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International Joint API Inspection Pilot Program Sees Positive Results

The international API pilot joint inspection program involving regulatory authorities in the EU, US, and Australia is resulting in rapid sharing of inspection reports for non-compliant sites, follow-up inspections at other facilities owned by the companies found to have non-compliant sites, and prompt notification of regulatory actions taken.

European Medicines Agency (EMA) Scientific Administrator Oliver Gross told the DIA Annual Meeting in June that the pilot program – now extended an additional six months to the end of 2010 – has been successful and has allowed “real collaboration” between the participating agencies.

The EMA official cited a joint inspection of a facility in India conducted by the European Directorate for the Quality of Medicines (EDQM) and Australia’s Therapeutic Goods Administration (TGA) as an example of this collaboration process at work.

The Indian facility was found to be non-compliant.  Because the EDQM is not a national regulatory authority, it could not issue a “non-compliance statement,” so it was issued by TGA, which has a mutual recognition agreement (MRA) with EMA.  TGA then sent a copy of the report to all EU member states.

“Because one site was non-compliant, we had suspicions that another site may be non-compliant also,” Gross commented.  In fact, the other site was inspected and found to be more seriously non-compliant than the first one.  This inspection resulted in product recalls, and the inspection report was shared with all of the pilot participants.

In another case, a Japanese site was inspected by the Italian authority and found to be non-compliant. In addition, TGA found issues with a CAPA the firm had submitted.  The result was a joint inspection by EMA Italian inspectors and TGA in June.

The joint API inspection pilot was initiated in response to several factors:  • increased demand for international collaboration on inspections as part of the Transatlantic Administrative Simplification Action Plan (2006-7) • the heparin contamination situation in 2008 • concerns with globalization of the API supply chain, and the lack of guidance equivalent to Q7 outside the ICH regions (IPQ, Nov./Dec. 2008 Report).

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The primary objectives of the program were to improve the efficiency of API inspections and the use of agency resources through collaborative inspection planning and conduct.

Data from 2005 to 2008 showed many duplicate inspections were being performed.  Out of 85 inspections examined, 46 of them were performed at the same site by two different authorities within 12 months, and eight of these were conducted during the same month.

Participants in the pilot include: the TGA; the EMA, as well as member states France, Germany, Ireland, Italy, and the United Kingdom; the EDQM (targeting European Pharmacopoeia specifications); and the FDA.

The key performance indicators chosen at the start of the pilot, Gross explained, were to:

• “increase the transparency and the visibility of participation in inspection planning – so we are changing planning and knowing who is inspecting where
• decrease duplicate inspections, when one, two or sometimes three inspectorates from different regions inspect the same manufacturer within months or within six months…
• increase the number of inspections applied to more than one authority, and
• have a positive assessment of the deliverables – so we wanted people participating in this pilot to be happy at the end of the pilot.”

Beginning in July 2008 through June 2010 about fifteen teleconferences were held during which initial planning and later information sharing took place.  In the earlier sessions, the participants agreed that all would continue to plan and perform inspections outside the pilot.  In the context of the pilot, Q7 was the agreed-upon standard.

The plan was to “more or less agree on common conclusions after the joint inspection whenever possible,” Gross explained.  Each authority would be involved with follow-up actions in cases of non-compliance, with possible joint follow-up actions. In addition, a confidentiality agreement was signed between the participating authorities to allow sharing of inspection information.

To aid in planning and sharing of information, a spreadsheet referred to as the “master list” was created containing a table of sites to be inspected and site actions.

“We have two parts in this master list where we have a table of sites [providing] the most possible information on each site, and then we have a table of actions which summarizes actions we can do together on the different sites” – for example, exchange of inspection reports or charting the inspections, the EMA official noted.

The master list includes information on approximately 1000 sites – 192 from TGA, 315 from FDA, and 483 from EMA.  Removing the duplicate sites provided by more than one agency, a total of 636 different sites resulted.  From these, it was determined that 89 sites were shared by all three regions – the sites for which joint inspections by all three regions could be considered.

46 of these shared sites are in India, and fifteen are in China.  These 61 sites supply APIs to all three regions and will be primary considerations as joint inspection targets.

In addition to planning and conducting joint inspections, the participants share reports of inspections conducted by the individual inspectorates.

So far, Europe has requested 36 inspection reports from the other regions, FDA 22 and TGA 14.

As of June 2010, six joint inspections have been conducted under this program and four more are planned before the end of the year.  For these inspections, each inspectorate produced its own inspection report using its own format but containing similar content.

“When we do a joint inspection, we usually ask the inspectors to give us some feedback because we are interested to know how this joint inspection between the regulatory authorities is going – where they are having problems, what we can improve,” Gross explained.

The feedback has been that:  early communication and agreement of the team composition, scope and duration of the inspection is important inspectors having one day before the inspection for preparation facilitates better inspections inspectors are able to work well together and there have been no major problems,  and there have been no major differences noted in interpretation of the GMP standards.

Gross pointed out that there has been especially good feedback from Europe and TGA “because the way they conduct inspections is more similar.”

The EMA administrator commented that there remains room for improvement in the joint inspection system, “because even after our collaboration we observed that we still do duplicate inspections and the system does not know that they are being done.”  He predicted that “it is going better and better because the planning and exchange of planning [information] has improved.”

Gross pointed out that participants are “sending the updates more regularly so we can really share up-to-date information.”  In the future, the group plans to share a web-based database for inspection planning, perhaps similar to the EudraGMP inspection module.

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