Transitional mandatory requirements
for an effective submission
Applicable for submissions lodged under the
streamlined submission process and received by
the TGA from 1 March 2011
Version 1.4, January 2011
Therapeutic Goods Administration
About the Therapeutic Goods Administration (TGA)
 The TGA is a division of the Australian Government Department of Health and Ageing, and is
responsible for regulating medicines and medical devices.
 The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management
approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards
of quality, safety and efficacy (performance), when necessary.
 The work of the TGA is based on applying scientific and clinical expertise to decision-making, to
ensure that the benefits to consumers outweigh any risks associated with the use of medicines
and medical devices.
 The TGA relies on the public, healthcare professionals and industry to report problems with
medicines or medical devices. The TGA investigates reports received by it to determine any
necessary regulatory action.
 To report a problem with a medicine or medical device, please see the information on the TGA
website.
Copyright
© Commonwealth of Australia 2011
This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any
process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights
should be addressed to the Commonwealth Copyright Administration, Attorney General’s Department, National Circuit, Barton
ACT 2600 or posted at http://www.ag.gov.au/cca
Transitional mandatory requirements for an effective submission
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Therapeutic Goods Administration
Version history
Version
Description of change
Author
Effective date
V1.0
First version – appendix 3 to the
Consultation document
OPM
02/10
V1.1
Amendments to reflect
consultation outcomes and current
status of business rules
OPM
10/10
V1.2
Amendment to reflect final
refinements
OPM
28/10/10
V1.3
EU Module 3 – Quality:
OPM
01/11
OPSS
04/11
 Inclusion of specific
requirements relating to sterile
products, sterile drug
substances and biologicals.
V1.4
Transferred to new template
Transitional mandatory requirements for an effective submission
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Page 3 of 20
Therapeutic Goods Administration
Contents
Overview _______________________________________________________________________ 5
Scope ___________________________________________________________________________ 5
Legislative and policy requirements _________________________________________ 5
Specific mandatory requirements____________________________________________ 5
Justifications ______________________________________________________________________________ 6
Related documents ________________________________________________________________________ 6
Opportunity to correct minor deficiencies __________________________________ 6
Australian-specific module 1 and other administrative requirements ____ 7
EU Module 2 – CTD Summaries _____________________________________________ 8
EU Module 3 – Quality _______________________________________________________ 9
EU Module 4 – Safety (non-clinical study reports) _______________________ 16
EU Module 5 – Efficacy (clinical study reports) __________________________ 17
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Therapeutic Goods Administration
Overview
This document details the mandatory requirements for a prescription medicine submission to be
considered effective during the transition period for the streamlined submission process.
Scope
 These requirements for an effective submission apply to applications to register a new
prescription medicine or changes to a prescription medicine that involve clinical, non-clinical or
bioequivalence data (i.e. category 1 and 2 submissions) that are lodged with the TGA from 1
March 2011.
 These requirements do not apply to applications seeking only the registration of one or more
additional trade names.
Legislative and policy requirements
Prescription medicine submissions lodged with the TGA to support applications must comply with
the requirements of the:
 Therapeutic Goods Act 1989
 Therapeutic Goods Regulations 1990
 all relevant:
–
–
Therapeutic Goods Orders
ICH and CHMP guidelines that have been adopted by the TGA
 Transitional prescription medicine streamlined submission process
 Australian regulatory guidelines for prescription medicines (ARGPM)
 transitional draft CTD Module 1 – Administrative Information and Prescribing Information for
Australia
 EU Common Technical Document (CTD) format documents adopted by Australia.
Any departures from relevant requirements or guidelines should be explicitly justified in the
submission and some may require prior liaison with the TGA (e.g. lodgement of a US CTD format
dossier). (See Justifications section below.)
In submitting a pre-submission planning form, the sponsor is required to declare that they
understand the TGA’s requirements for a submission to be considered effective and accepted for
evaluation.
Specific mandatory requirements
As described above, there are a number of legislative and policy requirements that a prescription
medicine submission must comply with.
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Therapeutic Goods Administration
However, it is the TGA’s experience that out of these requirements, there is a subset of
requirements that are frequently overlooked. Such issues are thus common causes for considerable
delays in evaluations and routinely result in the sponsor being asked to provide clarification or
additional information.
