Regulatory agencies in the US, European Union, and Japan are moving forward with plans to achieve greater cooperation and harmonization of good manufacturing practices (GMPs). DCAT Value Chain Insights examines the latest developments.

Common approaches in the inspection process for active pharmaceutical ingredient (API) manufacturing are important considerations in managing a global manufacturing network. DCAT Value Chain Insights highlights recent regulatory developments to achieve greater cooperation and harmonization in GMP inspections.

Recent activity
European Medicines Agency. The European Medicines Agency (EMA) has issued, a “Concept Paper on Good Manufacturing Practice and Marketing Authorization Holders” to provide further clarity on the responsibilities of marketing authorization holders (MAHs) with respect to good manufacturing practice (GMP) under the European Union (EU) EU GMP Guide. These responsibilities range from performing a task (e.g. review of periodic quality review) to acting at the interface with manufacture and control of the medicinal product (e.g. provision of current dossier information to facilitate the manufacturer’s compliance with the marketing authorization). These responsibilities for MAHs are spread over various chapters and annexes of the EU MP Guide and are quite numerous, so the concept paper seeks to provide better clarity of these requirements.

“There appears, however, to be a lack of clarity and understanding as to what these responsibilities actually are in their totality, and what they mean for MAHs at a practical level,” explained the concept paper. The paper points out that this has led to a situation in which there is a lack of knowledge and understanding among some MAH companies of the need to comply with those responsibilities, a situation observed from the experiences of those inspectorates that perform regulatory compliance inspections at the offices of MAH companies as well on the general experiences of GMP inspectors.

To address that, the concept paper proposes how to better document existing requirements, so that MAHs (and manufacturers) have increased clarity as to what their respective responsibilities are. The paper does not intend to introduce any new responsibilities. The EMA is proposing that the GMP/GDP Inspectors Working Group should produce a reflection paper intended for Part III of the EU GMP Guide or in another appropriate location (e.g. as proposed by the working group) that would capture all of the responsibilities that apply to MAH companies to enable manufacturers to comply with GMP. As part of this, the concept paper proposes that the working group should also provide any clarifications or explanations in the reflection paper on those responsibilities, where required, and the reflection paper should also provide a degree of flexibility in relation to the management of future GMP Guide changes by structuring the paper in a way that highlights the general themes of the MAH’s responsibilities.

To achieve this, the EMA issued the proposed concept paper in September 2016 and is seeking public comment through the end of November 2016. Once that is completed, the EMA is proposing that a reflection paper be prepared by a drafting group by mid-January 2017, and that the reflection paper by reviewed by the GMP/GDP Inspectors Working Group in February 2017 with the final agreement of the reflection paper occurring in June 2017.

Swissmedic and the MHRA. Swissmedic, the Swiss Agency for Therapeutic Products, reported on progress made at the International Summit of Heads of Medicines Regulatory Agencies held in Interlaken, Switzerland this week. With approximately 75 agency representatives from 23 countries attending, the two-day summit was held in Switzerland for the first time and organized by Swissmedic. The objective of the annual meeting of medicinal and therapeutic products authorities is to promote information sharing and improve networking among agencies. The topics addressed at this year’s meeting included regulatory transparency as well as best practices in cooperation and dialogue with stakeholders.

Separately, Swissmedic agreed to collaborate more closely with the UK regulatory agency, the Medicines and Healthcare Products Regulatory Agency (MHRA). Ian Hudson, chief executive of the MHRA and Swissmedic Executive Director Jürg H. Schnetzer signed a memorandum of understanding (MoU) on October 10, 2016. The MoU establishes a foundation for reciprocal information exchange and for bilateral projects. It also provides a basis for intensified cooperation under multilateral initiatives. Swissmedic’s performance mandate requires it to improve international cooperation primarily with therapeutic products agencies in the EU and in countries of strategic interest to Switzerland.

”Both agencies view networking with partner authorities as a key instrument in addressing shared challenges, such as the globalization of therapeutic products research and production and the increasing complexity of scientific and technological developments,” said Swissmedic in a statement.

EDQM and Japan. The European Directorate for the Quality of Medicines and HealthCare (EDQM) has agreed with Japanese regulatory authorities to improve the sharing of information related to therapeutic products that are common to both Europe and Japan and to strengthen collaboration between the European and Japanese Pharmacopoeias. The EDQM is a standards-setting organization that supports the development, implementation, and monitoring of quality standards for medicines and their safe use through the European Pharmacopoeia, which provides a legal and scientific reference for the quality control of medicines. It is legally binding in 37 member states that have signed the Convention on the Elaboration of a European Pharmacopoeia.

On September 13, 2016, two regulatory agencies in Japan, the Pharmaceutical Safety and Environmental Health Bureau of the Ministry of Health, Labor and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency of Japan, exchanged letters with the EDQM that detailed how communication between the parties will be enhanced while respecting the confidentiality of information that is not in the public domain. The sharing of information will mainly concern the outcome of GMP inspections of manufacturing sites of active pharmaceutical ingredients of interest to both Europe and Japan.

In addition, the EDQM and the MHLW signed a five-year memorandum of cooperation that defines concrete measures for strengthening collaboration between the European and Japanese Pharmacopoeias (Ph. Eur. and JP, respectively). These include the option of organizing bilateral meetings, workshops and internships between the Ph. Eur., the JP, and various Japanese regulatory bodies in either region/country, in order to share experiences and information on the development of monographs and methods of testing. To this end, the EDQM and the MHLW also agreed to set up an ad hoc Technical Working Group involving staff members of the EDQM and Japanese regulatory bodies as well as relevant experts.

US Food and Drug Administration. In September 2016, the US Food and Drug Administration (FDA) issued final guidance, Self-Identification of Generic Drug Facilities, Sites, and Organizations, to assist human generic-drug facilities, sites, and organizations by describing how to comply with the self-identification requirement contained in the Generic Drug User Fee Amendments of 2012 (GDUFA). Under GDUFA, human generic drug facilities, sites, and organizations are required to submit identification information electronically to the FDA annually. Self-identification is required for two purposes: to determine the universe of facilities required to pay user fees and to promote global supply-chain transparency. The FDA issued the guidance to help human generic drug facilities, sites, and organizations meet the self-identification requirement. The guidance also explains generally which types of generic facilities, sites, and organizations will be required to pay user fees.

On a procedural note, the FDA issued final guidance, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, in September 2016 to provide guidance regarding GMP for the manufacturing of active pharmaceutical ingredients under an appropriate system for managing quality. The guidance revises and replaces the guidance, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. This revision changes the ICH codification from Q7A to Q7 and also adds the ICH section numbers in parentheses at the end of each paragraph in Sections II (2) through XIX (19) of the guidance. The guidance was first developed within the Expert Working Group (Q7A) of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and was subject to consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process, the final draft was recommended for adoption to the regulatory bodies of the European Union (EU), Japan, and the US.