Over the Counter (OTC) Medicines Registration Requirements in Australia

My previous two blogs gave an idea about the general regulatory framework and prescription medicine registration requirements in Australia. Today’s blog, which is the third one in the series will cover aspects regarding Over the Counter (OTC) Medicines – drugs which can be purchased directly from a retail pharmacy or supermarket and does not need any prescription. The first thing to understand about OTC medicines is that these are less risky than prescription medicines. TGA has a defined framework for OTC just like in the case of prescription medicines but the requirements have been defined considering the risks associated with it, so it is not as stringent as prescription medicines. A medicine having paracetamol as an active ingredient with a long history of safe use would require less assessment as compared to a new antibiotic drug. A few other examples of medicines falling under these categories are cough and cold remedies, anti-fungal drugs or analgesics like aspirin.

Let us understand some basic and key aspects of TGA regulations for OTC medicines.

1)      OTC medicines can be supplied as a pharmacy medicine (included in schedule 2 to the Poisons Standard) or pharmacist-only medicines (included in schedule 3 to the Poisons Standard) or general category sales medicines not included in any schedules to the Poisons Standard.

2)      OTC medicines also need to be included in the ARTG for which the sponsor should lodge an application to the TGA.OTC medicines are either listed (low-risk medicines containing pre-approved ingredients and limited claims) or registered (high-risk) on the ARTG depending on the risk associated with its use. Registered OTC may be less risky than prescription medicines, but they still need to be assessed for certain aspects of quality, safety and efficacy before it is allowed to be marketed as an over the counter drug.

3)       An OTC application is submitted on-line through TGA business services (TBs). The legislative and regulatory requirements are outlined by TGA in their guidelines, Australian regulatory guidelines for OTC medicines (ARGOM). The format of the dossier is CTD which requires data submission to support safety, efficacy, quality of the product along with Module 1 requirements which include labelling, Product Information (PI), Consumer Medicine Information (CMI), as applicable, along with administrative documents.

4)      If the OTC medicines must be listed rather than registered, few more guidelines need to be referred to such as Australian Regulatory Guidelines for Complementary Medicines. If the OTC falls under the category of sunscreens, it must be registered and the TGA guideline-Australian Regulatory Guidelines for Sunscreens - has to be referred to.

5)      TGA keeps a tab on the OTC medicines by various mechanisms such as monitoring of adverse reactions or medicines defect through their ‘problem reporting system’, random sampling of approved products by TGA labs, GMP audits of sites manufacturing OTCs, Advertisement, and claim controls. Surveillance data collected through these mechanisms help them to re-assess benefit vs risk of medicines, and TGA may request from time to time labelling changes or changes to manufacturing as applicable. Product Recalls and removal of products from ARTG may be done as deemed necessary.

So, once you have understood the level of risk and the classification your OTC falls into, you would begin the registration process. As mentioned in my earlier blog on registration of medicines in Australia, you should have the client ID number and password to access the TGA business service. You will begin by first checking whether your OTC product/medicine has any new ingredient which would need assessment or whether it is already available on the approved ingredients list. If any ingredient is not listed, then ‘Notification of a Proprietary Ingredient Form’ must be submitted to get a proprietary ingredient number.

An important point to note is that sometimes even though the ingredients have been listed in the ingredients table, it may not have been approved for the proposed use or at the proposed concentration as mentioned in our medicines. In such cases, we should contact the OTC medicines team of TGA by email and seek the necessary clarifications and decide further course of action as per their suggestions.

If any of the ingredients used in our product require an assessment of safety or efficacy, then the required data should be submitted as mentioned in the TGA guideline – Guidelines for OTC applications for new substances. One of the most important guidelines to check at this stage would be -The Poisons Standard (SUSMP). Another guideline which needs to be looked into is ‘Adventitious agent safety of medicines.

Determining the correct application level is another important aspect that needs to be considered right at the onset, as the OTC medicines are classified into five levels, based on the risk. Also, each of these levels have different fees and evaluation timelines. TGA guideline for determining the correct application level required for OTC medicines provides various tools such as OTC application categorisation framework, OTC application route for umbrella branded medicines, OTC application flowchart and OTC application placement question and answer tool.

