Notifications process: requests to vary registered medicines where quality, safety and efficacy are not affected

Version 2.0, December 2017

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23 November 2017

Notifications for prescription medicines (biological medicines)

This guidance is subject to the finalisation of legislative amendments.

This guidance outlines the kinds of variations to biological medicines that are considered as requests made under the provisions of section 9D(2C) of the Therapeutic Goods Act 1989 (known as 'notifications'). The conditions outlined below the description of each variation type must be met for the request to be processed as a notification.

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Drug substance or excipient changes

Certified product details (CPD) documents

For many biological medicines, critical tests are conducted on the drug substance and not repeated on the drug product because of low concentrations of the drug substance or interference by excipients.

If any of the notification requests below result in changes to the drug substance or drug product specifications or the non-pharmacopoeial test methods, please provide a new copy of the entire document, including testing methodology, even if these details have not changed. The CPD document can be provided using the CPD form available on the TGA website.

ISAM: Drug substance or excipients specifications - change of test method

Change to test method of the drug substance, where it is replaced with a pharmacopoeial method.

  • The method being changed must not be a viral safety testing method.
  • The in-house test method being changed must be replaced with a pharmacopoeial method. If there are differences in specifications between the two methods, the more stringent specifications should apply.
  • The stringency of the specifications should not decrease as a result of the change.
  • Batch analytical data for at least three commercial batches should have been generated to demonstrate compliance with the new test and limit.

You must submit:

  • Details of the new method.
  • An updated CPD document, if applicable.

ISNL: Drug substance or excipients specifications – narrowing of limits

More stringent limits for test results of the drug substance, starting materials, intermediates or excipients in the drug product.

  • The proposed limits must be consistent with the relevant TGA standards and guidelines.
  • Do not change the composition of the substance tested. For example, you cannot narrow the test limits for isoelectric point, as this could alter the substance by resulting in the omission of a charged isoform of a protein.
  • The change must not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation application).
  • The change must be within the range of currently approved limits.
  • The test procedure remains the same, or changes in the test procedure are minor.

You must submit:

  • The revised set of specifications for the substance.
  • An updated CPD document, if applicable.

ISPT: Drug substance or excipients specifications – amendments resulting from pharmacopoeial or TGO changes

Changes resulting from amendments to pharmacopoeial requirements or the requirements of Therapeutic Goods Orders.

If a substance complies with the requirements of an earlier edition of an official pharmacopoeia, such as the British pharmacopoeia [BP], it would be appropriate to substitute the requirements of the current edition of that pharmacopoeia. However, any tests that were performed in addition to those of the pharmacopoeial monograph should continue to be applied.

Changing from the requirements of one pharmacopoeia to those of another (such as from the USP to the BP) is not covered by this section and may require evaluation of data by the TGA.

  • The change should not involve changing from the requirements of one pharmacopoeia to those of another.
  • Any tests that were performed in addition to those of the pharmacopoeial monograph or TGO must continue to be performed.
  • The new pharmacopoeial monograph or amended TGO must be applicable to the substance.

You must submit:

  • The revised set of specifications for the drug substance.
  • An updated CPD document, if applicable.

Drug product specification or test changes

PMPL: Drug product specification – minor changes to physicochemical test methods and limits

Minor changes to physicochemical tests.

  • There is no change in test method other than minor changes to existing test methods for physicochemical parameters of the drug product such as pH, density, specific gravity, optical rotation, extractable volume, osmolality, osmolarity or viscosity.
  • The test limit must either remain unchanged or be more stringent.

You must submit:

  • A summary description of the change and details of the new method.
  • An updated CPD document.

You must generate the following data:

  • Appropriate validation data demonstrating the new test is at least equivalent to former procedure.

PSNL: Drug product specification - narrowing of test limits

Revision of the approved specifications for testing of the final drug product, to make the limits applied to test results more stringent.

  • The new limits must be either the same as, or more stringent than, any applicable standard or guidelines.

You must submit:

  • The revised set of specifications.

PSNT: Drug product specification - addition of test and limit

Addition of a new test and limit to the existing specifications.

  • The additional test must have been previously evaluated by the TGA.
  • The proposed limit (release and expiry) must be based on batch analytical data and comply with, or is more stringent than, any applicable official standard or relevant accepted guidelines for such a test.
  • The test method must only be used at a registered quality control testing site that has appropriate GMP clearance.

