GxP Lifeline Feature Article

The Effect of Quality Management on Compliance with European Union GMP Standards
by James Jardine

How crucial is Europe to the global pharmaceutical market? First consider that Europe, North America, and Japan comprise 80 percent of the world's pharmaceutical market. Take that statistic in conjunction with the estimation from Report Buyer, a renowned market research firm, that the Western European market alone is expected to grow to $245.3 billion by 2012.

The engine that drives the European pharmaceutical market machine is, without question, the European Union (EU). With 27 member states, the EU represents the bulk of the European market. The 10 individual European markets that joined the EU in 2004 continue to show strong growth and contribute to the EU pharmaceutical market's overall strength. Pharmaceutical companies searching for further success in Europe or those wanting to capitalize on these strong growth trends by entering the European market for the first time must efficiently and cost-effectively obtain and maintain marketing authorization (MA).

While individual member states may have different regulation criteria for the sale of medicines in their jurisdictions, they all adhere to the quality management principles set forth in the European Union's Good Manufacturing Practice (GMP) standards. Marketing authorization and subsequent success in the EU pharmaceutical market is therefore contingent upon the effectiveness of a company's quality management systems.

The Role of the European Medicines Agency
To fully understand the European pharmaceutical market, it is vital to know what the European Medicines Agency (EMEA) is and what it is not.

The EMEA is:

  • The entity responsible for conducting scientific evaluations of applications for medicinal products MAs
  • An organization based in London and established in 1993 to harmonize the efforts of various European drug agencies by centralizing procedures for submitting MA applications

The EMEA is not:

  • Like the U.S. Food and Drug Administration (FDA) in that it is not a regulatory body
  • An entity that grants drug approvals
  • An agency that replaces the efforts of agencies in individual EU states

Various EMEA committees conduct individual evaluations for every MA application for specific medicinal products intended for human or veterinary use, including those derived from biotechnology processes, orphan drugs, and medicines containing new active substances for the treatment of diseases such as cancer and AIDS. Any positive opinion adopted by an EMEA committee goes to the European Commission (EC), which has the authority to grant validity for MAs throughout the European Union. Individual member states retain the ability to approve other types of medicinal products not covered by the EMEA.

The EMEA specifically defines GMP as "That part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use." The GMP inspection services group has developed detailed GMP guidelines. These GMP principles and guidelines and the interpretation thereof are collected in the Guide to Good Manufacturing Practice. The Guide and its supplemental annexes are collectively published by the EC as Volume 4 of EudraLex.

EU GMP Key Factors
Manufacturers intending to sell most types of medicinal products in the EU must comply with a variety of EC guidelines and regulations such as those described above. Another standard of note is Commission Directive 2003/94/EC, which sets forth GMP principles and guidelines requiring manufacturers to operate effective quality management systems. The Directive specifies the following areas to which GMP principles and guidelines should be applied:

  • Quality management
  • Personnel
  • Premises and equipment
  • Documentation
  • Production
  • Quality control
  • Contracting out
  • Complaints and product recall
  • Self-inspection

The 19 articles that comprise Directive 2003/94/EC provide specific direction for a variety of GMP practices, including:

  • Quality Assurance: Article 6 mandates that quality assurance systems must be established and implemented. A quality assurance system in this instance is defined as the total sum of arrangements that must be made in order to ensure that medicinal products and investigational drugs are up to the quality standards for their intended use.
  • Quality Control: Article 11 directs manufacturers to establish and maintain quality control systems under the authority of a qualified person who is independent of the production process. According to the Directive's definition, the examination of starting and packaging materials and the testing of intermediate and finished products are considered to be necessary components of quality control.
  • Personnel: Article 7 indicates that manufacturers should have a sufficient number of qualified personnel at each manufacturing site to ensure that pharmaceutical quality assurance objectives can be achieved.
  • Documentation: Article 9 provides that manufacturers are required to establish and maintain documentation systems that are based on the specifications, manufacturing formulas, processing and packaging instructions, procedures, and records pertaining to the various manufacturing operations performed. Electronic systems used for managing and storing documentation must first be validated. Audit trails must be maintained and methods to prevent the loss or damage of electronic data are to be implemented.
  • Complaints, Recalls, and Emergency "Unblinding": In keeping with Article 13, manufacturers must implement systems for recording and reviewing complaints as well as systems for the prompt recall of products. Defect complaints must be investigated and recorded. The Directive also requires that any defect that could potentially result in a recall must be reported to appropriate authorities and procedures for swift "unblinding" must be in place if necessary for recalls.
  • Inspections: While Article 3 of the Directive points to the definitive inspections guidelines delineated in the Commission's compiled Community procedures and Directive 2001/83/EC, direct instructions are provided for self-inspections. Repeated self-inspections, according to Article 14, must be conducted in order to monitor the implementation of GMP. Corrective measures, should they be necessary, are to be derived from such self-inspections.