The five levels have been briefly covered below. One of the main criteria for each of these levels (except level N4) is that the medicine name must not include the risk associated with an umbrella branding segment which requires a higher level of assessment. Umbrella branding segment means a part of the medicine name used in two or more medicines is marketed to create a ‘brand’ for a range of medicine. Due to the possibility of potential consumers getting confused between the proposed medicine and the currently approved medicine within the umbrella brand, TGA only accepts extensions to Umbrella brands against meeting the specific requirements outlined in their guidelines in the relevant sections of ARGOM.

The first two levels namely N1 and N2 are for medicines with negligible risk.

N1- This includes ‘clone’ applications and an application for a flavour/fragrance/colour (FFC) variants of a Generic medicine (parent medicine). This means the OTC medicine is identical to an already approved medicine or the parent medicine apart from certain permitted differences. So, in this case, the data requirement is less as it is identical to a parent medicine. Some specific criteria to be met for this type of application is

i)         the total content of the FFC in the clone application is less than or equal to 2%w/w or w/v.

ii)       Parent medicine must not be a ‘grandfather medicine’ but instead would have been fully evaluated for safety, efficacy, and quality.

iii)     the medicine must comply with all relevant current requirements of standards including RASML [advisory statements for medicine labels]

iv)      and in case the sponsor of the parent medicine and the clone is not the same, full access rights to the parent medicine must be provided to TGA to access the data while reviewing the OTC clone application.

N2- New medicine application route for an OTC medicine. These medicines primarily need to meet two requirements

i)    it should fully comply with the specific OTC monograph provided by TGA on their website

ii)  data requirements provided in the guideline for N2 applications which includes requirements for labelling, active substances, formulation, manufacturing, control of excipients and finished product, container/measuring device requirements, stability and Certificate of Analysis (C of A) of two batches of finished product. N2 applications do not require extensive data submission or review and assessment by TGA and hence have shorter evaluation times. So to confirm that the products meet requirements, it also requires the list of assurances from the sponsors or agent or applicant, wherein you fill in a form providing the assurances concerning aspects of labelling, CMC data and submit the signed form in Module 1 of the application.

The next two levels are for medicines with low risk

N3- New application for generic medicines other than those in levels N1, N2 or N4. These submissions require submission of full quality data (CTD module 3) but do not require evaluation of safety and efficacy data. In cases where the quality aspects of the product are identical to a product already evaluated or approved by TGA then an abbreviated module 3 dossier including the finished product specification can be provided for the proposed product for which the OTC application is being submitted.

N4- is an application for generic medicine that requires data supporting safety and /or efficacy (clinical/toxicological) as well as quality data. These also include medicines that have not been included as OTC medicine following down scheduling, or it includes a risk assessment with an Umbrella branding segment requiring a higher level of assessment. Few example of medicines are – modified-release medicines (excluding enteric-coated tablets /capsules), generic medicines requiring bioequivalence study, medicines with a new excipient, or an excipient with a new route of administration or an excipient with a higher concentration than that which has been previously approved, applications that require both a brand equivalence statement, formulation dependent topical medicines. In N4 applications also there is a provision for providing an abbreviated Module 3 quality data in case the product is identical to a product already evaluated and approved by TGA. Justifications will be required for any data which is not being submitted as required for an N4 application.

N5- this includes a non-generic medicine such as generic extensions or a new chemical entity as an active ingredient with moderate risk. Extension to generic medicine may include new therapeutic indications, new strength, new dosage forms, new directions for use, new combination medicines or different populations. Here again complete information on safety, efficacy, and quality would be required unless similar/identical product has been approved in which case abbreviated module 3 and justifications may be provided for not providing complete information as required.

As soon you decide the type of application, the next step is getting well versed with the mandatory requirements, any OTC specific requirements, and guidelines adopted from the EU for these types of applications. Just like in the case of prescription drugs there are general dossier requirements that also need to be complied with. The labelling requirements as mentioned in TGO 92, standards for labels of non-prescription drugs should be complied with, as applicable. The OTC applications must be submitted electronically through online submissions via TGA business services (TBS) or via electronic media delivery. An email submission through TGAs eBusiness Services may be acceptable for certain submissions such as an eCTD submission through an email that contains a single compressed (zipped) attachment less than 30 MB in the size. Paper submissions are not accepted for OTC medicines.

