Information on quality for the medicine/finished product

Description and composition of the medicine

Provide the medicine name and a description of the finished product that includes a visual description of the dosage form, including any special characteristics, for example: modified release.

Medicine development

Formulation details for the medicine

Include a table of all the ingredients in the product (using Australian approved name (AAN) terminology) which details:

• the purpose of each ingredient in the formulation, for example: active, disintegrant, antimicrobial preservative
• amount of each ingredient on a per unit basis
• any overages (additional amounts of ingredients, over the amounts nominated in the product's formulation, added during manufacture)
• a reference to the quality standard for each of the ingredients, for example: a pharmacopoeial monograph reference or manufacturer's specifications number.

Each excipient ingredient included in a formulation must have a justifiable excipient role and be used in appropriate amounts to achieve its technical purpose.

Formulation development

Information on the development of the medicine should be provided, including a discussion of the studies that led to the proposed dosage form, formulation, method of manufacture and container.

Overages and batch to batch variation

If an overage of an active ingredient (an additional amount of an ingredient added during manufacture and greater than the amount nominated in the product's formulation) is used during manufacture, details and justification of the overage used should be included in the medicine development summary.

For some active ingredients, such as herbal substances, the weight of the active raw material used in a batch of the formulated product may vary according to the content of a standardised component. The formulation given in the application should have an annotation indicating that the actual weight of active raw material will vary according to its estimated amount, and a formula should be provided showing how the amount of adjustment will be calculated. Validation data should be provided for the extremes of proposed ranges. Critically, where the product is a tablet or capsule, the validation data should include dissolution or disintegration data, using the test method in the proposed finished product specifications.

It is recognised that it may be necessary to vary the quantities of certain excipients from batch to batch in order to achieve acceptable results during manufacturing. Table D6 lists the changes to the nominal amounts of certain excipients that may be made in the manufacture of immediate release registered complementary medicines.

Physiochemical and biological properties

Where a medicine has modified release characteristics or an unusual method of manufacture, the medicine development summary should include a detailed discussion of the development of those characteristics or method and any relationship with the finished product specifications. For example, for an enteric-coated tablet, dissolution and formulation studies performed during development should be discussed and related to the dissolution test in the finished product specifications.

Manufacturing process development

The selection and optimisation of the manufacturing process, particularly its critical aspects, should be explained. Where relevant, the method of sterilisation should be explained and justified.

Describe any significant changes made to the manufacturing process of the medicine used in producing scale-up, pilot and production-scale batches that may affect the composition of the substance.

Container closure system

The suitability of the container closure system used for the storage, transportation (shipping) and use of the medicine should be discussed. The discussion should consider such things as: choice of material, protection from moisture and light.

Microbiological attributes

Where appropriate, microbiological attributes of the dosage form should be discussed, including such things as the rationale for not performing microbial limits testing for non-sterile products. For sterile products, the integrity of the container closure system to prevent microbial contamination should be discussed.

Compatibility

Where applicable, the compatibility of the medicine with reconstituent diluents or dosage devices should be addressed to provide appropriate and supportive information for the labelling.

Manufacture of the medicine

Manufacturer information name/s

All medicines must be manufactured in accordance with the principles of good manufacturing practice. The manufacturer of each step in the manufacture of the medicine that occurs in Australia must be licensed to perform that step. If a step in manufacture is carried outside Australia then the manufacturing and control procedures used in the manufacture must be acceptable. Australian manufacturers must comply with the PIC/S Guide to Good Manufacturing Practice for Medicinal Products.

The TGA has produced guidance for sponsors who rely on international manufacturers for any part of their production process. Refer to:

• GMP clearance guidance
• Questions & answers on the code of good manufacturing practice for medicinal products.

Batch formula

A batch formula should be provided in a table format. It should include all of the components that will be used in the manufacture of the finished product and their amounts on a per batch basis (including any overages).

Description of manufacturing process and process controls

Details of the manufacturing process for the finished product should be provided for each manufacturing site. Typically, these steps may include the manufacture of the dosage form, packaging and labelling, chemical and physical testing, microbiological testing and release for supply. The manufacturing details should include a manufacturing formula and also information on:

• solvents that are used, even if they are evaporated from the medicine during manufacture
• polishing agents that do not appear in the formulation.

Control of critical steps and intermediates

Tests and acceptance criteria that are applied to critical steps or intermediates in the manufacture of the finished product should be provided, such as: manufacturing acceptance criteria for a tablet granulation or in-process controls for pH during mixing of a syrup.

