Harmonized international standards

The FDA emphasizes that there are three routes to development of a harmonized international standard, all of which are favored under the FDA policy (1) The U.S. voluntary standards community or an agency, such as the FDA, develops a U.S. standard and takes it to an international forum so it can be made an international standard (2) A standard already developed in an international forum (or by another country or a regional standards body) is adopted as a U.S. voluntary or regulatory standard or (3) A new international standard is developed, from scratch, in an international forum. Which of these routes is followed in the particular case will vary with the facts of that case. While starting a standards activity in an international forum offers many efficiencies in avoiding duplication of effort, there will continue to be times when it makes sense first to develop a domestic standard (voluntary or regulatory) and then to take it, as appropriate, to an international forum. 

The fine chemicals standards discussed herein are primarily those originating in the United States. Much discussion has occurred regarding harmonization of the wodd s standards. It is not yet clear, however, what impact the International Standards Organization QuaHty Management Standards (ISO 9000) may have on the manufacture and specifications of fine chemicals. 

Determination of the potency of Factor VIII is also difficult. This is normally measured by the abiUty of the sample to correct the clotting time of plasma deficient in Factor VIII. A number of methods and practices have evolved for this purpose (231), but these give very different results, particularly when activation of products may also occur (232). International standards have been used, but further standardization of the analytical method and harmonization of working standards is underway (233,234) under the auspices of the ISTH and the EC. 

Presently efforts of Ukrainian scientists in field of analysis of toxic organic substances directed on harmonization of the developed methods of analysis with the requirements of international standards and on wide introduction in practice of the quality control system in chromatographic researches. 

New controls may also be needed if there are unusual contractual relationships, such as overseas subcontractors, international consortia, or in-plant surveillance by the customer. There may be language problems, translation work, harmonization of standards, and other matters arising from international trade. 

The 1982 White Paper on Standards, Quality and International Competitiveness was concurrent with increasing interest in the techniques of quality assurance and the need for international harmonization of standards and the reciprocal recognition of certification. It is worth noting that the ISO 9000 series of standards on Quality Systems 1987 followed the layout of BS 5750 1979 almost clause by clause. ISO Guide 39 covers the general requirements for inspection bodies. Auditing on behalf of certification bodies is part of the inspecting authorities role. 

Where there is a dosing device provided with the product, the dose reproducibility and accuracy should be demonstrated. Examples include dropper devices, dose-measuring devices, and pen injectors. The instructions for use should also be discussed for such devices and may be particularly important for devices such as two-chamber cartridges and the like containing suspension products. It might be necessary to discuss how dosing devices meet the relevant Essential Requirements of the Medical Device Directives with reference to appropriate and relevant harmonized and other European (EN) and International Standards Organization (ISO) standards. 

Three key issues for codes and standards include better synchronization of codes and standards development with RD D, performance- versus design-based (or prescriptive) standards, and coordinating national codes and standards development with international standards development. For all the three issues, the critical need is to establish a scientific foundation for requirements incorporated in codes and standards. If the science underlying these requirements can be established, harmonization of requirements and consensus among international experts can be more readily achieved, and the DOE can focus on the critical RD D needs as identified in the Roadmap to facilitate harmonization and consensus. 

The United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS) includes an internationally standardized guidance procedure on Transformation/Dissolution Protocol (T/DP) for metals and sparingly soluble metal compounds (United Nations, 2007), recently validated by the OECD (Organization for Economic Cooperation and Development). To establish the acute aquatic hazard classification level of a metal-bearing substance under the GHS, data from the T/DP are compared with an acute ecotoxicity reference value (ERV) derived under conditions similar to those of the T/DP. 

The ideal validated method would be the one that has progressed fully through a collaborative study in accordance with international protocols for the design, conduct, and interpretation of method performance studies. A typical study of a determinative method conducted in accordance with the internationally harmonized International Organization for Standardization (ISO)/International Union for Pure and Applied Chemistry (IUPAC)/AOAC International (AOAC) protocol would require a minimum of up to five test materials including blind replicates or split-level samples to assess within-laboratory repeatability parameters, and eight participating laboratories (15). Included with the intended use should be recommended performance criteria for accuracy, precision and recovery. 

In 1993, the Global Harmonization of Standards (GHOST) discussion document was published by FEDESA. This sets out a program for the international harmonization of registration requirements for veterinary pharmaceuticals and biologicals. 

Increased harmonization offers clear benefits for public health. It can increase the safety and quality of food produced and sold in foreign countries or food imported from other countries, as more countries participate in the international standard setting process. Harmonization benefits industry by replacing many different standards with one international standard that must be met. In the long run, harmonization will bring cost savings to industry, open markets, enhance opportunities for export, and, in some cases, lessen the time needed to bring new products to market. 

Method validation has received considerable attention in the literature and from industrial committees and regulatory agencies. The international standard ISO/ IEC [1] requires validation of nonstandard methods, laboratory designed/devel-oped methods, standard methods used outside their intended scope, and amplifications and modifications of standard methods to confirm that the methods are suitable for their intended use. The Guidance on the Interpretation of the EN 45000 Series of Standards and ISO/IEC Guide 25 includes a chapter on the validation of methods [2] with a list of nine validation parameters. The International Conference on Harmonization (ICH) of Technical Requirements for the... 

As for all other analytical methods, methods for the analysis of products derived from modern biotechnology need to be validated. This validation should follow international standards (e.g. ISO 5725) and comply with, The IUPAC/AOAC/ISO harmonized protocol of method validation [6] or the standards cited above. Validation of testing methods is greatly facilitated by the use and availability of the appropriate reference materials. The following paragraphs specify some important... 

AERS. A pilot program for electronic submission of individual case safety reports is now being conducted with pharmaceutical manufacturers with approved products. The format follows the International Conference on Harmonization (ICH) standards. For more information on the ICH, please contact Timothy Mahoney at mahoneyt cder.fda.gov. 

The basic safety studies, including the International Conference on Harmonization (ICH) standard series of preclinical tests, receive close attention in the NDA review. Even if specific ICH studies were never discussed in the pre-IND meeting, the IND review, and the pre-NSDA meeting, they should be addressed in the NDA. 

The Branch also works with international organizations, including regulatory authorities in other countries, to harmonize regulatory standards and processes for therapeutic products. 

The FDA is announcing the Agency s policy on the development and use of standards with respect to international harmonization of regulatory requirements and guidelines. Specifically, the policy is intended to address the conditions under which the FDA plans to participate with standards bodies outside of the FDA, domestic or international, in the development of standards applicable to products regulated by the FDA. The policy also covers the conditions under which the FDA intends to use the resultant standards, or other available domestic or international standards, in fulfilling its statutory mandates for safeguarding the public health. 

The purpose of this document is to articulate the FDA s policy on development and use of standards with respect to international harmonization of regulatory requirements and guidelines. As used throughout this document, the term standards includes what are commonly referred to as consensus standards, voluntary standards, and industry standards. Also, the FDA sometimes accepts standards and makes them mandatory regulatory requirements. Although the draft policy focuses on international harmonization and international standards, its principles are applicable as well to domestic standards activities in which the FDA participates. 

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