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GMP clearance guidance

4 January 2019

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Step 3 - Identifying what documentation is required

The documentation required to support your GMP clearance application depends on the pathway you select in step 2 and the type of manufacturer you are seeking GMP clearance for.

Important - If you are unsure what evidence is required, please utilise the GMP Clearance Application Assistance Tool (CAAT) or contact us before submitting your application.

If your application scope is incorrect, or you do not submit the required or requested evidence, you may not be issued a GMP clearance and any fees you have paid may be forfeited.

GMP clearance is usually issued for manufacturers of:

  • non-sterile APIs for example:
    • non-sterile API's manufactured by chemical synthesis
    • non-sterile API's manufactured by "classical" fermentation
  • non-sterile finished products for example:
    • tablets or oral liquids
  • sterile or biotech APIs for example:
    • API's manufactured by biotechnology fermentation/cell culture
    • API's that are sterilised
  • sterile or biotech finished products for example:
    • injections or lyophilisates
    • recombinant products
  • contract testing laboratories or contract sterilisers.

Consider whether:

  • the substance or product in your GMP clearance application is for the purpose of registering a biological medicine
  • the processes used to manufacture your product are considered to be biotechnology processes

This could impact your GMP clearance processing times and the documentation required to be submitted.

MRA pathway documentation

If you are using the MRA pathway, the following documentation needs to be provided as evidence for each manufacturer type. Select the evidence in the table to see further information on the requirements.

MRA pathway Non-Sterile API Non-Sterile Finished Product Sterile or Biotech API Sterile or Biotech Finished Product Contract Testing Lab or Steriliser
GMP Certificate

Applicable

Applicable

Applicable

Applicable

Applicable

CV pathway documentation

If you are using the CV pathway, the following documentation needs to be provided for each manufacturer type. Select each piece of evidence in the table to see further information on the requirements.

CV pathway Non-Sterile API Non-Sterile Finished Product Sterile or Biotech API Sterile or Biotech Finished Product Contract Testing Lab or Steriliser
GMP Certificate

Applicable

Applicable

Applicable

Applicable

Applicable

Most recent inspection report

Applicable

Applicable

Applicable

Applicable

Applicable

Regulatory inspections list

Applicable

Applicable

Applicable

Applicable

Applicable

Regulatory action details

Applicable

Applicable

Applicable

Applicable

Applicable

Site Master File (SMF), quality manual or equivalent

Applicable

Applicable

Applicable

Applicable

Applicable

List of products intended for supply

Applicable

Applicable

Applicable

Applicable

Not applicable

GMP agreement or equivalent

Where requested by applicant or required

Applicable

Where requested by applicant or required

Applicable

Applicable

Release procedure(s)

Where requested by applicant or required

Applicable

Where requested by applicant or required

Applicable

Not applicable

Validation Master Plan (VMP)

Where requested by applicant or required

Where requested by applicant or required

Applicable

Applicable

Where requested by applicant or required

Latest Product Quality Review (PQR)

Where requested by applicant or required

Where requested by applicant or required

Applicable

Applicable

Not applicable

List of authorised tests

Not applicable

Not applicable

Not applicable

Not applicable

Applicable

Applicable= Required Not applicable= Not Required Where requested by applicant or required= Not required unless requested

Other types of evidence that are not listed in the tables above may be provided as an alternative to, or to supplement the required evidence for both the MRA and CV pathways. For example, a Letter of Access (LoA) or an API declaration.

To avoid unnecessary delays with your application, these should be provided upfront when lodging an application where applicable. Please refer to step 6 - Providing your evidence.

Important - We may request any additional documentation or clarification during the GMP clearance assessment process.

General documentary requirements

Any document you provide as evidence in support of a GMP clearance application must be:

  • an accurate and complete copy of the original document. As the applicant, you are responsible for the authenticity of documents supplied. Heavily redacted or altered documents will not be accepted
  • in English, or accompanied by an English translation by an independent certified translator that states it is a true and accurate translation of the original
  • the most current and effective version of that document. Draft, expired or superseded documents are not acceptable.

Additionally, to avoid unnecessary delays, any ambiguity or discrepancies in the documentation provided must be clarified upfront via a cover letter submitted with the application.

We may request certified copies of submitted documents at any time during the GMP clearance assessment process.

