The Overseas GMP Scheme

The APVMA is seeking public comment on the proposed review of the Overseas GMP Scheme.

Assuring the GMP Status of Overseas Manufacturers of Veterinary Chemical Products

The Overseas GMP Scheme ensures that overseas manufacturers of veterinary chemical products comply with good manufacturing practices comparable to those required by the Australian Code of GMP. There are two parts to the scheme: initial approval of an overseas manufacturer (as part of the product application process), and maintaining and assessing GMP evidence after registration (the post-registration process).

Registrants of veterinary chemical products manufactured overseas need to obtain documentary evidence that foreign manufacturers comply with the APVMA’s Manufacturing Principles. The regulation of veterinary chemical products differs between countries and the APVMA’s Guidelines for Providing Evidence of GMP Status of Overseas Manufacturers" describe the type of evidence (the record) acceptable to the APVMA.

The questions and answers below provide information about the two parts of the scheme, acceptable evidence of GMP compliance, and contacts for further information. Comments and suggestions are welcome.

The key documents included below are:

Guidelines for Providing Evidence of GMP Status of Overseas Manufacturers"
Mutual Recognition Agreement on Conformity Assessment
EU-Australia MRA List of Competent Authorities
Template for EU GMP Certificate
Preparation of Plant Master File

1. Does the APVMA license overseas manufacturing sites? (Oct 05)

Imported products represent a significant share of the total Australian market for veterinary chemical products. The APVMA does not have the legislative power to licence overseas manufacturers under the Manufacturer’s Licensing Scheme (MLS). Consequently, foreign manufacturing sites are recognised as being compliant on presentation of appropriate documentary evidence.

However, Registrants of those products are required to provide acceptable evidence that an overseas manufacturer complies with a standard of manufacture comparable to that which would apply if the product were manufactured in Australia. Post-registration, conditions of registration require the registrant to ensure that this GMP compliance is maintained and that evidence of this is kept current and submitted to the APVMA on request.

2. There are two parts to the Overseas GMP Scheme: (Oct 05)

a) Initial approval of an overseas manufacturer

Applications for product registration or a change of formulator should include evidence of GMP compliance. Overseas GMP clearance is done as part of the product application process, during screening and evaluation. GMP conditions are added to the product registration details when the application is granted. GMP evidence can also be submitted directly to QA prior to a product application being submitted.

b) Post-Registration Process

Conditions of product registration for a registered veterinary chemical product with at least one overseas manufacturer include the requirement to maintain current evidence of GMP compliance and submit this to the APVMA when required. Under these conditions, registrants are expected to ensure GMP compliance throughout the life of a product, maintain evidence of this, and submit this evidence within ten days when requested by the APVMA. The type of evidence required is identical to the type of evidence required for initial approval of an overseas manufacturer.

Periodically, the Quality Assurance and Compliance Program will write to registrants requesting submission of this evidence. The APVMA will evaluate this evidence according to the following guidelines. Failure to submit adequate evidence will be a failure to comply with conditions of registration.

3. How can I obtain recognition of the GMP compliance of an overseas manufacturer? (Oct 05)

If evidence is submitted with a product application, the evidence of GMP compliance will normally be assessed by the APVMA's Quality Assurance and Compliance Section as part of the screening process. If further information is required, this will be requested. If the submitted evidence appears complete but a more detailed assessment is required (such as evaluation of an audit report), that assessment will be conducted as part of the evaluation process.

The time period involved in resolving GMP compliance issues can be lengthy, particularly when audits are undertaken. Applicants are encouraged to submit evidence to the Quality Assurance and Compliance Section prior to submitting a product application, so that GMP issues do not delay the product application process.

A facility will only be recognised as GMP compliant for the specific types of products and steps of manufacture described in the evidence supplied. Conditions of registration will require the registrant to ensure that this GMP compliance is maintained and that evidence of this is kept current and submitted to the APVMA on request.

After registration of a product or approval of a new overseas manufacturer for a product, the registrant is required to ensure that GMP compliance is maintained and current evidence of this is also maintained. Periodically, the APVMA will request submission of this evidence to the Quality Assurance and Compliance Section.

