ICH Works to Update API GMP Guideline with Q&A Document

An ICH question and answer document aims to bring aging Q7 API GMP guideline up to date with the increased globalization and regulatory oversight of the active pharmaceutical ingredient manufacturing sector.

The International Conference on Harmonization is updating its GMP guidelines for active pharmaceutical ingredients, with an assist from a group of leading pharmaceutical inspectorates, to answer some of today’s more pressing API manufacturing challenges.

As API supply chains have grown more complex, regulatory authorities have focused more attention on them and placed more responsibility on drug product manufacturers to ensure they are produced correctly.

An ICH implementation working group and a group in the Pharmaceutical Inspection Cooperation Scheme, or PIC/S, are responding by developing question and answer documents. PIC/S, which currently has 44 participating authorities and four partner organizations, started first, but agreed to defer to the ICH group, since the output will be an ICH document.

The ICH group is addressing the scope of API GMPs, the responsibilities of API quality units including what they can and cannot delegate, and several other topics.

The answers could be ready sometime next year. ICH member authorities will incorporate them into harmonized regulatory guidance in the U.S., the European Union and Japan.

Other authorities are participating in the ICH process, and may also incorporate the results into their regulatory schema. However, regional differences have surfaced in the deliberations and it remains possible that eventual guidance stemming from this process could vary regionally.

The first harmonized GMP document

Two participants in the Q7 implementation working group discussed progress Nov. 6 at the International Society for Pharmaceutical Engineering annual meeting in Washington on the eve of the Nov. 9-14 ICH meeting in Osaka, Japan.

Betsy Fritschel, director of quality and compliance at Johnson & Johnson, provided some historical background.

The guideline on GMPs for APIs, which went final in November 2000, was the first internationally harmonized GMP document, and the first GMP guidance that regulators and industry developed together, she noted.

The World Health Organization, or WHO, didn’t adopt it until 2009 out of concern that it would be too expensive for many of the emerging countries to adopt, Fritschel said.

Even though Q7 dates back 13 years and has been widely adopted by regulatory authorities, the International Conference on Harmonization decided there is a need to answer some questions about it due primarily to recent changes with industry and regulatory authorities.

API supply chains have become much more complex, more health authorities are regulating and inspecting them, and drug product manufacturers have more responsibility to make sure their APIs were made in accordance with GMPs, Fritschel explained.

The role of the EU’s FMD

A big factor is the European Union’s July 2011 Falsified Medicines Directive, which requires manufacturing authorization holders to audit their API manufacturers and distributors. Since January 2013 the directive has required API importers to comply with Q7 and since July 2013 it has required regulatory authorities of exporting countries to confirm that compliance in writing, unless they obtain a waiver from the EU, which the U.S. and four other countries have done.

“API manufacturers are now being audited by companies and health authorities that have not previously had as much experience or understanding with API GMPs,” Fritschel said.

She noted that many small countries, particularly in East Asia where there is a lot of contract API manufacturing, are not applying for the waiver.

Warning letters show need for guidance

FDA’s Alicia Mozzachio noted that the number of FDA warning letters to international manufacturers has increased substantially over the past five years.

However, she suggested that this may be due to an increase in FDA inspections overseas rather than a decline in product quality.

Mozzachio is the branch chief in the Office of Compliance in FDA’s Center for Drug Evaluation and Research who oversees evaluation of international FDA drug inspection reports.

Given the increase in international FDA inspections since 2002, “I would venture to say that the ratio is still the same of the number of warning letters to the number of inspections, but it looks like this huge growth in warning letter output because of the number of inspections that we now do overseas.”

Even so, from FDA’s point of view, it’s a good time for a Q7 Q&A document, because “we’re still finding issues. We’re still finding deficiencies in API manufacturing sites … that meet our threshold for a warning letter.”

And those warning letters can lead to import alerts and drug shortages. “You cannot manufacture until you have qualified a new API or you have to wait for that API facility to come back into compliance,” she noted.

ICH is narrowing its focus

The Pharmaceutical Inspection Cooperation Scheme, or PIC/S, started developing the questions and answers, but then passed it all over to ICH, since Q7 is an ICH document, Mozzachio said.

The implementation working group first came together at a November 2012 ICH meeting in San Diego, Calif., where it decided that Q7 requires clarification in some areas. Rather than revise the guideline, the group decided it just needed to craft a Q&A document to go with Q7.

