An update on TGA experience with GMP clearances and an overview of the range of process improvements underway.

1. GMP Clearance Requirements for Medicines
Manufactured Overseas
Hongxia Jin
Director
Licensing & Certification, Manufacturing Quality Branch
Medical Devices and Product Quality Division, TGA
2017 ARCS Annual Conference
August 2017

2. Presentation
• Assessment of overseas manufacturers and GMP clearance
• Evidence requirements for desk top assessment
• Sponsor responsibilities
• Challenges
• Current initiatives
• Roadshows
GMP Clearance Requirements for Medicines Manufactured Overseas 1

3. Approval of Medicine Manufacturers
• All medicine manufacturers must receive an approval from the
TGA before manufacture and supply, subject to exemption
provisions and other requirements
• Approvals – demonstrate compliance to the principles of Good
Manufacturing practice
– Australian manufacturers - GMP licence
– Overseas manufacturers - GMP clearance to product sponsors
• An application must be lodged via the TGA business portal
(licence, GMP clearance or GMP certification)
GMP Clearance Requirements for Medicines Manufactured Overseas 2

4. Assessment of O/S Medicine Manufacturers
GMP clearance
• GMP Clearance process is a non-statutory mechanism used to verify
that overseas manufacturing sites comply with the principles of good
manufacturing practice
• GMP clearances are required for the purpose of ARTG registration and
listing, and continued supply once products are registered or listed
• GMP clearances are granted to Australian sponsors for a specific time period
• Two pathways to obtain a GMP clearance:
– Desk top based assessment
– TGA on-site inspection
GMP Clearance Requirements for Medicines Manufactured Overseas 3

5. GMP Clearance Data
FY 10/11 FY 11/12 FY 12/13 FY 13/14 FY 14/15 FY 15/16 FY 16/17
Clearance Applications 2,418 3,900 3,941 4,222 4,048 5,657 6,506
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
NumberOfApplications
GMP Clearance Requirements for Medicines Manufactured Overseas 4

6. GMP Clearance – Desk top assessment pathway
• If current evidence is available from a recognised regulator using an equivalent standard
and it covers the required scope, a GMP Clearance may be issued to the Australian
sponsor via desk top assessment pathway
The TGA reserves the right to undertake an inspection of an overseas manufacturing site,
irrespective of any other evidence supplied
• Evidence required will vary depending on the international agreements, location of the
manufacturer, the competent authority and complexity of the manufacturing process
– MRA assessment
– Compliance verification (CV) assessment
GMP Clearance Requirements for Medicines Manufactured Overseas 5

7. GMP Clearance - Desktop based assessment – MRA
Mutual Recognition Agreement (MRA):
• MRAs - treaties between Australia and other countries and are enforceable under
international law
• The parties to an MRA recognise and accept the certification issued by the relevant
regulatory agency in each country in relation to manufacturers located within that country.
• Evidence required for MRA assessment – GMP certificate
– The manufacturer must be located within the boarder of the MRA partner
– The manufacturer must be assessed against an equivalent GMP standard
– The inspection must be recent
– The inspection must cover the scope of the clearance application
– The manufacturer must be rated acceptable
GMP Clearance Requirements for Medicines Manufactured Overseas 6

8. GMP Clearance - Desktop based assessment – MRA
Countries which are recognised participants in an MRA (or equivalent) with Australia
Austria France Latvia Poland
Belgium Germany Liechtenstein Portugal
Canada Greece Luxembourg Singapore
Cyprus Hungary Malta Spain
Czech Republic Iceland Netherlands Sweden
Denmark Ireland New Zealand Slovak Republic
Finland Italy Norway Switzerland
United Kingdom
GMP Clearance Requirements for Medicines Manufactured Overseas 7