Process validation and/or evaluation

Description, documentation and results of the validation and/ or evaluation studies should be provided for critical steps or critical assays used in the manufacturing process.

Control of excipients

Excipient ingredients subject to a specific monograph in a default standard must comply with the requirements of that monograph. If there is no relevant monograph for the ingredient, full details of the specifications for each excipient are required.

Note that there are additional restrictions and requirements for ingredients that are of animal or human origin or that are genetically modified organisms or genetically modified products.

Colours permitted in oral medicines are specified in the guidance 'Colourings used in medicines for topical and oral use' is available on the TGA website. While topical products may include colours other than those listed in this document, the specifications for colourings used in topical products should be comparable with those permitted for oral use.

In the absence of a default standard, colours should generally conform either to the specifications in the FAO/WHO Compendium of Food Additive Specifications or to those defined in the European Commission Directive 95/45/EC.

Specifications

The specifications of excipients should be provided.

Analytical procedures

The analytical procedures used for testing the excipients should be provided, where appropriate.

Validation of analytical procedures

Analytical validation information, including experimental data for the analytical procedures used for testing the excipients should be provided, where appropriate.

Justification of specifications

Justification for the proposed excipient specifications should be provided, where appropriate.

Excipients of human or animal origin

For excipients of human or animal origin, information should be provided regarding adventitious agents.

Novel excipients

For excipients used for the first time in a medicine or by a new route of administration, full details of manufacture, characterisation and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the medicine ingredient format.

Control of the finished product

Specifications

The finished product specifications should be provided. Refer to Finished product specifications, certificate of analysis for guidance on the information required in a finished product specification.

The specification should include both the batch release and expiry specifications. Where the expiry specifications differ from the batch release specifications, this should be noted. The batch release limits must be chosen in order to guarantee that all batches will comply with the expiry specifications throughout the product's shelf life. The limits applied at batch release should be discussed in terms of their ability to ensure this.

The specifications should take into account any overages and the results obtained in the stability studies.

Where the product is subject to a default standard the expiry specifications must include all of the tests and limits therein. If the applicant considers that nominated test methods are unsuitable for the product, the applicant may propose other, appropriately validated, methods.

Useful guidance on the development of product specifications is provided in the following scientific guidelines:

• Specifications: Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances CPMP/ICH/367/96

For demonstration of quality for herbal complementary medicines, the following scientific guidelines provide useful guidance:

• Quality of herbal medicinal products/ traditional herbal medicinal products EMA/CPMP/QWP/2819/00 Rev. 2
• Test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products CPMP/QWP/2820/00 Rev. 2
• Quality of combination herbal medicinal products/ traditional herbal medicinal products EMEA/HMPC/CHMP/CVMP/214869/06

Specifications should also take into account Australian legislative requirements for finished products.

The general monographs of the BP, Ph. Eur. and USP are also relevant, for example: the BP monograph for oral liquids, which includes requirements for dose and uniformity of dose of oral drops and also uniformity of delivered dose from multidose containers. The most recent edition of the cited pharmacopoeia should be used.

Where a finished product does not comply with Australian legislative requirements, for example: Therapeutic Goods Order No. 78 - Standard for Tablets and Capsules (TGO 78), a consent to supply the product is required - refer to Consent to supply goods that are not compliant with prescribed standards.

Analytical procedures

Details of analytical methods should be provided for all tests proposed in the specifications. Appropriately validated methods should be used.

Validation of analytical procedures

Details of the analytical method validation should also be provided in the dossier.

Batch certificates of analysis

You must provide at least three certificates of analysis for the final product to demonstrate compliance with batch release specifications. These certificates should relate to one or more production batches of the medicine or to trial batches if production batches have not been manufactured. In such a case, you should identify any differences between the trial process and the manufacturing process and undertake to provide certificates of analysis for at least two production batches after registration has been achieved.

Characterisation of impurities and requirements for non-pharmacopoeial products

Solvent residues

It is necessary to consider the total amount of residual solvents that may be present in the finished product. This includes solvent residues resulting from the manufacture of the finished product. Depending on the amounts and types of solvent residues, it may be appropriate to include a test and limits for residual solvents in the finished-product specifications. Tests and limits in the specifications, or justification for not including them, should be based on the BP Appendix VIIIL - Residual Solvents.

