TGA Laboratories Chemistry Section - Testing Program

Presentation to GMP2 Forum

Dr Bill SherwinDirector, Chemistry sectionTGA Laboratories Branch

GMP2 ForumNovember 2019

Laboratories Branch (LB): Fast facts• ~ 100 Staff; ~ 2200 samples tested per year • Operates under a Quality Management System compliant with ISO 17025 - accredited by NATA (National

Association of Testing Authorities).• All scientific sections perform essentially the same work:

• Testing of therapeutic goods to established standards• Evaluation of quality aspects for products seeking entry on ARTG• Advice – to internal and external stakeholders• Standards development (e.g. pharmacopoeial monographs)

• WHO Collaborating Centres for Drug Quality Assurance, and Vaccines & other Biologicals

Laboratories Business

Operations

Biomedicines and Influenza

Vaccines

Chemistry

Immunobiology (vaccines)

Biomaterials and

Engineering

Microbiology

Biochemistry

LB chemistry overview• 19 Staff (11 bench analysts)

• Variety of backgrounds, qualifications and experience (academic and industry).

• NATA (external) accreditation to ISO17025 for pharmaceutical analysis by various techniques

• Designated WHO Collaborating Centre for Drug Quality Assurance

• Undertakes chemical testing of pharmaceuticals, complementary medicines, OTC products including sunscreens; medicinal cannabis, chemical components of medical devices (e.g. silicone breast implants)

• Forensic-style testing of unregistered products for TGA Compliance sections

• Provides scientific advice in relation to quality aspects of medicines and medical devices (e.g. disinfectants) to regulatory areas of TGA and externally.

• Input to international standards and regulatory collaborations

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Instrumental resources• HPLCs (High Performance Liquid Chromatography)• UPLCs (Ultra High Performance Liquid Chromatography – next gen HPLC) -UV/PDA, ELSD, Refractive index,

charged aerosol detector (pending)• LCMS (Liquid Chromatography Mass Spectrometry) – quadrupole-time-of-flight, orbitrap, single quad UPLC

detector, further instrument(s) pending• GC (Gas Chromatography)• GC/MS (Gas Chromatography Mass Spectrometry) – triple-quad headspace MS• MP-AES (microwave plasma - atomic emission spectrophotometry) – for metals• Disintegration apparatus, particle counter, K-F/Autotitrator, optical rotation• Dissolution Baths (Baskets and Paddles)• UV/Vis (Ultraviolet/Visible) Spectrophotometry• IR (Infrared) Spectrometry• Cytotoxic testing facility

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LB chemistry testing programResponsive Testing

• Priority testing in response to a complaint or adverse event investigation• May lead to further ‘programmed’ testing or directly to recall of products• Includes testing of unregistered products for Compliance sections

Programmed Testing• Testing performed to investigate a potential risk of non-compliance and to monitor continuing compliance if required.• Governed by a risk management framework (in-house risk assessment tool)

Maintenance Testing• Testing to maintain accreditation, and currency with developing technologies and methods; e.g. proficiency studies,

collaborative studies • Ensures the responsiveness, robustness and reliability of testing capabilities

External Testing• Testing for external agencies such as WHO and other government organisations when resources are available, includes

standards development• WHO Collaborating Centre for Drug Quality Assurance

Supporting external agencies in Australia and overseas• Pacific Medicines Testing program -12 Pacific Island Countries, funded by DFAT; plus complaint testing

on a fee for service basis to government agencies or regional countries

• International collaboration with other regulators, WHO, pharmacopoeial organisations e.g. British/ United States/ International Pharmacopoeias (IP).

– Examples – developed specific monographs in IP; BP – lab testing support, corresponding member on BP Expert Committee; USP collaborative studies; member of International Laboratory Forum on Counterfeit Medicines (ILFCM)

• Fee for service testing for other government agencies – occasional basis:

State government agencies (health, food, law enforcement)

THC/CBD assay on medicinal Cannabis cultivation samples for Office of Drug Control

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Responsive Testing

COMPLAINTSconsumer,

practitioner, pharmacist, competitors UNREGISTERED

PRODUCTSimport intercepts; domestic seizures

ISSUESarising from

GMP Inspections

FOLLOW UPto risk issues arising from programmed

testing

ALERTSoverseas,

publications, media

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Responsive: Compliance support - import samplesProducts with scheduled ingredients – either declared or suspected• Weight loss supplements - typically contain Sibutramine and/or Phenophthalein (both Schedule 4)

• Libido supplements - mostly Sildenafil but over 45 different PDE-5 inhibitor substances have been detected in the past. All are Schedule 4 substances.

• Sports supplements - including performance enhancing peptides and SARMS

• Alerts put up on TGA website - www.tga.gov.au/alerts

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Responsive: Compliance support - locally sold products• Unregistered therapeutic products being sold and sometimes manufactured in Australia - obtained via

covert purchase or seized under warrant Sports supplements – SARMs, steroids, peptides, growth factors, (Schedule 4) stimulants e.g.

alkylamines such as DMAA (Schedule 10)

Locally manufactured products – e.g. black salve, MMS (chlorine dioxide), skin whitening products

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Responsive: Testing complaint samples

• Samples relating to consumer or practitioner complaints, adverse drug reaction reports or manufacturing concerns

– e.g. testing disintegration rates of glyceryl trinitrate sublingual tablets– resulting in recall of the affected product which was slow to

disintegrate and difficult to subdivide. Problem arose from new formulation and tablet shape.

