Therapeutic Goods Regulation and the GMP Inspection Process (an inspectors perspective) GMP Forum

Greg Orders Senior Inspector Manufacturing Quality Branch 26 June 2018

The role of the TGA What we regulate The supply, manufacturing and advertising of: Æ 1) Medicines 2) Biologicals 3) Medical devices

MEDICINES

• Prescription − e.g. antibiotics, contraceptive pill,

monoclonal antibodies

• Complementary − e.g. multi-vitamins, some herbal teas,

essential oils

• Over-the-counter (OTC) − e.g. Paracetamol, lozenges, sunscreens,

some cold and flu medications

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The role of the TGA What we regulate The supply, manufacturing and advertising of: 1) Medicines Æ 2) Biologicals 3) Medical devices

• BIOLOGICALS

• Things that are made from or contain human cells or human tissues, or live

animal cells, tissues or organs.

• Human stem cells • Products derived from tissue (e.g. skin,

bone) • Products derived from cells • Products derived from both tissues and

cells (e.g. collagen scaffolds)

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The role of the TGA What we regulate The supply, manufacturing and advertising of: 1) Medicines 2) Biologicals Æ 3) Medical devices

• MEDICAL DEVICES

• Instruments − e.g. surgical tools, catheters, syringes

• Appliances

− e.g. pacemakers, defibrillators, MRI scanners

• Materials

− e.g. sterile bandages, adhesive dressings, artificial joints

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The role of the TGA What we don’t regulate

Australian Pesticides and Veterinary Medicines Authority (APVMA)

Food Standards Australia & New Zealand (FSANZ)

Australian Prudential Regulation Authority (APRA)

National Industrial Chemicals Notification and Assessment Scheme (NICNAS)

Australian Health Practitioner Regulation Agency

(AHPRA)

• veterinary medicines

• food

• health insurance

• cosmetics

• industrial chemicals

• healthcare professionals

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Market authorisation If you want to do one or more of the following: • manufacture therapeutic goods for supply within Australia or elsewhere • import therapeutic goods into Australia • export therapeutic goods from Australia • arrange for the import, export or manufacture of therapeutic goods

… you will need to apply for market authorisation through the TGA.

You must be a resident of Australia, part of a company in Australia, or conducting business in Australia.

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Market authorisation

• Once you’ve obtained market authorisation, you become known as the sponsor. • The sponsor bears all associated responsibilities and is financially liable for the

good.

Sponsor

Remember, you will have ongoing responsibilities even after approval has been given. It is a continuous process.

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Overview of the regulation of medicines

Australian Register of Therapeutic Goods (ARTG)

AUST L

Listed medicines

• No premarket evaluation BUT: • GMP approved manufacturers • pre-approved ingredients • low level indications

Lower Risk

AUST R

Registered medicines

• Premarket evaluation for: • quality • safety • Efficacy

Higher Risk

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Pre-approved ingredients: Listed

• Low risk

• Some restrictions: • Limits • Route of

administration • Plant parts, type of

preparation

• Container type • Warning statements

Ingredients database available online (https://www.ebs.tga.gov.au/).

Pre-approved ingredients

GMP

Low level therapeutic

claims

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Benefit vs. risk approach

Registered and listed medicines

LISTED (AUST L) =

lower risk REGISTERED (AUST R) =

higher risk Prescription none always

OTC a few most

Complementary most a few

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What is a complementary medicine?

Why regulate complementary medicines? • Safeguard the health of the Australian public • Manage adverse events

Complementary Medicines

Herbal medicines

Vitamins and minerals

Nutritional supplements

Homeopathic medicines

Traditional medicines

Ayurvedic medicines

Traditional Chinese

medicines Other traditional

medicines

Aromatherapy products

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Australian Register of Therapeutic Goods (ARTG)

• In most cases, when market authorisation is granted, the product is added to an electronic register of therapeutic goods that can be lawfully supplied in Australia - the ARTG.

• Provides information such as the product name, active ingredients, classification and manufacturer.

• The ARTG entry is under the sponsor’s name.

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GMP inspection process (an inspectors view)

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Prior to the inspection

q At least two weeks prior to the inspection you will be contacted by the Lead inspector.

• Site Master File requested and maybe other documents. • Review previous inspection report and close out. • Check recalls • Check ARTG • Announcement letter is sent to company confirming dates and which inspectors

will be conducting the inspection

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The inspection

• Introductions and show TGA identification

• Agenda provided

• Scope of inspection verified

• Company presentation (optional)

• Attendance record

• Daily close out (verbal) and final hard copy of observations (final day)

The OPENING meeting

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At inspection, we will look at:

• Personnel • Training • Quality System- Deviations, Change Controls, Complaints, • Annual Product reviews, Recalls, self inspections, returned goods, hygiene

and gowning, GMP Agreements, Supplier Approval, Rework, Reprocessing, Risk Management

• Production • Engineering –calibration and maintenance • Utilities- HVAC, water systems, compressed air. • Validation documents • Chemistry and Microbiology • Batch records

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Our expectations at inspection

• Be honest and open. Identify your SME’s and have them available. • Don’t use delaying tactics. • Don’t deflect or try to steer the conversation in another direction • Have documents ready- have a runner and “war room”. • Want to see manufacturing happening.

From the inspector • We have empathy as we have been there as well. • I don’t want to make people nervous or “trip” them up. • Will raise issues when found and will discuss –up to a point!! • Daily verbal close out. • Leave site with a copy of all our observations.

From the company

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Expectations at inspection

• Do demonstrate knowledge and confidence- not arrogance or defiance. • It’s not productive to argue. • It’s okay to say “I don’t know.” • Be aware of your body language.

Words to avoid

• I think… I’m not sure….. In my opinion….. As I recall….. • Honestly….. Usually….. Typically……..

Phrases to avoid • That’s the way we’ve always done it. • Off the record,………. • I shouldn’t say this but……

The company

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What does a GMP compliant company look like

• They do what they say they will do- they follow their own procedures. • Procedures are easy to follow and describe the process. • They use good science to justify their processes and investigations. • They have well established risk assessments and they don’t use these to try

and justify not following the code. • Allow staff to be involved in the inspection process. QA does not try to

dominate the process. • Value staff - training is seen as an important element of GMP. • Looking for ways to improve and understand “You never arrive” • See the inspection process as an opportunity for improvement

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Classification of Deficiencies Deficiency Few examples for illustration

CRITICAL Lack of sterilization validation Intention falsification or misrepresentation of test results or records Inadequate segregation

MAJOR Lack of appropriate validation Cleaning program not followed No or grossly inadequate air filtration

OTHER GMP issue but not classified as a critical or major. A single hand amendment to a procedure. A single missing signature on a document

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Post inspection

Post Inspection Letter (PIL) • Deficiencies issued and now classified as Critical, Major or Minor

Close Out Record

• Company responds to the deficiencies. How you are going to correct identified issues and timelines.

• Inspector reviews the close out and accepts or rejects your proposals. • Three attempts to rectify • Once all have been accepted then a final Report will be issued • The report will contain both the good and areas for improvement seen at

inspection.

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RISK Third and subsequent consecutive A1

Second consecutive A1

First A1 A2 A3

HIGH 36+reduced scope

36 24 18 12

MEDIUM 36+reduced scope

36 30 20 15

LOW 36+reduced scope

36+reduced scope

36 24 18

re-inspection frequency For medicines and API’s

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Questions?

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