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GMP clearance for overseas manufacturers

Book pagination

16 May 2011

2. GMP Clearance application requirements

Figure 1 - Overview of the GMP clearance process

Figure 1 - Overview of the GMP clearance process (pdf,93kb)

Text version of Figure 1

This text representation of this flowchart is provided as a list with numbered steps.

  1. 2.1 Requirement for GMP Clearance application
    A separate application is required for each sponsor and for each overseas manufacturing site. Applications are required for renewals, changes to scope, changes to steps of manufacture and major facility changes.
  2. 2.2 Pathways for obtaining GMP Clearance
    Assessment of an application is based on the following evidence:
    • Mutual Recognition Agreements (MRA)
    • Compliance Verification (CV)
    • a TGA on-site audit (Applications for a TGA audit will not be accepted while an MRA or CV assessment is in progress.)
  3. 2.3 Identify and obtain required documentation
    The extent of the review process increases with product risk and the complexity of manufacture.
    Refer to Tables 1(a) and 1(b).
  4. 2.4 Submit electronic Clearance application and pay application fees
    Refer to Appendix E and the current 'schedule of fees' at Schedule of fees and charges. Additional fees may be payable if the TGA is requested to obtain evidence from an overseas regulator or if the application is subject to a CV.
  5. 2.5 and 2.6 TGA assessment
    • If requested submit additional information (Go to Step 5)
      TGA may request additional information. Application may be rejected if information is not supplied within due dates. Assessment timeframes can be found in appendix I
    • Ineffective application (Go to Step 5)
      If the application is ineffective and requested information cannot be presented, the TGA will notify the sponsor of a proposal not to issue a clearance and provide the sponsor the opportunity to respond.
  6. Clearance Letter or GMP Certificate
    Sponsor is issued a GMP Clearance letter following a successful MRA or CV assessment or a TGA on‑site audit. A Certificate of GMP Compliance may be issued to the manufacturer on request following a successful TGA on-site audit.

2.1. GMP Clearance application requirements

GMP Clearance

GMP Clearances are required for all the steps of manufacture of registered and listed medicinal products (including APIs used for the manufacture of registered products) before the products can be supplied in Australia.

Although the TGA does not currently require sponsors to submit Clearance applications for APIs used in listed medicines or registered over-the-counter (OTC) and complementary medicines, sponsors must ensure that any step of manufacture undertaken outside of Australia is undertaken in GMP compliant facilities. Evidence of licensing or approval of the manufacturer of the API(s) does not need to be submitted to the TGA unless it is an intermediate product (eg premixes).8

Renewing a GMP Clearance

GMP Clearances relating to overseas manufacturers are provided for a specified period and have an expiry date. Sponsors must therefore apply periodically to renew their clearances for overseas manufacturing sites for as long as they continue to use that manufacturer. This permits the TGA to review the manufacturing and quality controls and provide continuous confidence to the public of the manufacturer's compliance with relevant international GMP standards.

Changes to a GMP Clearance

The TGA expects sponsors to remain vigilant in ensuring the regulatory compliance of the overseas manufacturing sites they use. When a sponsor becomes aware of a need to change or renew a GMP Clearance, a new application with all required documentation must be submitted, and applicable fees paid.

Examples of circumstances where a sponsor may need to amend or cancel a GMP Clearance include:

  • If products are transferred between sponsors; an amendment of the Clearance must be requested within 3 months from the date of transfer.
    • Where products on the ARTG have been transferred to another sponsor, the new sponsor must provide the details of all affected clearances (products, Manufacturers Information System (MIS) clearance numbers etc.) and enclose a letter from the transferring sponsor indicating assent to the clearance transfers. A copy of any sale/transfer agreement may also be acceptable.
    • Each sponsor must have a GMP agreement with each manufacturer with whom they have a direct relationship.
    • There is no need to submit a new clearance application as long as the clearances in question are current.
      Note: There is currently no fee attached to this change.
  • A change in the trading name of an overseas manufacturer following a change in ownership.
    • Sponsors should provide a copy of the certificate of registration or a letter from the registrar in the manufacturer's country confirming the change of name9.
  • Changes in the scope of manufacture of the existing GMP Clearance, for instance where the Current GMP Clearance is for the manufacture of hard capsules and the sponsor now wishes to include soft gel capsules.
    • A new GMP Clearance application must be submitted. Fees are payable.
  • New manufacturing site or a new manufacturing facility at the existing site.
    • A new GMP Clearance application must be submitted if manufacture for supply to Australia is to occur at the new site/facility. Fees are payable.
  • Supply of products from the manufacturing site ceases.
    • The sponsor should notify the TGA GMP Clearance Unit in writing and the clearance will be cancelled.
      Note: There is currently no fee attached to this change.
  • Significant new manufacturing steps, or significantly different technology, in the manufacture of an existing product on the ARTG where the overseas manufacturer has current GMP Clearance approval that does not include the new steps or technology. (e.g. fermentation in addition to chemical synthesis for an API Manufacturer).
    • A new GMP Clearance application must be submitted. Fees are payable.
  • A reduction in the scope of a GMP Clearance may be required where the manufacturing site decommissions facilities, or has ceased manufacture as a result of regulatory actions by an overseas agency. Sponsors should monitor their manufacturers and communicate these changes to the TGA promptly.
      • The sponsor should notify the TGA GMP Clearance Unit in writing and the clearance will be amended.
        Note: There is currently no fee attached to this change.

Extension of a GMP Clearance

A short term extension (generally 3 to 6 months) to a GMP Clearance may be granted under certain circumstances at the request of a sponsor. The circumstances might include for instance when an inspection has taken place (or is scheduled to take place) and there is a delay in the issuing of the GMP Certificate and/or inspection report. Documentation indicating the scope of the proposed inspection is relevant and should be supplied to the TGA when the application for extension is made.

Applications should be made to the GMP clearance unit.

The reasons for the extension must be clearly set out and relevant supporting documentation provided. Sponsors should not expect that the TGA will grant an extension where the application is made after the Clearance has expired.

Where an inspection report or other documentation received after an extension has been granted is found by the TGA to be unacceptable, any extension to a GMP Clearance previously granted may be cancelled.

2.2. Pathways for obtaining GMP Clearance

A GMP Clearance of an overseas manufacturer will always be based on the assessment of evidence of GMP Compliance that includes a recent inspection of the manufacturer by a competent regulatory agency.

There are three procedures used to grant a GMP Clearance:

  • under a Mutual Recognition Agreement (MRA);
  • through Compliance Verification (CV); or
  • after a TGA on-site audit.

The available procedure for assessment will depend on:

  • whether the TGA has agreements with the regulatory agency that has inspected a manufacturing site;
  • where the site is located;
  • the TGA's level of confidence of compliance with an equivalent Code of GMP demonstrated by the evidence submitted by the sponsor;
  • the type of product(s) or manufacturing steps undertaken at the site; and
  • the timing of the inspection.

GMP Clearances issued under a Mutual Recognition Agreements (MRA)

In accordance with international agreements with certain countries, the TGA accepts compliance of an overseas site with the local GMP requirements based on a current GMP Certificate issued by the regulatory agency of the other party to the MRA.

Clearance may be granted by the TGA on the basis of a current GMP Certificate issued within the scope of a MRA agreement.

MRA-based assessments are limited to GMP Certificates issued for manufacturing sites located within the borders of the other party to the MRA.

The scope of the manufacturing activities for which approval is sought in the Clearance application should be within the scope of the activities covered by the GMP Certificate.

A list of countries with which Australia has an MRA or equivalent is contained in Appendix B

GMP Clearances issued through GMP Compliance Verification (CV)

Compliance Verification involves a detailed assessment by the TGA of specified documentary evidence supplied by the manufacturer/sponsor.

The assessment will include a review of recent inspection reports of the relevant manufacturing site undertaken by a competent overseas regulatory agency together with other available regulatory information. Compliance verifications are permitted wherever the TGA has an international cooperation arrangement, such as a memorandum of understanding or PIC/S membership.

The documentation required for these assessments is listed in Tables 1(a) and 1(b) below.

More detailed assessments are undertaken for higher risk products or if the inspection reports from overseas regulatory agencies identify marginal GMP compliance.

TGA on-site audit

If a sponsor is unable to provide current documentary evidence of acceptable GMP compliance for an overseas manufacturer, or if the TGA's assessment of evidence does not support a GMP Clearance, the TGA will advise the sponsor of the need to conduct an on-site audit. Clearance will be granted by the TGA if the audit concludes that the facility operates at an acceptable level of GMP compliance.

