Minor variations to prescription medicines, Appendix 1: Variation change types - chemical entities

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Version 1.0, June 2017

29 June 2017

Introduction

The Therapeutic Goods Administration (TGA) takes a risk-based approach to assessing variations to prescription medicines. This means that the higher the risk associated with the variation, the greater the level of assessment required by the TGA for a decision to be made.

This guidance outlines the following types of minor variations and changes that can be made to chemically derived (non-biological) prescription medicines currently on the Australian Register of Therapeutic Goods (ARTG):

  • Changes that do not require prior approval. These are:
    • changes that can be implemented without informing the TGA and
    • changes that can be implemented before you inform the TGA of the change.
  • Corrections to an ARTG entry – a minor change to correct or complete information that was inadvertently recorded incorrectly or omitted in the ARTG entry, including the product information (PI).
  • Minor Editorial Changes to product information (MEC)
  • Self-Assessable Requests (SARs) - lower risk variations for which the sponsor can provide an assessment of their own data for the TGA to verify.
  • Safety Related Requests (SRRs) – requests to either reduce the patient population that can receive the medicine or add a warning or precaution.
  • Category 3 requests - variations that require evaluation of quality-related data only.

Major variations (Category 1 applications) are not covered by this guidance. These require evaluation of a full dataset, or any combination of quality, nonclinical, clinical and bioequivalence data. See the Prescription medicines registration process for information on how to lodge a Category 1 application.

Data supporting minor variations requests

The conditions outlined within each variation type set out the minimum documentation required for regulatory purposes, but depending on the particular circumstances surrounding the change, additional data may be needed. Additional data may also need to be generated to meet requirements under Good Manufacturing Practice.

Some of the types of data that may be needed are listed below, but refer to each type of change for full data requirements.

Comparative batch data - Active Pharmaceutical Ingredient (API) and drug product

Comparative batch data means a comparison of data between the pre-variation API/drug product and the proposed post-variation API/drug product.

Unless otherwise specified in these conditions, these data should compare at least the last three batches that were manufactured under existing conditions (using retention samples, if necessary) and the first batch made under the proposed new conditions, before the first batch is released. The second and third batches manufactured under the new conditions should be reviewed as soon as they become available, and the TGA should be promptly informed of any differences.

For manufacturing changes where multiple strength (three or more) products are involved and the various strengths are either direct scales (that is, the quantity of all excipients increases proportionally with the quantity of active ingredient) or have closely similar formulations, comparative data may be generated for the lowest and highest strengths only.

Comparative dissolution profiles

'Comparative dissolution profiles' means that data should be generated on three recent pre-variation batches and at least one batch of post-variation product as follows:

  • At least 12 dosage units (for example, tablets, capsules) of each batch must be tested individually, and mean and individual results reported.
    • The percentage of nominal content released should be measured at a minimum of three suitably spaced time points (excluding zero time point) to provide a profile for each batch (for example, at 5, 15, 30 and 45 minutes, or as appropriate to achieve virtually complete dissolution).
    • The batches should be tested using the same apparatus and, if possible, on the same day.
    • Test conditions should be those used in routine quality control or, if dissolution is not part of routine quality control, any reasonable, validated method.
  • To demonstrate the similarity of two dissolution profiles, the similarity factor, f2, should be calculated using the equation and conditions stated in Appendix I of the European Medicines Agency (EMA) Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr) (pdf,233kb).
    • The f2 value should be between 50 and 100.
    • In cases where more than 85% of the active substance is dissolved within 15 minutes in all tested batches, dissolution profiles are considered to be similar without the need to calculate the similarity factor.
  • Insufficient quantities of recently manufactured batches may be available to meet this requirement. In these cases, it is acceptable to test retention batches, and to explain in the test report why this was done, stating the age and storage history of the samples.

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