Drug regulatory agencies around the world are beginning to coordinate their inspection processes, which could reduce global drug manufacturers’ burden of hosting multiple GMP inspections.Some are piloting joint inspections, with a pilot for active pharmaceutical ingredient manufacturers concluding next month, and a second for drug product manufacturers under way.

Many are joining an international association of pharmaceutical inspection agencies, the Pharmaceutical Inspection Cooperation Scheme (PIC/S), that can build trust among inspection programs and help them harmonize their efforts, and that can play a major role in strengthening developing inspectorates.

Especially encouraging was the decision by the PIC/S Committee at its Nov. 8-9 meeting in Kuala Lumpur, Malaysia, to accept FDA’s application for membership.

But for every step forward, there always seems to be a step backward. Every year more emerging powers add their unique GMPs to the list of requirements for which drug manufacturing facilities anywhere could be inspected.

At the Parenteral Drug Association’s PDA/FDA meeting in September, FDA’s Edwin Rivera-Martinez described a vision for a “global allegiance” of drug regulatory authorities.

“When it comes to ensuring drug product quality and ultimately consumer patient safety in today’s global economy, we need to think and act globally. We can no longer think and act as separate regulatory agencies,” said Rivera-Martinez, an FDA enforcement official who had played a key role in efforts to establish a global regulatory framework for active pharmaceutical ingredients.

“That’s why you see more collaboration, more interaction between the regulators, because we realize that in order to deal with a global industry, we have to become an allegiance of regulators to deal with this industry, and only by thinking and acting together will we be successful in dealing with these challenges,” said Rivera-Martinez, who has since retired from the agency and taken a position with Boston-based Parexel Consulting.

A global proliferation of inspections

Drug manufacturers must devote substantial resources in support of largely duplicative inspections by multiple national and regional authorities, Roche’s Stephan Roenninger told the PDA/FDA conference in Washington.

Roenninger, who is Roche’s head of external relations for Europe and Japan, summarized the latest results of an annual survey by the European Federation of Pharmaceutical Industries and Associations on inspection activities.

Pharmaceutical regulatory agencies from 37 countries inspected facilities of 23 manufacturers who responded to EFPIA’s 2009 survey. The survey’s 23 respondents together had 683 facilities.

Since EFPIA began this annual survey, 49 countries have performed foreign inspections of member companies. The list would be even longer if EFPIA did not count the 27-country European Union as a single country. Three countries joined the list last year: Ivory Coast, Malaysia and Turkey.

Of the 49 inspectorates, the U.S. has performed the most foreign inspections of EFPIA survey respondents since 2003, followed by the European Union, Japan, Brazil and South Korea. The foreign inspection rates of these top-five countries have generally been increasing year to year.

The same five agencies also are the most frequent inspectors of Japanese and U.S. drug manufacturers, EFPIA learned in a meeting two years ago with members of the Japan Pharmaceutical Manufacturers Association and the Pharmaceutical Research and Manufacturers of America, Roenninger said.

Roenninger called attention to an important disparity: While multiple authorities inspect some facilities, there are other facilities that no one inspects.

He showed that, at least in Europe, facilities that receive a lot of foreign inspections also receive a lot of domestic inspections. All told, of the 683 facilities that EFPIA’s 2009 respondents reported, 34 percent were inspected by anywhere from two to 16 countries. Thirty-eight percent received one inspection – and 28 percent of the facilities received no inspections at all.

Furthermore, 45 percent of respondents to the EFPIA survey said that multiple inspections of their sites overlapped in content or focus to a high degree. The rest said there was medium overlap. None said there was low overlap.

A July 2010 report on a study by Japan’s Ministry of Health, Labor and Welfare provided more evidence of substantial overlap among inspection authorities. The MHLW study showed that FDA, EU, Japan’s PMDA and others all dedicated similar amounts of time during inspections on each of six areas of focus – management, premises, storage, production, packaging and lab.

Roenninger called attention to Colombia’s “countries of reference” approach as a possible model.

Roenninger went on to suggest how inspection agencies could use a risk management approach to allocate their resources better and inspect more facilities less redundantly.

Risk-based inspection scheduling

Over time, regulatory authorities could do more joint inspections, share more inspection results and, through the International Conference on Harmonization and PIC/S processes, work toward harmonizing their approaches to inspections and strengthening their trust in each other, Roenninger suggested.

Ultimately, he said, “Inspection scheduling can be even more risk-based and provide a broader coverage of cooperative arrangements among trusted regulatory authorities.”

