INTERNATIONAL PHARMACEUTICAL QUALITY IPQ Inside the Global Regulatory Dialogue IPQPUBS.COM VOL. 8, NO. 5 MONTHLY UPDATE - AUGUST/SEPTEMBER 2016 UNITED STATES ● Review/Inspection Control Strategy Communications Key to Advancing Biotech p. 4 Regulation, FDA Biotech Official Stresses ● More Clarity Sought in FDA’s Inactive Ingredient Database Regarding Drug Delivery Devices p. 13 EUROPE ● Protein Sequence Variants, Process Development and Spec Setting Are Generating Queries p. 20 from EU Biopharmaceutical CMC Assessors ● Procedures, Eligibilities and Goals of EMA’s Accelerated Access Efforts Are Taking More p. 32 Concrete Shape INTERNATIONAL ● Goal of FDA/EU Mutual Inspection Reliance is Nearing Realization p. 36 UPDATES IN BRIEF p. 47 U.S. CMC: ● GDUFA II Agreement ● ANDA Impurity Refusals ● Capsule Supplier Changes ● Co-Crystal Classification ● ANDA Impurity Refusals U.S. GMP: ● Insanitary Compounding ● NIH Clinical Manufacturing ● Establishment Registration ● Generics Facility ID'ing ● USP on Analytical Lifecycles EUROPE CMC: ● EMA Streamlining ● EMA Adaptive Pathways Workshop ● EDQM on ICH Q3D EUROPE GMP: ● EMA WFI Q&A ● EC on Plastics INTERNATIONAL CMC: ● Antimicrobial Resistance Roadmap ● WHO on Variations ● Canada on ICH Q3D INTERNATIONAL GMP: ● China on Drug Manufacturing ● India Manufacturing Self-Assessment FDA WARNING LETTERS, EMA NON-COMPLIANCE REPORTS, AND FDA RECALLS POSTED IN AUGUST/SEPTEMBER p. 51 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 INTERNATIONAL PHARMACEUTICAL QUALITY provides in-depth coverage of emerging drug, biologic and combination product CMC and GMP issues and developments with a mission of helping advance and harmonize the quality regulatory process globally. Headquartered in Washington, D.C., IPQ is read by regulatory agencies, manufacturers, suppliers, consultants, law firms, and universities around the world. IPQ tracks the industry/regulator dialogue at key international forums along with the developments, initiatives, regulations, guidances and standards in the quality regulatory arena to create a uniquely valuable resource for the intelligence gathering and knowledge management needs of the pharmaceutical community. IPQ is all-electronic, and the substantial archive at From breaking news to in-depth analysis — IPQpubs.com is easily searchable through keyword and the quality regulatory intelligence you need advanced search indexes. Links to documents referenced at your fingertips! and cross-links to related previous IPQ coverage in the area are included, allowing readers to quickly dig as deeply into an issue and its context as needed. IPQ’s “News Alerts” provide links to the first few paragraphs of the stories newly posted online. Subscribers and license holders can click through to the full stories. The “Monthly Updates” organize the stories that went online during the previous month by region (US, Europe, and international) and topic area (CMC/review and GMP/ inspection) and are an easy way for subscribers to keep up with the current critical developments impacting the quality regulatory process worldwide. Included are "Updates in Brief" on recent developments in the CMC/ GMP global arena with links to the referenced documents and to our related in-depth analysis. Also included are an annotated listing of FDA drug GMP warning letters and recalls as well as EU GMP non-compliance statements posted during the month. Editor-in-Chief Editorial Staff–Europe Bill Paulson Nuala Calnan [email protected] [email protected] 202-841-5027 +353 87 9786968 Publications Editor Janine Jamieson We do the work so you don’t have to. Charles R. Kiss [email protected] Subscribe to IPQ and relax. [email protected] +46 722 106 159 202-409-6708 Sales/Marketing Editorial Staff–US Wayne Rhodes IPQ takes Its readers from: Chris DeMerlis [email protected] [email protected] 202-841-9470 ● headlines to the forces driving them 215-233-4890 Food/Drug Law Advisor ● regulations to their underlying intent Aaron Kozloff Eve Bachrach [email protected] ● puzzle pieces to their interconnection [email protected] 240-678-4637 202-342-9220 ● rules to implementation pathways Lois Andre [email protected] ● random data to critical trends 508-280-8416 ● the sidelines to shaping the outcome © 2016 INTERNATIONAL PHARMACEUTICAL QUALITYTM (ISSN 1937-6898) All rights reserved. IPQ Publications LLC, 3836 Fulton Avenue, Washington, ● compliance problems to proactive tools DC 20007. Content cannot be transmitted except for internal use by companies/organizations that have licenses. For copies/reprints for other ● information to strategic intelligence use, contact Wayne Rhodes (rhodes@ ipqpubs.com, 202-841-9470). MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 NOTE ON THE ISSUE: Two of the stories in our August/September