Note: Onsite audits cannot be cancelled by the submission of a desktop application within three months of the scheduled audit date.

2.3. Identify and obtain the required documentation

The following tables set out the assessment methods available and documentation required for the assessment of GMP Compliance for medicines and APIs where a step in the manufacturing process is undertaken outside Australia.

Table 1(a) identifies the method of assessment and applicable list of evidence required (Evidence List) where a Compliance Verification is required. Note that GMP Clearances are required where contracted laboratory and sterilisation services are engaged to support the release of a product or API.

Table 1(a) - Required assessment type

Current Certification

Product/Activity

MRA Regulator
(own country)
US FDA
(all locations)
or
PIC/S Regulator
(own country)
or
Medsafe
(in New Zealand)
or
MRA Regulator
(outside own country)
PIC/S Regulator
(outside own country)
or
All non-PIC/S Regulators
or
no certification
Listed
medicines
(see note below)
MRA Clearance
Evidence List A
Compliance Verification
Evidence List B
TGA on-site audit
Registered medicines
(non-sterile)
MRA Clearance
Evidence List A
Compliance Verification
Evidence List B
TGA on-site audit
API
(non sterile)
Registered medicines
(sterile)
MRA Clearance
Evidence List A
Compliance Verification
Evidence Lists B and C
TGA on-site audit
API
(sterile and biotech)
Contract
testing laboratories
MRA Clearance
Evidence List A
Compliance Verification
Evidence List D
TGA on-site audit
Contract sterilisers

Note: A TGA on-site audit will usually be required where the sponsor's listed or registered medicine is not regulated by the regulatory agency of the country in which the manufacturing site is located. Complementary Medicines and Traditional Chinese Medicines are commonly not regulated as medicines in other countries.

Table 1(b) lists the specific documents required for the Compliance Verification assessment. Explanatory notes for some of these documents are set out in Appendix C.

Table 1(b) - Documentary evidence requirements
Reqired Evidence Comments/Exclusions
Evidence List A Current GMP Certificate.
(GLP for testing laboratory, certification to relevant ISO Standards for sterilisation facility).
Certificates must be sufficient to cover the scope of the Clearance application.

Evidence List B

Compliance Verification for: APIs (other than sterile and biotech)

Non-sterile and listed medicines

Current GMP Certificate.10 GMP agreements may be requested if the overseas manufacturer performs the release for supply function.

A list of all regulatory inspections conducted within the past 3 years and a copy of the most recent inspection report.

(Processing can be expedited if reports for two or more of the above inspections are provided).

Inspection reports must be applicable to the scope of the application. These may be sent to the TGA directly from the manufacturer.
Details of any regulatory actions in past 3 years. For example, product alerts, warning letters, import alerts, recalls due to defects.
Site Master File, Quality Manual or equivalent. Not required if the scope of the application is only for the step of release for supply.
GMP agreement between the sponsor and the manufacturer.

Only applicable to products and related steps of manufacture in the Clearance application.

Not required for APIs unless requested.

List of products intended for supply in Australia.
Copy of the procedures for release for supply of products included in the Clearance application).

Not required for APIs unless requested.

An applicant may also be requested to provide a Validation Master Plan or Product Quality Review (applicable to Finished Product medicines included in the Clearance application).

Evidence List C

Compliance Verification for:

Finished sterile medicines

Sterile and biotech APIs

Validation Master Plan. Not required if the scope of the application is only for the step of release for supply.
Latest Product Quality Review. Applicable to APIs listed in the Clearance application only.

Evidence List D

Contract testing laboratories

Contract sterilisers

Current GMP Certificate.

For contract testing laboratories a Good Laboratory Practice (GLP) certificate issued by a recognised Regulatory Authority or a current ISO 17025 accreditation certificate may be used in lieu of a GMP Certificate.

For contract sterilisation facilities certification to applicable ISO sterilisation standards (eg ISO 11137, ISO 11135) may be used in lieu of a GMP Certificate.

A list of all regulatory inspections conducted within the past 3 years, and a copy of the most recent inspection report.

(Processing can be expedited if reports for two or more of the above inspections are provided.)

