GUIDANCE ON THE GMP CLEARANCE OF OVERSEAS MEDICINE MANUFACTURERS

GUIDANCE ON THE GMP CLEARANCE OF OVERSEAS MEDICINE MANUFACTURERS 16 th Edition March 2008 www.tga.gov.au/manuf/gmpsom.htm Page 1 of 18

Table of Contents Introduction... 3 International Arrangements... 4 Mutual Recognition Agreements (MRA)... 4 Pharmaceutical Inspection Cooperation Scheme (PIC/S)... 4 US Food and Drug Administration (US FDA)... 4 General requirements for GMP documentary evidence... 5 The GMP Clearance Process... 6 How do I obtain GMP Clearance?... 6 What if I can t obtain a certificate issued by an MRA country?... 6 What is a Desktop Audit?... 7 What fees are payable for GMP Clearances?... 7 How can I track the progress of a GMP Clearance application?... 8 Can I refer to another Sponsor s GMP Clearance for the same site?... 8 What if I need to make changes to a current GMP Clearance?... 8 Will the TGA always issue a GMP Clearance when I apply for one?... 8 What do I do if the TGA rejects (i.e. fails) my GMP Clearance application?... 8 Acceptable GMP evidence... 9 Medicines (Finished Products)... 9 Active Pharmaceutical Ingredients (APIs)... 14 GMP Clearance Timeframes... 16 Expiry of GMP Clearance... 16 Tables Table 1: Documents for Desktop Audit of Finished Products... 13 Table 2: Documents for Desktop Audit of APIs... 16 Figures Figure 1 - GMP Clearance Assessment for Finished Product Manufacturers... 17 Figure 2 - GMP Clearance Assessment of API Manufacturer... 18 Page 2 of 18

Introduction The Therapeutic Goods Act 1989 (the Act) requires that the standard of manufacture, and quality control of therapeutic goods manufactured outside Australia, be taken into consideration for the registration or listing of those goods 1 on the Australian Register of Therapeutic Goods (ARTG), unless the goods are exempt 2 from this requirement by the Act. A Sponsor applying to the Therapeutic Goods Administration (TGA) for registration or listing of therapeutic goods manufactured outside Australia, in the absence of a TGA audit, must provide documentary evidence to show that the manufacture of the goods is of an acceptable standard. 3 TGA requires that this standard be equivalent to that expected of a Licensed Australian manufacturer. This guidance document is intended to provide information to Sponsors and manufacturers on the documentary evidence required to demonstrate acceptable GMP compliance for an overseas manufacturer, and, outline the process for the submission of such evidence to the TGA for assessment. It is not intended to provide a definitive list of the types of documentary evidence that are considered acceptable or unacceptable. This guidance document should be read in conjunction with the Australian Code of GMP for Medicinal Products (www.tga.gov.au/docs/html/gmpcodau.htm), and the ICH GMP Guide for Active Pharmaceutical Ingredients (www.tga.gov.au/docs/pdf/tgmp0201g.pdf). The term Manufacture is defined in the Act to mean: (a) to produce the goods; or (b) to engage in any part of the process of producing the goods or of bringing the goods to their final state, including engaging in the processing, assembling, packaging, labelling, storage, sterilising, testing or releasing for supply of the goods, or of any component or ingredient of the goods, as part of that process. Sponsors of therapeutic goods manufactured outside Australia must obtain GMP Clearance for the overseas manufacturer(s) before the goods are entered on the Australian Register for Therapeutic Goods (ARTG). Sponsors must ensure that current GMP documentary evidence is retained thereafter. It is a standard condition of registration, or listing, to provide this evidence when requested. Failure to supply this information is likely to result in the product s registration/listing being cancelled. The TGA reserves the right to conduct an audit 4 (inspection) of any overseas manufacturer, irrespective of the documentary GMP evidence submitted to the TGA, even if there is a current GMP Clearance. In addition to the information outlined below, the TGA also reserves the right to request additional documents for the assessment of the GMP Clearance application. If questions concerning GMP Clearance remain after reading this guidance, Sponsors may contact the TGA at gmp@tga.gov.au or by phone on 1800 446 443 or (02) 6232 8708, or via facsimile on (02) 6232 8426. Sponsors may also use these contacts if they wish to arrange for an audit of an overseas manufacturer. 1 Therapeutic Goods Act 1989 Subsections 25(1)(g), 26(1)(g), 26A(3) 2 Therapeutic Goods Act 1989 Subsections 25(2D), 26(2C), 26A(7) 3 Therapeutic Goods Act 1989 Subsections 25(2)(a), 26(2)(a), 26A(4)(a) 4 The term audit is used in Australia, whereas overseas regulatory agencies may use the term inspection. These two terms may be used interchangeably. Page 3 of 18

