Pharmaceutical manufacturers increasingly are facing more detailed "how to do" requirements focusing on a widening scope of activities (e.g., distribution) in Europe as the European Union continues to upgrade CMC and GMP requirements.

There are three major drivers for regulatory change in the European Union in recent years:

• The new ICH quality paradigm on "a harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science" (ICH Brussels, 2003) and the respective guidelines on ICH Q8, Q9, Q10, and Q11.
• The revised Clinical Trials Directive (CTD)
• Regulations such as the Falsified Medicines Directive (FMD, 2011/62/EC), amending the Community Code (2001/83/EC) [Editor's Note: See "Unprecedented EU Rule Changes Shake Industry," page 34 of this issue for more on this Directive and the Clinical Trials Directive. Plus, Figure 1 outlines how this and other guidelines fit into the legislative framework.]

With more "how to do" (prescriptive) regulation, industry is now expected to apply updated guidance not just to newly licensed products, but also to legacy products and processes following a transitional period of a few years. The focus on supply chain oversight for all activities is raising the bar as well as costs in Europe

CMC Updates (Scientific Guidelines)

The CMC Guidances are intended to help in preparing the marketing authorization. Following the revision of several of these guidelines, applicants now have the opportunity to file either according to the "traditional approach" or the "enhanced approach" to development. The enhanced approach is characterized by implementing Quality by Design (QbD) and/or Process Analytical Technology (PAT). This is intended to provide industry more flexibility and allow for quicker implementation of innovative, science- and risk-based approaches to development, manufacturing and release.

The CMC dossier should be clear and support the overall development story. Applicants are required to completely describe the manufacturing process, including identification of critical manufacturing steps and references to noncritical aspects. The applicant should demonstrate full understanding of the process, the lifecycle approach and continual improvement. The dossier should be simple and understandable, and use ICH terminology for increased clarity.

The Quality Working Party at EMA will focus this year on updating filing related procedures to include the ICH Q8–Q11 principles, such as guidelines on the manufacture of the finished dosage form, the chemistry of active substances, genotoxic impurities (see ICH M7), quality risk management for the assessment of applications, stability testing for applications for variations to a marketing authorization and metal impurities (ICH Q3D).

Figure 1 EU Legislation and Guidelines for Pharmaceuticals

EU GMP updates

Over the last two years, more than 50% (18/35) of the guidelines in the EU GMPs (EudraLex Vol 4) have either been updated or are under revision. It is important to highlight that the PIC/S GMPs will also be updated accordingly to ensure similarity to the EU GMPs, with the exception of Annex 16 on qualified persons and GDP regulations as these are not overseen by health authorities in some member inspectorates.

In Part I of the EU GMPs for Medicinal Products, Chapter 1, "Pharmaceutical Quality System" has changed to align with ICH Q10 and to implement quality risk management (QRM) principles. The guidance is clear that the product quality system (PQS) is regarded as a framework to manage all GMP topics, such as appropriately qualified and trained personnel, adequate premises and space, suitable equipment and services, correct materials, containers and labels management, approved procedures and instructions, suitable storage and transport and quality control. Chapter 2, "Personnel" now includes training requirements for senior management.

Revisions to Chapter 3, "Premises and Equipment" as well as Chapter 5, "Production" are about to be issued, potentially addressing appropriate risk reduction measures (e.g., single-use or dedicated facilities) for the issue of cross-contamination. The discussions between agencies and industry with regard to taking safety aspects into account are ongoing. Other prominent changes include traceability of supply chain and testing of starting materials.

Chapter 6, "Quality Control," contains a new section on technical transfer of testing methods and handling out-of-specification results. Chapter 7, "Outsourced Activities," was also updated to include a focus on assessments of suppliers and contractors prior to outsourcing an operation. Emphasis is placed on defining the responsibilities and the communication processes among the parties. Monitoring and review of the performance of suppliers is expected as well as oversight of incoming ingredients and materials.

The requirements for complaints and product recalls outlined in Chapter 8 have been updated with the expectation to implement risk management principles and workflows.