Inspection reports must be applicable to the scope of the application. These may be sent to the TGA directly from the manufacturer.
Details of any regulatory actions in past 3 years. For example, product alerts, warning letters, import alerts, recalls due to defects.
Quality Manual/Laboratory Manual or equivalent.
GMP agreement between the sponsor and the contract test laboratory or steriliser. For contract test laboratories and 3rd party sterilisation companies sub-contracted by an overseas manufacturer, a contract/ agreement may not exist with the Australian sponsor. A copy of the agreement between the manufacturer and contract test laboratory should be submitted in such a case.

A list of tests a laboratory is authorised to perform.

For botanical ingredients, evidence that authenticated standard reference materials are used.

For contract testing laboratories only.

Note: Adequate supervisory control of contract testing laboratories or contract sterilisers by a principal manufacturer through a validated supplier qualification process may be accepted on a case-by-case basis. In such cases, the same expiry period will be assigned as for the "principal manufacturer". If a TGA on-site audit is required of the principal manufacturer then this may also include an audit of the contract test laboratories under its supervisory control.

General documentary requirements

Documentary evidence must adhere to the following requirements:

  • all certificates and other supporting documents must be in English or supplied with a certified translation into English;
  • translated documents must be accompanied by a signed and dated statement, by the certified translator, stating that it is a true and accurate translation of the original document;
  • documents must be the most recent and reflect current manufacturing conditions and practices and dated (expired/superseded documentation cannot be used);
  • documents must provide sufficient information to cover the scope of dosages for which clearance is sought; and
  • documented evidence must be unambiguous, clearly demonstrating that the overseas manufacturer operates with an adequate level of GMP Compliance (ambiguous material will be disregarded).

All documents are to be submitted electronically and are not required to be certified as original copies unless requested by the TGA. Certification of a document may be requested if for example, there was concern over the validity of the supplied documents.

The TGA can request certified copies of original documents at any time. Certified copies must be legible and authenticated as true copies by any one of the following:

  • an official of the regulatory agency of a country that is a party to an MRA or is a Memorandum of Understanding (MOU) partner;
  • an Australian embassy or consulate office; or
  • a Justice of the Peace, Public Notary or a lawyer, solicitor or accountant (include details of the relevant practice certificate or licence number).

The following is an example of a declaration that should appear on the front page of the document being certified:

Declaration of Authenticity

As a ...... for the state of (xxxxx), (country xxxxx), I declare that the attached copy of the document issued by (xxxxx) (certificate) is a true and accurate copy of an original certificate presented to me for review.

Signed (xxxxx) Date (xxxxx)

GMP Certificates

GMP Certificates provided with an application must be:

  • current, and whenever possible, should be not more than two years since the date of the last inspection in order to avoid a short expiry date on a GMP Clearance;
  • for the products, APIs, steps of manufacture and/or dosage forms requested in the GMP Clearance application; and
  • clear in identifying the expiry date and the name of the person authorised to issue the certificate and be duly signed and dated.
  • For MRA-based applications, GMP Certificates must also be:
  • issued by a regulator of an overseas country that is a party to the MRA; and
  • relate to a manufacturing site located within the borders of that country.

Where the sponsor has been unable to obtain the GMP certification issued by the MRA country, the sponsor may request that the TGA attempt to obtain evidence from the relevant MRA regulator. An additional fee is payable for this service.

Manufacturer's declarations for Active Pharmaceutical Ingredients

Sometimes various types of APIs are produced using similar manufacturing processes and the same quality system. A GMP Certificate for a site issued by another overseas regulatory agency may only list one or some of the APIs which are of interest to the country inspecting the site.

The TGA therefore permits a sponsor to submit a declaration consisting of a dated and signed letter from the manufacturer that the API for which a clearance is sought is manufactured by the same process, in the same plant and under the same quality system as those specified on a GMP Certificate. The form for a manufacturer's declaration is in Appendix D (Manufacturer's Declaration for APIs).

If such a declaration cannot be submitted in these circumstances, a TGA on-site audit may be required.

Documents for a TGA on-site audit

A TGA on-site audit of an overseas manufacturer will be required where:

  • the evidence supplied is inadequate to support clearance for supply to the Australian market, or
  • where there has not been a recent inspection by a recognised competent regulatory agency covering the scope of the GMP Clearance application, or
  • where GMP compliance was rated as unacceptable by another regulatory agency.