4. What evidence of GMP compliance is acceptable to the APVMA? (Oct 05)

Acceptable evidence is considered to be as detailed in the table Guidelines for Providing Evidence of GMP Status of Overseas Manufacturers" In general, acceptable evidence is considered to be as follows:

a. Where manufacture occurs in a country with which Australia has a Mutual Recognition Agreement on Conformity Assessment with respect to veterinary chemical products, the evidence required is a current and acceptable Certificate of GMP Compliance of a Manufacturer from the relevant competent authority (see EU-Australia MRA List of Competent Authorities ).

b. Where manufacture occurs in another country whose GMP program is recognised by the APVMA, eg USA, NZ and Canada, the evidence required is a current and acceptable certificate of GMP compliance, a licence and/or an audit report from a Recognised Authority. In some instances, the APVMA will also recognise audit reports from competent authorities that are members of the Pharmaceutical Inspection Convention/Cooperation Scheme (PIC/S).

c. Where manufacture occurs in a country with which Australia does not have a Mutual Recognition Agreement (MRA) or whose regulatory program is not recognised by the APVMA, the acceptable evidence of GMP compliance might include:

i) a current and acceptable certificate of GMP from a Recognised Authority, which is based on a satisfactory audit by them.
ii) a satisfactory audit report by an auditor from a Recognised Authority, confirming that the premises complies with a GMP Code recognised by the APVMA as comparable to the relevant Australian GMP Code.
iii) a satisfactory audit report by an Australian APVMA-authorised GMP auditor, confirming that the premises complies with the Australian Code of GMP. All fees incurred for such an audit are to be met by the Registrant or overseas manufacturer.

In order to establish what objective evidence is required in such instances, Registrants are advised to contact the APVMA’s Quality Assurance and Compliance Section well before lodging an application for product registration.

5. What are the requirements for Audit/Inspection Reports?(Oct 05)

The APVMA will consider audit reports from:

a. an APVMA-authorised GMP auditor from Australia;
b. a Therapeutic Goods Administration (TGA) auditor from Australia;
c. an auditor from one of the overseas authorities recognised by the APVMA (ie EU, USA, Canada, NZ).

In certain circumstances, the APVMA may consider an audit report from an alternative quality assurance certifying body that is internationally recognised. However, agreement must be obtained from the APVMA's Quality Assurance and Compliance Section before the audit takes place.

6. What are the requirements for certificates? (Oct 05)

All certificates submitted as evidence that the product has been manufactured to comparable GMP standards must be either the original certificate or an original copy that has been certified by a Notary or other suitably qualified person as a true copy of the original. Faxed copies are not acceptable.

If the certificate has been issued in a language other than English, a certified English translation must be provided, as well as a certified copy of the original certificate.

The certificate should be dated and it must be clear from the certificate that the manufacturing facility is authorised to manufacture the type of product under consideration, and that the facility is regularly inspected for compliance with the relevant GMP Code. Note that some countries do not provide all this information on their certificates, and if there is any doubt in these situations, the APVMA will require the applicant to provide an original letter from the issuing agency clarifying the area of concern. Such letters must be not more than 12 months old, addressed directly to the APVMA, and confirm that the certificate does certify compliance with GMP for the type of product being considered.

The APVMA will not accept:

a. certificates that are more than 3 years old (unless they are accompanied by an agency letter confirming currency);
b. certificates made out to another company (even though the original company may now be owned by the present applicant) - unless they are accompanied by a letter from the present owner (or the relevant agency) confirming that the facility has changed ownership from Company A to Company B and that the certificate is still valid;
c. certificates that state "This certificate may not be reproduced and is solely destined to the Government of XYZ" (where XYZ is not Australia), or something similar;
d. certificates that make no mention of GMP compliance, other than the ones specifically mentioned in the table;
e. copies of certificates that are illegible in places, have bits missing from them (eg missing edges), etc;
f. ISO certificates or other types of Quality Assurance certificates;
g. letters from, or certificates issued by, the applicant or the manufacturer certifying that the product is made in accordance with GMP.

