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Guidance on the two mechanisms to provide information about a drug substance sourced from a third-party manufacturer.
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This guidance is intended for manufacturers of drug substances for prescription medicines, and sponsors of prescription medicines sourcing drug substances from a third party manufacturer.
There are two mechanisms by which a sponsor can provide information about a drug substance sourced from a third-party manufacturer:
A CEP does not contain sufficient information and will not alone be accepted.
A DMF is required for all drug substances that are sourced from a third-party manufacturer, except for the following substances:
However, sponsors should include information (e.g. a certificate of analysis) to demonstrate that any common inorganic salts or simple organic compounds used as drug substances:
Note
- Any nonpharmacopoeial specifications need to be assessed by the TGA to determine their appropriateness and adequacy to ensure the quality of the substance.
- The evaluation of an application will not commence until the TGA receives the DMF.
- Mention the specific version number of the DMF in the application.
For a drug substance and drug product manufactured by the same company, include information on the production, quality control and stability of the drug substance as either:
The preferred format for DMF is the European Common Technical Document (CTD) format or the European format. However if the manufacturer has not used either of these formats, the TGA will accept a drug master file in the United States format.
Guidance for sponsors
A Proforma Letter of Access to DMF is available in Module 1.6.3 of the CTD.
Request the manufacturer to:
Note
The proforma for Letters of Access used in Europe is not acceptable.
Sponsors have an obligation under the standard conditions of registration, imposed under s. 28(3) of the Therapeutic Goods Act 1989 (the Act), to ensure no changes are made to the product, including the drug substance, without their knowledge and TGA approval (if required).
Sponsors need a formal agreement with the manufacturer of the drug substance that ensures they will be notified before any changes are made to the drug substance.
Sponsors are responsible for determining whether:
DMFs should be updated periodically to reflect any changes, and ensure that one of the following is forwarded to the TGA before the changes are implemented:
The TGA has adopted the European Medicines Agency (EMA) Guideline on active substance master file procedure (CPMP/QWP/227/02 Rev 1) adopted with annotation. In addition to the requirements of the above EMA guideline; further information is required in the DMF for the following types of drug substances:
For drug substances that are the subject of a pharmacopoeial monograph in a default standard (British Pharmacopoeia [BP], European Pharmacopoeia [Ph. Eur.] or United States Pharmacopeia–National Formulary [USP–NF]):
Include the following in the DMF:
Alternative test procedures may be used if it can be demonstrated that both:
Provide justification (including toxicological data, if appropriate) if:
For drug substances (and/or excipients) that are terminally sterilised and do not undergo further sterilisation during manufacture of the drug product, ensure the DMF includes:
For drug substances (and/or excipients) that are aseptically manufactured and do not undergo further sterilisation during manufacture of the drug product, ensure the DMF includes:
The TGA guidance Adventitious agent safety of medicines details the information to be included in the DMF for materials of animal or human origin.
Manufacturers that use heparin products should strictly control all the starting materials and intermediates used in the manufacture of the product.
Hence the information that is included in the DMF for heparin should form part of Module 3 of the CTD information provided in support of the drug product.
Collection and control of the starting material for human albumin will be described in the plasma master file (PMF). The DMF for human albumin should describe the manufacturing processes used, which is essential to assess the safety of the final product.
Guidance on fermentation and nomenclature of substances of natural or semisynthetic origin can be found in the relevant pharmacopoeial monograph of the default standard, such as:
Note for guidance on quality of biotechnological products: derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95). This guideline outlines information relating to the manufacture and stability of drug substances produced by fermentation.
In addition to the requirements of the above European Union guideline, further information is required for substances produced wholly or in part by fermentation:
For each facility involved in the manufacture and/or testing of the drug substance (including contract manufacturers and testing laboratories) provide the name, address and manufacturing responsibility for the operations or processes performed.
Provide pharmaceutical development reports that describe the scientific rationale for the chosen manufacturing process(es) and controls for fermentation-derived drug substances.
Provide a flow diagram illustrating each step in propagation from the original inoculum (e.g. cells from one or more vials of the WCB) through to the final harvesting operation. Include relevant information such as:
Identify critical steps and intermediates for which specifications are established, along with sampling plans and testing time points.
