GMP Obligations for Small and Medium Enterprises (SMEs): Therapeutic Goods regulation and the GMP inspection process: An inspector’s perspective

1. Therapeutic Goods Regulation and the GMP
Inspection Process (an inspectors
perspective)
GMP Forum
Greg Orders Senior Inspector
Manufacturing Quality Branch
26 June 2018

2. 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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3. 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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4. 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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5. 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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6. 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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7. 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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8. 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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9. 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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10. 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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11. 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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12. 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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13. GMP inspection process
(an inspectors view)
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14. 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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15. 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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16. 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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17. 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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18. 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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19. 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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20. 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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21. 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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22. 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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23. Questions?
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