International Arrangements Australia participates in several international arrangements including Mutual Recognition Agreement (MRAs), the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and other arrangements that provide for the exchange of regulatory information. The scope of these arrangements is summarised below. For details of international arrangements please refer to www.tga.gov.au/international/index.htm#intagree Mutual Recognition Agreements (MRA) The TGA will accept Certificates of GMP Compliance, issued under the provisions of an MRA (for types of products covered by the MRA), where the manufacturer is located in the same country as a Regulator that is a recognised participant in the MRA ( MRA Regulator ). The manufacturer may request a Certificate of GMP Compliance by contacting the relevant MRA Regulator. The scope of an MRA does not include audits conducted in countries outside the country of an MRA Regulator. Audits and GMP Certification, from MRA Regulators, for manufacturers in third countries will no longer be automatically accepted. This is because audits in these countries may not include all aspects of the manufacture of medicines for supply to Australia. Audit reports from National Regulators from audits which predate their official inclusion as an MRA participant will not be accepted. The countries of the Regulators who are recognised participants in an MRA (or equivalent) with Australia include the following: EC and EFTA Countries - The countries currently included are: Austria Belgium Denmark Finland France Germany Greece Iceland Ireland Italy Liechtenstein Luxembourg Malta Netherlands Norway Portugal Spain Sweden UK Please note that the list above may be updated if new countries are added following assessment by the TGA. Canada - Complementary medicines are not included in the MRA with Canada. Singapore Switzerland - Arrangements generally equivalent to an MRA Pharmaceutical Inspection Cooperation Scheme (PIC/S) Australia is a member of the Pharmaceutical Inspection Cooperation Scheme (PIC/S) (www.picscheme.org). PIC/S is not a Mutual Recognition Agreement. The TGA does not automatically accept GMP Certification from PIC/S member countries; the only exceptions to this is where the Regulator in the PIC/S member country is also a Regulator who participates in an MRA with Australia, and the certificate is issued under the provisions of the MRA. Audit reports from Regulators from audits which predate their official inclusion in PIC/S will not be accepted. US Food and Drug Administration (US FDA) The TGA has an agreement with the US FDA that provides for the exchange of information in relation to manufacturers for regulatory purposes. This is not a Mutual Recognition Agreement. The TGA does not automatically grant a GMP Clearance to Sponsors of US manufacturers inspected by the US FDA. Page 4 of 18

General requirements for GMP documentary evidence 1. Original or notarised copies of GMP certificates must be submitted. 2. Notarised copies must be legible and authenticated as true copies of the original document by an independent authority such as a Justice of the Peace, Public Notary, an official of a recognised regulatory agency, or an Australian embassy or consulate office. As an example, wording for such a declaration could be: Declaration of Authenticity As a registered notary public for the state of (xxxx), (country xxx), I declare that the attached copy of the certificate/licence issued by (xxxx) (certificate or licence number xxxx) is a true and accurate copy of an original certificate/licence presented to me for review. Signed (xxxxx) Date (xxxxx) 3. Copies of documents originally issued by the TGA do not need to be notarised. 4. Supporting documents from an overseas regulator are not required to be original or notarised as their authenticity may be independently verified with the relevant Regulator. 5. Faxed copies of documents will not be accepted, except for documents originally issued by the TGA. 6. All certificates and other supporting documents must be in English. If a document has been translated, a signed and dated statement by the translator that it is an accurate translation of the original document is required. 7. Documents which have passed their date of validity will not be accepted. 8. Mandatory requirements for certification submitted in support of a GMP Clearance application: a) Full legal name of the manufacturer of the goods; b) Street address of the manufacturing site (a PO Box is not acceptable); c) Date of the last audit/inspection; d) Standard of manufacture with which the manufacturer of the product(s) complies; e) Product(s) or type(s) of product(s) described in sufficient detail to be able to verify relevance to the clearance request; f) Step(s) of manufacture undertaken at the site; g) Period of validity or expiry date; h) Signature and date. Note: The period of GMP Clearance granted will be decided by the TGA on a case by case basis, and may not align with the expiry date of the submitted non-mra certificate of GMP Compliance. The TGA will not accept a request from a Sponsor to access GMP evidence previously submitted by, or obtained for, another Sponsor without written authorisation from the other Sponsor. Page 5 of 18

