As health authorities around the world wrestle with how to conduct manufacturing inspections during the 2020 global pandemic, as well as with shrinking resources and the need to better leverage them, mutual recognition agreements (MRAs) between the authorities are providing some relief.

For example, the MRA between the U.S. FDA and the European Union has provided FDA with over 200 inspection reports this year from European health authorities and it has deferred nearly as many European inspections.  These all represent inspections of drug manufacturing facilities that FDA did not have to spend resources to accomplish.

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At the 2020 ISPE Europe Annual Conference held virtually in September, Ireland Health Products Regulatory Authority (HPRA) Inspection Manager and Pharmaceutical Inspection Cooperation Scheme (PIC/S) 2020-2021 Chair Anne Hayes provided insight into the international regulatory organization she chairs and its GMP inspection reliance guidance.

PIC/S Membership is Global

PIC/S is a non-binding, informal cooperative arrangement between regulatory authorities in the field of good manufacturing practice of medicinal products for both human and veterinary use.

The PIC/S mission is to lead in the development, implementation, and maintenance of harmonized GMP standards and quality systems for inspectorates in the field of Medicinal Products.

It is a global organization representing 53 participating authorities from six continents.  In addition, current applications for membership include authorities from Armenia, Brazil, Bulgaria, and Saudi Arabia. In the pre-accession or pre-applicant process are Jordan, Pakistan, Bangladesh, and Azerbaijan (Figure 1).

https://redica.com/wp-content/uploads/PICS-Current-and-Aspiring-Members.png
FIGURE 1 | PIC/S Current and Aspiring Members

PIC/S Strives for International Regulatory Harmonization

To become PIC/S members, authorities must have GMP processes that are acceptable to PIC/S as determined by a rigorous assessment process.  The PIC/S quality system requirements must be implemented by each authority before becoming a member, which is aimed at creating agency harmonization and quality system improvements.  “Leveraging work from other inspectorates can result in cost savings and being part of the PIC/S organization can facilitate export of medicines to certain markets,” Hayes pointed out.

Members have use of the PIC/S GMP Guide, “which benefits industry as it removes the need for companies to familiarize themselves with individual country-specific standards,” Hayes said.  The PIC/S guide is aligned in most aspects to the EU GMP guide, and they are updated in tandem through joint working groups, providing an avenue for international harmonization.

Development of international GMPs happens through the various working groups and expert circles that PIC/S has implemented.

“PIC/S is very much involved in the exchange of best practices,” the PIC/S chair emphasized. “It uses the meetings of the committee to illustrate those with updates from members.  It also provides networking opportunities for participating authorities.”

Training is Key

Training of inspectors is one the core fundamental activities of the PIC/S organization.

The Pharmaceutical Inspectorate Academy is a very recent initiative within PIC/S.  It is a global capacity-building project in the field of training that is under development with input from all PIC/S authorities.

Its objective is to develop harmonized and standardized training to around 2,000 inspectors to train them in assessing good manufacturing practices.  It also looks to establish a harmonized qualification process for inspectors.  PIC/S considers this the key to the consistent interpretation and uniform application of GMP requirements by inspectors worldwide.

This project and the initiatives discussed are a fundamental part of confidence-building and development of trust between member authorities.

Inspection Reliance

In June 2018, PIC/S adopted a guidance on GMP inspection reliance that had originally been developed by the International Coalition of Medicines Regulatory Authorities (ICMRA) GMP group.

The guidance provides a framework to help parties prioritize resources for GMP inspections and covers both human and veterinary medicines.  It involves a desktop assessment of GMP compliance of overseas facilities to identify that an acceptable level of compliance can be confirmed from the activities of another party without the need for an onsite inspection at the facility.

The guidance has been implemented as a non-binding guidance and therefore its application is on a voluntary basis.  It is high level and applies to all participating authorities.  “It is very much promoted within the PIC/S circles and annual surveys are being conducted to gather information on its use within the PIC/S,” Hayes explained.

The PIC/S guide is aligned in most aspects to the EU GMP guide

“The introduction of the GMP reliance framework in June 2018 brought an extra layer of working together and information sharing to PIC/S authorities.  Confidence building and information sharing has been a key fundamental part of the PIC/S,” Hayes said. 

