presentation: gmp clearance requirements for medicines ...€¦ · – you maintain gmp / quality /...

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

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

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)


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 Data

FY 10/11 FY 11/12 FY 12/13 FY 13/14 FY 14/15 FY 15/16 FY 16/17Clearance 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

Num

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f App

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ions


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

G MP Clearance Requirements for Medicines Manufactured Overseas

5

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

GM P Clearance Requirements for Medicines Manufactured Overseas 6

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 - 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


8

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


9

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 - 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 - 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

GM P Clearance Requirements for Medicines Manufactured Overseas 12

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

G MP Clearance Requirements for Medicines Manufactured Overseas 13

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 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


Contract Testing Laboratories

MRA Clearance

Compliance Verification – Type C


Contract Sterilisers MRA Clearance

Compliance Verification – Type D



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 – 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


17

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


18

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 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 - 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 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

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 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


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

G MP Clearance Requirements for Medicines Manufactured Overseas 25

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 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 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 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


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


Questions?


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