Impurity requirements for non-pharmacopoeial products

The specifications for finished products for which there is no default standard, should include tests and limits for impurities related to the active ingredient. For impurity limits, the results of stability studies should be taken into account and reference should be made to information on toxicity. Specifically, the amount and types of impurities that were detected in the stability studies should be consistent with the expiry specifications and the proposed shelf life. Consideration also needs to be given to the materials examined in the toxicity studies so that the product is consistent with the submitted safety data.

Where the active ingredient is a chemical entity, guidance on the amount and type of information needed on degradation products of the active ingredient can be found in the scientific guideline: Note for Guidance on Impurities in New Drug Products CPMP/ICH/2738/99.

Microbiological requirements for non-sterile products

All non-sterile dosage forms should include limits for microbial content in the finished product batch release and expiry specifications. The Therapeutic Goods Order No. 77 - Microbiological Standards for Medicines (TGO 77) specifies the minimum microbiological requirements with which a medicine must comply throughout its shelf life.

It is not a requirement that every batch of a product (with a low risk of contamination) be tested at batch release. Once it has been demonstrated, by testing a number of routine production batches to establish a product history, that the manufacturing processes do not permit contamination by excessive numbers of microorganisms, testing may be reduced to once every 6 to 12 months or some other selected basis, for example: every tenth batch.

Products with significant water content (for example: creams, gels and oral liquids) are likely to support microbial growth. Such products should include tests and limits for microbial content in both the batch release and expiry specifications.

For products containing an antimicrobial preservative, both the batch release and expiry specifications should include physicochemical tests and limits for content of preservatives. Given that the effectiveness of many preservatives is pH dependent, the specifications for such products should usually include requirements for pH that will ensure preservative efficacy. The expiry limits for the preservative should be supported by preservative efficacy testing that is performed during stability testing.

Microbiological requirements for sterile products

The official requirements for sterility tests in Australia are those specified in the current default standards. The TGA Guidelines for sterility testing of therapeutic goods provide guidance for sterility testing of sterile therapeutic goods supplied in Australia for human use. These guidelines, however, are not mandatory for industry.

Generally, products that are required to be sterile (for example: for ophthalmic use) will require extremely stringent microbiological specifications together with detailed information on manufacturing steps that ensure sterility.

Justification of finished product specifications

The suitability of the tests, limits and test methods proposed for the finished product should be discussed with reference to relevant standards, the results of the method validation studies and the ability of the specifications to guarantee the quality and consistency of the finished product.

Reference standards or materials

Information on the reference standards or reference materials used for testing of the medicine should be provided, if not previously provided.

Container closure system

A description of the container and closure system should be provided, including the materials used. The suitability of the container should be discussed in terms of its compatibility with the medicine and also its performance in protecting the medicine physically, including from exposure to moisture and light.

In the case of 'standard' package types, it may be sufficient to simply describe the packaging. Many applicants provide diagrams of the packaging material, identifying bottle or box dimensions, and this is helpful. If the packaging material is unusual, very detailed information should be provided on its composition, as well as an assessment of the potential for undesirable material to be leached from the packaging into the medicine.

Child resistant closures

TGO No. 80 - Child-Resistant Packaging Requirements for Medicines (TGO 80) specifies requirements relating to the use of child-resistant packaging (CRP) for medicines which may present a significant risk of toxicity to children if accidentally ingested and also specifies the performance requirements that packaging must meet in order to be considered child-resistant. TGO 80 applies to medicines containing any of the ingredients specified in the First Schedule to the Order, as well as other medicines that imply, through their presentation, that the packaging is child-resistant. Presentations considered to indicate child-resistant packaging include closures with the push-down and turn graphics, typically used on child-resistant caps, and label statements referring to the closure as being child-safe or designed to prevent access by children.

Tamper-evident packaging

Tamper-evident packaging (TEP) of therapeutic goods that may be vulnerable to tampering (either deliberate or accidental) is important in ensuring consumer safety and the integrity of the goods. Where sponsors may choose to apply TEP to therapeutic products, the products should meet the requirements of the Tamper-evident packaging (TEP) code of practice. This code of practice refers to therapeutic goods that are unscheduled or in Schedule 2 or 3 to the Poisons Standard and are administered transdermally, orally or come into contact with mucous membranes.