If any evidence is to be provided directly by the manufacturer, it is the Australian sponsor's responsibility to ensure that they meet the requirements of that evidence as detailed below.

GMP certificates

Why we require it

A GMP certificate from an overseas regulatory authority, issued after an on-site inspection was performed, is required because it demonstrates the manufacturer’s compliance with the applicable GMP standard.

What you should provide

Provide a copy of the original GMP certificate or EudraGMDP certificate, if available, with your application. Ensure that the:

  • certificate is complete, is from a recognised regulatory authority and corresponds to the inspection report provided (where applicable)
  • manufacturer's name and site address are correct
  • certificate is current - that is, that the site was inspected not more than three years ago
  • scope of the certificate covers the scope of the application - that is, the sterility, dosage form, and steps of manufacture etc.
  • conditions and/or clarifying remarks on the certificate are understood, because these will be applied to the GMP clearance where applicable.

Take particular care

Ensure that the certificate has:

  • not been issued as a result of a desk top assessment by an overseas regulator
  • not been redacted in any way. Redacted certificates will not be accepted
  • been issued for human medicinal products

Veterinary or investigational medicinal product certificates are not acceptable to support a GMP clearance to register or list a product on the ARTG.

Alternative evidence (for MRA pathway only)

We may accept a Good Laboratory Practice (GLP) or International Standards Organisation (ISO) certificate in lieu of a GMP certificate for some contract laboratories or sterilisers for the MRA pathway.

  • GLP certificates for contract laboratories will only be accepted if they are accredited to ISO 17025 (General requirements for the competence of testing and calibration laboratories), relevant to the scope of the application
  • ISO certificates for contract sterilisers will only be accepted if they are issued to the specific site and accredited to the relevant sterilisation accreditation - for example, ISO 11137 (Sterilisation of healthcare products - Radiation).

Important - Not all regulatory authorities routinely issue GMP certificates as part of their regulatory framework. For example:

  • Health Canada issues an inspection 'Exit Notice' or 'certificate of GMP compliance', which is acceptable in lieu of a GMP certificate
  • Singapore Health Sciences Authority (HSA) issues a 'Letter to attest GMP compliance of a manufacturer', which is acceptable in lieu of a GMP certificate.

Liaison

You may request the TGA to obtain a GMP certificate or equivalent on your behalf for applications made via the MRA or CV pathways. There are some instances where this is a mandatory requirement for the CV pathway.

MRA pathway

If you are unable to obtain the GMP certificate issued by a regulatory authority within an MRA country, you may request that we attempt to obtain it. Please note:

  • you will be charged an additional fee for this service
  • We can only attempt to liaise for GMP certificates. We do not liaise for GLP or ISO certificates
  • the evidence may not be available from the regulatory authority for reasons beyond our control. In such cases you will be notified by email and your GMP clearance will not be issued.
CV pathway

Where you have provided US FDA evidence to be assessed, we are required to perform a check of the US FDA's compliance status (COMSTAT) database. Please note:

  • You will be charged an additional fee for this service
  • as this is a real-time check of the site's compliance status, it is required for every variation or renewal of your GMP clearance where USFDA evidence is used, irrespective of the duration between applications.

Most recent inspection report

Why we require it

The most recent inspection report issued after a successful on-site inspection is required because it provides detail about the overseas regulatory authority's inspection activities including, but not limited to, which buildings, systems, processes and products were covered during the inspection.

What you should provide

Provide the most recent inspection report. Ensure that the:

  • report is from an on-site inspection performed by a recognised regulatory authority and corresponds to the GMP certificate provided (where applicable)
  • manufacturer's name and site address are correct
  • report is current - that is, it is not more than three years since the last inspection
  • scope of the inspection report covers the scope of your application - that is, the sterility, dosage form, API, steps of manufacture and buildings covered etc.
  • inspection was conducted to the equivalent GMP standard, for example, the relevant USFDA compliance program
  • time taken to inspect and the size of the inspection team is clearly recorded in the report
  • inspection report provided, if from a PIC/S participating authority, aligns to the standard operating procedure PIC/S inspection report format.

Take particular care

Ensure that the:

  • inspection report contains sufficient information and detail regarding the inspection activities performed

    Insufficient information or lack of detail in the report may be insufficient to issue a GMP clearance.