He said Japan’s model for scheduling risk-based inspections already takes into consideration information from other inspectorates.

FDA and the U.K.’s Medicines and Healthcare products Regulatory Agency also have risk-based approaches to inspections, he noted.

“In principle, the model for each agency is the same from my point of view,” Roenninger said. “At the end, you have a selection process and you perform or delay inspections, and this is the black box of risk-based scheduling of inspections.”

Roenninger noted that there are barriers to overcome for inspection results-sharing to make a difference.

“There’s still a lack of certainty in arrangements for the protection of the confidentiality … in the sharing of inspection reports,” he said, adding that in some cases, regulatory agencies can be required to get permission from the manufacturer before sharing an inspection report with their counterparts from other countries. One approach to this issue could be to share the outcome of the inspection rather than the report itself, he said.

Also some agencies don’t accept GMP certificates issued by other agencies – and some are required by law to conduct their own foreign inspections.

How inspectorates can build mutual trust

There are alternatives to the current practice of each country conducting its own separate onsite or desktop inspection, Roenninger said. The key, he explained, is to build trust and share information by:

joining PIC/S;
signing confidentiality agreements with each other; and
participating in joint inspection pilots.

Government agencies can foster cooperation by signing memorandums of understanding and mutual recognition agreements, although Roenninger noted that by law, MRAs are not an option for the U.S.

Roenninger added that it would also be possible for inspection authorities to accept the GMP certificates issued by counterparts in other countries.

Similarly, they could rely on certificates of pharmaceutical product, or CPPs, that World Health Organization member countries issue to attest that exports are manufactured at facilities that were found through regular inspections to comply with WHO drug GMPs.

Roenninger called attention to Colombia’s “countries of reference” approach as a possible model.

He noted that Colombia, which ordered the 12th-most foreign inspections in 2008 according to that year’s EFPIA survey, only inspects drug manufacturing facilities that are in Latin America.

Colombia conserves inspection resources by maintaining a list of “countries of reference.” Because the U.S. is on the list, Colombia will not inspect a drug manufacturing facility located in the U.S. or inspected by FDA but will instead accept the results of FDA inspections.

The joint API inspection pilot

Brendan Cuddy told the PDA/FDA meeting about a joint API inspection pilot program that addressed some of the problems plaguing the global inspection process, and that could serve as a model for a broader solution.

The master list has really increased the transparency and visibility of the inspection planning process, Cuddy said.

“This project has given us a foundation at least going forward to improve inspectional information-sharing on API manufacturing sites and also to facilitate a more risk-based approach at a global level,” said Cuddy, who coordinates GMP inspections for the European Medicines Agency, or EMA.

FDA and the European Commission decided at a November 2007 Transatlantic Administrative Simplification Workshop to conduct joint inspection pilots.

In November 2008, there was an 18-month collaboration, later extended to 24 months, among FDA, the EU and Australia’s Therapeutic Goods Administration, or TGA, to jointly inspect active pharmaceutical ingredient manufacturers in countries outside the U.S., the EU and Australia.

Participants within the EU included EMA, the European Directorate for the Quality of Medicines, or EDQM, and the inspectorates of France, Germany, Ireland, Italy and the UK.

The participating authorities agreed that each had the right to do its own inspections, but that it would inform the others of any negative outcomes. They also agreed on a common GMP standard, the International Conference on Harmonization’s Q7 guideline, and that with joint inspections they would reach an agreed conclusion, “prior to leaving the site preferably,” Cuddy said.

The authorities would follow up with their own enforcement actions, though there could be joint follow-up as well.

There were seven joint inspections in the API pilot, four in India and one each in Croatia, Mexico and Japan.

The creation of the master list

The project started with each authority sharing “a list of manufacturing sites which they had inspected within the last two to three years, and also a list of sites that were planned to be inspected within the next year to 18 months,” Cuddy said.

This led to the creation of a master list, which gave the name and address of each site, the APIs made there, the date and outcome of the last inspection and the date of the next inspection. The authorities circulated the master list every month after updating it with information about new sites of interest, inspection outcomes and planned inspections.

The authorities signed confidentiality agreements so they could share inspection reports and plans, and they prepared “rules of engagement” to govern their interactions during the program. They could, for example, decide whether another agency’s previous inspection would suffice for them, or whether they would need to go out to the site as well, perhaps to inspect another API there, or whether they could ask another authority to expand an upcoming inspection to cover their API of interest.