As a result, the TGA has developed a list of specific mandatory requirements that must be met for a
prescription medicine submission to be considered effective. These requirements are detailed in
Attachment A to this document and have been provided in order to assist sponsors in the
preparation of submissions so as to ensure they can be processed through the streamlined
submission process without unnecessary delay.
Where a submission does not include the requirements specified in the table, consideration will be
given by the TGA to whether it is not effective and therefore will not be evaluated. Most of these
requirements are existing requirements and are not additional requirements determined by the
new streamlined submission process.
It should be noted that Attachment A does not contain all the requirements necessary for an
effective submission and is not intended to replace the legislative and policy requirements listed
above. Further, some of the requirements may not be applicable to all types of category 1 and
category 2 submissions.
Justifications
The TGA recognises that not all of the requirements listed in this document will apply to all
submissions and all application types. Wherever possible, the conditions under which a
requirement is applicable have also been specified. However, in certain cases, the TGA will require
a robust scientific justification from the sponsor to demonstrate why a given requirement is not
relevant or applicable to the submission. (For a definition of a ‘robust scientific justification’, see to
the Q&A page on the TGA website.)
Where relevant, this document indicates where a justification may be appropriate.
It should be noted that for certain requirements, the TGA provides detailed information to assist
sponsors to construct a robust scientific justification (e.g. Appendix 15 of the ARGPM provides the
points to address for a justification for not conducting biopharmaceutic studies). However, where
such information is not provided, sponsors should contact the TGA for advice on what needs to be
addressed in a justification. Enquiries should be directed to the BPR project team.
Related documents
The current CTD requirements for quality, safety and efficacy, as adopted in Australia from the
European Union (EU) will be supplemented with these specific requirements in due course.
Opportunity to correct minor deficiencies
During the transition period, the TGA will notify sponsors of minor deficiencies in the submission
and allow two working days for them to be addressed. Failure to do so within the allocated time
may result in the TGA considering the submission to be not effective.
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Attachment A - Specific mandatory
requirements
Australian-specific module 1 and other administrative requirements
Section
Issue
Requirement
All
Requirements in the
transitional draft CTD Module 1
– Administrative Information
and Prescribing Information
for Australia
 The submission must meet all the relevant administrative and Module 1 requirements described in
the transitional draft CTD Module 1 – Administrative Information and Prescribing Information for
Australia document.
All
Electronic data
 Electronic copies of submissions must be provided. Each table of contents in an electronic copy of a
submission must have active links. Approval to be exempt from this requirement must be sought
from the TGA prior to lodging the submission.
All
Submissions that have
previously been rejected or
withdrawn
 Sponsors must identify how the deficiencies in the previous submission have been addressed in the
letter of application and must provide:
–
–
1.0
Letter of authorisation
full data set for each new submission. This is to ensure that the data evaluated by the TGA are
the current data relevant to that submission, or
completely new module 1 plus replacement volumes for those volumes that have changed, plus
any additional volumes. The letter of application must specify which modules and data volumes
from the previous submission should be used for the current submission.
 If a sponsor is acting on behalf of another sponsor, a letter of authorisation must be provided.
 Where the sponsor is using another company's name and/or livery on labels, a letter of authorisation
from the company owning the name/livery must be provided.
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EU Module 2 – CTD Summaries
Section
Issue
Requirement
2.4
Generic submissions
 A module 2.4 must be supplied for all new generic applications where the active ingredient is a different
salt/ester from the innovator’s active ingredient.
2.5
Generic submissions
 Module 2.5 must be supplied for all new generic applications.
2.7
Generic submissions
 Module 2.7 must be supplied for new generic applications where biopharmaceutic studies have been
provided in support of the application.
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EU Module 3 – Quality
Section
Issue
Requirement
3.2.S
Drug substance (name,
manufacturer)
 There are four options for providing the supporting data for the drug substances (active ingredients) in
a product – one of these options MUST be used:
–
–
–
–
drug master file (DMF) submitted
certificate of suitability (CEP) submitted
all aspects of drug substance manufacture (including sterile manufacture, if applicable) and control
has been previously approved by the TGA
drug substance is fully described in Module 3.2.S.
