Appendix B - Advice to applicants on manufacturing sites

Where Module 3 information will form part of the application, or the application makes reference to a previously submitted Module 3, DMF or PMF, applicants must provide detailed information in the PPF about manufacturing sites.

On this page: How much information is required? | Information not required | Good manufacturing practice requirements | Meeting the manufacturing regulatory requirements | Forward preparation for the delegate's decision | Timeframes for TGA manufacturer approval | Applicant responsibilities | Forced change of manufacturer

How much information is required?

The PPF must identify all Australian and overseas manufacturers involved in the supply chain of the medicine to the point of batch release to the Australian market.

Details of all manufacturers directly involved in the production of the substance or medicines are provided by the applicant in Part 2: Modules 1.7, 3.2.S (substance) and 3.2.P (product) of the PPF. Applicants must provide the actual details in the PPF. Applicants cannot complete this question by referring to information that will subsequently be provided in Module 3 of the application.

Information not required

The TGA does not regulate the distribution of therapeutic goods. Details of companies involved in activities after batch release are not required (for example, those that undertake stability testing of the finished product).

Similarly, manufacturers of simple active ingredients as the only identifiable 'active ingredient(s)' in a product (which are salts or sugars, or other substances generally regarded as excipients), and that meet the requirements of a major pharmacopoeia, need not be included.

Good manufacturing practice requirements

Manufacturers conducting steps of production pivotal to the safety and efficacy of a final medicine must hold TGA approval for the specific steps of the manufacturing process they undertake. TGA approval is provided on the basis of evidence the manufacturer complies with the Code of Good Manufacturing Practice (GMP).

Applicants identify at Part 2, Modules 1.7, Good manufacturing practice of the PPF, the subset of manufacturers (from the total identified in  CTD Module 3.2.S and CTD Module 3.2.P) for whom GMP approval (a valid licence or GMP clearance) must be held at the time of the delegate's decision on the application.

GMP clearance is required for sites that:

• manufacture a sterile active ingredient if there is no subsequent sterilisation step
• manufacture and sterilise sterile syringes
• manufacture and sterilise large volume parenteral infusion bags.

Applicants should consider expiry dates of GMP clearance and timeframes for conduct of an overseas audit if relevant, to ensure manufacturers have GMP clearance at the time of the delegate's decision.

Applicants will be advised if a manufacturer identified in CTD Module 3.2.S or CTD Module 3.2.P (but not CTD Module 1.7) requires GMP approval.

Decisions on whether GMP approval for a particular manufacturer is required can be complex. In general, prior category 1 and category 2 applications processed by the TGA can be used as a guide to which manufacturers (and manufacturing activities) will require GMP approval.

Manufacturers involved in the supply chain that do not require GMP approval must still operate to a standard that ensures the integrity of the final medicine. The responsibility for ensuring the soundness of operational arrangements rests with the applicant.

Meeting the manufacturing regulatory requirements

A PPF will be considered non-compliant with section 23 of the Act, the legislative instruments issued under section 23 of the Act and the regulatory documents specified in the legislative instruments if the following are not addressed:

• key manufacturers are not listed in CTD Modules 1.7, 3.2.S or 3.2.P
• details of TGA-issued GMP licence, clearance or tracking numbers are not provided in CTD Module 1.7
• the range of manufacturing steps covered in the list of manufacturers identified in CTD Module 1.7 fails to cover the necessary steps in manufacture of the drug substance, the drug product (medicine), packaging, labelling, and release of the medicine
• MIS tracking numbers provided for applications are in either draft or submitted status. Applications cited in the PPF must have been submitted and the appropriate fees paid before the PPF is lodged. Draft status means the details have been entered in eBS but the applicant has not pressed the 'lodge' button allowing the TGA to begin processing. Submitted status means the applications have been lodged but the relevant fees have not been paid.

Forward preparation for the delegate's decision

At the time of the delegate's decision on an application all:

• Australian manufacturer(s) involved must hold a valid licence for the relevant production steps
• overseas manufacturer(s) involved must hold a valid GMP clearance for relevant production steps.

Applicants must take appropriate action prior to lodging their PPF to ensure all approvals for manufacturers are in place by the time of the delegate's decision. This is particularly important where the manufacturing site requires initial licensing or certification through a TGA audit.

Timeframes for TGA manufacturer approval

• For Australian sites, the TGA will usually schedule a licensing audit within three months of receiving a valid application. Where no GMP compliance issues are identified, a licence will usually be issued around 30 days following the issue of the audit report.
• Where an overseas site is located in a country with which Australia has a mutual recognition agreement (MRA), a GMP clearance will typically be processed within one month. However, delays can be encountered if clarification is required from the overseas regulatory agency issuing the certification.
• Where an overseas site is eligible for a compliance verification (desktop) assessment, a GMP clearance will typically be processed within three months. Additional processing time will be required if the application data is incomplete or further information is required to decide the clearance application (refer to the 17th edition of Guidance on the GMP clearance of overseas medicine manufacturers).
• Where a site requires an initial certification audit, the TGA will typically schedule the audit within six to nine months of application. A minimum of a further three months is required to issue the audit report, assess responses, and process a GMP clearance. Significantly more time may be involved if the manufacturer has poor GMP compliance or is slow in responding to the audit report.

Applicant responsibilities

• Applicants should take steps prior to lodging the PPF to verify the adequacy of the manufacturer's GMP compliance. Delays in securing GMP clearance for a site due to poor compliance can result in the application being rejected by the delegate.
• Applicants must monitor existing GMP clearances that may be due to expire prior to the delegate's decision. Applicants must make an application for a new GMP clearance to ensure all sites hold a licence or GMP clearance prior to the delegate's decision.

Forced change of manufacturer

Circumstances beyond the control of the applicant may lead to an unanticipated need to alter the manufacturing arrangements identified in the PPF. Should such circumstances arise and force the applicant to alter manufacturing arrangements, the applicant must write to the TGA, providing a detailed explanation of the new manufacturing arrangements and the reason for the change. This will be considered on a case by case basis.