You must submit:

  • Details of the new test method.
  • The revised set of drug product specifications at release and expiry.
  • An updated CPD document.

You must generate the following data:

  • Appropriate validation data for the proposed method.

PSPT: Drug product specification - changes resulting from amendments to a TGO or pharmacopoeial requirement

Changes resulting from amendments to pharmacopoeial requirements or the requirements of Therapeutic Goods Orders.

  • The new pharmacopoeial monograph or TGO are suitable for the product.
  • The change must not involve changing from the requirements of one pharmacopoeia to those of another.
  • Any tests that were performed in addition to those of the pharmacopoeial monograph or TGO must continue to be performed.
  • The test method must only be used at a registered quality control testing site that has appropriate GMP clearance.
  • If the change involves updating microbiological test requirements for non-sterile products to meet TGO No. 77—Microbiological standards for medicines (TGO 77), the product must have undergone a risk assessment for objectionable microorganisms, in addition to those specified in the pharmacopoeias that form the basis of TGO 77.
  • The change must not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation application) unless the supporting documentation has been already assessed and approved within another procedure.
  • The change must not result from unexpected events arising during manufacture, e.g. new unqualified impurity; change in total impurity limits.
  • The change must be within the range of currently approved limits.
  • The test procedure must remain the same, or the changes in the test procedure are minor.

You must submit:

  • The revised set of drug product specifications at release and expiry.
  • An updated CPD document.
  • For updating microbiological test requirements for non-sterile products to meet TGO No. 77, an assurance that the report of the risk assessment for objectionable microorganisms is available for review, if required by the TGA.

You must generate the following data:

  • Appropriate validation data must have been generated where applicable.

PSQC: Drug product specification - change to quality control testing equipment

Changes to equipment used for quality control testing of the final drug product (including sterility, microbiological, chemical, physical and bacterial endotoxin or pyrogen testing).

  • The change must meet any previously approved test method validity criteria.

You must submit:

  • A description of the new equipment.
  • An updated CPD document.

You must generate the following data:

  • Appropriate validation data must have been generated for the changed equipment using the previously approved criteria and, where applicable, the same validation protocol as was used for the previously approved equipment.
  • If the type or brand of consumables used with the equipment is critical (that is, included in the protocol), appropriate validation data must also be generated for the relevant consumables.

Site of manufacture changes

OAMS: Albumin – change of manufacturer's name or contact details

Change in details of albumin manufacturer or supplier.

  • The change may apply to the name or contact details of albumin suppliers or manufacturers, but not to the site or process of manufacture.

You must submit:

  • Details of the new manufacturer or supplier.
  • Evidence of GMP clearance, showing the changed name.
  • An assurance that the albumin still complies with relevant TGO and other standards such as Ph Eur or BP.

PMRS: Drug product site of manufacture - addition of new site of release-for-supply operations for a registered drug product

Addition of a new manufacturer for release for supply of the final drug product.

  • The new site must either have:
    • for Australian manufacturers, a current manufacturing licence issued by the TGA for this type of manufacture or
    • for overseas manufacturers, current GMP clearance issued by the TGA and valid at the time of this application for this type of manufacture.

You must submit:

  • Details of the new manufacturing site
  • The Australian licence and/or GMP clearance number.

In-house reference standard changes

IRSR: In-house reference standard – replacement

Replacement of an in-house reference standard.

  • The TGA should have explicitly approved the protocol and acceptance criteria including traceability for establishing a replacement standard. The protocol should have been submitted with the application for registration or a subsequent Category 3 application to change the in-house reference standard. This also includes a change in shelf life of the reference standard.

You must submit:

  • Details of the new reference standard, including assigned values.
  • The reference to the TGA approval of the protocol (that is, TGA submission number).
  • The proposed date of implementation, allowing time for TGA approval.
  • An updated CPD document.

Purification process changes

PPCR: Purification process—column life reduction

Reduction in the approved column life for columns used in the purification process.

You must submit:

  • A scientific justification for the column life reduction.

PPHR: Purification process—holding time reduction for a non-plasma-derived product

Reduction in the holding time for the drug substance, or intermediates created during manufacture of the drug substance, where the final drug product is non-plasma derived.

You must submit:

  • A scientific justification for the holding time reduction.

Changes to storage of drug substance

ASRS: Drug substance storage conditions – reduction in shelf life

Reduction in shelf life.