After receiving an application, but prior to confirming an audit, the TGA will require the Site Master File (SMF). The sponsor should ensure the manufacturer supplies a current, up-to-date SMF.

The SMF provides an overview of the manufacturer, its manufacturing activities and its quality system. The SMF is necessary to allow effective planning of the audit.

Guidance for preparing a SMF can be found in PIC/S document PE 008, Explanatory Notes for Industry on the preparation of a Site Master File.

Sponsors may submit other documents from the manufacturer, such as a Plant/Equipment File or a Quality Manual, which individually or collectively provides the same details.

Where the TGA will be undertaking an initial audit in a non-English speaking country, English translations/versions of the following will be required:

  • Site Master File
  • Validation Master Plan.
  • Deviation/Out of Specification Procedures.
  • Release for Supply Procedures.
  • Product Quality Reviews (as requested).

For any subsequent TGA audit, a list of products (with batch numbers) manufactured over the last 2 years for Australia will also be required.

The TGA lead auditor may request other documents prior to commencing an audit overseas.

Sharing of documentary evidence between sponsors and manufacturers

To reduce the regulatory burden on industry and avoid unnecessary re-assessments of clearance applications, the TGA has established Manufacturer Master Files in a limited number of cases. By employing a Manufacturer Master File an overseas manufacturer may be invited to submit all necessary documentation for GMP Compliance Verification (of a site) on behalf of multiple sponsors. Information from the overseas manufacturer is then passed directly to the TGA on an ongoing basis. This removes the need for Australian sponsors to obtain such documentation in order to support a Compliance Verification application.

It should be noted that, in order to maintain ongoing Clearance of a site, the sponsor is still required to submit a fully funded application in the normal manner. This must include a copy of the relevant GMP contract (where required).

The manufacturer may provide a letter of access for any Australian sponsor seeking clearance for products manufactured at the relevant site. The letter of access must identify the manufacturer's profile number.

If an applicant provides written authority from another sponsor to allow the TGA to refer to an existing GMP Clearance, an additional clearance for the site can be issued if the scope of the application is consistent with the scope of the existing GMP clearance.

If an applicant provides written authority from another applicant for a GMP clearance to allow the TGA to use evidence submitted in the latter's application, the TGA will refer to the evidence and a normal assessment will be conducted.

Note: Each Sponsor must obtain their own separate GMP Clearance and pay the relevant fees.

2.4. Submit application and pay fees

Lodging an application for clearance by MRA and Compliance Verification

Sponsors applying for a GMP Clearance must complete the Overseas Manufacturer Clearance application found on the TGA online business system - eBusiness (eBS).

Note: New users will need to establish an eBS account - refer to Appendix E.

The online system allows the progress of an application to be tracked by the Sponsor and the TGA. For assistance contact the TGA - GMP Clearance Unit by email at .

To complete a GMP Clearance application the following requirements are essential:

  • the full legal name of the manufacturer;
  • the street address and workshop details (eg building or plant number) of the manufacturing site (a P.O. Box is not acceptable);
  • the standard to which the manufacturer complies in relation to the required dosage form (product) or API (eg PIC/S, ISO 11137 etc);
  • a description of the products or types of products (dosage forms) in sufficient detail to be able to verify the relevance of the clearance request;
  • the steps of manufacture undertaken at the site;
  • the date of last inspection of the electronically attached GMP Certificate (if this date is unknown, enter a date earlier than the application date);
  • a visible and legible signature and date for signed documents; and
  • Dosage Form selected in the drop down menus within eBS.

Copies of GMP Certificates and any other documents required to support the application are to be submitted electronically. A file size of 100MB is available and files may be zipped. Paper copies may be accepted if they cannot be submitted electronically.

An electronic application checklist is provided in Appendix F which is to be attached to the application.

Failure to provide adequate GMP evidence

Where applications that are lodged with incomplete or missing documentation and where the sponsor has not been able to provide the requested documents within a reasonable time period after being requested by the TGA, the application may be rejected.
In such a case a letter of rejection will be sent to the sponsor (or its agent).

Note: Application fees will be forfeited where an application is rejected.