The GMP Clearance Process How do I obtain GMP Clearance? To apply for a GMP Clearance of an overseas manufacturer, Sponsors must complete an electronic Overseas Manufacturer Clearance Application via the Manufacturers Information System (MIS) (www.tgasime.health.gov.au/) for each manufacturing site, and pay the applicable fee. If available in electronic form, the Sponsor may attach the relevant documentary evidence of the manufacturing standard to the MIS application. Alternatively, documents in hardcopy, or on other electronic media, can also be provided. Original or notarised copies of GMP certificates must be submitted in hardcopy as described in the section, General Requirements for GMP Document Evidence above. GMP Clearance applications may be subject to one of two assessment processes. Where documentary evidence is submitted under the provisions of an MRA, a brief assessment may be undertaken. In all other cases it will be necessary to conduct a desktop audit of the documentary evidence. The GMP Clearance application will be thoroughly assessed in accordance with the guidance below and the Sponsor will be informed of the decision. Applications for an initial TGA audit of a site should not be made at the same time as an application for GMP Clearance of that site. In such cases the processing of the application for a TGA audit will be delayed until the outcome of the GMP Clearance application is known. Notes: Only the Dosage Form Codes in the drop down menus within MIS must be used when completing an Overseas Manufacturer Clearance Application. This is necessary to ensure proper integration of clearance information within the TGA s SIME databases. Where an overseas manufacturer changes name, evidence of the name change can be in the form of a letter from the health authority in the manufacturer's country or a declaration from the manufacturer that there has been a change in the manufacturer s name. A copy of the current Site Master File can also be used to provide evidence of a name change. Where a GMP Clearance has expired, or is about to expire, a new GMP Clearance application must be submitted for assessment prior to a further clearance being considered. If a Sponsor no longer sources a finished product from a particular overseas manufacturer, the Sponsor must inform the relevant TGA product Regulator of this change, in accordance with any relevant guidelines appropriate to the product. If GMP Clearance for the manufacturer is no longer required, the TGA must also be notified so that the MIS database can be updated. What if I can t obtain a certificate issued by an MRA country? In exceptional circumstances, and where the Sponsor has been unable to obtain the certification issued by the MRA country, the Sponsor may request that the TGA attempt to obtain evidence from the relevant MRA Regulator. An additional fee is payable for this service. Please note that this will only apply to audits performed under an MRA, i.e. where the manufacturer is located in that MRA country, and if all steps of manufacture are carried out in that MRA country. When the TGA is requested to attempt to obtain GMP evidence for a Sponsor, the timeframe for GMP Clearance is outside the TGA s control. Sponsors will be advised if the TGA does not Page 6 of 18

receive a response from the MRA Regulator within 16 weeks. When this occurs the TGA will have no option but to reject the application (without refund of fees) and the reason for rejection will be noted as no response from the MRA Regulator. The TGA is not responsible for the actions of, or delays caused by an MRA Regulator. What is a Desktop Audit? An Australian Sponsor must demonstrate that the overseas manufacturers, from which they source medicines and APIs, comply with the standard equivalent to that expected for Licensed Australian manufacturers. The acceptable standards are the Australian Codes of GMP for Medicinal Products, APIs or Sunscreens. The desktop audit process provides an opportunity for the Sponsor to establish that the manufacturing site complies with an acceptable standard. This is performed by submitting the required documentary evidence, which is thoroughly assessed by the TGA (See Table 1or Table 2) The documentary evidence must be complete and unambiguous, clearly demonstrating that the proposed overseas manufacturer operates with an adequate level of GMP compliance. Where the submitted documentary evidence has been assessed as being unsatisfactory, the Sponsor will be informed. In such cases the Sponsor may need to apply for a TGA on-site audit of the manufacturing site. Desktop audits are not required for manufacturing sites where the Sponsor has been able to obtain the relevant certification issued under the terms of an MRA and non-sterile APIs as described in Figure 1 and Figure 2 attached. What fees are payable for GMP Clearances? Fee for processing of GMP Clearance or a variation to an existing GMP Clearance applicable to every application for GMP Clearance of an overseas manufacturing site. Fee for obtaining GMP evidence - this fee is in addition to the processing fee above, and is only applicable if the TGA is requested to obtain evidence of GMP compliance from the Regulator in an MRA country or from the US FDA. Please note, for evidence obtained from an MRA Regulator, this service is only available if the manufacturer is located in that MRA Regulator s country. The fee applies to every application of such a request. Fee for desktop audit of GMP documentation this fee is applicable in all instances where this guidance requires supporting GMP documents to be provided for a desktop audit. A decision on GMP Clearance will be made on a case by case basis, after comprehensive assessment of key documentation submitted. Notes: If an applicant provides written authority from the original Sponsor of a GMP Clearance for a manufacturing site, allowing the TGA to apply their existing Clearance to the new Sponsor, only the fee for processing applies. If an applicant provides written authority from another applicant allowing the TGA to use evidence submitted in their GMP Clearance application to the new Sponsor s application, only the fee for processing applies. Current fees are described in the Summary of Fees and Charges on the TGA website at www.tga.gov.au/docs/html/feesach.htm Page 7 of 18