The group won the ICH Steering Committee’s approval of a concept paper for the Q&A document in October 2012, and began working toward an ambitious 2014 completion deadline. “We still hope to meet it,” Mozzachio said. But she acknowledged that such deadlines “are sometimes moving targets.”

Japan, the EU, FDA and their industry counterparts participated, with Health Canada, WHO and the European Free Trade Association as observers, as well as health authorities for Singapore and Korea and interested parties, including PIC/S, the European Chemical Industry Council’s Active Pharmaceutical Ingredients Committee, the Biotechnology Industry Organization, the European Directorate for the Quality of Medicines & HealthCare, and the World Self-Medication Industry.

Brazil was going to join as an observer or interested party for the meeting in Osaka, she said.

The working group began in November 2012 by reviewing the draft that PIC/S had developed.

“We determined where the inputs for Q&As would come, and what they would include, and it was basically a review of the existing Q&As included in the draft currently being developed by PIC/S,” she said. PIC/S subteams developed and reviewed a series of questions and answers. “That final document is going through PIC/S approval in order to be transferred over to ICH for review, evaluation and agreement and/or disagreement.”

The working group also decided to survey its own constituencies for technical issues. FDA, for example, distributed the survey among agency investigators and staff in its drug and biologics centers “to find out where they may have some questions about certain aspects of Q7.”

They developed guiding principles for the document. It would not, for example, enlarge the scope of Q7, or add new requirements or too much detail. It would not address regional matters, she said: “It differs from region to region and that becomes painfully clear when we’re in our negotiation stages of the Q&As.”

She said some of the questions dated back to the original Q7 training sessions in 2001-2003, adding that many of those questions have since been resolved, and others can be addressed by training.

Holistic view of Q7 stressed

The ICH parties brought their survey findings to the next ICH meeting in Belgium, where in June 2013 they consolidated the questions from about 200 to about 50. They did not review the PIC/S Q&A document because it was not yet available.

“What was agreed upon was that an introduction in the Q&A would stress the need to read Q7 as a whole,” Mozzachio said. “It’s important to understand it from the top and not just take little sections, because little sections may not apply to what you’re doing.” Or, she said, they may refer to other sections that provide additional information or perspective.

The group decided to organize the Q&A document by topic rather than section because topics such as quality assurance or quality unit are mentioned in multiple sections, she noted.

Mozzachio added that unlike some previous ICH Q&A documents, this one won’t go out piecemeal. The group will finish all the answers before issuing any.

At the June meeting, the group began drafting Q&As, divided the questions into groups and assigned them to subteams, she said.

Much as PIC/S did, the ICH group established regional subteams to clarify the questions and prepare answers, then switched questions and reviewed other groups’ questions and answers.

They would review and discuss the draft Q&As at the meeting in Osaka the following week, she said. She was expecting to get a few questions from the PIC/S group at that meeting “that they would like us specifically to answer.” She expects PIC/S to have its full Q&A draft ready by the next ICH meeting in June 2014.

The issues they’re addressing

“While we can’t discuss the specific Q&A document yet, there are some common themes that we have seen throughout our review of the survey questions,” Mozzachio said.

One is the scope, in terms of what’s included in the way of cell banks and vaccines, she said, noting that there are regional differences of opinion in this area.

Another big issue concerns the responsibilities of the quality unit, with lots of references to Section 2.2 in the Q7 document, which outlines 15 responsibilities, and with clarifications on what can and cannot be delegated. “While some tasks can be delegated, ultimate quality and the responsibility cannot,” she stressed.

Process validation and cleaning validation also are hot topics, she said, particularly with the introduction of the lifecycle approach to process validation that came along well after Q7 was written.

There have been a lot of questions around retesting and expiry dating, she noted.

With supply chain controls, there are questions about the responsibility for starting materials and other excipients and chemicals used in the API process.

Another issue is when the active ingredient is en route from the API manufacturer to the finished dosage manufacturer, “who’s responsible along the way to follow these GMP expectations that are in Q7,” she said. “You have the traders and the brokers and the distributors, and so who has to follow what? There are a lot of questions on those types of issues.”

In addition, she said, “Anytime that we can, we’re going to address the link between Q7 and the Q documents that came after it, like Q9 and Q11.”

Mozzachio promised further updates on the Q&A document next year.