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 MEDICINES The supply, manufacturing • Prescription and advertising of: − e.g. antibiotics, contraceptive pill, ˘ 1) Medicines monoclonal antibodies 2) Biologicals 3) Medical devices • Complementary − e.g. multi-vitamins, some herbal teas, essential oils • Over-the-counter (OTC) − e.g. Paracetamol, lozenges, sunscreens, some cold and flu medications 2
The role of the TGA What we regulate • BIOLOGICALS The supply, manufacturing and advertising of: • Things that are made from or contain human cells or human tissues , or live 1) Medicines animal cells , tissues or organs . ˘ 2) Biologicals 3) Medical devices • 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) 3
The role of the TGA What we regulate • MEDICAL DEVICES The supply, manufacturing • Instruments and advertising of: − e.g. surgical tools, catheters, syringes 1) Medicines 2) Biologicals • Appliances ˘ 3) Medical devices − e.g. pacemakers, defibrillators, MRI scanners • Materials − e.g. sterile bandages, adhesive dressings, artificial joints 4
The role of the TGA What we don’t regulate • veterinary medicines Australian Pesticides and Veterinary Medicines Authority (APVMA) • food Food Standards Australia & New Zealand (FSANZ) • health insurance Australian Prudential Regulation Authority (APRA) • cosmetics National Industrial Chemicals Notification and Assessment Scheme (NICNAS) • industrial chemicals • healthcare professionals Australian Health Practitioner Regulation Agency (AHPRA) 5
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. 6
Market authorisation Sponsor • 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. Remember, you will have ongoing responsibilities even after approval has been given. It is a continuous process. 7
Overview of the regulation of medicines Australian Register of Therapeutic Goods (ARTG) AUST L AUST R Listed medicines Registered medicines • No premarket evaluation BUT: • Premarket evaluation for : • GMP approved manufacturers • quality • pre-approved ingredients • safety • low level indications • Efficacy Lower Risk Higher Risk 8
Pre-approved ingredients: Listed • Low risk Pre-approved ingredients • Some restrictions: • Limits • Route of administration GMP • Plant parts, type of preparation • Container type • Warning statements Low level therapeutic Ingredients database claims available online (https://www.ebs.tga.gov.au/). 9
Benefit vs. risk approach Registered and listed medicines LISTED (AUST L) = REGISTERED (AUST R) = lower risk higher risk none always Prescription a few most OTC most a few Complementary 10
What is a complementary medicine? Complementary M edicines Herbal Vitamins and Nutritional Traditional Homeopathic Aromatherapy medicines products medicines minerals supplements medicines Traditional Ayurvedic Other traditional Chinese medicines medicines medicines Why regulate complementary medicines? • Safeguard the health of the Australian public • Manage adverse events 11
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 . 12
GMP inspection process (an inspectors view) 13
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 14
The inspection The OPENING meeting • 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) 15
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 16
Our expectations at inspection From the company • 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. 17
Expectations at inspection The company • 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…… 18
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 • 19
Classification of Deficiencies Deficiency Few examples for illustration CRITICAL Lack of sterilization validation Intention falsification or misrepresentation of test results or records Inadequate segregation M AJOR Lack of appropriate validation Cleaning program not followed No or grossly inadequate air filtration OTHER GM P issue but not classified as a critical or major. A single hand amendment to a procedure. A single missing signature on a document 20
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. 21
re-inspection frequency For medicines and API’s RISK Third and Second First A1 A2 A3 subsequent consecutive consecutive A1 A1 HIGH 36+reduced 36 24 18 12 scope M EDIUM 36+reduced 36 30 20 15 scope LOW 36+reduced 36+reduced 36 24 18 scope scope 22
Questions? 23
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