Note: If the drug substance is sterile and is not subjected to further sterilisation during finished product
manufacture, a CEP alone does not provide sufficient information for evaluation of sterility aspects. It may be
submitted in conjunction with one of the other options.
3.2.S
If a DMF is submitted
 The full quality control specifications applied to the bulk active ingredient by the finished product
manufacturer must be provided in module 3.2.S.
 If the drug substance is sterile and not subjected to further sterilisation, then full details of sterile
manufacture, its validation and associated microbiological validation of container integrity and
transportation, if applicable, must be provided as per guidance in 3.2.P and 3.2.P.7.
 Batch analytical data generated by both the drug substance and the finished product manufacturer(s)
must be supplied for typical batches of bulk active substance from each supplier.
3.2.S
If a CEP is submitted
 Documentation detailed in Appendix 11C of the ARGPM and module 1.6 of the CTD must be provided.
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Section
Issue
Requirement
3.2.S
If all aspects of a drug
substance manufacture
(including sterile
manufacture, if applicable)
and control has been
previously approved by
the TGA
 Details and scientific justifications must be provided of any additional tests and requirements (e.g. for
particle size distribution, polymorphic form, etc.) applied to the bulk drug substance before use in the
manufacture of the drug product(s) covered by the current submission
If the drug substance is
fully described in module
3.2.S
 A flow diagram of the synthetic process(es) must be provided.
3.2.S
 Validation data must be provided for these additional tests.
 Representative batch analytical data must be provided.
 For biotechnology products:
–
–
–
–
–
protein and DNA sequences of the drug substance must be provided
information on post-translational modifications and functional characteristics of product-related
substances must be included
information on the manufacturing process including fermentation, modification reactions and
purification should also be included.
information on development genetics, generation of cell substrate, cell banking and cell bank
stability must be provided (see ICH Topic Q5E: Comparability of biotechnological/biological
products.)
detailed validation data must be provided for all critical steps.
 For similar biological medicinal products, additional characterisation studies must be provided to
demonstrate comparability with reference product.
 If the drug substance is sterile and not subjected to further sterilisation, then full details of sterile
manufacture, its validation and associated microbiological validation of container integrity and
transportation, if applicable, must be provided as per guidance in 3.2.P and 3.2.P.7.
3.2.S
If any raw material or
excipient is plasma
derived
 The epidemiological data for the previous calendar year must be provided.
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Section
Issue
Requirement
3.2.S.4.3
Validation of test methods
 Validation reports for each test method must be provided within the PMF.
 All raw data supplied (e.g. SDS-PAGE photos or HPLC traces) must be clear and legible.
3.2.P
Drug product (name,
dosage form)
 The composition of each product and strength must be clearly defined.
 All ingredients must be listed as Australian Approved Names (AANs)/Australian Biological Names
(ABNs) or appropriate documentation submitted to the TGA for a new AAN/ABN to be created (also see
1.2.2 and module 4).
 Safety data (non-clinical and/or clinical) must be provided for any new ingredient which has not been
included in the ARTG previously or any ingredient administered via a new route of administration or
intended to be used for a different purpose.
 If tablets are scored to allow division, data must be provided to confirm that splitting is clean and the
portions produced comply with pharmacopoeial limits for uniformity of weight/content.
 For injections that are intended for single use, anti-microbial preservatives must not be included in the
formulation.
 For modified release dosage forms, investigation of the effect of ethanol on in vitro dissolution/release
must be included.
 Detailed validation data must be provided for all critical steps in the manufacturing process (including
any cleaning and/or sterilisation steps).