For the standard format required for a certificate of GMP compliance of a manufacturer from the EU, see EU GMP Certificate.

If a Certificate to a Foreign Government from the US Food and Drug Administration (FDA) is submitted, it must confirm that the product and the facility which produces it are subject to the jurisdiction of the FDA, the manufacturing facility is subject to periodic GMP type inspections/audits, and that the products and the manufacturing facility are in compliance with GMP.

7. Are Plant Master Files acceptable? (Oct 05)

Plant or Site Master Files (PMF) ARE NOT acceptable as sole evidence of GMP compliance. However they may be submitted as supporting evidence with audit reports from overseas agencies.

Plant Master Files must be complete and should provide a detailed description of the manufacturing facility and the manufacturing processes carried out in it, as well as a detailed description of the quality control procedures in place. Further guidance on APVMA requirements is available in the guideline Preparation of Plant Master File or for a more detailed description, see the PIC/S web site.

The Plant Master File should be accompanied by a letter or certificate from the inspecting agency confirming that the manufacturing facility has been recently inspected by the agency and that the document accurately describes the facility and manufacturing process carried out in it.

However, it is important to note that these are not accepted as evidence of GMP compliance.

8. What evidence is acceptable for Ectoparasiticides? (Oct 05)

In the EU, ectoparasiticides are regarded as medicinal products and their manufacture is subjected to GMP inspection in the same way as other veterinary medicines.

In the USA, ectoparasiticides are not regarded as medicinal products and hence are not subjected to US Food and Drug Administration (FDA) jurisdiction. They are regulated by the US Environmental Protection Agency (EPA) and are not required to be made to GMP standards. The manufacturers of such products will be required to have an audit by an APVMA-authorised GMP auditor, unless alternative arrangements can be made with the APVMA’s Manager Quality Assurance.

In Canada, the situation is similar to that of the USA. The manufacture of ectoparasiticides is regulated by the Pest Management Regulatory Agency. The manufacturers of such products will be required to have an audit by an APVMA-authorised GMP auditor, unless alternative arrangements can be made with the APVMA’s Manager Quality Assurance.

9. What evidence is acceptable for Stockfeed Additives (eg direct-fed microbials, enzymes etc)? (Apr 06)

In Australia, these products need to be manufactured in GMP compliant facilities. Consequently, overseas manufacturers of such products imported into Australia are required to demonstrate a satisfactory level of compliance with GMP. That may be demonstrated as follows:

In the EU, manufacturers of such products are not subjected to the normal GMP requirements applying to veterinary medicinal products, but they are required to comply with the requirements of Regulation (EC)183/2005, which sets out the conditions and arrangements for approving and registering establishments operating in the animal feed sector. Manufacturing establishments are expected to comply with the requirements described in Annex II of that Regulation. The APVMA will accept certificates from an appropriate authority in the country of origin (usually the national or regional Veterinary Service) stating that the facility has been inspected and that products are manufactured in accordance with the requirements described in Regulation (EC)183/2005. If the Regulation has been transposed into national legislation, it must be clear from the certificate or supporting documentation from the agency that the certificate relates to Regulation (EC)183/2005.

In the USA, such products are regulated by State Departments of Agriculture and not normally subjected to GMP inspection unless they are regarded as medicated stock foods. Regulatory requirements vary from State to State, but most State Departments of Agriculture will issue "Certificates of Export" stating among other things that the product has been made in accordance with "Government requirements or Regulations for stockfeeds, animal nutrition products, medicated feeds and feed additives, etc". The APVMA will not normally accept these Certificates of Export, unless we can be satisfied either by the certificate or by other documentation (eg a letter from the agency) that the Certificate is based on a satisfactory GMP inspection. If a satisfactory Certificate of GMP cannot be obtained from an overseas agency recognised by the APVMA, the manufacturing facility will need to be audited by either an Australian APVMA-authorised GMP auditor or an overseas GMP auditor acceptable to the APVMA.

