Overview of Impurities

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1 Overview of Impurities Regulatory and GMP aspects presented by Dr Clive Simon The SPD Company 2 September 2014

2 Definition Substances that provide no therapeutic benefit but have potential to cause adverse effects Unwanted chemicals that remain with API or drug product formulations

3 What you don t know can hurt you. There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we know we don't know. But there are also unknown unknowns. There are things we don't know we don't know Don't blame the boss. He has enough problems Donald Rumsfeld CV 1976 CEO G. D. Searle & Company, led legalization of Aspartame to 1993 CEO of General Instrument 1997 to 2001 Chairman of Gilead Sciences USA Defense Secretary

4 Impurities need to be controlled during: Product Development Manufacture API / drug substance Manufacture drug product Registration Dispensing Consider the product examples in relation to this..

5 Example: Budesonide Plastic ampoule, air sensitive, suspension of API with excipients

6 Example: Adalimumab PFS mab

7 Sources of impurities Limits Identification, qualification, quantification Guidelines Reporting Registration details Testing methodology Reference standards Genotoxicity Toxicology

8 Sources of Impurities What are likely sources of impurities for Adalimumab and Budesonide? -Active Pharmaceutical Ingredient

9 Sources of Impurities What are likely sources of impurities for Adalimumab and Budesonide? -Active Pharmaceutical Ingredient Traditional Synthetic impurities (starting materials, reaction by-products, intermediates, reagents, ligands and catalysts) Inorganics and heavy metals Residual solvents (synthesis, crystallisation) Others Stereo-isomers and enantiomers Polymorphs Other materials (e.g. filter aids, charcoal) Microbial (bacterial, viral, prions) Biotech products: Host cell DNA and protein, endogenous retroviruses Herbal substances

10 Sources of Impurities What are likely sources of impurities for Adalimumab and Budesonide? -Drug Product

11 Sources of Impurities What are likely sources of impurities for Adalimumab and Budesonide? -Drug Product Organic degradants (hydrolysis, oxidation, photolytic cleavage. decarboxylation, racemisation, excipient and packaging reactions) Organic synthetic impurities Inorganics and heavy metals Process related (granulating solvents, lyophilisation dissolution liquids) Packaging related (leachables and extractables) Microbial contamination (bacterial, viral, prions)

12 Identification, qualification, quantification -How do we set limits for Adalimumab and Budesonide?

13 Identification, qualification, quantification -How do we set limits for Adalimumab and Budesonide? Toxicology, Non-clinical and Clinical testing/trials conducted using API with inherent impurities. Predict impurities from manufacturing process, interaction with excipients, If impurities profile changes when commercial batches made (NCE or Generic) then this has to qualified. Harmful impurities in drug product controlled to below regulated limits. Impurity Detection Isolation Characterisation

14 Identification, qualification, quantification How do we set limits for Adalimumab and Budesonide? Drug Product: ICH Q3B(R2)

15 Identification, qualification, quantification How do we set limits for Adalimumab and Budesonide? Drug Product: ICH Q3B(R2)

16 Identification, qualification, quantification How do we set limits for Adalimumab and Budesonide? API (Drug Substance): ICH Q3A(R2)

17 Identification, qualification, quantification How do we set limits for Adalimumab and Budesonide? API (Drug Substance): ICH Q3A(R2)

18 Identification, qualification, quantification How do we set limits for Adalimumab and Budesonide? Residual solvents: ICH Q3C

19 Identification, qualification, quantification How do we set limits for Adalimumab and Budesonide? Residual solvents: ICH Q3C Class I avoid; Class II daily exposure, Class III 50 mg/day

20 How do we set limits for Adalimumab and Budesonide? -Toxicology considerations

21 How do we set limits for Adalimumab and Budesonide? -Toxicology considerations ICH Q3A limits are insensitive to highly toxic chemicals ICH Q3B does not address impurities from excipients or leachables ICH Q3B does not cover biopharmaceuticals, peptides, oligonucleotides, fermentation products, radiopharmaceuticals, herbal semi-synthetics, animal or plant origin, polymorphs and enantiomers.

22 How do we set limits for Adalimumab and Budesonide? -Toxicology considerations Prescribing and consuming medicines involves risk / benefit assessment 5% risk of treatment related tumour acceptable when life-saving chemotherapy used Drug impurities are pharmaceutical pollutants Degradation product is qualified if present at comparable or higher levels in safety and clinical trials, or is a metabolite. Residual solvents: PDE = (NOEL x weight adjustment) / (Fanimal extrap x Finter-indiv var x Fstudy duration x Ftoxicity severity)

23 How do we set limits for Adalimumab and Budesonide? -Genotoxicity considerations

24 How do we set limits for Adalimumab and Budesonide? -Genotoxicity considerations Genotoxins are harmful at low concentrations therefore special limits apply May be mutagenic and cause cancer Inconsistent requirements from different organisations and expert position papers Demonstrated genotoxic in appropriate test model Reactive materials for synthesis can interact with DNA Herbal substances need to be assessed Threshold of Toxicological Concern (TTC)

25 How do we set limits for Adalimumab and Budesonide? -Genotoxicity considerations Source: Agilent primer on Genotoxic impurities in pharmaceutical products PGI = Potential Genotoxic Impurity

