Drug Registration in Australia – An Overview of the Regulatory Framework.

Registration of drugs in Australia requires a good understanding of its regulatory framework. The Therapeutic Goods Administration (TGA) regulates the approval and distribution of drugs in Australia. They have laid down rules and regulations concerning the import, supply, export, and manufacturing of drugs. In Australia, any therapeutic good is classified under three categories, i.e. Medicines, Biologics and Medical Devices. The TGA site gives detailed information about each classification and has devised a tool that helps to identify the category of a product/therapeutic good.

The TGAs assessment process is simple to understand as it is based on the risk associated with a product and its safety. A high-risk product requires more information and undergoes a rigorous assessment process for quality, safety, efficacy, and performance. Accordingly, the fee structure has been defined with higher fees for any product with higher risk and more data submission.

There are some key aspects very specific to Australia which we need to understand before initiating a registration and these have been listed below: -

1)   Australian Register of Therapeutic Goods (ARTG) - The ARTG is an electronic register that includes a list of all products that are marketed or supplied in Australia. It provides critical information such as the product name, API details, formulation details, details about the manufacturer or sponsor of the product. This is a good source of information to check which products are already approved and authorized for supply in Australia. For eg, if you are looking for the innovator drug available in the market for generic development you just need to check it in the ARTG database. The ARTG database includes products that have been registered (for example Prescription Medicines) as well as products that have been listed (for example Complementary Medicines). For import or export of any drug, you need to have an ARTG entry for your own product. Two important things to do before applying for entry in ARTG is –

a)         Set up as a sponsor

b)         Set up an account in TGA business service (TBS).

2)  Sponsor of the product – A sponsor is very critical for any registration in Australia. The sponsor of a product is a person or an organization who is responsible for the import, export or manufacture of drugs. They must be a resident of Australia, having a business of their own or associated with any company in Australia. They apply for registration and their name appears on the ARTG after the approval of the drug by TGA. Only after the entry of drugs in ARTG can it be sold in Australia. In most cases, the Australian manufacturers are the sponsors, but for overseas manufacturers, the application procedures need an eligible sponsor who would act as their representative and undertake a range of responsibilities on their behalf. Detailed information on sponsor’s responsibilities is available on the TGA website.

3)  TGA Business Service (TBS) – To manage a registration application and for using the online services of TGA, be it electronic submissions of registration dossiers or entry into ARTG, a manufacturer, sponsor or agent will need to have access to TGA’s secure online TGA Business Service (TBS). A client identification number (client ID) is needed and this will be the first step to get started with the TGA. Complete information on how to get this access is available on the TGA website and it is a simple process of applying through an organization form, by filling the required information and sending a signed form to TGA.

4)  In Australia, the medicines and chemicals are classified into schedules via a national classification system. This is done based on regulatory control required to ensure public health and safety. There are 10 schedules, and these are published in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) also known as the Poisons Standard. The SUSMP No. 24 (Poisons Standard June 2019) is available in electronic format at the TGA website and should be read and understood well to identify the correct schedule under which a medicine falls. It is a mandatory requirement to identify and mention the correct schedule in any application for registration or listing of drugs.

Similarly, another important aspect during the registration of a medicine or drug is to determine the type of category under which the medicine will classify. As per TGA, the medicines are categorised into the following categories :

Prescription medicines – any drug which needs to be prescribed by medical practitioners. This includes new drugs as well as generics medicines.

Over the Counter (OTC) medicines – any medicines which can be purchased directly without any prescription from retail pharmacy or supermarket.

Complementary medicines – generally include vitamins, homeopathic, ayurvedic and traditional medicines.

Biologics – generally a product of human origin.

Medical devices are another category that includes a range of goods like pacemakers and in-vitro diagnostic tools. Combination product is again a category which may include a combination of drug and device.

Understanding the category in which our medicine falls is of utmost importance as the application process, and regulatory requirements is different for each category. The fees, legal, technical, GMP, labelling, and packaging requirements may also vary for each of the above-listed categories.

For medicines, the legal requirements include many aspects such as manufacturing of drugs with highest GMP standards as applicable, maintaining labelling standards, generating data to support therapeutic claims, performing pharmacovigilance activities related to the product, taking recall actions as and when required, timely notification of adverse events, advertising of drug, paying registration fees and annual charges to maintain ARTG entry and notifying TGA about any change to the registered product.

The scientific or technical guidelines for TGA registrations are aligned with international standards and approaches. Predominantly, TGA has adopted many EU and ICH guidelines for registration of prescription, OTC or complementary medicines. TGA has provided information on its site with regards to EU guidelines adopted by TGA as well as the EU guidelines not adopted by TGA and these must be referred to in detail before initiating the registration process in Australia. In terms of default standards, TGA accepts any of the British Pharmacopeia (BP), European Pharmacopeia (EP), and United States Pharmacopeia – National Formulary (USP-NF).

TGA lists the ingredients (both API and excipients) with their approved names. All products must use ingredients with approved names during the manufacturing of the medicines/drug products for marketing in Australia. These are recorded in the ARTG and should be referred to during formulation development. This information can be accessed through the TGA business service. If the product contains any ingredients whose approved name is not in the ARTG, the applicant will need to propose a new ingredient name for approval and entry into ARTG. After the new ingredient name is approved and included in the ingredients table, the medicine/drug product will be considered for approval.