 For sterile products, validation data must be included and must cover the following:
–
–
for all products, bioburden information including presterilisation bioburden limits and for extended
processing times (including hold times), evidence to show that sterility or microbiological quality
(as applicable) is not compromised
products that are sterilised by filtration and aseptically filled or aseptically manufactured (as
applicable):
 containers/closures:
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Section
Issue
Requirement


parameters of the sterilisation processes and confirmation that these have been physically
and microbiologically validated to a SAL of 10-6
statement that processes to remove endotoxin have been validated to demonstrate a
reduction in endotoxin units of > 3-log
 sterilising filter:


confirmation that the membrane filter is tested for integrity before and after use
validation of the bacterial retention capabilities of the filter conducted in the presence of the
product
 statements of maximum permitted processing (holding, storage and filling times) during
manufacture
 media fill studies to validate the aseptic manufacturing process. Media fill studies should be
conducted under worst case conditions including maximum processing and filling times, and
should include simulation of all aseptic manufacturing processes, including those using previously
sterilised components
 for terminally sterilised products or sterilised active or excipients not subjected to further
sterilisation:


Transitional mandatory requirements for an effective submission
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physical and microbiological performance qualification studies and confirmation that these
studies show that a SAL of 10-6 is achieved throughout the maximum and minimum loads
statements of processing times (e.g. from start of compounding until terminal sterilisation).
Page 12 of 20
Section
Issue
Requirement
3.2.P.5
Control of drug product
 The proposed specifications for the finished product must be provided.
 Impurity limits which are above the ICH threshold(s) must be qualified by toxicology data or by
reference to an appropriate pharmacopoeial monograph. For generic medicine submissions, limits
above the ICH threshold may also be qualified by comparison with the Australian innovator product
near or just past expiry date.
 For endotoxin testing, the sponsor must provide the bacterial endotoxin specification.
 For sterility testing, the sponsor must provide a statement that sterility testing is performed according
to the current version of the harmonised pharmacopoeial (USP/BP/ Ph Eur) method.
3.2.P.5.2
Analytical Procedures
3.2.P.5.3
Validation of test methods
 A full copy of all test methods must be provided.
 Validation reports for each test method must be provided.
 All raw data supplied (e.g. SDS-PAGE photos or HPLC traces) must be clear and legible.
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Section
Issue
Requirement
3.2.P.7
Container Closure System
 The immediate and outer packaging and packaging materials (e.g. type of glass or plastic), pack sizes,
any dosing device, any induction seals and any desiccant or cotton wool contained in the package must
be defined and described – samples are not required.
 The full specifications and routine tests on the proposed marketing containers and closures must be
provided.
 If the product is packaged in a child-resistant container, a summary must be provided of the tests that
have been performed to ensure that the child-resistant properties of the packaging are not affected by
the contents and are retained throughout the product shelf-life, including during routine use. An
assurance must be provided that full details of compliance are held by the applicant and are available
for submission to the TGA upon request.
 For sterile injectable products:
–
–
–
for containers closed by fusion (i.e. ampoules), confirmation that containers are subjected to 100%
integrity testing
for containers closed by other means (i.e. vials, syringes), information on container/closure
integrity tests such as dye penetration or microbial ingress tests
for multi-dose injectables, confirmation that additional integrity tests are as per Ph Eur 3.2.9.
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Section
Issue
Requirement
 In the case of liquid products in a stoppered container, stability trials carried out on the product stored
in the inverted position must be provided.
 If there were any changes in test procedures during the course of the trials, comparison and correlation
of results generated by the alternative methods must be provided.
 For multi-dose products:
3.2.P.8
Stability
–
–
information on antimicrobial preservative efficacy data at the beginning and end of the closed shelf
life, as specified in TGO 77 Microbiological Standards for Medicines
information on microbiological challenge testing/simulated use testing as applicable, to support the
open shelf life (in-use) period.
 In the case of biological products, no less than 6 months real-time stability data should be supplied and
the shelf-life allowed will be no more than the amount of real-time data supplied.
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EU Module 4 – Safety (non-clinical study reports)
Section
Issue
Requirement
4
Non-clinical data for category 1 submission
type:
 Non-clinical data or a scientific justification for the absence of non-clinical data must
be provided.
 new chemical entity (new salt ester)
 new chemical entity (New combination of
active ingredients)
 major variation (new route of
administration; change in dosage, dose
regimen or maximum daily dose; change in
patient group)
 generic application (new isomer, mixture of
isomers, complex of, derivative of or salt of a
registered substance)
4
Excipients
 If the medicine contains an excipient used for the first time in a therapeutic product
in Australia, an assessment of the information relating to safety must be provided in
the non-clinical overview (Module 2.4) Non-clinical data must be provided for a new
excipient, an excipient with a new route of administration or an increased daily dose
or a justification for not providing data must be included in the submission. Also see
1.2.2 and 3.2.P.