issue build on the dis- cussions that took place at the opening plenary session of the 2016 CASSS European CMC Strategy Forum. The session followed the traditional forum model of bringing together a panel of regulators from different agencies around the world to highlight and compare ideas with the forum participants on the key issues they are facing and their recent initiatives to address them. Irish regulator Sean Barry led off the session with a review of recent developments in Europe. Bill Paulson, Editor-in-Chief Our story highlights, in particular, his insights on the CMC questions that European assessors are having in reviewing biotherapeutic marketing applications. Barry also covered: ● EMA’s priority medicines (PRIME) and adaptive pathways approaches and how they relate to each other ● the CMC challenges presented by these accelerated approaches and how they can be dealt with by industry and regulators, and ● the implica- tions of EMA’s recently published guideline on process validation for biotech-derived active substances. Complimenting Barry’s European update is a story honing down on how the procedures, eligibilities and goals of EMA’s accelerated access approaches have been taking more concrete shape, informed by its growing implementation experience. A wave of releases on EMA’s PRIME and Adaptive Pathway efforts has been forthcoming since March that provide insight into their progress and interrelationships. Barry was followed to the podium at the Paris forum by FDA Office of Biotechology Products’ Sarah Kennett, who pro- vided the FDA vantage point. Like Barry, Kennett provided updates on the progress being made and the CMC challenges involved in accelerating the development and review of new therapies that warrant the extra regulator resources involved. She also followed the Irish regulator's lead in probing the issues that are being seen in reviewing biotech product applica- tions – emphasizing the need for strong regulator/industry communication in shifting to a more flexible and continuous improvement-friendly lifecycle regulatory paradigm. Also in focus in this issue is an aspect of drug/device combination product regulation that is getting more attention – the expectations for the excipients/materials involved in their formulation. The story focuses on the dialogue that took place at a session of the 2016 IPEC-Americas/ExcipientFest Conference on the regulatory issues encountered in formulating prod- ucts like transdermal patches, metered dose inhalers and implants, and how FDA’s inactive ingredient database (IID) can be restructured to make it a more relevant and useful resource for both industry and regulators. And in this issue we also pick up the thread of the impact of globalization and the rapid growth in foreign manufacturing facilities on quality regulatory processes, and the need for international coordination in addressing the challenges involved. Included in the 2012 FDASIA legislation in the U.S. was a mandate and some additional tools for FDA to pursue partner- ships with other countries that would extend the agency’s ability to reach into the more high-risk elements of its inventory. With 40-50% of FDA’s overseas inspections being performed in Europe, where a healthy regulatory oversight process al- ready exists, the EU became a prime candidate. Our story builds on an engaging presentation by Associate Commissioner Dara Corrigan in which she shared her expe- rience as head of FDA’s European office in Brussels tasked with driving forward a mutual inspection reliance agreement between FDA and the EU. Corrigan explains how – with strong support coming from the new FDA Commissioner, Robert Califf, for questioning and moving beyond the status quo – the vision of a unified inspectorate across the US and EU is now taking shape. The plethora of warning letters posted by FDA during August and September that are reviewed in this issue also sheds light on these global enforcement challenges. Also clear in assessing the recent warning letters is how much energy FDA is putting into its effort to oversee pharmacy compounding in the U.S., and why this is a very real priority. WWW.IPQPUBS.COM AUGUST / SEPTEMBER 2016 3 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 UNITED STATES Review/Inspection Control Strategy Communications Key to Advancing Biotech Regulation, FDA Biotech Official Stresses Advancing biotech product and process knowledge has She charted the progress the biotech industry has made in created the foundation for regulatory changes, but close developing an array of new products as well as in advancing communication and coordination between manufacturers the processes and technologies. This “back and forth” and the and regulatory agencies will be necessary to realize those knowledge