TGA regulates product labelling and packaging. For labelling applicable rules and regulations are TGO 91 and TGO 92, which includes standards for labels for prescription and non-prescription medicines respectively. Another important requirement is on advisory statements which must appear on labels for warning about specific risks about medicines. As a mandatory practice one should refer to the most recent versions of the above requirements before finalizing the labels for registration. Similarly, the Product Information (PI) and Consumers Medicine Information (CMI) are extremely critical elements of labelling and these must include relevant information as per requirements of TGA. The labelling guidelines require proper spacing in a label, placing of all critical information such as product name and strength, active ingredients, batch number, expiry date, storage conditions, dosage form, packaging colour and design, with some Australia specific requirements such as potassium labelling, methotrexate labelling, to name a few. In terms of packaging, there are requirements concerning tamper-evident packing, child-resistant packing and blister packing.

TGA’s GMP principles are based on quality by design (QbD) with emphasis on quality being built in the product. For the manufacturing of medicines or drugs, TGA follows Pharmaceutical Inspection Co-operation Scheme (PIC/S) GMP principles and guidelines. TGA is a member of PIC/S. TGA also accepts GMP of equivalent standards and hence recognises inspections and GMP clearance provided by stringent authorities like EMEA, EU authorities and FDA. The regulatory framework for registration of medicines/drugs requires TGA GMP clearance for overseas manufacturers as part of the registration of a drug. Approval is granted only after TGA has assessed that the required GMP criteria have been met by the manufacturers of finished formulations and API. TGAs GMP clearance guidelines of July 2019 provides complete information. GMP clearance can be obtained by any one of the pathways,

a) a mutual recognition agreement (MRA) desktop assessment,

b) a compliance verification (CV) desktop assessment or

c) an on-site inspection by TGA.

There is a GMP clearance fee applicable for such assessments and detailed information about fees as well as timelines of assessment is available on the TGA site.

In today’s blog, I have provided an overview of the regulatory framework in Australia. My next few blogs will delve more into requirements for Prescription, OTC and Complementary Medicines. See you soon!!


Resource:

TGA website: https://www.tga.gov.au/industry

Quality Metrics – FDA’s initiative towards a better Quality Management System (QMS).

Quality Metrics is an initiative to assess the effectiveness of the quality system of a firm. FDA’s guidance on quality metrics requests firms to provide data for an establishment manufacturing an API or finished formulation which would help them to understand the robustness of the process, laboratory operations and quality complaints.

The main goal of the FDA in implementing quality metrics is to measure the quality of a site and its systems. This will allow them to do a risk-based evaluation and better management of site inspections. FDA would work more closely and transparently with firms to ensure compliance of any site. They strongly believe that quality metrics will play an important role to achieve their vision of the desired state of quality in the 21^st century. It will also help to manage supply disruptions and drug shortage issues.

FDA draft guidelines published in Nov 2016 gives information concerning data submission and reporting of quality data. The initial phase is a voluntary program wherein the pharmaceutical firms will share data or observations gathered from their self-inspections. The FDA does not intend to take any enforcement action based on the data submitted by Industry provided the data is submitted in good faith. There are a lot of benefits of participating in this program, with the FDA working with sites informally for early resolution of their potential quality problems.

Most firms currently have some or other forms of quality metrics to continuously monitor the effectiveness of their quality system. The current process includes – annual product reviews (APR) or periodic product reviews (PPR), trend analysis, process validations and verifications, periodic inspections of the site and the systems. FDA recommends firms to go a step further and include more parameters such as compare metrics of different products manufactured at the same site, compare metrics of same product manufactured at different site and, the trend of data from a facility or site over sometime. These can be assessed by simple calculations such as :-

1) Lot acceptance rate

2) Invalidated out of specification (OOS) rate and

3) Product quality complaint rate

Another critical aspect is understanding the effectiveness of a firm’s Corrective and Preventive Action (CAPA). A CAPA is an important tool which helps to understand how well a firm can complete the root cause analysis of any quality problem and what measures are taken by the firm to ensure continuous improvement of the quality systems.

FDA suggested metrics will be extremely useful in having a common standard of measurement while there is a flexibility to measure additional indicators as deemed necessary by the firms to maintain their quality culture.

FDA data proves that adopting quality management programs early on has obvious advantages for firms such as operational excellence and high-quality culture which ultimately leads to good business and less surveillance by the FDA for high performing firms.

FDA intends to make this requirement mandatory after the voluntary phase is over as it will encourage the implementation of innovative quality management systems while helping the FDA to develop its compliance and inspection policies. It will surely help to resolve the issues of drug shortages which occurs predominantly due to either quality or manufacturing problems.

In June 2018, FDA announced two more voluntary programs, viz. quality metrics feedback program and quality metrics site visit program and posted frequently asked questions regarding both these programs.

The obvious question is will FDA’s vision turn into reality, and will the industry shift its focus on the use of science and risk-based principles rather than focussing on their current approach which is based on compliance of minimum requirements while managing the quality system. Looking at the way things are progressing through industry participation in voluntary programs and exchange of information between FDA and industry through pilot and feedback programs, there is a high probability that quality metrics are adopted as key indicators and will be implemented soon by the pharmaceutical industry.

My next blog onwards I will be sharing information on drug registration procedures and I will begin with sharing information about TGA’s (Australia’s) regulatory framework. See you soon!!