The format of an OTC application is CTD but not all information would be required for each type and the specific technical data requirements for each type of application have been specified in the OTC guidelines – Mandatory requirements for an effective Over-the-counter medicines’ application. For example – Module 2.3 Quality Overall Summary will be required for an N5 application that has new active ingredients. It is not required for other N5 applications. Modules 2.4 to 2.7 which is for providing Non-clinical and Clinical Overviews and Summaries are required for only N4 and N5 applications. Such details about requirements of data for Module 3,4 and 5 have been provided in tabular form for ease of reference in the appendix of the guidelines and should be referred to while preparing an application. Any deviations from submitting the requirement or data will require a justification from the applicant.

One of the important aspects for an OTC application, just like prescription medicine applications, is ensuring you have valid evidence of GMP. The manufacturers of an OTC medicine that needs to be registered should have been certified to perform each step of manufacturing. Unless you include this in the application, the OTC medicine application will not be validated or accepted for review. For all local manufacturers, a GMP license issued by TGA is required whereas for foreign manufacturer a GMP clearance issued by TGA will be required. GMP evidence is required for each manufacturer mentioned in your application. The GMP clearance should not expire while the application is under review. So the minimum validity of the same should be 3 months for N1 applications, 4 months for N2 applications and 6 months for N3, N4, and N5 applications. If the applicant has applied for a renewal or extension of the GMP clearance while the application is being made the same has to be mentioned in the cover letter of the application. It is always better to apply for renewal than a request for extension.

Whenever an applicant submits an OTC medicine which need to be registered, he will be invoiced for the application fee and the evaluation fee. The screening of the application happens only after the payment of both the above fees. TGA has provisions for reduced fees for a concurrent application. So if an applicant submits an application and an additional application at the same time which has the same sponsor, same application level, same active ingredients, and common data set which will enable simultaneous evaluations, then the applicant is eligible for this concurrent fee reduction. Other waive off in fees are also possible which is detailed by TGA on their website under Schedule of fees and charges.

TGA will screen and validate the application after payment of fees and decide if it is effective or not effective application. Effective ones are taken ahead for evaluation, while the not effective ones are rejected by TGA citing reasons for the same. The evaluation fee is refunded in this case but the applicant will have to forfeit the application fee. TGA has target timelines for evaluation of different types of application which has been provided in detail on their website under target evaluation times for OTC medicine applications. It’s important to note that the timelines mentioned here are only TGA timelines and does not include the sponsor time (time taken by sponsor to respond to any additional request or query raised by TGA during review of an application), even though some standard response time allowed for providing response is mentioned by TGA. Similar to prescription medicines, unsolicited responses are not encouraged for an OTC application barring few related to updated safety information about the medicine and updated GMP status of manufacturing sites.

TGA sends their decision letter once the evaluation is completed and OTC medicine is approved to be registered. As soon as a decision letter is received the applicant should submit the patent certification and comply with all conditions mentioned in the decision letter. After receipt of the completed notification form and patent certification, TGA will register the medicine on the ARTG.

I hope this overview of OTC medicines registration will give you some insight into the requirements. Complete information on registration of OTC medicines is available on the TGA website on the following links:

https://www.tga.gov.au/over-counter-medicines

https://www.tga.gov.au/publication/australian-regulatory-guidelines-otc-medicines-argom-0

https://www.tga.gov.au/publication/otc-dossier-documents-matrix-0

OTC monographs https://www.tga.gov.au/publication/otc-n2-applications-and-otc-medicine-monographs

TGO labelling requirements for non-prescription drugs https://www.legislation.gov.au/Details/F2017C00744

See you soon with my next blog!!

Prescription Medicines Registration Requirements in Australia

TGA regulates prescription medicines (drugs that are prescribed by a medical practitioner) and has provided many guidelines to meet the regulatory and legislative requirements. Section 9 D (applicable for variations) and section 23 (applicable for new registrations) of the Therapeutics Good Act 1989, provides legislative basis for the regulatory requirements for applications which requires non-clinical, clinical and/or bioequivalence data along with quality and other information to prove safety, efficacy and quality of prescription medicines. Such applications fall under category 1 and category 2 and will include new drugs as well as generics.

The process defined for prescription drugs have certain key elements: -

1)     Management by Milestones – TGA’s process includes 8 phases with 8 milestones and established timelines for each phase. These phases include pre-submission, submission, first and second round assessment phase, consolidated section 31 request (queries) after first round assessment, expert advisory reviews, and two decision-making phases. TGA’s guideline - ‘Prescription Medicines Registration Process’ provides details about the phases and timelines that help in proper planning of dossier submission/lodgement to meet the product launch timelines. A brief overview of some of the initial phases has been presented below for ease of understanding of the regulatory process.