  • inspection report is sufficiently un-redacted so that an assessment can be conducted. Excessively redacted inspection reports will not be accepted
  • inspection covered the specific buildings, systems, processes, API or products applicable to the scope of your application
  • full inspection report is provided. Inspection cover letters, Post Inspection Letters (PIL), close out letters, observation or deficiency lists etc. are not acceptable.

Regulatory inspections list

Why we require it

The regulatory inspections list is required because it provides information on the compliance history of the site including the frequency and outcomes of past inspections performed by local and/or international regulatory authorities.

What you should provide

Provide a list of inspections performed at the manufacturing site. Ensure you include:

  • all on-site inspections conducted within the three years prior to the application submission
  • the name of the inspecting authority and the dates, scope and outcomes of the inspections. For example, the observation of critical deficiencies should be specified.

Take particular care

Ensure that the:

  • evidence provided is from the manufacturer
  • inspections list does not contradict other evidence provided with the application.

Regulatory action details

Why we require it

The regulatory action details are required because they provide additional information about the manufacturer's compliance history, particularly in relation to product alerts, warning letters, import alerts or recalls due to defects applicable to the site.

What you should provide

Provide details of any regulatory actions taken by or against the manufacturing site. Ensure that:

  • the details are current and account for three years prior to the date of submission
  • where applicable, provide further details about the action or event that occurred. This should include information about the subsequent investigation and root cause analysis conducted, and any resulting corrective or preventative actions that were implemented.

Take particular care

Ensure that the:

  • evidence provided is from the manufacturer
  • regulatory action details include any actions relating to the entire manufacturing site, not just specific products or dosage forms included in your application.

Alternative evidence

If there have been no product alerts, warning letters, import alerts or recalls due to defects within the past three years for the manufacturing site, provide a declaration from the manufacturer stating this on their company letter head.

Site master file, quality manual or equivalent

Why we require it

The Site Master File (SMF) or equivalent document is required because it provides information about the manufacturer's operations, facilities and quality management system.

What you should provide

Provide the complete SMF or equivalent. Ensure that the:

  • manufacturer's name and site address are correct
  • SMF contains the required information as per the PIC/S explanatory notes for pharmaceutical manufacturers (if applicable)
  • complete document including all appendices are provided for assessment. Appendices (including facility drawings) must be legible.

Take particular care

Ensure the SMF contains information regarding cross contamination controls for high-risk or highly sensitising products (if applicable).

Alternative evidence

Depending on the scope of your application, you may instead provide other documents, such as a plant/equipment file or a quality/laboratory manual, which individually or collectively provide the same details.

List of products intended for supply

Why we require it

The list of the sponsor's products is required because it provides additional information about the substances or products intended for supply in Australia.

What you should provide

Provide the product list and ensure that:

  • the substances or dosage forms are reflected in the scope of the application
  • the AUSTR/AUSTL numbers are provided where relevant.

Take particular care

Ensure that the list of substances or products does not contradict other evidence provided with the application.

For API applications, a separate product list may not be required if the name of the substance has been entered in the application e-form and corresponds to the Australian Approved Name (AAN) in the ingredients database, where applicable.

GMP agreement or equivalent

Why we require it

GMP, quality or technical agreements are required because they provide information about the roles and responsibilities of each party in relation to the critical aspects of GMP and any specific technical aspects related to the product’s manufacture. It also provides further information as to the roles and responsibilities of the Australian Marketing Authorisation (MA) holder (the sponsor) in relation to the product's manufacture and the relevant post market surveillance obligations.

What you should provide

Provide the signed GMP, quality or technical agreement relevant for the scope of your application. Ensure that it:

Take particular care

Ensure that the GMP, quality or technical agreement:

  • clearly identifies the products, steps of manufacture (activities) and manufacturing site (where there are multiple sites contained in the one agreement) relevant to the scope of your GMP clearance application
  • clearly describes the role of each party subject to the agreement, particularly the communication processes agreed upon
  • has been signed by all parties to the agreement.

Additional entities and alternative evidence

Recognising there may be multiple entities involved in the pharmaceutical supply chains, and depending on the timing and scope of your application or the relationship you have with each entity, you may provide:

  • For new registrations or New Chemical Entity (NCE) submissions, we will accept a draft GMP, quality or technical agreement between the manufacturer and the sponsor that demonstrates the intended roles and responsibilities will be appropriate along with a declaration/statement from the Australian sponsor that the agreement will be signed by all relevant parties prior to commencing commercial supply to Australia.