26 Testing methodologies -How do we test for impurities in Adalimumab and Budesonide?

27 Testing methodologies -How do we test for impurities in Adalimumab and Budesonide? Type of Impurity Organic Inorganic / elemental / trace metals Residual solvents Bioburden Extractables / Leachables Biologicals Genotoxicity Technologies FTIR, Preparative LC, HPLC-UV/RI/MS, UV, NMR, SFC, Capillary electrophoresis, Forced degradation studies, Extraction and purification. Polymorphism: XRF. Enantiomeric: chiral column. ICP-OES, ICP-MS GC-FID/MS BET, microbial HPLC/GC/ICP Immunogenicity, RNA, DNA, Stray proteins, Prions, Viruses, Peptide sequence Ames, Repeat dose toxicity

28 What reference standards would we use for impurities in Adalimumab and Budesonide?

29 What reference standards would we use for impurities in Adalimumab and Budesonide? Reference standards Source Chemical Biotechnological (e.g. biosimilar, cell therapy, gene therapy) Herbals Radiopharmaceuticals Characterised Primary reference or working standards? Purchased or synthesised? Correction factors (e.g. UV detector)

30 How do we integrate the impurities data into Adalimumab and Budesonide submissions?

31 How do we integrate the impurities data into Adalimumab and Budesonide submissions? Complementary Medicine (Listed) Application for a new listable substance Prescription Medicine and OTC CTD module 3.2.S S P P P.2, 3.2.P.8, 3.2.P.7 or 3.2.S P.7 Impurities in API Stability of Drug Substance Characterisation in Drug Product Stability of Drug Product (degradation, leachables, extractables) Forced degradation (mandatory in Australia) Container leachables and extractables

32 What guidelines would we consult regarding impurities in Adalimumab and Budesonide?

33 What guidelines would we consult regarding impurities in Adalimumab and Budesonide? ICH Q2(R1) Q3A(R2) Q3B(R2) Q3C(R5) Q3D Q5A to E Q3D Method validation New substance/api New drug products Residual solvents Heavy metals (under development) Biologicals Elemental impurities TGA Relevant adopted ICH guidelines Relevant adopted EU guidelines Relevant TGO s Q6A M7 SR(R1) Specifications New Drug Substances and Drug Products (Chemical) Assessment and Control of DNA (Mutagenic) Impurities Genotoxic testing EMEA/CPMP/QWP/251344/2006 Genotoxic impurities limits

34 What guidelines would we consult regarding impurities in Adalimumab and Budesonide? BP/Ph.Eur. Individual drug substance, product and excipient monographs General monographs (Parenteral preparations (0520), glass, plastic containers and elastomers (3.2.1, 3.2.2, 3.2.9) USP Individual drug substance, product and excipient monographs <237> <232> <233> Heavy metals <467> Residual solvents <1> Injections <660><661> Glass and plastic containers <351> Elastomeric closures FDA Guidance for Industry Q3B(R2) July 2006 (Draft): Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches (2008)

35 Drug product manufacture GMP Product development API manufacture

36 Product Development GMP Controls -What part of the product development would we do under GMP to control impurities in Adalimumab and Budesonide?

37 Product Development GMP Controls -What part of the product development would we do under GMP to control impurities in Adalimumab and Budesonide? Level and identification of Impurities at the start should be in the biobatch and commercial batches. Source: FDA Perspective on Approaches for Complying with CGMPS During Phase I INDs, Laurie Norwood, FDA, CBER, 2006

38 Product Development GMP Controls -What part of the product development would we do under GMP to control impurities in Adalimumab and Budesonide? QbD QTPP, CQA TGA Adopted EU guidelines TGO s BP Individual drug substance, drug product and excipient monographs General monographs

39 Product Development GMP Controls -What part of the product development would we do under GMP to control impurities in Adalimumab and Budesonide? FDA HEALTH CANADA USP Individual drug substance, drug product and excipient monographs General monographs Individual product monographs Phase 1 IND Products (manufacture in accordance with cgmp 21CFR 210, 211 and ICH Q7A, Draft FDA guidance) Meet Reference Profile for raw material testing Do not need to retest synthetic impurities in finished products. Exclude from total impurity limits Establish that impurities can be controlled with test or compendial methods

40 Manufacturing GMP Controls -What part of the manufacture of Adalimumab and Budesonide impacts on impurities?

41 Manufacturing GMP Controls -What part of the manufacture of Adalimumab and Budesonide impacts on impurities? AREAS OF GMP COVERING IMPURITIES Specifications, test methods and analytical validation (drug substance, drug product, excipients, container materials) Identification and qualification (including chiral and polymorphs) Stress tests, impurity profiles and stability Laboratory structure and processes Contamination control, including personnel Control of raw materials, components and excipients Control of production services, e.g. water system, gases (air, nitrogen), steam Manufacturing process from receipt to shipping

42 Manufacturing GMP Controls -What part of the manufacture of Adalimumab and Budesonide impacts on impurities? API Impurities are specifically mentioned in a number of clauses of PIC/S cgmp, incl: Receipt and testing of raw materials (7.22) Residue control (8.50) API specifications (11.13) and testing (11.21 /11.22) Process validation (12.44 / 12.52) Reworking (14.32) Cell culture manufacture (18,17) Note: All parts of the API and drug product cgmp are geared towards controlling impurities. Glossary (20) Drug Product Only specific mention of impurities is in stability program (6.23)

43 Impurities control- - it s all about risk assessment Is all this effort worth it?

44 2014The SPD Company Pty Ltd

45 Thanks..for attending this Seminar! (If you enjoyed it, tell others, if not, please tell us).

Regulatory expectations on impurities in drug substances - Pavia, October 2, Luisa Torchio Euticals SpA

Regulatory expectations on impurities in drug substances - Pavia, October 2, 2015 Luisa Torchio Euticals SpA An Impurity is defined as any substance or element present in a drug substance (DS) that is