1. If an API manufacturer is already supplying a number of APIs to a company and they have been audited previously to confirm compliance with GMP, is it necessary to perform another audit if a new API is to be sourced from them?
2. Do API audits have to be product specific if a number of APIs from one manufacturer are used in the same dosage forms?
3. Are there any plans to inspect all API manufacturers by European Union (EU) Regulatory Authorities?
4. What can a company do if an API manufacturer refuses to sign a technical agreement?
5a. A company has an established product which requires a variation to be submitted for a particular change. As part of the change the company has to submit a QP declaration for compliance of the API manufacturer with GMP, however the API manufacturer is not meeting GMP standards. What should the company do?
5b. If the scenario in part a of the question was not for an atypical active but an established API which was not found to be in compliance with ICHQ7A, does this mean the QP cannot certify batches made with API from this site?
6. For natural and semi-synthetic APIs, how far back should you audit for compliance with GMP?
7. Some excipients are coming under the same expectations for GMP compliance as APIs. What are the timescales for guidelines?
8. Can a GMP certificate issued by an EEA Competent Authority, MRA partners or other recognised authority be used in lieu of an audit by a manufacturing authorisation holder to confirm GMP Compliance of an active substance manufacturer / supplier?
1. If an API manufacturer is already supplying a number of APIs to a company and they have been audited previously to confirm compliance with GMP, is it necessary to perform another audit if a new API is to be sourced from them?
It may not be necessary to re-audit but this will depend upon the exact circumstances. There should be a documented review and risk assessment to justify receiving the new API from the current manufacturer. The company’s ongoing audit programme should ensure the new API is covered during the next audit.
2. Do API audits have to be product specific if a number of APIs from one manufacturer are used in the same dosage forms?
API audits do not have to be product specific. You need to consider what dosage forms the APIs are being used in. The focus should be on GMP compliance. Changeovers, cleaning and cleaning validation should also be reviewed. Ensure that APIs are coming from facilities that you have actually audited.
3. Are there any plans to inspect all API manufacturers by European Union (EU) Regulatory Authorities?
The EC proposals to combat counterfeits mentions API manufacturers, this is currently awaiting consultation feedback. Some EU Regulatory Authorities and the European Directorate for the Quality of Medicines & HealthCare (EDQM) perform audits of API manufacturers which are recorded on the European Union Drug Regulatory Authorities (EUDRA) database. There is currently a pilot programme between the EU, the Food and Drug Administration (FDA) and the Therapeutic Goods Administration (TGA) to share inspection outcomes, focusing on API manufacturers. ICHQ7 is the internationally recognised standard used. Inspection findings and reports are shared and some joint inspections are being performed. See European Medicines Agency (EMA_ website for more details. There is the possibility this programme will include manufacturing sites in the future.
4. What can a company do if an API manufacturer refuses to sign a technical agreement?
Technical agreements are important to ensure each party understands its responsibilities, particularly surrounding management of changes. If an API manufacturer refuses to sign an agreement, then an alternate supplier should be found.
5a. A company has an established product which requires a variation to be submitted for a particular change. As part of the change the company has to submit a QP declaration for compliance of the API manufacturer with GMP, however the API manufacturer is not meeting GMP standards. What should the company do?
If the API is an atypical active (eg honey or glycerine and pharmaceutical business is small volume of sales) then the expectations are that there should be a clear specification, the site should have been audited, changes should be controlled, appropriate checks should be made on incoming goods. Each atypical active scenario should be assessed on a case by case basis.
5b. If the scenario in part a of the question was not for an atypical active but an established API which was not found to be in compliance with ICHQ7A, does this mean the QP cannot certify batches made with API from this site?
The deficiencies are known at the API site and there are plans to address the issues.
The QP should establish exactly what is being done to address the issues and build up a case to justify what they are doing. Work with the manufacturer to improve compliance. Document the situation; assess the risks and the action plan with the company. Conventional API manufacturers should be more willing to comply than atypical active manufacturers as the pharmaceutical industry is their main business. If serious deficiencies are found consider public health implications. The MHRA should be informed in these circumstances and a ‘for cause’ inspection of the manufacturer may be initiated. Ultimately if a site is not compliant with GMP then it should not be used and a QP should not certify it as such.
6. For natural and semi-synthetic APIs, how far back should you audit for compliance with GMP?
Guidance on establishing the point at which production of the API begins is outlined in 1.2 and Table 1 of Part II of the Guide. A risk assessment should be performed to identify potential problems eg supplier history, process control, variation in starting materials, how difficult these are to control and to identify how far back in the past there is the potential for problems that are unlikely to be removed or detected during later processes. Consideration should also be given to the revisions of Annex 2 of the Guide and the learning points from the recent Heparin contamination issue, where a low molecular weight Heparin used widely in Europe contained low levels of contaminant.
7. Some excipients are coming under the same expectations for GMP compliance as APIs. What are the timescales for guidelines?
The EC in consultation with industry representatives developed a questionnaire and regulatory impact assessment. This was circulated to excipient manufacturers and users and the output has been analysed and recommendations have been put forward. We await further developments. The list of ‘certain’ excipients is still to be confirmed by the EC. The MHRA considers guidance such as that published by the Pharmaceutical Quality Group (PQG) and The International Pharmaceutical Excipients Council Europe (IPEC) provides a useful contribution to supply chain management.
8. Can a GMP certificate issued by an EEA Competent Authority, MRA partners or other recognised authority be used in lieu of an audit by a manufacturing authorisation holder to confirm GMP Compliance of an active substance manufacturer / supplier?
Article 46(f) of Directive 2001/83/EC as amended requires the holder of a manufacturing authorisation to use as starting materials only active substances which have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials. Compliance with this obligation should be gained through audits of the active substance suppliers by the manufacturing authorisation holder themselves or a third party acting on their behalf. GMP certificates issued by EEA, MRA partners or other recognised authorities cannot fulfill this statutory obligation or the requirements of section 5.25 of the GMP Guide.
GMP certificates can however provide useful information to manufacturing authorisation holders and may be used together with other supporting information in a risk-based approach by the manufacturer in establishing priorities for its own audit programme of active substance suppliers.