Annex 13
In 2003, the EC published Good Manufacturing Directive Annex 13, in order to unite the current GMP guidelines with the EU Clinical Trials Directive. Annex 13 offers a glossary of essential terms and provides compliance directives for the following areas:

  • Quality Management
  • Personnel
  • Premises and Equipment
  • Documentation
  • Production
  • Quality Control
  • Release of Batches
  • Shipping
  • Complaints
  • Recalls and Returns
  • Destruction

Annex 13 also includes a summary of labeling details and a list of issues to be taken into account prior to clinical trial processing and after clinical trial processing.

PIC/S Guide to Good Manufacturing Practice for Medicinal Products
In 2004, an effort was made to harmonize the GMP rules of the Pharmaceutical Inspection Convention (PIC) and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S) with those of the EU Guide to Good Manufacturing Practice for Medicinal Products and its associated annexes. The resulting guidance yielded principles intended to "further facilitate the removal of barriers to trade in medicinal products" and promote uniform licensing decisions and the maintenance of "high standards of quality assurance in the development, manufacture and control of medicinal products throughout Europe."

Concerning both quality control and production, Section 1.3 of the guide provides comprehensive guidelines for companies seeking to comply with EU GMP standards for medicinal products. The essential principles require that all manufacturing processes should be:

  • Clearly defined
  • Systematically reviewed according to experience
  • Capable of consistently manufacturing products of the required quality that are in compliance with their specifications

Validation is a key component of the PIC/S guideline. According to Section 1.3ii, critical processes and significant changes to the manufacturing processes must all be validated. The basic requirements also mandate that all necessary GMP facilities be provided including:

  • Appropriately qualified and trained personnel
  • Adequate premises and space
  • Suitable equipment and services
  • Correct materials, containers, and labels
  • Approved procedures and instructions
  • Suitable storage and transport

Section 1.3 of the guide also offers the following useful guiding principles for GMP and quality systems:

  • Instructions and procedures should be contained in instructional forms that are written in clear and unambiguous language, specifically applicable to the facilities provided
  • Operators must be trained to correctly carry out procedures
  • Either manually or through the use of recording instruments, records are to be made demonstrating that all the steps required by defined procedures and instructions are taken and that the quantity and quality of the end product was achieved as expected
  • Any significant deviations are to be fully recorded and investigated
  • Manufacturing records, including those pertaining to distribution that enable the complete history of a batch to be traced, must be retained in a comprehensible and accessible form
  • The distribution (or wholesaling) of products should minimize any risk to product quality
  • Systems must be in place to recall any batch of product, from sale or supply
  • Complaints regarding marketed products should be examined, causes of quality defects investigated, and appropriate measures taken to prevent reoccurrence.

EU GMP standards have been established to provide a comprehensive framework that serve as valuable tools for manufacturers intending to produce and distribute high-quality medicines in the European Union. Based on these standards, efficient and effectual quality management systems have a direct and extensive impact on the quality and effectiveness of those medicinal products. For more detailed information about EU regulations, European GMP requirements, and compliant quality management, please see the list of related links provided below.

James Jardine is a marketing communication specialist at MasterControl Inc., a global provider of GxP process and document management software solutions for life science companies (www.mastercontrol.com).

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Additional Articles
PIC/S Guide to Good Manufacturing Practice for Medicinal Products Full Article

Official Journal of the European Union — Official Directive 2003/94/EC
Full Article

WHO Guide to GMP Requirements
Full Article

Annex 13 — Manufacture of Investigational Medicinal Products
Full Article