4
Impurity qualification
 Toxicology data or scientific justification for impurities that are above the ICH
qualification threshold must be provided.
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EU Module 5 – Efficacy (clinical study reports)
Section
Issue
Requirement
5.3.1
Reports of
biopharmaceutic studies
 For a biopharmaceutic study using an overseas reference product:
–
–
5.3.1
Generic Medicine:
Immediate release oral
dosage forms
evidence must include comparative, quantitative analytical data from at least two batches of both the
Australian and overseas products
validation data for analytical test methods must be provided for the excipient analyses.
 Comparative bioavailability data must be provided to establish the bioequivalence of the generic
medicine and the corresponding innovator product/market leader in Australia, unless a scientifically
valid justification is included in the submission.
 If the in vivo data do not cover all strengths of the product, a comprehensive scientific justification in
accordance with ARGPM Appendix 15 must be provided.
5.3.1
Generic Medicine:
Modified release oral
dosage forms
 The following studies are required:
–
–
–
fed and fasted
steady state study versus an appropriate immediate release reference product or an appropriate
scientific justification must be included in the submission
in vitro-in vivo correlation studies or an appropriate scientific justification must be included in the
submission.
 If the ‘reference product’ used in the bioequivalence study(ies) was not obtained from Australia:
–
–
–
evidence must be provided (in accordance with ARGPM Appendix 15) to establish the physical,
physicochemical, qualitative and quantitative identity of the reference product used and the
corresponding product available in Australia
validation data must be provided for the procedures used in the quantitative analyses of the
excipients
data must be provided for at least two batches (including the batch used in the relevant study) from
the overseas country concerned AND at least two batches from Australia.
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Section
Issue
Requirement
5.3.1
New chemical
entity/biological entity:
Immediate release oral
dosage forms
 The following studies must be submitted unless justified:
–
–
–
–
–
5.3.1
5.3.1
absolute bioavailability study
study to establish that the proposed formulation is optimal (e.g. a study versus an oral solution of the
drug)
bioequivalence studies between the proposed registration formulation and pivotal clinical trial
formulations
bioequivalence studies amongst the various strengths proposed for registration
food effect study.
New chemical
entity/biological entity:
Modified release oral
dosage forms
 In addition to the studies required for immediate release oral dosage forms, the following studies must be
submitted or an appropriate scientific justification must be included in the submission:
Individual comparative
bioavailability studies
 The source from which the batch of reference products was obtained must be provided.
–
–
steady state versus an appropriate immediate release reference product
in vitro-in vivo correlation studies.
 If the batch of reference product was obtained from outside Australia, evidence that it is identical to the
corresponding product distributed in Australia must be provided.
 The individual calculated pharmacokinetic parameters (Tmax, Cmax, AUC, etc) together with their means,
standard deviations, etc. must be provided in tabular form.
 The statistical analyses (ANOVA, estimated ratios and 90% confidence intervals for the ratios) of Cmax
and AUC (and Cmin and degree of fluctuation for a steady state study) must have been carried out using
parametric analyses of log-transformed data and the results reported.
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5.3.1.1
Bioavailability study
 All submissions to register a new:
–
–
chemical entity, or
route of administration
must be supported by an absolute bioavailability study. Scientific justification for not supplying such a study
must have a scientific basis (for example where it is not feasible to prepare an intravenous formulation or
there is robust evidence to support lack of systemic absorption) and must not be based on a claimed lack of
necessity for the study.
5.3.4,
5.3.5
PD and dose ranging,
efficacy and safety studies
 The EU guidelines relevant to the specific product, as adopted by the TGA, must be taken into account. In
particular there must be:
–
–
–
adequate dose ranging studies to support the dose selected;
an appropriate pivotal study that relates explicitly to the indication proposed;
safety data should take into account the proposed duration of use and include information on
stopping the drug.
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Therapeutic Goods Administration
PO Box 100 Woden ACT 2606 Australia
Email: info@tga.gov.au Phone: 02 6232 8444 Fax: 02 6232 8605
www.tga.gov.au
Reference/Publication #