Payment of application fees (for MRA and CV)

A TGA invoice will be generated as part of the online application process. This invoice can be printed off and payment should be made as per the instructions provided on the invoice.

Once the application fees are paid, the application can be assessed and processed.

Lodging an application for a TGA on-site audit

Simultaneous applications for a GMP Clearance by Compliance Verification and a TGA audit are not permitted. Where an application has been made for both, the application for the on-site TGA audit will not be considered.

Sponsors applying for a TGA on-site audit must complete the Application for On-site Audit for Certification which can be found on the TGA online business system - eBusiness (eBS).

The online system allows the progress of an application to be tracked by the sponsor and the TGA. For assistance contact the TGA Office of Manufacturing Quality by email at .

Fees for TGA on-site audit

There is no application fee for a TGA on-site audit. When the audit is scheduled, the sponsor will be advised of the audit fees that will be payable. The basis of calculation of the fees can be found on the Schedule of fees and charges page.

The audit will commence only after payment of the applicable fees.

Schedule of fees

The current 'Schedule of fees' includes details of the following charges:

  • overseas manufacturers GMP Audit Fee (this covers the issuing of a GMP Clearance to the sponsor and GMP Certification to the manufacturer);
  • assessment of GMP evidence in support of a GMP Clearance application (fees for an assessment using evidence from MRA will be different from those for a Compliance Verification);
  • fee for obtaining evidence from an overseas regulatory agency (also referred to as a 'liaison fee') which is applicable if the sponsor requests the TGA to obtain evidence of GMP Compliance from the regulator in an MRA country;
    • Please note this service is only available if the manufacturer is located within the boundaries of the relevant MRA country.
  • reinstatement of an expired GMP Clearance approval.

The TGA is fully cost-recovered and collects its revenue primarily through fees and charges for the application, evaluation, audit and assessment.

The TGA is conscious of the costs associated with its regulatory responsibilities and is continually seeking to contain these costs through improvements in both efficiency and effectiveness.

2.5. TGA assessment

Target timeframes

The following targets for dealing with GMP Clearance applications enable orderly processing and assessment. The TGA is usually able to meet these targets unless the level of compliance demonstrated in the evidence supplied is low or there are delays in receiving any additional documentation requested. The relevant period starts when the TGA has received the application, supporting data and fees.

Any application for a GMP Clearance that is not accompanied by correctly completed documentation will be considered ineffective and the sponsor will be notified within 20 working days (with forfeiture of the fees paid).

Where a GMP Clearance involves Compliance Verification of documentary evidence, the processing and assessment time will vary, depending on the risk of the products or substances manufactured, the manufacturing steps and the level of compliance identified in the most recent GMP Inspection Report supplied.

A schedule of the target timeframes for the different types of assessments and tasks is available in Appendix I

2.6. Outcomes of TGA assessment

Clearance approval

Once a GMP Clearance application has been assessed and considered to be acceptable, the TGA will update the status of the application to 'Approved'. Sponsors are able to view this status through eBS.
A notification letter of the clearance approval will be mailed to the applicant.

GMP Certification

Where a TGA on-site audit has found acceptable compliance, a GMP Certificate will be issued and mailed to the manufacturer.

Conditional Clearance

Where marginal compliance has been demonstrated through the Compliance Verification process or other issues have been identified, the TGA may grant a conditional GMP Clearance. The conditions may relate to the scope of the GMP Clearance or the expiry date, and/or may stipulate that the next GMP Clearance will only be granted following a successful outcome of an on-site TGA audit.

Rejection of an application

If the TGA determines that the evidence available does not demonstrate that the manufacturer complies with relevant GMP standards the sponsor will be notified of the deficiencies and provide the sponsor with the opportunity to respond.

If the GMP Clearance application was assessed through a Compliance Verification, an on-site TGA audit may be required. If so, the sponsor will have to lodge an application on eBS.

Where a TGA on-site audit has taken place and the TGA has not found acceptable compliance, the GMP Clearance application will be rejected and any current GMP Clearances will be revoked.


Footnotes

  1. See ARGOM section X.2.1
  2. If either of these is not available, a declaration from the manufacturer on its letterhead stating the change in the manufacturer's name may be accepted.
  3. Not required for US FDA sites - TGA will check the compliance status on the FACTS database.

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