– e.g. sunscreen testing in response to efficacy concerns

• Supporting the TGA Pharmacovigilance and Special Access Branch

GTN tablets

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Responsive: Testing of alert samples

• Carcinogenic nitrosamine contaminants detected at low ppm concentrations in ARB medicines with tetrazole ring-containing sartan drugs. Some valsartan and irbesartan products recalled.

• International regulatory collaboration for lab testing, information sharing, and harmonised international response.

• 6 nitrosamine impurities identified so far. Testing by LCMS or GCMS. Formed by trace amounts of secondary amines reacting with sodium nitrite residues, e.g.

• Requirements placed on sponsors and manufacturers see: https://www.tga.gov.au/n-nitroso-compounds-sartan-blood-pressure-medicines

Nitrosamine impurities in sartan medicines

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Responsive: Nitrosamine testing

• Alert from US FDA in July 2019 to presence of low levels of NDMA in ranitidine products. Subsequent recall of nearly all products from the marketplace in Australia (based on TGA testing results) and overseas.

• Testing by HR-LCMS. Note: GCMS not suitable as heat causes ranitidine to decompose to NDMA. TGA tested all products on our market (not all batches) in order to assess risk and inform need for recalls. Limit of 0.3ppm NDMA in API.

• https://www.tga.gov.au/tga-laboratories-testing-ranitidine-medicines

• https://www.tga.gov.au/alert/ranitidine-0

• At this stage not certain how many other medicines may contain nitrosamines.

• Nizatidine currently being tested; metformin also to be investigated.

• EMA has put a general requirement on MAHs to review and risk assess all synthetic APIs used in human medicines.

NITROSAMINE IMPURITIES IN RANITIDINE AND OTHER MEDICINES

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Programmed Testing

Complementary Medicines

OTC Medicines

Unregistered Therapeutics

Medical Devices – chemical

aspects

Prescription Medicines

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Risk based programmed testing• Assesses the risk of a therapeutic good not complying with required quality standards• Consistent with ISO 31000:Risk management – principles and guidelines• Testing projects are proposed by product areas

– Annual Workshops to discuss current and future priorities– Informed by available information and signals

• Relative risk of project proposal determined using the Risk Analysis – Programmed Testing (RAPT) tool– Assesses the proposal against 16 risk sources– Assists in prioritising proposals for testing

• Independent review of testing plan– Ensure the testing plan is appropriate, risk-based and addresses priorities of product areas

Testing of complementary (listed) medicinesCurrent or planned programmed testing projects:

– Turmeric products – adulteration, heavy metal contamination (completed)

– Issues with herbal adulteration – e.g. black cohosh, Lepidium meyenii, TCMs

– Heavy metals (arsenic, mercury, lead, cadmium) in traditional medicines

– Aconitum alkaloids in listed medicines (completed)

– Toxic alkaloids in green-lipped mussel extracts (development phase)

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Testing of complementary (listed) medicines

• Aristolochic acids are potent nephrotoxins and carcinogens found in certain Chinese herbs e.g. Aristolochia, Bragantia and Asarum spp.

• Updated condition of listing requires LCMS analysis by best practice according to contemporary scientific literature. Confirmation to TGA prior to batch release.

• Included in Schedule 10 dangerous poisons – no lower scheduling limit; current LOD in our lab = 20 ppb.

Routine testing for Aristolochic acids in TCMs

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Programmed Testing: OTC medicinesRecent and planned projects:

• Sunscreen UV absorbance testing according to ISO 24443:2012; testing content of active ingredients by UPLC.

• Compliance testing of products accepted via N2 application pathway (complies with specific OTC medicine monograph), e.g. paracetamol, bromhexine, pholcodine, ethanol hand sanitisers

• Testing generic versions of medicines to ensure quality is equivalent to innovator medicines, e.g. paracetamol +/- codeine, salbutamol products

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Testing prescription (registered) medicinesRecent and proposed programmed testing projects:

– Stability survey of Thyroxine tablets – dissolution issues

– Compliance of Enalapril products – following issues of degradations and low potency noted in PMTP testing (attributed to inadequate packaging)

– Compliance surveys of products containing particular active ingredients to confirm that quality of generic versions is equivalent to innovator medicines

– Critical medicines – sole supplier/grandfathered products e.g. GTN tablets

– Products with updated pharmacopeial requirements – check compliance

– Newly registered medicines on the ARTG – to maintain currency with latest developments in product and testing technology.

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Current and emerging issues• Nitrosamine contaminants in medicines with synthetic APIs – international approach

• Medicinal Cannabis – survey of the most highly imported products via SAS to check their quality

• Growing number of unregistered bio-active sports drugs in imported supplements or manufactured locally, e.g. SARMs, peptides.

• Cosmetic surgery products – e.g. dermal fillers (particularly imported products)

• Ongoing monitoring of heavy metals and toxic alkaloids in herbal medicines• Counterfeiting of biological and cytotoxic (cancer) drugs (high value products) – not yet observed in

Australia however growing problem overseas.

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Publishing results• Testing results are now published on the TGA website on a twice yearly basis

– see https://www.tga.gov.au/ws-labs-index

Summaries of individual testing projects e.g. alkyl nitrite testing, NDMA in ranitidine

– https://www.tga.gov.au/testing-alkyl-nitrite-poppers

– https://www.tga.gov.au/tga-laboratories-testing-ranitidine-medicines 19