Measuring devices

Under current Australian legislation some measuring devices or dose delivering devices may be considered as Class 1 medical devices - please refer to the Australian Regulatory Guidelines for Medical Devices (ARGMD) for further guidance.

Finished product stability

Stability summary and conclusion

The types of studies conducted, protocols used and the results of the studies should be summarised. The summary should include, for example: conclusions with respect to shelf life and, if applicable, in-use storage conditions and shelf-life.

Stability data

The stability data must be sufficient to demonstrate, or indicate with a high probability, that the medicine intended for market will remain safe, of consistent quality and efficacious throughout the its shelf life. The stability data will form the basis for setting a shelf life and recommended storage conditions. Refer to the scientific guideline: Guideline on Stability Testing: Stability Testing of Existing Active Substances and Related Finished Products CPMP/QWP/122/02 rev 1 corr.

Post-registration requirements

Sponsors of therapeutic goods are required to carry out an ongoing stability testing program on each product (refer to the PIC/S Guide for Good Manufacturing Practice for Medicinal Products).

Where a shelf life has been allocated on the basis of:

• accelerated testing
• data generated on a related formulation
• data generated on the same formulation in a different container; or
• data generated on batches other than production batches.

It is a requirement to provide an assurance that full stability testing will begin on at least the first two production batches and continue for the full period of the product's shelf life (at the recommended storage condition) and that any adverse trends will be reported to the TGA.

Data may be requested for review at any time or followed up by the TGA's inspectors during GMP inspections of the manufacturing site. If it is found that the required testing has not been carried out or that adverse trends have not been reported to the TGA, appropriate action may be taken, which may include cancellation of the medicine's registration.

Stability protocol for self-assessable shelf life extension

A medicine's shelf life may be extended on the basis of stability testing conducted according to a protocol specifically approved for this purpose. For a stability protocol to be considered for the purpose of self-assessable shelf life extensions, it is normally necessary for at least twelve months data, generated at the maximum recommended storage temperature, to be available on at least two production batches of the proposed formulation, in the container proposed for marketing or one that is less protective.

To provide a suitable margin of safety, the limits for results of critical test parameters should normally be a little tighter than the expiry limits. Where some results are outside these limits, the sponsor may submit the data for evaluation by the TGA.

The protocol should be a stand-alone document, which includes:

• a statement of the intended purpose (for example: 'This protocol is intended for notification of shelf life increases of up to x years following self-assessment of stability data')
• a statement of the criteria for notifying a shelf-life increase (for example: 'Full-term stability data will be generated using two production batches stored at x°C'. All analytical results obtained will comply with the protocol acceptance criteria; otherwise, the TGA will be notified immediately')
• the precise formulation of the medicine (if overages are included, this should be stated and a justification provided)
• the immediate container specifications
• the storage conditions to be included on the label
• the finished product expiry specifications and the protocol acceptance criteria (including acceptable limits for results of each test)
• a statement of the proposed tests and validated test methods (validation data should be included if it has not already been supplied to the TGA)
• a matrix indicating the time stations at which each of the tests will be conducted as well as the storage conditions to be used in the study.

Shelf life extensions according to an approved protocol

Provided that a protocol for self-assessable shelf life extensions has been approved by the TGA for a particular product, the shelf life extension for that medicine may be implemented following notification to the TGA, provided that:

• all results up to the end of the notified shelf life fall within the acceptance criteria as specified in the approved stability protocol
• no other changes to the information previously provided to the TGA about this medicine (other than as specified in the notification) have been made, or are currently proposed to be made
• a stability testing protocol has been approved and a copy of the approval letter is attached to the notification
• at least two full production batches of the Australian formulation packed in the approved container have been used in the studies
• the shelf life is not longer than the time for which stability data meeting the approved protocol are available, and in any case is not longer than five years.

Prospective extensions of shelf life for individual batches

Under certain circumstances, the TGA may approve a limited extension of shelf life for individual batches approaching their expiry date in the absence of the stability data. The prerequisites are as follows:

• the existing shelf life should be at least two years
• stability data should be available to the TGA which validate the existing shelf life
• a recent (less than two months old), dated certificate of analysis should be supplied for the batch, showing compliance with specifications, together with the results obtained at batch release
• the sponsor should provide an assurance that it has commenced or intends to commence a stability study to validate a permanent extension of the shelf life, unless it is intended as a purely one-off event to ensure continued supply.

Prospective extensions of more than six months, or to a shelf life of more than five years, are not normally acceptable.