    A condition will be placed on your GMP clearance to reflect this and the expiry date may be reduced. Your GMP clearance may be cancelled if it is determined that the condition has not been adhered to.

  • For contract labs, sterilisers, packagers and/or authorised persons performing release for supply, provide the signed GMP, quality or technical agreement between the principal manufacturer and the subcontractor or multiple documents that comprise the same.
  • For subsidiaries of the same parent company (either the manufacturer’s or sponsor’s), provide the equivalent signed documentation that clearly outlines the roles and responsibilities of the Australian MA holder (Sponsor) and other entities in the supply chain (i.e. Global Head Quarters). Particular attention should be paid to provide the information as required by PIC/S chapter 7.

    For subsidiaries of the same parent company (either the manufacturer’s or sponsor’s), provide the equivalent signed documentation that clearly outlines the roles and responsibilities of the Australian MA holder (Sponsor) and other entities in the supply chain (i.e. Global Head Quarters). Particular attention should be paid to provide the information as required by PIC/S chapter 7.

  • When using a distributor or other intermediary, provide the relevant signed GMP, quality or technical agreements you have in place with them in addition to the signed agreement they have in place with the manufacturer. Both documents, when assessed together, should provide clear roles and responsibilities between all the entities in the supply chain for Australia.

    When using a distributor or other intermediary, provide the relevant signed GMP, quality or technical agreements you have in place with them in addition to the signed agreement they have in place with the manufacturer. Both documents, when assessed together, should provide clear roles and responsibilities between all the entities in the supply chain for Australia.

  • For generic medicines, when sourcing product from another Sponsor, provide the signed GMP, quality or technical agreement you have in place with them in addition to the signed agreement they have in place with the manufacturer. Again both documents, when assessed together, should provide clear roles and responsibilities between all the entities in the supply chain for Australia.

    For generic medicines, when sourcing product from another Sponsor, provide the signed GMP, quality or technical agreement you have in place with them in addition to the signed agreement they have in place with the manufacturer. Again both documents, when assessed together, should provide clear roles and responsibilities between all the entities in the supply chain for Australia.

To avoid unnecessary delays with your application, all relevant agreements or documentation should be provided upfront when lodging an application.

Additionally, any ambiguity in terminology or responsibilities should also be clarified upfront via a cover letter. This should include reference to any commercial considerations that may prevent the provision of the required evidence.

Release procedure(s)

Why we require it

The release procedure is required because it provides information about how the authorised person at the site performs the release for supply or release for further processing (if applicable) step of manufacture.

We do not routinely require release for further processing procedures to be provided however these may be requested.

What you should provide

Provide the release for supply procedure(s). Ensure that:

  • the procedure is applicable to the product types and dosage forms in your application
  • sufficient information about how the authorised person ensures each batch has been manufactured and checked for compliance with the relevant Marketing Authorisation (MA) is provided
  • all relevant appendices to the procedure are provided - for example, batch release checklists.

Take particular care

Ensure the procedure describes in detail how the release for supply process operates, for example, the process for reviewing critical records and verifying compliance with GMP and the MA.

For more information please see Guidance on release for supply.

Validation master plan

Why we require it

The Validation Master Plan (VMP) is required as it provides further information about the validation and qualification activities of the manufacturing site and its operations. We need to know that the components and processes used for manufacture of the medicines and APIs are appropriately qualified and validated and have a suitable re-validation schedule.

What you should provide

Provide the VMP and ensure that it meets the requirements outlined in Annex 15, of the PIC/S Guide to GMP for Medicinal Products.

Take particular care

Ensure the VMP:

  • includes the relevant equipment and processes applicable to the products intended to be supplied to Australia
  • provides a reference to the existing specific equipment or process validation documentation and a re-validation schedule.

Latest Product Quality Review

Why we require it

The Product Quality Review (PQR) is required because it provides information on how effective and consistent the existing manufacturing process of a product is. It also provides information on variations to marketing authorisations and market complaints.

What you should provide

Provide a copy of the most recent PQR of the product you are supplying or intend to supply to Australia. Ensure that:

Take particular care

Ensure that:

  • the PQR is complete and does not contradict other evidence in the application.

