Transitional mandatory requirements for an … · Web viewOverview This document details the mandatory requirements for a prescription medicine submission to be considered effective

Transitional mandatory requirements for an effective submissionApplicable 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 2011This 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 submissionV1.4 January 2011 Page 2 of 20


Version history

Version Description of change Author Effective dateV1.0 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: Inclusion of specific requirements relating to sterile products, sterile drug substances and biologicals.

OPM 01/11

V1.4 Transferred to new template OPSS 04/11

Transitional mandatory requirements for an effective submissionV1.4 January 2011 Page 3 of 20


ContentsOverview________________________________________________________________________5Scope____________________________________________________________________________5Legislative and policy requirements_______________________________________5Specific mandatory requirements__________________________________________5Justifications________________________________________________________________________________6Related documents_________________________________________________________________________6Opportunity to correct minor deficiencies________________________________6Australian-specific module 1 and other administrative requirements____________________________________________________________________________________7EU Module 2 – CTD Summaries______________________________________________8EU Module 3 – Quality_________________________________________________________9EU Module 4 – Safety (non-clinical study reports)______________________16EU Module 5 – Efficacy (clinical study reports)__________________________17



OverviewThis 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 requirementsPrescription 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 requirementsAs described above, there are a number of legislative and policy requirements that a prescription medicine submission must comply with. 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 Transitional mandatory requirements for an effective submissionV1.4 January 2011 Page 5 of 20

http://www.tga.gov.au/industry/pm-ctd.htm



http://www.tga.gov.au/industry/pm-argpm.htm

http://www.tga.gov.au/industry/pm-ssp.htm

http://www.tga.gov.au/industry/pm-euguidelines-adopted.htm

http://www.tga.gov.au/industry/legislation.htm




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. JustificationsThe 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 documentsThe 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 deficienciesDuring 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.



mailto:[email protected]

http://www.tga.gov.au/industry/pm-ssp-qa.htm

Attachment A - Specific mandatory requirementsAustralian-specific module 1 and other administrative requirements

Section Issue RequirementAll 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:– 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.1.0 Letter of authorisation 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.


EU Module 2 – CTD Summaries

Section Issue Requirement2.4 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.


EU Module 3 – Quality

Section Issue Requirement3.2.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.


Section Issue Requirement3.2.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 Validation data must be provided for these additional tests. Representative batch analytical data must be provided.

3.2.S If the drug substance is fully described in module 3.2.S A flow diagram of the synthetic process(es) 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.


Section Issue Requirement3.2.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:


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:

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).


Section Issue Requirement3.2.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 A full copy of all test methods must be provided.

3.2.P.5.3 Validation of test methods 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.


Section Issue Requirement3.2.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.


Section Issue Requirement

3.2.P.8 Stability

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:

– 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.


EU Module 4 – Safety (non-clinical study reports)

Section Issue Requirement4 Non-clinical data for category 1 submission type: 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)

Non-clinical data or a scientific justification for the absence of non-clinical data must be provided.

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.


EU Module 5 – Efficacy (clinical study reports)

Section Issue Requirement5.3.1 Reports of biopharmaceutic studies For a biopharmaceutic study using an overseas reference product:– 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.5.3.1 Generic Medicine: Immediate release oral dosage forms 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.


Section Issue Requirement5.3.1 New chemical entity/biological entity: Immediate release oral dosage forms The following studies must be submitted unless justified:

– 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.5.3.1 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:– steady state versus an appropriate immediate release reference product– in vitro-in vivo correlation studies.5.3.1 Individual comparative bioavailability studies The source from which the batch of reference products was obtained must be provided.

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.


5.3.1.1 Bioavailability study All submissions to register a new:– chemical entity, or– route of administrationmust 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.


Therapeutic Goods AdministrationPO Box 100 Woden ACT 2606 AustraliaEmail: [email protected] Phone: 02 6232 8444 Fax: 02 6232 8605www.tga.gov.auReference/Publication #

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Transitional mandatory requirements for an … · Web viewOverview This document details the mandatory requirements for a prescription medicine submission to be considered effective