How can I track the progress of a GMP Clearance application? The TGA s MIS system allows the progress of an application to be tracked on-line. If an applicant is experiencing difficulties they may contact the TGA - GMP Clearance Unit by email at gmpclearance@tga.gov.au Can I refer to another Sponsor s GMP Clearance for the same site? If an applicant provides written authority from another Sponsor to allow the TGA to refer to an existing GMP Clearance, an additional Clearance for the site can be issued if the scope of the application is consistent with the scope of the existing GMP Clearance. Each Sponsor must have a GMP contract between the manufacturer and the Sponsor. The contract is to include the scope of products for supply in Australia. (See Table 1 or Table 2 below) If an applicant provides written authority from another applicant for a GMP Clearance to allow the TGA to use evidence submitted in the latter s application, the TGA will refer to the evidence if the scope of manufacture is identical in both applications. Each Sponsor must have a GMP contract between the manufacturer and the Sponsor. The contract is to include the scope of products for supply in Australia. (See Table 1 or Table 2 below) Each Sponsor must obtain a separate and distinct GMP Clearance for each manufacturer requiring a GMP Clearance. The relevant fees apply for each application. What if I need to make changes to a current GMP Clearance? Changes to any aspects of the GMP Clearance require a new GMP Clearance application to be submitted. Changes may include, but are not limited to: New manufacturing site. Alternative manufacturer(s) for products on the ARTG. Significant new steps, or significantly different technology, in manufacture, for an existing product on the ARTG where the overseas manufacturer has current GMP Clearance approval that does not include the new steps or technology. (e.g. fermentation in addition to chemical synthesis for an API manufacturer) Extension of the scope of the existing GMP Clearance. For example, current GMP Clearance is for the manufacture of hard capsules; however, the Sponsor now wishes to include a soft gel capsule on the ARTG. When products are transferred from one Sponsor to another, the new Sponsor is required to make a GMP Clearance application in their own name no later than 3 months from the date of transfer. Each Sponsor must have a GMP contract between the manufacturer and the Sponsor. The contract is to include the scope of products for supply in Australia. (See Table 1 or Table 2 below) Will the TGA always issue a GMP Clearance when I apply for one? GMP Clearance will only be issued if the TGA is satisfied that the manufacturer meets an acceptable standard. In addition, the TGA will cancel/revoke/suspend any previously issued GMP Clearance unless it is satisfied that the manufacturer continues to meet an acceptable standard. What do I do if the TGA rejects (i.e. fails) my GMP Clearance application? There are two options available: The Sponsor may submit a new GMP Clearance application. The relevant fee(s) will be applied. The Sponsor may submit an application requesting the TGA to perform an audit of the overseas manufacturer. The manufacturer must agree to the audit. All costs including the relevant audit fee, travel and accommodation costs must be paid before the audit takes place. Page 8 of 18