9. GMP Clearance - Desktop based assessment – MRA
Common “deficiencies” for MRA applications:
• Scope not supported by GMP certificate
• Human investigation medicinal GMP Certificate provided instead of human
medicines
• Expired certificate provided
• Manufacturer’s authorisation/Establishment licences provided instead of GMP
certificates
GMP Clearance Requirements for Medicines
Manufactured Overseas
8

10. GMP Clearance - Desktop based assessment – CV
Compliance Verification (CV) assessment
• Compliance verification assessments are permitted when there
is an international cooperation arrangement with the
competent authority:
 MRA regulators outside own country
 US FDA inspections
 PIC/S authorities within own country
• Compliance Verification involves a detailed assessment by the TGA of specified
documentary evidence provided by the sponsor/manufacturer
GMP Clearance Requirements for Medicines Manufactured Overseas 9

11. GMP Clearance - Desktop based assessment – CV
CV – non sterile dosage form and non sterile APIs
• Current GMP Certificate
• a copy of the most recent inspection report
• A list of all regulatory inspections conducted within the past 3 years
• Details of any regulatory actions in the past 3 years
• Site Master File, Quality Manual or equivalent
• List of products intended for supply in Australia
• GMP agreement between the sponsor and the manufacturer*
• Copy of the procedures for release for supply of products included in the Clearance application*
GMP Clearance Requirements for Medicines Manufactured Overseas
10

12. GMP Clearance - Desktop based assessment – CV
CV – Additional Evidence for sterile/biotech APIs and Sterile Dosage forms
– Every document included in the previous slide
– Validation Master Plan
– Latest Product Quality
GMP Clearance Requirements for Medicines Manufactured Overseas 11

13. GMP Clearance - Desktop based assessment – CV
CV – Evidence for QC Testing Laboratories and Contract Sterilisers:
• Current GMP Certificate or relevant ISO certificate
• a copy of the most recent inspection report
• A list of all regulatory inspections conducted within the past 3 years
• Details of any regulatory actions in the past 3 years
• Quality Manual/Laboratory Manual or equivalent
• A list of tests a laboratory is authorised to perform
• GMP agreement between the sponsor and the contract testing laboratory or steriliser*
• For botanical ingredients, evidence that authenticated standard reference materials are used
GMP Clearance Requirements for Medicines Manufactured Overseas 12

14. GMP Clearance – Desk Top Assessment Pathway
Common “deficiencies” for CV applications:
• Incomplete application:
– GMP agreement, when applicable
– A copy of the most recent inspection report
– Latest Product Quality Review (PQR), when applicable
– List and details of regulatory Inspections in the last three years
– Manufacturer's declaration for APIs (when not covered during most
recent inspection), when applicable
• Inadequate evidence supporting the scope of applications
GMP Clearance Requirements for Medicines Manufactured Overseas 13

15. GMP Clearance – Desk Top Assessment Pathway
GMP clearance assessment outcome:
• Issue a GMP clearance
• Issue a GMP clearance with condition(s), or issue a GMP
clearance with reduced scope
• Not issue a GMP clearance
GMP Clearance Requirements for Medicines Manufactured Overseas 14

16. GMP Clearance Assessment Pathways
Product / Activity
MRA Regulator
(own country)
US FDA (all locations) or
PIC/s Regulator (own country) or
MRA Regulator (outside own
country)
PIC/s Regulator (outside
own country) or
All non-PIC/s regulators or
No Certification available
Non Sterile Medicines or
non Sterile API
MRA Clearance Compliance Verification – Type B TGA on-site inspection
Sterile Medicines or Sterile
API (including biotech)
MRA Clearance Compliance Verification – Type C TGA on-site inspection
Contract Testing
Laboratories
MRA Clearance Compliance Verification – Type C TGA on-site inspection
Contract Sterilisers MRA Clearance Compliance Verification – Type D TGA on-site inspection
GMP Clearance Requirements for Medicines Manufactured Overseas 15