“This builds towards recognition between members and within inspectorates.  There is of course recognition under the PIC scheme, which is a convention that was implemented at the very outset of the establishment of the organization.  It still exists and it is used by some members as part of the mutual recognition program.”

PIC/S Recognition, Reliance Tools Recognized by NASEM

Work done by the National Academies of Science, Engineering and Medicine (NASEM), which PIC/S participated in, resulted in the publication of a book titled, Regulating Medicines in a Globalized World.

“It has some particularly useful references on the importance of reliance and recognition between authorities,” Hayes commented.  “It states that formal and informal recognition and reliance arrangements are highly effective tools that help regulatory authorities address public health challenges posed by complexity in medicines and globalized supply chains.  Such arrangements were seen by the National Academies to be 21st century best regulatory practice.”

She pointed to a statement in the book that she particularly liked, which stated that regulatory systems could be reviewed with an eye to effectiveness—that is that they do the right thing—and efficiency— that is that they do the thing right.

The book emphasizes the need for leveraging the work of other trusted authorities in order to make progress in this area.

GMP Inspection Challenges Continue

Hayes pointed to some of the conclusions in the NASEM book regarding the evolution of reliance and ultimately recognition and postulated on a way forward.

“We know that there are changing supply routes within the pharma industry,” she said.  “PIC/S plays a part by engaging with China’s CFDA and the Indian Central Drug Standards Control Organization (CDSCO) to discuss actively with them their accession towards PIC/S membership.

“We recognize the pharmaceutical industry is continually advancing and we know that regulators must deal with new technologies and developments.  And we see that strengthening the systems of reliance builds a network of trusted experts.

We know that there are changing supply routes within the pharma industry

“The way I see inspection reliance in terms of the future, things will be found in functional regulatory networks of agencies that increasingly specialize and rely on the work of others and in parallel will decrease their efforts to avoid duplication with other parties.  This is part of the thinking also in the National Academies.”

Swissmedic Implements Mutual Reliance Model

At the same ISPE session, Swissmedic Inspectorate Head Christian Schaerer discussed his agency’s experience with implementing the PIC/S inspection reliance guidance and how it complemented other agreements his agency already had in place.

He explained that Swissmedic is a small agency and is responsible for about 2,400 assessments each year of foreign manufacturers.  To successfully meet this challenge the agency must rely on cooperation with other regulatory authorities.  At present, it has mutual recognition agreements with the European Union, Canada, and Korea, as well as varying kinds of agreements with other smaller partner authorities.

In addition to being a PIC/S member, Swissmedic has mutual cooperation agreements with the World Health Organization (WHO) and the European Directorate for the Quality of Medicines (EDQM). Switzerland’s legislation requires that the agency issue a list of countries with which it has agreements. The Inspectorate Head also noted that his government has legal requirements for importers of medicinal products (Figure 2).

Swissmedic Reliance on Equivalent GMP Control Systems
FIGURE 2 | Swissmedic Reliance on Equivalent GMP Control Systems

Schaerer explained that a combination of information from MRA partners and PIC/S in the context of the mutual reliance guidance is required to achieve all of the information it needs to assess foreign manufacturers.  It also found that it needed to augment its inspection coverage for active pharmaceutical ingredients (APIs) by building a small, limited foreign inspection program.

He explained that his agency also appreciates the opportunity to regularly contribute to assessments of new PIC/S candidates, characterizing them as, “a confidence building exercise in which we gain a lot of information about these members or new candidates whose information we will be relying on.  We also rely on robust PIC/S processes.  That means that when a new member is being assessed by PIC/S, that they are assessed appropriately and equivalency is really assured.”

In addition to the mutual recognition and cooperation agreements with other health authorities, Swissmedic also has a pilot project with Brazil’s ANVISA with a goal of mutual reliance.  “Although ANVISA is not yet part of PIC/S, a new challenge is new inspection quality policies from other regions of the world, and especially the inspections by Eurasian Economic Union, including Russia, which are increasingly doing inspections in Switzerland.”

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