An on-line MIS certification application for requesting an audit of an overseas manufacturer is available at www.tgasime.health.gov.au. The current schedule of fees is also available at www.tga.gov.au/docs/html/feesach.htm. Acceptable GMP evidence Medicines (Finished Products) Figure 1 attached illustrates the requirements for a desktop audit where international arrangements provide for the submission of GMP certificates. Audits by an MRA Regulator in their country GMP Clearance will be issued on the basis of an MRA Certificate of GMP Compliance. The TGA will only request an MRA Certificate of GMP compliance from an MRA Regulator in exceptional circumstances. This service attracts a fee. It should also be noted that some Regulators participating in the MRA require a manufacturer to make this request. GMP Clearance will remain current until the date of expiry on the MRA certificate, unless the TGA has documentary evidence to vary the expiry date of the GMP Clearance. Audit reports from Regulators from audits which predate their official inclusion in the MRA will not be accepted. Audits by an MRA Regulator outside their country GMP Certification with key supporting documentation will be considered in lieu of a TGA audit on a case by case basis. (See Figure 1 attached) Audits of manufacturers of high risk products including blood products and biological products will NOT be considered for a desktop audit. Where a country does not inspect or regulate complementary medicines (such as herbal, vitamin, mineral or homoeopathic preparations) to a medicine standard, an audit conducted by the regulatory agency in that country cannot be considered in lieu of a TGA audit. Applications for GMP Clearance cannot be processed unless accompanied by the documentation listed below (as applicable) and the payment of all relevant fees. A decision on GMP Clearance will be made after assessment of documentary evidence provided by the Sponsor or manufacturer. The list of documentation in Table 1 below is provided as a guide only and additional documentation may be requested. The expiry of GMP Clearances will depend on the type of product manufactured and the outcome of the desktop assessment process. The period of GMP Clearance given to a manufacturing site will be determined using a risk based criteria similar to that used by the TGA to determine the re-audit period for any manufacturer (domestic or overseas) audited by the TGA. This is consistent with the TGA s level playing field approach to GMP regulation. Page 9 of 18

In some cases, a condition will be applied to the GMP Clearance, stipulating that the next clearance will only be granted following a successful outcome of a TGA audit of the relevant manufacturing site. No other evidence will be considered in lieu of a TGA audit in such cases. If a GMP Clearance is rejected (i.e. fails), following review of this documentation, an on-site audit by the TGA is the only remaining option if a Sponsor wishes to pursue a GMP Clearance for that manufacturer. It is recognised that Sponsors may not always have access to proprietary documents, including the manufacturer s commercial-in-confidence documents. In such circumstances, these documents may be sent directly to the TGA by the relevant manufacturer; it is essential that the relevant clearance reference number(s) is stated in the correspondence. All documents must be in English. If the audit / inspection report has been translated into the English language, the translation must be performed by a technically competent translator and accompanied by a signed and dated declaration that the translation is an accurate translation of the original document. A copy of the original non-english language audit report must also be provided. Documentary evidence should be presented in a clear and well formatted manner that will allow the relevant documents to be easily identified. Failure to provide all relevant documents is likely to result in the application being rejected (i.e. failed). It is recognised that the required type of document may be identified by the manufacturer as an equivalent document under a different name in its Quality Management System. In such cases, a written explanation and the equivalent documentation must be provided with the application. Audits by PIC/S Regulators, New Zealand Medsafe and the US FDA in their own countries. GMP Certification (or equivalent in the case of FDA) with key supporting documentation will only be considered in lieu of a TGA audit on a case by case basis. (See Figure 1attached) Where a country does not inspect or regulate complementary medicines (such as herbal, vitamin, mineral or homoeopathic preparations) to a medicine standard, an audit conducted by the regulatory agency in that country 5 cannot be considered in lieu of a TGA audit. A decision on GMP Clearance will be made after assessment of documentary evidence provided by the Sponsor or manufacturer. The list of documentation in Table 1 below is provided as a guide only and additional documentation may be requested. If a GMP Clearance is rejected (i.e. fails) following review of this documentation, an on-site audit by the TGA is the only remaining option if a Sponsor wishes to pursue a GMP Clearance for that manufacturer. The expiry of GMP Clearances will depend on the type of product manufactured and the outcome of the desktop assessment process. The period of GMP Clearance given to a manufacturing site will be determined using a risk based criteria similar to that used by the TGA to determine the re-audit period for any manufacturer (domestic or overseas) audited by the TGA. This is consistent with the TGA s level playing field approach to GMP regulation. 5 The TGA will consider US FDA inspections in Puerto Rico as being eligible for a desktop audit. Page 10 of 18