“If, for whatever reason, it wasn’t possible for the inspecting authority to accommodate that request, then the next step was to collaborate perhaps on a joint inspection. And it was only if that wasn’t possible, then it may be necessary for the other authority to organize their own inspection,” Cuddy explained.

Better inspection planning resulted

The master list has really increased the transparency and visibility of the inspection planning process, Cuddy said. And the sharing of inspection reports has increased the value of the inspections the three authorities conduct. In one case, a joint inspection of a non-compliant site led to a follow-up inspection of a sister site. Both sites were removed from the market and drugs made with API from the second site were recalled.

Despite the pilot, the authorities did conduct duplicate inspections in 2009, but there haven’t been any in 2010, Cuddy said. “I think it’s probably not surprising to have some duplicate inspections in 2009, given what we were trying to achieve and that perhaps inspection planning that would involve the authorities was still catching up with the inspection program and that perhaps there wasn’t full visibility of the pilot program within the authorities.”

He noted that EMA prepared an interim report in June, and that it plans to draft and circulate a final report by the end of December.

What’s next for API inspections

Anti-counterfeiting legislation expected in the European Union next year “foresees long-term international collaboration with a view to developing common approaches at a global level within the supply chain,” Cuddy said.

As part of that effort, the European Commission has proposed to formalize the EMA’s role in coordinating inspection-related functions. This could involve coordinating a risk-based approach to inspections for EU authorities and contributing to “an international platform” with other authorities.

Also, the pilot’s master list could serve as a model for a module on foreign, or “third-country” inspection planning that may be added to the EudraGMP database in a couple of years, he said.

Additionally, Cuddy noted, EMA, FDA and TGA have produced a concept paper proposing long-term international collaboration to enhance the quality assurance of APIs, “where increased cooperation and information-sharing between the agencies is proposed and will look to incorporate capacity-building measures in third countries seeking to further develop their regulatory system for supervision of API manufacturers.”

He concluded that the pilot project “has given us a foundation for more international collaboration in GMP inspections of API manufacturers. It has given us a template for other collaborative work with the U.S. FDA for example in the area of GMP inspections of finished product manufacturers and also in the area of joint inspections of clinical trial sites for GCP.”

The joint inspection pilot for drug products

U.S. and EU authorities in January 2009 updated the rules of engagement and procedures for the joint API inspection pilot to open it up to preapproval inspections of drug product manufacturing facilities as well.

In August 2010, they further expanded the pilot to include routine surveillance inspections of drug product sites, and invited drug makers to volunteer for joint inspections.

FDA and the Irish Medicines Board conducted the first joint inspection under this program at Pfizer’s Grange Castle site in Ireland in April 2009. There was a second joint inspection that July and an observed inspection in the U.S.

Pfizer’s Frank Hallinan discussed the company’s experience with the Grange Castle inspection Nov. 8 at the annual meeting of the International Society for Pharmaceutical Engineering in Orlando, Fla.

Hallinan is senior director for quality strategy at Pfizer, and was the quality site lead at the facility at the time of the inspection.

The joint preapproval inspection focused on a process for producing a freeze-dried antibiotic parenteral product in vials, which differed from the usual type of product made at the biotech manufacturing facility.

There were two inspectors from IMB, one of them the lead inspector, and two investigators from FDA. Each agency produced its own report. FDA left Pfizer with a Form 483 report and IMB provided verbal comments, followed by a May 15 written report. Pfizer responded in May and June and won approval from both.

Why did Pfizer participate in the pilot? “We saw it as an opportunity to partner with regulators and industry groups as part of an exciting and international collaborative effort, and to develop mutual confidences between regulators, with a view to potentially negating duplication of effort in the future,” Hallinan said.

There was the attraction, at a time when the Grange Castle facility had been hosting an inspection a month, of combining two inspections into one. And there was the opportunity, he said, “to share experiences gained with regulators and industry, and for us as a company to provide early input into the policies and programs in support of these schemes.”

The timing also was opportune, because Pfizer had planned submissions to EU and the U.S. for adding the Grange Castle facility as a site for making the parenteral antibiotic.

He said that under the project’s rules of engagement, both the U.S. and EU GMPs would apply, and where they diverge, the most stringent requirement would apply.

Under the program’s procedures, the host nation’s authorities take the lead on inspections in the EU and the U.S., with the lead assigned on a case-by-case basis for inspections elsewhere.