Include a narrative describing each manufacturing step in the process which identifies and describes:
Include a flow diagram and a narrative to describe all the steps involved in isolating the crude fermentation product and purifying it to its final form, along with any relevant information (e.g. volumes, pH, temperatures, holding times).
Identify critical steps and intermediates for which specifications are established, along with testing time points.
Identify all process controls and their associated numeric ranges, limits or acceptance criteria, and include the following:
Describe modification reactions as follows:
When a fermentation product is subjected to further molecular change through chemical means:
When the fermentation product is further modified using enzymes include the steps in the flow diagram and in the procedural narrative.
Additionally, because enzymatic functionality requires carefully controlled conditions (e.g. pH, temperature, osmolarity), include detailed information on:
Provide a list of materials used in the manufacture of fermentation-derived drug substances, including:
Provide information about the microorganism used for production (genus, species and type strain) and its known genotypic and phenotypic characteristics.
Identify or describe the origin of the source material (or isolate), including methods used to improve the strain. Cell bank system – master cell bank Provide a brief description of the procedures used to generate the MCB and the criteria used for qualification, including:
Preservation of the microbial purity of the MCB is an important factor in maintaining the production strain, and a WCB can be created to lower the likelihood of the MCB being compromised.
A WCB is created by propagating the MCB through defined culture conditions, and then keeping aliquots of the resultant homogeneous culture suspension in individual storage containers of an appropriate size for routine production purposes.
Controls are essential during the fermentation process to ensure consistency of the drug substance.
The manufacturing processes should be controlled to ensure that the drug substance meets previously identified quality attributes.
When the intermediate represents the end of the fermentation process and the beginning of a synthetic scheme, the controls warranted are generally more extensive than those used for other types of intermediates.
Identify and describe noncritical in-process controls.
These controls may not directly demonstrate that a process produces a quality product; however, a description of the tests being conducted and why they are not critical demonstrates understanding of the process.
When a fermentation-derived drug substance is sterilised provide the process validation information and data in support of the sterilisation process(es) as per sterile drug substances.
Non sterile process validation is conducted before commercial marketing.
The type and extent of the physicochemical characterisation information that should be provided depends on:
When a biological assay (e.g. antimicrobial activity for antibiotics) is used to assess the potency or strength of the intermediate or drug substance:
In some cases, the product of fermentation is a complex mixture of major and minor components that together make up a product's biological activity.
When evaluating the impurity profile for these fermentation products, try to identify and characterise the active components (major and minor) that contribute to the product's overall potency and distinguish them from impurities. This may not be practical or feasible in all cases.
Provide information about impurities in the fermentation-derived drug substance, such as:
Impurities may be either:
derived from the manufacturing process (e.g. residual media components, protein and nucleic acids from microbial cells, processing reagents, inorganic salts, filter aids, solvents)
structurally related to the desired fermentation product but not share the same properties with respect to biological activity, efficacy and safety (e.g. other microbial metabolites, precursors, by-products).
Process-related impurities derived from fermentation and downstream processing should be minimised through the use of a well-controlled and reproducible manufacturing process.
Structurally related impurities should be identified, tracked and controlled throughout the fermentation, isolation and purification processes.
Provide a summary of the impurities that are most likely to arise during:
Include:
For impurities of known structure, partially characterised or unidentified:
For specifications for fermentation-derived intermediates, drug substances or medicines include:
Present a rationale for the inclusion or exclusion of impurities in the specifications. As appropriate, this rationale should include a discussion of the impurity profiles observed in batches used for clinical, safety and stability testing, as well as batches representative of the proposed commercial process.
For complex fermentation products that are not well characterised in terms of structure, physicochemical properties, biological activity and purity, the levels for organic impurities should be determined on a case-by-case basis.
The acceptable levels for organic impurities will depend on how the fermentation product is to be used.
The levels will likely be less stringent for a drug substance or an intermediate that will be subjected to further modification and/or purification than for a drug product that does not undergo further processing.
The purification and downstream processing is expected to effectively remove process-related impurities, such as:
Therefore, in most cases, limits do not need to be included in the specifications for these impurities.
However, when studies suggest that process-related impurities are not effectively removed during the purification process, these impurities should be controlled with limits in the specifications, as appropriate.