In some cases, a condition will be applied to the GMP Clearance, stipulating that the next Clearance will only be granted following a successful outcome of a TGA audit of the relevant manufacturing site. No other evidence will be considered in lieu of a TGA audit in such cases. Applications for GMP Clearance cannot be processed unless accompanied by the documentation listed below (as applicable) and payment of all relevant fees. It is recognised that Sponsors may not always have access to proprietary documents, including the manufacturer s commercial-in-confidence documents. In such circumstances, these documents may be sent directly to the TGA by the relevant manufacturer; it is essential that the relevant clearance reference number(s) is stated in the correspondence. All documents must be in English. If the audit / inspection report has been translated into the English language, the translation must be performed by a technically competent translator and accompanied by a signed and dated declaration that the translation is an accurate translation of the original document. A copy of the original non-english language audit report must also be provided. Documentary evidence should be presented in a clear and well formatted manner that will allow the relevant documents to be easily identified. Failure to provide all relevant documents is likely to result in the application being rejected (i.e. failed). It is recognised that the required type of document may be identified by the manufacturer as an equivalent document under a different name in its Quality Management System. In such cases, a written explanation and the equivalent documentation must be provided with the application. Audits by non-mra PIC/S Regulators and New Zealand Medsafe outside their own countries. Audits by PIC/S Regulators (who is not an MRA Regulator) and New Zealand Medsafe are not eligible for GMP Clearance. Audits by the US FDA outside the USA. FDA GMP approval, with key supporting documentation, will only be considered in lieu of a TGA audit on a case by case basis. (See Figure 1 attached) Inspections of manufacturers of high risk products including blood products and biological products will NOT be considered for a desktop audit. Inspections of complementary medicine manufacturers including herbal, vitamin, mineral or homoeopathic preparations are not eligible for a GMP Clearance. Applications for GMP Clearance cannot be processed unless accompanied by the documentation listed below (as applicable) and payment of all relevant fees. A decision on GMP Clearance will be made after assessment of documentary evidence provided by the Sponsor or manufacturer. The list of documentation in Table 1 below is provided as a guide only and additional documentation may be requested. It is important to note that the expiry of GMP Clearances will depend on the type of product manufactured and the outcome of the desktop assessment process. The period of GMP Clearance given to a manufacturing site will be determined using a risk based criteria Page 11 of 18

similar to that used by the TGA to determine the re-audit period for any manufacturer (domestic or overseas) audited by the TGA. This is consistent with the TGA s level playing field approach to GMP regulation. In some cases, a condition will be applied to the GMP Clearance, stipulating that the next clearance will only be granted following a successful outcome of a TGA audit of the relevant manufacturing site. No other evidence will be considered in lieu of a TGA audit in such cases. If a GMP Clearance is rejected (i.e. fails), following review of this documentation, an on-site audit by the TGA is the only remaining option if a Sponsor wishes to pursue a GMP Clearance for that manufacturer. It is recognised that Sponsors may not always have access to proprietary documents, including the manufacturer s commercial-in-confidence documents. In such circumstances, these documents may be sent directly to the TGA by the relevant manufacturer; it is essential that the relevant clearance reference number(s) is stated in the correspondence. Documentary evidence should be presented in a clear and well formatted manner that will allow the relevant documents to be easily identified. Failure to provide all relevant documents is likely to result in the application being rejected (i.e. failed). It is recognised that the required type of document may be identified by the manufacturer as an equivalent document under a different name in its Quality Management System. In such cases, a written explanation and the equivalent documentation must be provided with the application. Page 12 of 18