The site prepared for the inspection in its normal fashion, even though it was the site’s first application for a sterile product and its first FDA inspection. Also, because this inspection preceded submission of the filing, the sections of the Common Technical Document that Pfizer provided for review during the inspection were still in draft.

A four-way challenge

The four inspectors divided into two teams, each with a U.S. and Irish inspector, one team focusing on aseptic practices and the other covering everything else.

During the inspection, Hallinan said, “what tended to happen was the inspection teams occasionally broke out into four independent work streams.” While that meant the agencies trusted each other, it also meant Pfizer would have to support a “pretty dynamic and pretty challenging” inspection.

Compared to the typical EU inspection, the joint inspection exhibited “more spontaneity with respect to requests for documentation and requests to tour and to observe certain operations,” he said.

Otherwise it was fairly standard, he added. About 40 percent of the inspection was out on the floor. IMB led daily debriefings, with concurrence from FDA.

Their reports reflected a common understanding of the deficiencies, though the way they worded observations might differ, he said. “They would be citing the same thing, but they would cite it in somewhat different language.”

In general, he said, “We felt there was good engagement throughout the inspection within the agencies themselves, between the different agencies and overall between the inspectors and the team at our facility.”

Hallinan concluded with four recommendations for future joint inspections:

It’s important for agencies to prepare as a group for a joint inspection;
It would be better if agencies could work toward producing a joint inspection report, despite the legal and procedural complications it would involve;
Agencies should reduce the priority of inspecting sites that have been through a joint inspection; and
The resources freed up by joint inspections should go toward greater inspection coverage of “areas that maybe we didn’t inspect so much in previous times.”

Inspectorates converging through PIC/S

FDA’s upcoming Jan. 1 accession to PIC/S is part of a broader coming together of inspectorates around the world that could have a wide-ranging impact on the global pharmaceutical inspection process.

The Pharmaceutical Inspection Convention, a 1970 treaty among 10 countries initially, has since evolved into the Pharmaceutical Inspectorate Convention Scheme, or PIC/S, which aims to lead the international development, implementation and maintenance of harmonized GMP standards and quality systems of inspectorates in the field of medicinal products.

To achieve its goal, PIC/S develops harmonized GMP standards and guidance documents, trains competent authorities, particularly GMP inspectors, and assesses GMP inspectorates.

It also facilitates the cooperation and networking of competent authorities and international organizations, according to Brenda Holman, executive director for strategic initiatives in FDA’s Office of Regulatory Affairs. Those initiatives include quality systems and joining PIC/S.

FDA’s five-year quest for membership

Speaking Sept. 14 at the PDA/FDA meeting, Holman talked about why, after FDA’s membership application languished for nearly five years, a PIC/S assessment team decided in August to recommend approval, which the PIC/S committee gave earlier this month.

In September 2005, when FDA began working on its application to join PIC/S, “we did not know how to approach this as an agency,” Holman said. So each office, including ORA, the commissioner’s office, the chief counsel’s office and the centers for drugs, biologics and veterinary medicine, “took the application and filled out our separate parts and threw it back over the wall to PIC/S and said, ‘you go figure it out.’”

When a PIC/S assessment team visited FDA in August 2009, “we continued in the onsite visit to FDA to show them the different pieces but not the connectors,” Holman said. “The only thing that made any sense in this two-week assessment was going out on inspections and actually going into a district office and looking at documentation and procedures and processes, and realizing that we did have some rules of engagement and we did have procedures in place.”

The PIC/S team’s assessment “was devastating to us,” Holman said. The team rated FDA on 89 indicators. The agency fulfilled only 68 of the indicators. It partially met 16 of them and failed to meet five. “This was a rude awakening for FDA and my colleagues that worked in putting together to application and the assessment questionnaire.”

FDA’s Rude Awakening

FDA was devastated when the PIC/S assessment team concluded it failed to meet five indicators and only partially met another 16. The 89 PIC/S indicators are built around 11 areas, FDA’s Brenda Holman said:

Legislative and regulatory requirements
Regulatory directives and policies
GMP standards
Inspection resources
Inspection procedures
Inspection performance standards
Enforcement powers and procedures
An alert and crisis system
Analytical capability, which PIC/S did not assess because FDA’s laboratories are ISO accredited
Surveillance programs
Quality management systems

FDA responded to the findings in January 2010, but when PIC/S requested further clarification in May, it was clear that that the organization believed the agency had corrected only one of the 16 partially met indicators.