The Post-Registration Process

10. When was the Overseas GMP Scheme introduced? (Oct 2005)

The new scheme was announced on 1 February 2005 and was effective from 17 February, 2005.

11. Are all veterinary chemical products affected? (Oct 2005)

No. Only veterinary chemical products that are manufactured overseas are affected by the new scheme. This includes products that are partially manufactured overseas, such as those involving bulk product manufacture or testing and analysis.

12. What costs and timeframes are involved? (Oct 2005)

Currently, the APVMA does not charge a direct fee for the new scheme. The cost to registrants will be that of maintaining current evidence of GMP compliance and the administrative cost of submitting this to the APVMA when it is requested. The cost of maintaining current evidence will be variable, ranging from obtaining a current certificate to funding an overseas audit.

13. What happens to my existing registered product? (Oct 2005)

Existing registered veterinary chemical products that are manufactured overseas have been reconsidered. Veterinary chemical products with overseas manufacturers should now have the overseas GMP conditions included in their product registration details.

14. What happens to my application currently before the APVMA? (Oct 2005)

Any applications before the APVMA on or after 17 February 2005 will have the GMP conditions of registration added if the applications relate to:

a) registration of a new veterinary chemical product that is manufactured overseas; or
b) addition of an overseas manufacturer for the first time.

15. What type of records do I need to maintain to comply with the conditions of product registration? (Oct 2005)

To comply with the conditions of registration, registrants must maintain satisfactory evidence of the GMP compliance of each overseas manufacturer. The type of evidence required is consistent with the type of evidence currently accepted by the APVMA for product registration. For more details, please see Question 4.

16. My product was reconsidered and I’ve just had the GMP conditions imposed. Will there be a transition period before the APVMA commences audits of GMP evidence? (Oct 2005)

The APVMA will begin auditing of records three months after the GMP conditions are imposed as a result of the reconsideration. However, during the three-month transition period, the APVMA will conduct “education” data call-ins to assist registrants in judging the adequacy of evidence.

17. How often will the APVMA be auditing records? (Oct 05)

The APVMA will continue to require evidence of GMP compliance at the time of registration.

The APVMA will develop a risk-based audit schedule for the Post-Registration Process.
Generally speaking, the APVMA will ask most registrants to submit evidence to the Quality Assurance and Compliance Program at intervals of approximately three years. Some will need to be checked as often as every year. This evidence will be audited by the Quality Assurance and Compliance Program.

In practice, the APVMA will ask most registrants to submit evidence to the Quality Assurance and Compliance Program at intervals of approximately three years. Some will need to be checked as often as every year. This evidence will be audited by the Quality Assurance and Compliance Program.

18. Will the APVMA be auditing evidence on an individual product basis, or by company or by manufacturing site? (Oct 05)

The APVMA will call in evidence on an individual product basis. However, where possible, evidence will be requested on the basis of groups of related products or a manufacturing site. When submitting evidence of compliance for a particular site, registrants may advise the APVMA of other products manufactured at that site.

19. When evidence is requested, what will the timeframe be for its submission? (Oct 05)

Registrants will be asked to submit evidence within ten days from the date of the letter of request. The onus is on registrants to maintain current evidence of GMP compliance, and it is not satisfactory to wait until evidence is requested by the APVMA before obtaining evidence.

20. What will happen if the submitted evidence is not satisfactory? (Oct 05)

If the evidence is not satisfactory, the APVMA will request the submission of more appropriate evidence. If a registrant is unable to supply satisfactory evidence of current GMP compliance, then the registration may be suspended or cancelled due to the breach of conditions of product registration.

21. Where can I obtain further information about GMP compliance of overseas sites? (Oct 05)

From time to time, new information may be released about the scheme. Further information can be obtained from the APVMA website, or by contacting:

Dr Toni Pike
Quality Assurance Reviewer
Australian Pesticides and Veterinary Medicines Authority
PO Box 6182
Kingston ACT 2604
Phone: (02) 6272 4408
Fax: (02) 6271 6442
Email: toni.pike@apvma.gov.au