Table 1: Documents for Desktop Audit of Finished Products Type of manufacture Documents required (A! means that the document is required) Full Manufacture Bulk dosage form QC Testing Packaging /Labeling Release for supply Sterilisation An original or notarised copy of a GMP certificate*!!!!!! A copy of the last audit report and the manufacturer s response to any deficiencies noted A copy of the GMP contract between the manufacturer and the Sponsor, including a list of the specific products for supply in Australia.**!!!!!!!!!!!! A copy of the Site Master File or equivalent***!!! A copy of the Validation Master Plan**** (covering process, media fill (if relevant), cleaning, computerised systems, etc as applicable and including a Risk Assessment used to determine the scope and extent of validation) Rationale for test method validation, procedure for method transfer etc. Copies of the procedures for handling deviations and out of specification test results Copy of the procedures for release for supply of product intermediates, bulk or finished products.!!!!!!!!!!!!!!! Important Explanatory Notes: *For medicine manufacturers located in the USA and inspected by the FDA, an acceptable rating on the FDA FACTS database for the relevant profile class (product type or manufacturing process), and given within the last three years, will be considered equivalent to a GMP certificate. The TGA has access to the FACTS computer database and will utilise this to verify GMP status as determined by the FDA. For Contract Testing Laboratories, other relevant certification may be submitted by the Sponsor, for example, a Good Laboratory Practice (GLP) certificate or appropriate ISO 17025 certification. **Guidance on the GMP Contract can be found in Chapter 7 of the Code of GMP for Medicinal Products. Written agreements are expected and must be established between the Australian Sponsor (or a person acting on behalf of the Sponsor) and the manufacturer who conducts the step of Release for Supply. If the Australian Sponsor is a subsidiary of the overseas manufacturer who is conducting the step of Release for Supply (and other manufacturing steps) then the TGA accepts that a formal GMP contract may not exist. In this circumstance, the Sponsor must provide a written explanation of the arrangements. ***It is recognised that Site Master Files may not be available for some US manufacturing sites. Equivalent information (e.g. Plant/Equipment File) should be supplied, if available, to assist with the assessment of the GMP Clearance application. Some information normally contained in a Site Master File may be requested. ****Guidance on aspects of validation and Validation Master Plans can be found in Annex 15 of the Australian Code of GMP for Medicinal Products. For Contract Testing Laboratories The application should include a copy of the laboratory s Standard Operating Procedure (SOP) for test method validation, method transfer and a document which records the validation status of the test methods used in the laboratory. When the laboratory is testing materials containing botanical ingredients, evidence that authenticated standard reference materials are used must be provided to the TGA. Page 13 of 18

Active Pharmaceutical Ingredients (APIs) There are three principle types of APIs: i. Non-Sterile; ii. Sterile; and iii. Other High Risk APIs including, for example, those derived from human or animal tissues or recombinant technology. Some APIs derived from tissues of animal origin may not be high risk e.g. fish extracts, probiotics or those derived by classical fermentation technology. Contact the MAB for further clarification in specific cases. Currently, evidence of compliance with GMP for API manufacture is usually only required for registrable medicines evaluated by the Drug Safety and Evaluation Branch of the TGA. This may also apply to active premixes evaluated by the TGA s Non-Prescription Medicines Branch. Contact the TGA s Non-Prescription Medicines Branch for further clarification in specific cases. If all steps of manufacture are not carried out at a single site, the manufacturer that conducts the final steps of manufacture, purification, drying, milling and sterilisation (if applicable) of the bulk active ingredient is responsible to ensure that key intermediates are also manufactured in accordance with GMP. Separate GMP Certification need not routinely be supplied for the manufacturers of these intermediates. However, the TGA reserves the right to request evidence of GMP compliance for the manufacturers of critical intermediates, if deemed necessary. Figure 2 attached illustrates the requirements for a desktop audit where international arrangements provide for the submission of GMP certificates. API audits conducted in the country of the Regulator Non-Sterile APIs The TGA will accept GMP Certification for manufacturers of non-sterile APIs from MRA Regulators, where the audit is conducted in the country of the Regulator. The GMP Certification evidence must refer to active pharmaceutical ingredients, active raw materials, bulk drug material or the name of a particular API. The TGA may consider accepting GMP Certification for manufacturers of non-sterile APIs (excluding Other High Risk APIs) from a PIC/S Regulator (who is not an MRA Regulator), where the audit is conducted in the country of the Regulator. The GMP Certification evidence must refer to active pharmaceutical ingredients, active raw materials, bulk drug material or the name of a particular API. For audits conducted by the US FDA an acceptable rating for the relevant profile class on the FDA FACTS database may be used to issue a GMP Clearance for non-sterile APIs (excluding Other High Risk APIs). Sterile APIs The TGA will accept GMP Certification for manufacturers of sterile APIs from MRA Regulators, where the audit is conducted in the country of the Regulator. The GMP Certification evidence must refer to active pharmaceutical ingredients, active raw materials, bulk drug material or the name of a particular API. For audits conducted by a PIC/S Regulator (who is not an MRA Regulator) in their country, for sterile APIs, a desktop audit (and payment of the fee) will apply. A decision on GMP Clearance will be made after assessment of the key documents outlined in Table 2 below. For sterile chemical APIs audited by the US FDA in the US, a desktop audit is required. Page 14 of 18