2)     Quality of Application –TGA does not accept any application for evaluation which is not of high quality and compliant to their requirements. The dossiers should be prepared according to the CTD format and TGA’s regulatory requirements. To achieve this objective the TGA’s guideline – ‘Mandatory requirements for an effective application’ must be well-understood and information provided accordingly. The technical requirements are as per ICH and CHMP guidelines adopted by the TGA.

3)     A pre-submission planning phase – This is the first phase and in this phase, TGA requires the lodgement of a pre-submission planning form (PPF) through the electronic business services (eBS). For doing this, refer to the TGA guidelines – ‘Pre-submission planning form’ and ‘Information for applicants completing a pre-submission planning form’. Another key requirement is the submission of CTD Module 2 that provides a brief summary of the pre-clinical, clinical and quality data. This helps TGA to plan their resources and define timelines/ milestones of the regulatory process. A planning letter providing key dates is provided by the TGA if it considers the PPF to be complete and acceptable. An applicant should lodge their PPF form with complete details at least 2_1/4 months before the submission of complete dossier. The applicants should propose a dossier lodgement date in the PPF form and ensure that the dossier submission happens as per the date mentioned here. The applicant should have clear visibility of data required and its availability before deciding to provide a date in the PPF.

4)     Submission of the complete dossier – After receiving the planning letter from TGA, a complete dossier must be provided in the second phase, understanding well that there is no scope of submission of any additional data after this phase, except if requested by the TGA. As per the procedure, the applicant certifies in the PPF that the information provided in the PPF and the dossier is completely aligned. Any new additional information, except those related to the safety of the medicines, new/renewed/updated TGA clearance certificate, or revised trade names will be considered as unsolicited information and a justification is required for any such data submission after the complete dossier submission phase. It is important to understand that the complete dossier submission needs to happen as per the date noted in the planning letter of the TGA. At the end of this Phase, TGA sends a notification letter to the applicant stating whether the application has been accepted or not accepted for evaluation.

5)     Initial evaluation phase and request for information under section 31 – In this phase, a consolidated list of queries or any additional information, as applicable is sent by the TGA after the initial evaluation of the complete dossier.

TGA’s regulatory framework has provided additional pathways for prescription medicines such as ‘Priority Review Designated Applications’ for faster assessment and approval of life-saving medicines and ‘Provisional Approval Pathway’ for medicines which has the potential for substantial benefit for patients. The eligibility criteria, step by step guidelines, and registration process for both the above pathways have been provided in detail at the TGA website.

For complex medicine submissions or for better understanding of requirements concerning an Orphan drug (medicines developed for rare diseases to treat small number of patients with specific conditions) status or eligibility for priority reviews, a pre-submission meeting may be requested by manufacturers, sponsors or agents, as this provides an opportunity for a face to face discussion with the TGA. A pre-submission meeting can occur any time before the submission of a PPF, but before requesting for a meeting, the process needs to be well understood by referring to the guideline ‘Pre-submission meeting with the TGA’. As per this guideline, certain information needs to be provided upfront to the TGA by completing the meeting request form and preparing a briefing package which may include an agenda, list of question for the TGA, summaries of studies and other relevant information. The briefing package must be sent at least 2 weeks prior to the scheduled meeting. More information regarding this is available on the TGA website.

There are some pre-conditions that must be met before starting the PPF phase of an application. For example, Orphan drug designation must be applied and granted by the TGA before lodging the PPF for orphan drug applications. Applications for orphan designation should be done at least 2-3 months in advance. The fee waivers applicable for orphan drug applications would be granted only if the ‘Orphan designation application’ has been approved by the TGA before lodging of the PPF. Similarly, for literature-based submissions (submissions which are not based on conventional approach of conducting a study and clinical trials, but instead solely depends on bibliographic data to support safety and efficacy claims), the applicant must seek the TGA’s agreement on the method or strategy employed for the search of literature and database to be searched. Here again, all discussions with the TGA should happen at least 3 months ahead of a PPF submission.