  • The change must not be due to unexpected events arising during manufacture or because of stability concerns.

You must submit:

  • Details of the new shelf life.
  • A reason for the planned reduction in shelf life.

Changes to storage of drug product

Stability testing

For biological medicine products requiring refrigeration or freezing, stability testing should be in real time at the specified storage temperature, for at least the requested shelf life.

The time out of refrigeration (which also includes time out of the freezer) during normal manufacturing processes, up to the point of return to the fridge or freezer following labelling and packaging, should have been defined and justified. This should be based on worst-case storage scenarios and include storage conditions inherent in the manufacturing process and transport.

From that point onward, all storage and shipping conditions should be justified by the real-time stability data:

  • the data for justifying any temperature excursions should include real-time studies of the proposed excursion followed by return to the normal storage conditions for the remainder of the shelf life.

Refer to guidance on Stability testing for prescription medicines for requirements for stability testing of biological medicines.

PSLD: Drug product storage conditions – reduction in shelf life

Reduction in shelf life.

  • The change must not be due to unexpected events arising during manufacture or because of stability concerns.

You must submit:

  • Details of the new shelf life.
  • A reason for the reduction in shelf life.

PSET: Drug product storage conditions ‑ changes to excursion temperature during manufacture

Changes to excursion temperature during manufacture

  • The change is one of the following:
    • a removal of an excursion temperature
    • a reduction in the time spent out of refrigeration, including time out of the freezer.
  • The change must not be due to unexpected events arising during manufacture or because of stability concerns.
  • All other changes to the excursion temperature require the TGA to evaluate the data. See PSLC: Shelf life - changes to shelf life or storage conditions of a drug product.

You must submit:

  • Details of the change.

PSAR: Drug product storage conditions – Addition of a restrictive shelf life or storage condition

Addition of a restrictive shelf life or storage condition.

  • The change should be to a more restrictive shelf life or storage conditions.
  • The change must not be due to unexpected events arising during manufacture or because of stability concerns.

You must submit:

  • Details of the change.
  • The reason for the change.

Fermentation process changes

FPFM: Fermentation—change of filter manufacturer

Change to the manufacturer of a filter used in the fermentation process.

  • Do not change the internal process controls.
  • Do not use the filter for steps that require viral safety validation.
  • The new filter meets the same acceptance criteria as the previous filter.
  • The new internal process controls for the filtrate have not been changed.

You must submit:

  • The reason for the change.
  • The new manufacturer's details.

FPNC: Fermentation—more stringent internal process controls

Introduction of more stringent internal controls on the fermentation process.

  • Do not change the quality characteristics of the product.

You must submit:

  • The reason for the change.
  • Details of the new internal process controls.

FPRP: Fermentation—reduction in fermentation period

Reduction in the fermentation period, i.e. the time required to culture and harvest the cell line.

  • Reducing the fermentation period must not change the batch size.
  • Do not change the internal process controls.

You must submit:

  • The reason for the change.
  • Details of the change.

Plasma fractionation intermediates changes

PFCR: Plasma - changes to fractionation intermediates - column life reduction

Reduction in the approved column life for columns used in plasma fractionation.

You must submit:

  • Details of the change.
  • A justification for the proposed reduction.

PFSC: Plasma - changes to fractionation intermediates - more stringent internal process control

Introduction of more stringent internal controls on the plasma fractionation process.

  • Do not change the quality characteristics of the product.

You must submit:

  • Details of the change.
  • The reason for the change.

Drug product packaging changes

PPAT: Packaging – introduction of anti-tamper packaging (materials not in contact with drug product)

Introduction of anti-tamper packaging for the drug product.

  • The packaging materials must not be in direct contact with the dosage form.
  • The change must not concern a part of the packaging material, which affects the delivery, use, safety or stability of the finished product.

You must submit:

  • Details of the change.

Product label changes

Requirements for labels

Mandatory labelling requirements for prescription medicines are set out in the Therapeutic Goods Order (TGO) that pertains to labels, as amended from time to time. It is the sponsor's responsibility to ensure that their product labels meet any state and territory government requirements.

LPCL: Label – addition or deletion of, or change to, the company logo or livery

  • There must be no other changes to the label made under this change request.
  • The changes must ensure continued compliance with the relevant TGO pertaining to labels and not contravene labelling best practice.