While ICH Q7 is the basis for Part II of the EU GMPs (GMP of APIs), Chapter 2.2 was recently added to include two principles from ICH Q9 on risk management. At this time, there is an ICH Implementation Working Group developing a Q7 Q&A document. The key message is that the ICH Q7 document is intended to be read in its entirety regardless of the nature of the manufacturing activities being conducted, in order to fully understand the links between certain sections and successfully implement appropriate GMPs at all stages of the API supply chain, including distribution.

In Part III, "GMP related documents," several guidance documents have been added such as Pharmaceutical Quality Systems (ICH Q10) and Quality Risk Management (ICH Q9) to underline the importance of harmonization within the ICH parties of the United States, European Union, Japan and beyond.

For harmonization purposes the "MRA batch certificate" has been updated to present specifications in a format acceptable to both EU and Mutual Recognition Agreement countries. The template for the Site Master File (SMF), originally developed by PIC/S, is widely used for explaining details of a site and is now included in the EU GMPs. The template for "written confirmation" for active substances exported to the European Union now follows the requirements of the Falsified Medicines Directive (FMD).

The Annex section contains several specific guidances. Unfortunately, the recent updates have added more administrative burden and, in our opinion, unproductive activities. Most of the new elements in these guidances provide a different interpretation than the guidance given in the other parts of the EU GMPs. Recent updates focused on GMPs for biologics (Annex 2), and require the zone classifications at the final stage of API manufacturing to be equivalent to the first step in the finished dosage form manufacturing. For air quality and facility design, this might be the case; in many companies, however, not with regard to the intensive testing during operation.

Annex 15, "Qualification and Validation," was open for commenting until May 31. It discusses Stage 3 of the lifecycle, which is called "Ongoing Process Verification," instead of "Continued Process Verification"—the term used in the U.S. guideline. The draft allows implementation of both the traditional and the enhanced development approaches.

The draft guideline on batch certification and release procedures (Annex 16) implements the additional clarification of the 2009 Qualified Persons (QPs) discretion paper from EMA and widens the scope to include QP oversight of the supply chain. This expands the areas of involvement for QPs which, previously, was not part of their education and experience.

One positive change allowed by the revised Annex 16 is the reliance on the quality system and related activities of a company. On the other hand, the draft requires that the sampling for import testing must be done in the European Union, which will have a major delay on the availability of the drugs due to additional time needed after shipment.

The revision of Annex 17 on parametric release now allows for the implementation of real-time release testing, if applied. This provides more flexibility to companies even if an established product is manufactured and a variation is filed.

The section Other documents related to GMP updates the GDP requirement. Major changes focus on supply chain and cold chain oversight as well as transport validation. The extensive content of the Compilation of Community Procedures on Inspections and Exchange of Information document was updated with new EU formats and procedures, including a series of guidances for regulators. These documents describe the regulators' procedures and provide relevant templates (e.g., inspection reports) seldom considered in the past.

Recent Changes in Pharmacovigilance Legislation

Adopted by the European parliament and the European Council in December 2010, the new pharmacovigilance legislation came into effect across the European Union in July 2012 as a result of changes set out in Regulation (EU) No1235/2010 and Directive 2010/84/EU. The legislation is reinforced by the legally binding Commission Implementing Regulation No 520/2012, published in June 2012 which provides details on the operational aspects for the new legislation and a series of modules on Good Pharmacovigilance Practice. Most of the legislation had to be implemented within 18 months of becoming law or by July 2012 (Figure 2).

Figure 2 Pharmacovigilance Legislation in the European Union

The new pharmacovigilance legislation represents the biggest change to the legal framework for human medicines in the European Union since 1995. The change was prompted by the need to strengthen the European safety monitoring system, establish a clear legal framework for postauthorization monitoring, and to reduce the number of potentially fatal adverse drug reactions.
In 2011, the legislation was tightened even further after the scandal involving Servier's diabetes drug Mediator (benfluorex), suspected to have caused more than 500 deaths in France. Amendments were published in October 2012 in Regulation (EU) No 1027/2012, applicable as of June 2013 and Directive 2012/26/EU, which applies as of October 2013. The amendments aim to further strengthen the protection of patient health by allowing prompt and appropriate regulatory action.

