 16?
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Aromatic Anilines
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Hidden PGI
• 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.
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Stability Studies
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Generics
Quelle: D.D. Wirth, B.A. Olsen, D.K. Hallenbeck, M.E. Lake, S.M. Gregg und F.M. Perry, Chromatographia, 1997, 46, 511-523
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Excipients
Source: Crowley, P.J.; Martini, L.G.; Drug-Excipient Interactions, Pharmaceutical Technology Oct 2001
Excipient Residue (Impurity)
Povidone, crospovidone polysorbates Peroxides
Magnesium stearate, fixed oils, lipids Antioxidants
Lactose Aldehydes, reducing sugars
Benzylalcohol Benzaldehyde
Polyethyleneglycol Aldehydes, peroxides, oeganic acids
Microcrystalline Cellulose Lignin, hemicelluloses, water
Starch Formaldehyde
Talc Heavy metals
Dibasic calcium phosphate dihydrate Alkaline residues
Stearate lubricants Alkaline residues
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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, 960-976
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Conclusion
Manufacturing
Chemistry
Control
Drug Master File
Knowledge and Experience
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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