You must submit:

  • Copies of the existing labels (with tracked changes) and final copies or mock-ups of the amended labels (for each strength, where applicable) which include any logos, design work or graphics. The copies must be to scale and verify the size/dimensions of the labels and indicate the colours to be used. Where there are multiple pack sizes available, one representative label can be provided (for each strength), as long as the only difference between the labels is the pack size.

LPCP: Label - addition or deletion of, or change to, the pictogram of a product or its dosage form

  • There must be no other changes to the label made under this change request.
  • The changes must ensure continued compliance with the relevant TGO pertaining to labels and not contravene labelling best practice.
  • The addition or change of a pictogram of a product or its dosage form must only be designed to clarify information about the medicine which is useful for the patient, to the exclusion of any element of a promotional nature
  • The change must not involve removal of information relating to the safe use of the product.

You must submit:

  • Copies of the existing labels (with tracked changes) and final copies or mock-ups of the amended labels (for each strength, where applicable) which include any logos, design work or graphics. The copies must be to scale and verify the size/dimensions of the labels and indicate the colours to be used. Where there are multiple pack sizes available, one representative label can be provided (for each strength), as long as the only difference between the labels is the pack size.

LPCS: Label – addition or deletion of, or change to, the name or address of the Australian sponsor or supplier of the product

  • There must be no other changes to the label made under this change request.
  • The changes must ensure continued compliance with the relevant TGO pertaining to labels and not contravene labelling best practice.
  • The new name or address must be the same as amended on the register.

You must submit:

  • Copies of the existing labels (with tracked changes) and final copies or mock-ups of the amended labels (for each strength, where applicable) which include any logos, design work or graphics. The copies must be to scale and verify the size/dimensions of the labels and indicate the colours to be used. Where there are multiple pack sizes available, one representative label can be provided (for each strength), as long as the only difference between the labels is the pack size.

LPDG: Label – deletion of existing graphics, pictures or diagrams, and any associated text

  • There must be no other changes to the label made under this change request.
  • The changes must ensure continued compliance with the relevant TGO pertaining to labels and not contravene labelling best practice.
  • The change must not involve removal of information relating to the safe use of the product.

You must submit:

  • Copies of the existing labels (with tracked changes) and final copies or mock-ups of the amended labels (for each strength, where applicable) which include any logos, design work or graphics. The copies must be to scale and verify the size/dimensions of the labels and indicate the colours to be used. Where there are multiple pack sizes available, one representative label can be provided (for each strength), as long as the only difference between the labels is the pack size.

LPDR: Label - deletion of repeated text (present elsewhere on a label) from selected side panels provided that the information is not mandatory

  • There must be no other changes to the label made under this change request.
  • The changes must ensure continued compliance with the relevant TGO pertaining to labels and not contravene labelling best practice.

You must submit:

  • Copies of the existing labels (with tracked changes) and final copies or mock-ups of the amended labels (for each strength, where applicable) which include any logos, design work or graphics. The copies must be to scale and verify the size/dimensions of the labels and indicate the colours to be used. Where there are multiple pack sizes available, one representative label can be provided (for each strength), as long as the only difference between the labels is the pack size.

LPIA: Label - addition of simple instructional/informational/anti-tampering statements, or information about a changed appearance of the dosage form

  • There must be no other changes to the label made under this change request.
  • The changes must ensure continued compliance with the relevant TGO pertaining to labels and not contravene labelling best practice.

You must submit:

  • Copies of the existing labels (with tracked changes) and final copies or mock-ups of the amended labels (for each strength, where applicable) which include any logos, design work or graphics. The copies must be to scale and verify the size/dimensions of the labels and indicate the colours to be used. Where there are multiple pack sizes available, one representative label can be provided (for each strength), as long as the only difference between the labels is the pack size.

LPOP: Label - addition or deletion of, or change to, label text of outer protective pouches or overwraps of the container or primary pack

  • There must be no other changes to the label made under this change request.
  • The changes must ensure continued compliance with the relevant TGO pertaining to labels and not contravene labelling best practice.
  • The new text must not be confusing, promotional or contradictory to text on the container or primary pack labels.

You must submit:

  • Copies of the existing labels (with tracked changes) and final copies or mock-ups of the amended labels (for each strength, where applicable) which include any logos, design work or graphics. The copies must be to scale and verify the size/dimensions of the labels and indicate the colours to be used.  Where there are multiple pack sizes available, one representative label can be provided (for each strength), as long as the only difference between the labels is the pack size.

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