The evidence must refer to active pharmaceutical ingredients, active raw materials, bulk drug material or the name of a particular API. A decision on GMP Clearance will be made after assessment of the key documents outlined in Table 2 below. Other High Risk APIs The TGA will accept GMP Certification for manufacturers of Other High Risk APIs from MRA Regulators, where the audit is conducted in their own country. The GMP Certification evidence must refer to active pharmaceutical ingredients, active raw materials, bulk drug material or the name of a particular API. Other High Risk APIs which are manufactured in a PIC/S member (who is not an MRA Regulator) country are not eligible for a desktop audit. Other High Risk APIs which are manufactured in the US are eligible for a desktop audit. API audits conducted outside the country of the Regulator Non-Sterile Sterile Where the GMP Certification is issued by an MRA Regulator for non-sterile APIs (excluding Other High Risk APIs), manufactured outside the country of the MRA Regulator, a copy of the last audit report must be submitted in order to verify that the specific or similar API referred to in the clearance application was included in the audit. The GMP Clearance processing fee applies. Audits conducted by a PIC/S Regulator (who is not an MRA Regulator) outside their country, will not be accepted. For inspections conducted by the US FDA for non-sterile APIs (excluding Other High Risk APIs) manufactured outside the USA, the last inspection report must be submitted in order to verify that the specific or similar API referred to in the Clearance application was included in the inspection. The GMP Clearance processing fee applies. Where the GMP Certification is issued by an MRA Regulator for a sterile API manufactured outside the country of the MRA Regulator, a desktop audit (and payment of the fee) will apply. A decision on GMP Clearance will be made after assessment of the key documents outlined in Table 2 below. Audits conducted by a PIC/S Regulator (who is not an MRA Regulator) outside their country, will not be accepted. Inspections conducted by the US FDA for sterile APIs manufactured outside the USA, a desktop audit (and payment of the fee) will apply. A decision on GMP Clearance will be made after assessment of the key documents outlined in Table 2 below. Other High Risk APIs Audits by an MRA Regulator of Other High Risk APIs, which are conducted outside the country of the Regulator, are only eligible for a desktop assessment. Audits conducted by a PIC/S Regulator (who is not an MRA Regulator) outside their country, of Other High Risk APIs, are not eligible for a desktop audit. Page 15 of 18

Inspections conducted by the US FDA for Other High Risk APIs manufactured outside the USA 6, are not eligible for a desktop audit. An on-site TGA audit will be required before a GMP Clearance can be granted. Table 2: Documents for Desktop Audit of APIs Documents Required (A! means that the document is required) APIs An original or notarised copy of a GMP certificate! A copy of the last audit report and the manufacturer s response to any deficiencies noted! A copy of the Site Master File or equivalent! A copy of the Validation Master Plan (including process, media fill (if relevant), cleaning,! computerised systems and analytical method validation) Copies of the procedures for handling deviations and out of specification test results! A copy of the procedure for finished API release! GMP Clearance Timeframes GMP Clearance Applications will not be processed without the payment of the relevant application fee. Where MRA certification is submitted as evidence under the terms of an MRA, the processing of the application will generally be completed within fifteen (15) working days. In cases where non-mra certification and supporting documentation is submitted as evidence the assessment (desktop audit) and decision process will be completed as soon as possible. If the required documents are not supplied, the GMP Clearance application will be rejected (i.e. fail). The application fee is not refundable. A new application will be required. Note: All documentary evidence described in this guidance for non-mra based GMP Clearance applications must be provided to the TGA within 30 working days after receipt of the application fee. An extension to this timeframe may be granted, on request, if an audit has occurred and there is a delay in the issuance of the audit report by the Regulator. Expiry of GMP Clearance The expiry of GMP Clearances will depend on the type of API manufactured and the outcome of the desktop assessment process. The period of GMP Clearance given to a manufacturing site will be determined using a risk based criteria similar to that used by the TGA to determine the re-audit period for any manufacturer (domestic or overseas) audited by the TGA. 6 Including Puerto Rico Page 16 of 18

Figure 1 - GMP Clearance Assessment for Finished Product Manufacturers Page 17 of 18

Figure 2 - GMP Clearance Assessment of API Manufacturer Page 18 of 18