Microbial impurity tests (e.g. for endotoxins) for medicines may be required.
Summarise details of the degradation products observed during stability studies of the drug substance or drug product, including:
Provide documentation to show that analytical procedures used in quantifying degradation products are properly validated or qualified.
Include limits for degradation products that are expected to occur under recommended storage conditions in the specifications for the drug substance or drug product.
Provide a rationale for excluding a degradation product from the specifications.
Provide the proposed specifications for the fermentation-derived intermediate, drug substance or drug product, including:
the tests that will be performed on each batch
a reference to the analytical procedure used in performing the test
the acceptance criteria for each test.
Focus the specifications on those characteristics found to be useful in ensuring the safety and efficacy of the intermediate or drug substance.
Provide a justification for the proposed specifications for the intermediate, drug substance and drug product.
For some fermentation-derived drug substances, a nonspecific bioassay (e.g. microbiological assays for antibiotics) may be proposed to determine the content of the drug substance.
In these cases, the development of a specific, stability-indicating assay (e.g. high-performance liquid chromatography [HPLC]) is encouraged because it offers considerable advantages in terms of separation of components, accuracy and precision.
Provide copies of the analytical procedures used in testing the fermentation-derived intermediate, drug substance or drug product.
Use specific citations when the analytical procedure is from an official compendium and is not modified in any way.
Provide validation data for the analytical procedures used in testing the fermentation-derived intermediate, drug substance or drug product.
Provide information about reference standards or reference materials used for testing. Relevant information includes:
Provide batch analysis data, using the proposed analytical procedures and specifications, for:
Include the following information on the label for intermediates and drug substances:
Provide information relating to the stability of the fermentation-derived drug substance.
The recommendations for stability are applicable to intermediates intended for resale, but generally not otherwise.
Provide a summary of the types of:
Provide conclusions regarding appropriate storage conditions and an appropriate retest or expiration date.
Studies should be conducted on three separate batches (if feasible, generated from three different WCB vials).
The batches can be pilot scale; however, the manufacturing process for the pilot-scale batches should fully represent and simulate the proposed full-scale production process.
A retest period or date may be appropriate in cases where the drug substance shows little change in potency and/or degradation products throughout the proposed shelf life.
Use an expiration date if there is a marked change or trend in the potency and/or degradation profile, such that there is a concern that an out-of-specification test result could occur during stability studies.
When an expiration date is assigned to a fermentation-derived intermediate or drug substance, the material is not to be used beyond that date and is to be discarded if that date has passed.
A retest date is a date before which the material meets all applicable specifications.
Beyond that date, the material may be retested and, if acceptable, used within a reasonable amount of time (e.g. within 30 days).
The retest date should include the test attributes that are critical to the fermentation-derived intermediate or drug substance (e.g. potency, moisture content).
Expiration dates and retest dates should both be established based on supportive stability data.
For fermentation-derived medicines
An expiration date should be established based on supportive stability data.
Retest dates are not appropriate for fermentation-derived medicines.
A CEP may be submitted instead of a DMF:
A CEP does not contain sufficient information and will not alone be accepted.
Sponsors need the written permission of the drug substance manufacturer to refer to a CEP in an application.
A proforma for a Letter of Access (available in Module 1.6.3 of the CTD) from the drug substance manufacturer, addressed to the TGA and indicating clearly the product sponsor to which it applies, should be sent directly to the TGA, either with the CEP or separately.
The proforma for Letters of Access used in Europe is not acceptable.
Sponsors:
Amendments to the CEP that are allowed by the EDQM are not automatically accepted in Australia. An amended CEP can be submitted in support of a request to make a variation to an Australian Register of Therapeutic Goods (ARTG) entry.
Further information is required by the TGA for the following types of drug substances.
Sponsors provide:
Note
If this information is confidential from the sponsor, the TGA may obtain this information from the CEP holder.
In addition to the nonsterile drug substances requirements listed above, a CEP is not sufficient for the TGA to assess the quality of a sterile drug substance (and/or excipients) that does not undergo further processing. Information regarding sterile manufacture, as specified in What to include in a Drug Master File for sterile drug substances, must be provided, but a full DMF is not required.
The TGA may request:
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