Alternative evidence

Where the substance or product has not yet been subject to a product quality review, you should state this fact and provide the PQR procedure.

List of authorised tests (for contract testing labs only)

Why we require it

A list of authorised tests is required because it provides further information on the testing capabilities of a contract testing laboratory applicable to the scope of the application.

What you should provide

Provide an accurate list of tests performed by the testing laboratory. Ensure that the information does not contradict any other evidence provided with the application.

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

Take particular care

The list of tests should match your application and the name of test references should clearly indicate the nature and type of testing performed.

Other types of evidence

API declaration

When we require it

An API declaration is required for the MRA or CV pathway when the substances in your application were not specifically covered as part of the most recent inspection provided as evidence. It provides assurance from the manufacturer that the specific APIs in your application are:

  • manufactured in the same facility (specific buildings) as those inspected and referenced in the inspection report or GMP certificate
  • using a similar manufacturing process as those inspected (for example, chemical synthesis)
  • AND
  • controlled under the same Quality Management System (QMS) or Pharmaceutical Quality System (PQS) as those inspected and referenced in the inspection report.
What you should provide

Provide a signed and dated declaration. Ensure that the declaration:

  • is provided by the manufacturer on a company letterhead
  • has been authorised by an officer of that manufacturer at the senior management level
  • confirms that the API(s) listed in the declaration and corresponding GMP clearance application are manufactured:
    • in the same facility (specific buildings) as those covered by and referenced in the inspection report provided as evidence
    • using a similar manufacturing process (for example, chemical synthesis) as those covered by and referenced in the inspection report provided as evidence
    • AND
    • controlled under the same QMS or PQS as those covered by and referenced in the inspection report provided as evidence
  • contains details of starting materials for the API(s) and confirmation that all steps of manufacture for each API are carried out in the nominated facility. If any steps of manufacture are carried out at another site or company, details should be provided
  • contains details of whether any previous inspection by any other recognised regulatory authorities have covered the API(s) included in the GMP clearance application. If so, a copy of that inspection report should also be provided.
Take particular care

Ensure that the:

  • GMP clearance application number is clearly referenced
  • declaration does not contradict other evidence provided with the application.

API declarations may not be used in conjunction with a LoA to clearance as these applications are reliant on the original clearance in all aspects including scope.

Letters of access

Each sponsor must obtain their own GMP clearance for a particular manufacturing site for their own specific product registration or listing. However, in an effort to reduce the regulatory burden on industry, you may provide us with a Letter of Access (LoA) obtained from another sponsor or manufacturer, which allows us to access information and/or evidence previously submitted.

There are three types of LoA which can be used for both the MRA and CV pathways:

  • A manufacturer LoA to evidence grants a sponsor permission to use evidence that has been previously submitted by the manufacturer for another GMP clearance application
  • A sponsor LoA to evidence grants a sponsor permission to use evidence that has been previously submitted by another sponsor for another GMP clearance application
  • A sponsor LoA to clearance grants a sponsor permission to use an existing GMP clearance as the primary evidence to allow an additional clearance to be issued on the condition that the scope of the application is identical or smaller. Applications using a LoA to clearance are reliant on the original clearance in all aspects including scope, processing times, determinations made and expiry.

While the use of LoA is intended to reduce the regulatory burden on industry, for the CV Pathway, certain sponsor-specific evidence is still required to be provided (where applicable) along with the relevant fees. These include:

To avoid unnecessary delays with your application, these should be provided upfront when lodging an application.

For both the MRA and CV pathways, ensure that:

  • only one LoA is provided per application
  • the application it allows access to was not issued using another LoA
  • the LoA is provided on a company letterhead
  • the LoA is signed and dated by the sponsor or manufacturer that is providing it
  • it clearly states the type of LoA (for example, whether it's for access to evidence or clearance) and to whom the access is being provided to
  • it clearly references the GMP clearance number of the existing application.

TGA certificates

TGA certificates issued as a result of a successful on-site inspection may be provided as evidence to obtain a GMP clearance if you were not using this manufacturer at the time the inspection was scheduled.

If you provide a TGA certificate as evidence, you will still be required to provide the following sponsor specific evidence (where applicable):

  • We will not accept a TGA issued certificate as evidence for a GMP clearance application if you have declined to contribute to the cost of the inspection without justification.

Additionally, you will be expected to contribute to the cost of the next on-site inspection.

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