The new legislation streamlines respective roles and responsibilities between EU Member States and the EMA. It strengthens transparency rules related to pharmacovigilance data and establishes clear standards (Good Pharmacovigilance Practices, or GVP) for the conduct of pharmacovigilance by both industry and regulators. GVP guidelines have been released by EMA and replace the EC's pharmacovigilance guidance for human medicinal products (EudraLex Volume 9A).

The new pharmacovigilance legislation has significant implications for applicants and holders of EU marketing authorizations. Some examples are given below.

Safety Monitoring

Periodic Safety Update Reports (PSURs) have a single assessment for the same active substance or a combination of active substances. Routine PSUR reporting is no longer necessary for products with low risk or for established products unless concerns arise. PSURs are sent directly to EMA in standardized electronic format. Format and content are based on the Periodic Benefit Risk-Evaluation Report (PBRER) described in the ICH E2C (R2) from 2012.

There is a strengthened legal basis for requesting Post-Authorisation Safety and Efficacy Studies (PASSs/PAESs) from the pharmaceutical industry. EMA's Pharmacovigilance Risk Assessment Committee (PRAC), formed in 2012, is responsible for assessing the protocols of imposed PASSs and for evaluating their results. Risk management systems are required for all newly authorised medicines. Companies must submit a risk management plan to the Agency at the time of application for a marketing authorization. Risk management plans are continually modified and updated throughout the lifetime of the medicine as new information becomes available.

Safety Referrals

All pharmacovigilance referrals are discussed by the PRAC and the Committee for Medicinal Products for Human Use (CHMP) or the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). Opinions are adopted as a result.

Adverse Event Reporting

Following a successful audit, marketing authorization holders submit adverse event reports only via EudraVigilance, a centralized Web-based information system designed to manage information on safety reports. Previously, reports were sent via the individual national competent authority.

Inspections and Pharmacovigilance Systems

The new legislation requires the introduction of a Pharmacovigilance System Summary in the marketing authorization and removes the requirement for new applications to contain a Detailed Description of the Pharmacovigilance System (DDPS). Marketing authorization holders are required to maintain a pharmacovigilance system master file (PSMF) permanently available for submission or inspection by the national competent authority. The file has to include all significant internal audit findings which can only be removed once corrected.

Products Under Additional Monitoring

Under the new pharmacovigilance provisions, some medicinal products for human use are subject to additional monitoring due to their specific safety profile. Those products have to bear a black inverted triangle on the package and package leaflet. With this measure, the EC aims to improve the safety of medicines and also to highlight to patients the importance of reporting suspected side effects to the medicines they are taking.

In early 2014, a three-year EU initiative, Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE), was launched to support implementation of the new legislation. SCOPE will help member states to harmonize pharmacovigilance activities, while ensuring that member states implement best practices and maintain the highest possible standards, measured against agreed benchmarks. The U.S. FDA and EMA have also initiated a new "cluster" on pharmacovigilance topics. Clusters are regular collaborative meetings between the EMA and regulators outside of the European Union, which focus on specific topic areas that have been identified as requiring an intensified exchange of information and collaboration. This cluster will provide a forum for a more systematic and focused exchange of information on the safety of medicines.

Final thoughts

The European Union's legislative framework for pharmaceuticals is undergoing major changes. Most of the recent and future changes have similar drivers: an expansion of the European Union to 28 member states—all with different national legislation—and the necessity for EU-wide harmonization; rapid progress in innovation which is giving rise to new technologies and novel therapies that need to be covered by additional regulations; and finally, globalization and the need to align with regulations outside of the European Union. Revised regulations focus on risk-based approaches and introduce a number of new requirements meant to support product quality and protect patient safety.

Acknowledgement

The authors thank Barbara Jentges, PhACT GmbH; Steven Mendivil, Amgen; and Carmen Monka, Novartis for their contributions.

About the Authors

Ursula Busse, PhD, MBA, currently holds a global position as Head of GxP Regulations Coordination at Novartis.
Stephan Rönninger, PhD, is the Head of External Affairs Europe, International Quality at Amgen (Europe) GmbH.