Things came to a head May 28 at the PIC/S meeting in Geneva. Holman recalled, “There was a conversation with the assessment team in which they said, ‘maybe by next May, we will put a vote on the table for FDA to be considered as a member.’”

That’s when she blurted out, “That’s not acceptable. We’ve been in the process of this application for over five years. There’s some rule in there that says after six years, you have to start all over again at the very beginning, so 2010 is it.”

There was a lot of movement in the room. The PIC/S assessment team conferred. Would FDA agree to a shorter visit in August?

The home stretch

FDA seized the opportunity to do a better job of putting together a more coherent explanation of its enforcement program.

The agency commenced weekly meetings on its PIC/S application. “We sought clarity and understanding of the specific deficiencies and refined our original responses to address these specific deficiencies,” Holman said.

A group of representatives from each of the offices involved “worked together as a team, now representing FDA as opposed to our individual parts of the organization,” Holman said. “We collaborated and reviewed each others’ responses; we talked through it, looked at documents and really worked as an agency team.”

The group updated some policy and guidance documents and revised others to address some of the PIC/S team’s concerns, she said. “We even had a dress rehearsal the week before the team arrived, just to make sure that we all were on the same place and could answer questions across the board.”

The Aug. 9-13 site visit went well. FDA convinced the assessment team that it had fulfilled nearly all the indicators. There would be some outstanding issues, like the agency’s ongoing implementation of a quality management system, and its training and certification of pharmaceutical investigators, but the assessment team would recommend that the PIC/S Committee approve FDA’s application in November.

Inspecting to a common standard

Discussions at the end of the PDA/FDA session on regulatory communication revolved around the anticipated evolution toward a common inspection standard.

Asked how organizations become comfortable accepting inspections done by other regulatory authorities, EMA’s Cuddy responded with a look at how the EU’s 48 competent authorities have managed to do it despite their differences, among them 22 official languages.

Cuddy pointed to four factors: Common legislation; a common inspection standard, the EU GMP guide; quarterly meetings of EU GMP inspectorates; and a common inspection report format.

“We hope with these kinds of tools that we can at least minimize differences, but of course we’ll always have some differences, it’s just inevitable,” he added.

Recent discussions would suggest that many such tools are in play at a global level as well.

The ICH process came too late to establish a global template for common drug GMP legislation, but its Q7 guideline has played such a role for API standards, and its Q8, Q9 and Q10 guidelines have provided a common globally adopted approach to meeting disparate GMP standards.

PIC/S provides a forum for periodic meetings of inspectorates at a global level, as well as a common document format, the PIC/S Site Master File form.

As for a global inspection standard, the PIC/S GMP guide comes close. Roenninger said that “it’s word-for-word the same as EU GMP with one exception, and that’s the QP (Qualified Person) Annex, which is missing.” He added that PIC/S regularly updates its GMP guide to reflect changes to the EU GMP guide.

Rick Friedman, the top GMP compliance official in FDA’s center for drugs, said he wants to hear from industry on “where specifically are the differences in the PIC/S guidance versus what FDA and EU and others have on the books.”

Freidman went on to assert that “FDA and EU essentially feel that we have harmonization between our documents,” although he suggested there may be nuances in how they are applied in inspections.

And he acknowledged that while agencies have harmonized on ICH Q7 for API inspections, people still see differences in the finished product GMPs.

Friedman went on to suggest that PDA could play a role in bringing a group together to do the gap analysis that’s needed.

What does FDA’s accession to PIC/S mean for drug manufacturers? In Holman’s view, it means “we’re sitting at the same table with other agencies that look at you and your products and your procedures. This is a major step forward. … We have a commitment at the agency level to sit at that table and to participate and be a full member in good standing to try to get to the harmonized and reasonable standards that we need to have out there internationally across the product lines.”

Meanwhile, the challenges facing inspection harmonization were nowhere more evident than in Turkey, which until this year has been accepting pharmaceutical imports without first inspecting the plants where they were manufactured.

Now the Turkish Ministry of Health is requiring U.S. and EU drug manufacturing facilities to pass inspection as a condition of access to the Turkish market. The thinking is that it is only fair, a representative of a Turkish drug maker explained at the ISPE meeting, because the U.S. and the EU have been subjecting Turkish drug makers to inspection as a condition of access to their markets.

The problem is that Turkey lacks the resources to conduct all the inspections needed to assure the continued flow of pharmaceuticals into the country.

By Bowman Cox

‘Global Allegiance’ of Inspectorates Emerging

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