17. GMP Clearance – sponsor responsibilities
• Maintain evidence of GMP compliance for all overseas manufacturing
sites used in the manufacture of their registered or listed medicine and
are responsible for these nominated sites at all times
• Prior to submission, ensure that:
– All information provided in the application is accurate, current and does not contradict the
corresponding information contained within the evidence provided
– The scope of the application is relevant to the activities carried out by the manufacturing site
and is reflected in the evidence provided
– All required evidence is attached when submitting the GMP certification or clearance application
or provided to TGA directly by the manufacturer
– For GMP clearance applications, that signed and effective GMP/Quality/Technical agreements
are in place and meet the relevant requirements, if required
GMP Clearance Requirements for Medicines Manufactured Overseas
16

18. GMP Clearance – sponsor responsibilities
• During processing, ensure that:
– Any additional information or clarification requested by the
TGA during the assessment of GMP certification or clearance
applications is provided within the specified timeframe
– Any updated evidence that becomes available while the
application is under review is provided to the TGA
GMP Clearance Requirements for Medicines Manufactured Overseas
17

19. GMP Clearance – sponsor responsibilities
• Post-approval, ensure that:
– You monitor regulatory actions by any competent overseas regulatory
authority (for example, recalls, unacceptable inspection findings,
warning letters, import alerts etc.) for manufacturing sites for which you
hold an active GMP clearance
– You maintain GMP / quality / technical agreements with your manufacturers
– You notify the TGA of these regulatory actions and of any significant changes to the
manufacturing site, quality management system (QMS), products or product range where the
changes could potentially impact the GMP compliance of the site
– You submit applications for renewal of a GMP clearance at least 6 months prior to the expiry of
the current clearance, or alternatively, if evidence for a renewal is not available, request TGA
certification
GMP Clearance Requirements for Medicines Manufactured Overseas
18

20. GMP Clearance Process Improvements
Initiatives implemented since June 2015
• Improved work management system (implemented June 2015) allowing better data
analysis
• Engaged additional staff with appropriate skill set and improved training process
• Updated internal guidance, work instructions and procedures
• Developed a forecasting tool for MRA applications to assist in managing processing
times
• Implemented a streamlined process for MRA applications
• Provided regular updates on the TGA website, via tBS and TIWGG
GMP Clearance Requirements for Medicines Manufactured Overseas 19

21. GMP Clearance Process Improvements
Achievements to date
• Reduced response time for emails received via GMP Clearance mailbox: from >3 weeks to ≤ 5
days
• Eliminated the MRA backlog of applications: from 800 to on average ~100-200
• Reduced MRA average processing timelines: from 18 weeks to ≤ 6 weeks
• Revised MRA processing target and consistently met the target timeline
• Eliminated the backlog of request for GMP Clearance extensions and transfers
• Eliminated the backlog of applications awaiting to be receipted: from >500 to on average ~50
• Reduced the total number of clearance applications in the system
GMP Clearance Requirements for Medicines Manufactured Overseas 20

22. GMP Clearance - Challenges
• Incomplete CV applications or inadequate evidence
• Inefficiency in processes:
• Unable to raise online invoices for CV assessment fee
• Multiple rounds of correspondence at receipt and assessment
phase
• Backlog of CV applications
GMP Clearance Requirements for Medicines Manufactured Overseas 21

23. GMP Clearance Data – Compliance Verification
Yet to be receipted
4%
Receipt In
Progress
1%
Awaiting Payment
7%
WOE
27%
Letters of Access
to be processed
8%
Yet to be assessed
- Total
35%
Assessment In
Progress - Total
18%
CV Applications
Data current as of 03rd July 2017
Total of ~1200 CV’s
WOE -
receipt
69%
WOE-
assessment
31%
Waiting on Evidence applications
332 applications are waiting on evidence
(almost 30% of all CV’s)
22