Other cases wherein pre-conditions apply are mentioned below. Complete information about the requirements for each of the listed applications is available in the TGA guidance ‘Prescription Medicines Registration Process’. 

a) Fixed-dose combination applications

b) Applications for registration of any new ingredients to be included in TGAs database 

c) Applications that may contain Genetically Modified Organisms (GMOs)

d) Applications which require rescheduling of existing substance in the Poisons Standard and 

e) Concurrent applications

All applicants are liable to pay the application fee (except for orphan drugs) upon lodgement of the PPF that allows the TGA to recover the cost for the processing of the PPF and arranging the resources for evaluation of the application. Please note that if the PPF is not effective or the dossier is not accepted for evaluation by the TGA, the application fees will be forfeited. There is another fee called evaluation fee which must be paid when the application is accepted for evaluation. The notification letter will specify the amount that must be paid. These fees must be paid within 2 months from the date of the notification letter. The fees and payment section on the TGA website provides information about the fees associated with different types of applications of prescription medicines.

TGA accepts electronic submissions and requirements have been provided for both eCTD and non-eCTD (like NeeS) in the respective guidelines available on the TGA website. TGA accepts hard copy submissions as well. There is another requirement for lodgement of application of all new chemical entity, new fixed-dose combination and new generic medicine application, which requires electronically lodging the application through eBS (electronic business service) prior to sending the hard copy or electronic copies of the dossier.  This means that applicants must create an application in eBS, take a printout of this same application form and the electronic lodgement cover sheet and include it in Module 1 of the dossier.

The TGA guideline - ‘mandatory requirements for an effective application’ includes details of all requirements applicable for new registrations as well as variations. It provides information about the legislative requirements, technical and administrative requirements, CTD format requirements and establishing bioequivalence or therapeutic equivalence requirements. Additionally, requirements concerning prescribing information, evidence of GMP, pharmacovigilance information (including a risk management plan, as applicable), studies required specifically for a new chemical entity or a generic application has also been provided in detail.

While all the requirements are mandatory, some exceptions may be accepted by the TGA, but only after assessment of a very robust scientific justification (which must be provided well before lodging a PPF) for not complying with the requirements. A few examples are justification for a generic application where the salt/ester form of a generic product is different from Australian reference product or a justification for including preservatives for single-dose injections.

Justification is also required for not providing a biopharmaceutics study against an Australian sourced reference product when the data is provided against an overseas reference product.

TGA’s guideline on the General dossier requirements provides further information on the language, measurements, provisions of Module 1 specific for Australia, and electronic data requirements. Labelling requirements are provided in Therapeutic Good Order No. 91 (TGO 91). These also need to be referred and complied with while preparing dossiers.

There may be cases when an application does not meet the TGA requirements, hence considered not effective and hence not accepted for evaluation. In such cases , an applicant may resubmit the application after ensuring all requirements and deficient aspects are met, by lodging a new PPF, and submitting a new dossier. Sometimes an applicant may realise that they will not be able to meet the dossier submission date. In such cases, the applicant should contact the TGA at the earliest. This allows the TGA to reallocate resources. But here again, the applicant will forfeit the application fee. If the applicant wishes to submit the same application on another date, they will need to lodge a new PPF again.

After submission of the dossier, the TGA will complete its first and second round assessments, request for any additional information as deemed necessary and complete all activities as per their defined phases and milestones and finally send the applicant a decision letter for approval of a new registration. After receiving approval, the applicant must provide a patent certification/notice. At this stage, the TGA will check all product information and then convert the provisional ARTG record, originally provided by the applicant during lodgement of the dossier, to an ARTG Record of Registration. There are certain obligations and conditions outlined in the decision letter which the applicant must meet, such as they must notify the TGA about the actual first date of commercial marketing. The final approved Product Information (PI) must be lodged with the TGA within 2 weeks of the date of registration of the product. The Consumer Medicines Information (CMI) for new products should be lodged prior to the first commercial supply of the product.

Since December 2009, the TGA has started publishing the Australian Public Assessment Report (AUSPAR) on it’s website, which includes decisions relating to the evaluation of prescription medicines and rationale for approving (or not approving) the same.

At the end of this blog, I would emphasise on the fact that before initiating any dossier for registration of the prescription medicine in Australia, take time to understand the legislative and regulatory requirements. There is a gamut of information available at the resource link provided below. Understand what is applicable for your specific application and ensure compliance!!

For first time readers, pls read this blog along with my previous blog titled Drug Registration in Australia-An Overview of the Regulatory Framework. My previous blog includes some general information that are also applicable for registration of prescription medicines.

My next blog will be on registration of OTC medicines in Australia. See you soon!!

Resource:

TGA website, https://www.tga.gov.au/prescription-medicines

Fees and charges, https://www.tga.gov.au/book-page/prescription-medicines-4