By Joseph X. Phillips

The International Conference for Harmonization (ICH) brings together the regulatory authorities of Europe, Japan, and the U.S. as well as pharmaceutical industry experts from those regions to discuss scientific and technical aspects of product registration. Drug product registration controls have always been and remain under the jurisdiction of the multiple regulatory bodies in the nations where the products are manufactured and/or marketed.

Beginning in the 1960s, in most countries there was a general increase in laws, regulations, and guidances to provide oversight and control over the quality, safety, and efficacy of drug products. About the same time, industry was becoming more international. If a given firm planned to manufacture and/or market its product in more than one nation, the firm would have to meet the different requirements of each nation. Sometimes this involved issues such as duplicate testing or different controls. With the ever-rising costs of health care, increasing costs of research and development, and public expectation that new products reach the consumer in an efficient process, stakeholders began to look for ways to harmonize regulatory requirements.

The idea of harmonizing requirements between nations was pioneered in Europe, as the European Union was organizing. Early success in Europe showed the concept was feasible. About this time, interested regulatory parties in Europe, Japan, and the United States began talks on harmonization. At a WHO Conference of Drug Regulatory Authorities in Paris in 1989, plans were made to move the concept forward. The regulatory authorities approached IFPMA to discuss a regulator-industry initiative on international harmonization.

A meeting in Brussels, hosted by EFPIA, led to the launch of ICH. Representatives from the regulators and Industry met to plan an international conference, and discussed wider implications and terms of reference for ICH. An ICH Steering Committee was established and held its first meeting, in which the terms of reference were established. Topics selected for harmonization were divided into categories of safety, quality, and efficacy to mirror the three criteria used as a basis for approving and authorizing new pharmaceutical products. The Steering Committee continues to meet twice each year, alternating meeting sites among the three ICH regions including the European Union, Japan, and the U.S.

It was agreed that a six-person Expert Working Group (EWG) would be formed to discuss scientific and technical aspects of each harmonization topic. The EWG would include a representative of each of the regulatory bodies from the three ICH regions (EMEA for Europe; MHLW for Japan and FDA for the U.S.) and a representative from the industry for each region (EFPIA for Europe; JPMA for Japan; and PHARMA for the U.S.).

In practice, when an EWG meets, there may be non-voting observers from nations outside the three regions or from interested stakeholders. For example, at the Q7A EWG meetings exploring cGMPs for active pharmaceutical ingredients, PIC/S, WHO and many non-voting nations were often present.

In 1992, the Steering Committee drew up a five-step process for identifying harmonization topics:

• Step 1: Consensus building
• Step 2: Consensus reached; topic submitted to the Steering Committee for acceptance
• Step 3: Regulatory consultation (regulators share document with their stakeholders, evaluate comments, prepare final regulatory version and three regulatory representatives sign off)
• Step 4: Submit harmonized document to Steering Committee for acceptance; Steering Committee signs off
• Step 5: Implementation in the three Regions

ICH harmonization topics are divided into four major categories and ICH topic codes are assigned as follows:

• Quality topics: Those related to chemical and pharmaceutical quality assurance (examples: Q1 - Stabilty testing, Q3 - Impurity Testing)
• Safety topics: Those related to in vitro and in vivo preclinical studies (examples: S1 - Carcinogenicity Testing, S2 - Genotoxicity testing)
• Efficacy topics: Those relating to clinical studies in human subjects (examples: E4 - Dose Response Studies And Carcinogenicity Testing, E6 - Good Clinical Practice)
• Multidisciplinary topics (examples: M1 - Terminology, M2 - Electronic Standards for Transmission of Regulatory Information, M3 - Timing of Preclinical Studies in Relation to Clinical Trials)

ICH efforts have resulted in development of the first cGMP harmonized guidance. This document, known as Guidance for Industry/Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, has been in effect for more than four years.

For more detailed information about ICH, visit the ICH Web site at www.ich.org.

About the Author
Joseph X. Phillips joined ISPE in 2003 as Regulatory Affairs Advisor and was appointed to the US Food and Drug Administration (FDA) as a special government employee on the Pharmaceutical Science Advisory Committee that is involved in the agency’s new “Risk-Based Approach to Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century” initiative. Previously, Phillips was Vice President, Pharmaceutical Services for Quintiles Consulting following a 44-year career with the FDA. At the FDA he served as Deputy Regional Director of the Agency’s Central Region. He was heavily involved in training of FDA Investigators and in planning and managing pharmaceutical programs including the Pre-Approval Inspection program and the SUPAC (Scale-Up and Post Approval Changes) for field operations. Phillips was a principal negotiator for the US/EU Mutual Recognition Agreement and was the FDA Lead to the International Conference on Harmonization (ICH) Expert Working Group for GMP Guidance for Active Pharmaceutical Ingredients (ICH Q7A Guidance)