24. GMP Clearance Process Improvements
Current Initiatives
• clearly document requirements for GMP Clearance applications
GMP Clearance Guidance
• web based assistance tool to assist applicants preparing GMP Clearance applications
GMP Clearance Application Assistance Tool (CAAT)
• redesign of online GMP Clearance application forms
GMP Clearance Interim Solution
Streamline receipt and assessment processes for CV applications
Roadshows
GMP Clearance Requirements for Medicines Manufactured Overseas 23

25. GMP Clearance Process Improvements
Revised GMP Clearance Guidance – Key updates
• Structure, look and feel – readability, ease for future update
• Application submission - Step by step guide to submitting
applications with screenshots
• Evidence - additional information about evidence requirements
split into three headings:
− Why we require it
− What you should provide
− Take particular care
• Publication to coincide with launch of redesigned e-form and CAAT
GMP Clearance Requirements for Medicines Manufactured Overseas
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26. Clearance Application Assistance Tool
(CAAT)
Scope & Timelines
• An interactive online tool to assist applicants in determining
the general evidence requirements for their GMP clearance
applications via desktop assessment pathways
• Complements the revised GMP Clearance Guidelines and
the redesigned e-forms
• Applicants will be able to access the tool directly from the
TGA website or via the new GMP Clearance application
forms
• Publication to coincide with launch of redesigned e-form and
revised GMP clearance guidance document
GMP Clearance Requirements for Medicines Manufactured Overseas 25

27. GMP Clearance Process Improvements
GMP Clearance Interim Solution – redesign of online application forms
• Improved user experience for applicants:
– reduce duplication in data entry - pre-populate information from Client database
– improved help functions
– More structured data entry
 drop down lists/pick lists/radio buttons
– display evidence based on the application types
• Improved invoicing - all fees can be selected & paid at the time of submission
• Allowing extension requests to be submitted via TBS
• Improved application management by TGA
GMP Clearance Requirements for Medicines Manufactured Overseas 26

28. GMP Clearance Process Improvements
GMP Clearance Interim Solution – redesign of online application forms – Timelines
• Internal UAT completed by TGA staff in July 2017
• External UAT by industry representatives - 10th August 2017
• Aim to launch the new form in September, coincide with the publication of
revised GMP clearance guideline and CAAT
• Short outage before the new eforms go live
• Updates will be published on TGA website
GMP Clearance Requirements for Medicines Manufactured Overseas 27

29. GMP Clearance Roadshows
Industry Information sessions
Information sessions:
• Two half day sessions to be held in Melbourne and Sydney and 1 session in Brisbane between
5-7 September
• Provide updates to the GMP clearance guidance and redesign of the current GMP clearance e-
form
• Showcase the new web-based GMP clearance application assistance tool (CAAT) to provide
greater assistance to sponsors prior to submitting GMP clearance applications
REGISTER NOW through the TGA website – CLOSES COB Wednesday 23 August
GMP Clearance Requirements for Medicines Manufactured Overseas 28

30. GMP Clearance Roadshows
Industry Information sessions
Targeted audience:
• involved in submitting and/or preparing a GMP clearance application
for medicines or APIs via the desk top assessment pathway
• sponsoring or looking to sponsor medicines which are manufactured
(or partly manufactured) overseas and require GMP clearance for
your product registration or listing
• does not include sponsors of medical devices/biologicals or sponsors who obtain a GMP
clearance via an on-site TGA inspection of an overseas manufacturing site
GMP Clearance Requirements for Medicines Manufactured Overseas 29

31. Summary
• Overseas manufacturers must be verified for compliance against the principles of good
manufacturing practice
• GMP clearances are granted to Australian sponsors for a specific time period
• GMP Clearance can be obtained by:
− Desk top assessment pathway – MRA or compliance verification
− Successful on-site TGA Inspection
• Sponsors must be aware of their responsibilities
• Note key TGA initiatives, attend industry information sessions and keep an eye on
notices published on TGA website
GMP Clearance Requirements for Medicines Manufactured Overseas 30

32. Questions?
GMP Clearance Requirements for Medicines Manufactured Overseas 31