Author: Nicole Tan
Formulated ingredients or premixes are commonly used in many medicinal products – such as inks, coatings and colourants, fragrances and flavours, dosage form bases, and triturations or extracts of active substances. Some ingredients may need to be emulsified, powdered, suspended or dissolved in other media so that they can be used in the manufacturing process for certain dosage forms, e.g. oily substances in powders or tablets, insoluble particles in liquid suspensions or semi-solid bases.
Fortunately, ingredient mixes with physicochemical attributes that suit a drug product manufacturer’s needs are often commercially available from specialist manufacturers or suppliers, therefore avoiding substantial investments in in-house technology, equipment and skills to produce these at low volumes. However, the intellectual property (IP) – including the exact formulation and detailed manufacturing process and controls of these ‘proprietary’ mixes and extracts – remains with their manufacturer, who may baulk at sharing confidential information to their customers without the protection of non-disclosure agreements (NDA).
IP disclosure must nevertheless be balanced against regulatory requirements to assess information on the safety and efficacy of medicines – including those containing proprietary blends, or proprietary ingredients (PI) as they are known in Australia. Additionally, some ingredients, such as actives and those inactives with potential allergenic effects, may need to be declared on the medicines’ labelling.
In Australia, the TGA’s mechanisms for notifications of proprietary ingredients and active herbal extracts provide an alternative with the following key advantages:
- The premix/extract supplier discloses the qualitative and quantitative formulation to the TGA if it opts to withhold these from its customer, i.e. the drug product manufacturer or local product sponsor;
- The supplier determines that all ingredients in the premix are permitted for use, identifies its principal function(s) and the categories of therapeutic goods where it may be used;
- Once a PI or active herbal extract is listed on the Australian register (ARTG), the supplier does not have to submit the same information again but can provide the PI identifier to other product manufacturers or sponsors;
- The product manufacturer and sponsor can list the PI or extract as a single ingredient in their product formulation and labelling instead of the individual components; and
- Where the PI has little or no impact on safety or efficacy because of low levels present in the product or because of the inertness of its component ingredients, there may be no further need for additional information during the TGA’s review of the product’s registration dossier.
Product sponsors should understand that a PI is unique to its manufacturer/supplier, its formulation, manufacturing process and other proprietary information, and cannot, therefore, use the PI identifier in its product formulation if sourced elsewhere.
The PI manufacturer/supplier is responsible for ensuring the quality and safety of its premix or extract by ensuring that:
- Substances used in the premix are suitably controlled, and that appropriate good manufacturing practices and quality management systems are applied. Although formal GMP and QMS certification may not be required for many PIs, manufacturers of premixes that contain an active substance still need TGA accreditation, either through GMP licences or clearances.
- The notified formulation is accurate and maintained, so that the TGA, product manufacturers and sponsor are informed about significant changes resulting in a new PI – which will prompt variations to the registered details and labelling of affected products.
- Product sponsors are given accurate information on the presence or absence of substances with known effects.
Proposed changes under consultation
The mechanisms for notification of PIs and active herbal extracts were meant to reduce the need for information on these ingredients required by the TGA to assess quality, safety and efficacy of a product prior to its marketing authorisation.
The TGA and industry have noted however that since detailed quality information on active ingredients and herbal extracts are necessary in product registration dossiers submitted for evaluation, prior notification of these substances as premixes or non-standard extracts has become redundant, has led to misconceptions and claims about their use in products, can lead to delays in submission while the PI or extract is being processed, and involves extra administrative resources in notification and maintenance with little benefit to sponsors.
Thus, the TGA has proposed to discontinue notifications for ingredients that contain actives, i.e. premixes and herbal extracts. While it is expected that new PIs for actives will no longer be added, the transition to full disclosure of information on existing PIs is still to be worked out.
Additionally, the general PI category for ‘Excipient mix’ will also be deleted since it is a non-specific description of the premix’s function(s) that should be identified more clearly. When implemented, the notification of new proprietary ingredients will only be suitable for adhesives, capsule shells, coatings, colour mixes, flavours, sweeteners and fragrances, printing inks, preservative mixes, oral and topical dosage form (cream/ointment) bases.