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Biologicals 37 (2009) 271e276 www.elsevier.com/locate/biologicals

Review

Review of regulation of biological and biotechnological products in Latin American and Caribbean countries
a L. Pombo, Jose L. Di Fabio, Mar a de los A. Corte s* Mar
Pan American Health Organization, Essential Medicines and Biologicals, 525 3rd Street NW, Washington, DC 20037-2895, USA Received 7 March 2009; revised 29 April 2009; accepted 13 July 2009

Abstract The regulation of the biological and biotechnological products constitutes a signicant challenge, since they are part of a sector of the pharmaceutical industry that is currently experiencing rapid growth. Unlike conventional medicines, the manufacture of these products involves the use of living organisms and processes that impede manufacturing consistency. Even though there are numerous international reference documents related to biotechnological product regulation, there is no consensus by ofcial entities that are considered reference institutions, with regard to the most important denitions used and the mechanisms for product regulation. The Pan-American Health Organization (PAHO), through the Technology, Health Care and Research Area, has developed a series of activities that are described in this document. The objective of this publication is to present the current picture of biotechnological and biological product regulation in the Latin American and Caribbean Region, in order to offer guidance that will facilitate the regulation of these products in a harmonized manner among the countries of the Member States, as well as responding to the request from some regulatory agencies to address the growing demand for licensing applications of these products. 2009 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.
Keywords: Biotechnological products; Regulation; Biosimilars; Biotech products; Biological products

1. Overview Biological products, as dened by the World Health Organization (WHO [1]), are medicines obtained from microorganisms, blood or other living tissues whose manufacturing procedures may include one or more of the following elements: growth of microorganism, strains in different types of substrate, use of eukaryotic cells, biological substances extracted from tissues, including human, animal and plant tissues, and also products obtained by recombinant DNA or hybridoma technology, and the propagation of microorganisms in embryos or animals, among others [2]. In its most recent denitions, the WHO [2,3] includes the following medicines as biological products: vaccines, allergens,

* Corresponding author. Tel.: 1 202 9 74 36 44; fax: 1 202 974 36 10. s). E-mail address: cortesan@paho.org (M. de los A. Corte

antigens, hormones, cytokines, enzymes, derivatives of human blood and plasma, immunological sera, monoclonal immunoglobulins, antibodies, fermentation products (including products made by recombinant DNA technology) and reagents employed for in vitro diagnosis. Medicines of biological origin constitute one of the largest sectors of growth of the pharmaceutical industry, and their regulation presents major challenges. Some of these challenges are related to the inherently variable nature of the source materials and the manufacturing methods used [4e6]. Likewise, there is a need for analytical methods, mostly bioassays, for facilitating the characterization of biological products. The use of these methods involves additional special efforts in their standardization and implementation. Unlike conventional medicines which are produced using technologies able to provide a high degree of homogeneity and manufacturing consistency, the manufacture of biological products involves processes that are difcult to reproduce, and

1045-1056/09/$36.00 2009 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.biologicals.2009.07.003

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the use of natural sources, such as cell cultures or the extraction of materials from live organisms which tend to generate heterogeneous products in the absence of strict manufacturing controls. Thus, one of the main challenges in the manufacture of these products is to achieve consistency in their production. Therefore, the manufacture of biological products implies the need for a comprehensive system of quality management which covers all staffs and stages in the production, to ensure the quality, safety and effectiveness of the nal product. The development of such products requires the participation of regulatory agencies in a role different from that which they usually play in relation to conventional medicines. The development of such specialized production methods requires a very specialized process control which rests mainly on the manufacturer. Likewise, provision of evidence of specic quality control in the nished product becomes very complex and sophisticated, and may even have to be tailored for each particular product, which can diminish the value of prescriptive laboratory tests. That is why the assessment of compliance of Good Manufacturing Practices (GMP), the demonstration of effectiveness in clinical trials, and the post-marketing surveillance, become fundamental pillars for the products approval by the regulatory agency. At present, there are multiple reference documents issued by the WHO, as technical report series which are product specic, training manuals, guidelines and other general documents, which provide guidance and direction to the regulators, manufacturers and users of biological medicines. While many of these documents are oriented toward production and control of vaccines as part of the category of biological products, there are also documents aimed at production and control of biotechnological products made by recombinant DNA technology [6e9]. Likewise there are reference preparations available, such as cytokines/growth factors, endocrine substances and recombinant coagulation factors [12]. Despite current availability of multiple reference documents issued by the WHO [6e11], European Commission of Medicines (EMEA) [13e24], and by the International Conference on Harmonization (ICH) [25e28], related to biotechnological and biological products, there is no consensus among these reference institutions for the countries of the Region, on some important denitions used, and the mechanisms for the regulation of biotechnological products. As an example, we can cite that the WHO uses the name therapeutic biological medicines, while the EMEA and the ICH use the names biological medicinal products containing biotechnology-derived proteins and biological/biotechnological products, respectively, for referring to the same type of biological product. Considering this international context, the objective of this publication is to present the current picture of biotechnological and biological product regulation in the Latin American and Caribbean Region, in order to offer guidance that will facilitate the regulation of these products in a harmonized manner among the countries of the Member States, as well as responding to the request from some regulatory agencies to address the growing demand for licensing applications of these products.

2. Biological and biotechnological product regulation in Latin American and Caribbean countries The Pan-American Health Organization (PAHO), with the aim of giving technical support to the National Regulatory Authorities (NRAs) of the Member States, in view of the urgent necessity to rationalize and to harmonize biotechnological and biological product regulation, has begun to develop a series of activities with the countries of the Region, including the meeting on the Biological and Biotechnological Regulation Challenges, held in Montevideo, Uruguay, in November of 2007. This meeting focused especially on the regulation and similarity conditions of these products. At the same time the update on regulation at world-wide level of biosimilar products was presented. Simultaneously and as part of the activities established by the PAHO, the following challenges were established: - Evaluating the needs and/or strengths of NRAs of the Region in the matter of biotechnological and biological product regulation in general, including biosimilars and therapeutic biological medicines. - Identifying the existing regulatory differences among the Latin America and Caribbean countries for the above products. - Providing technical support to the NRAs in required areas, as well as to motivate harmonization in the regulation of biological and biotechnological products in the Region of the Americas. The PAHO, through the Essential Medicines and Vaccines Project, part of the Technology, Health Care and Research Area, has developed a survey to evaluate the needs of NRAs of Latin America and the Caribbean Region in biological and biotechnological product regulation, which was sent to a total of 27 countries: Republic of Argentina, Bahamas, Barbados, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Ecuador, El Salvador, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Dominican Republic, Surinam, Trinidad and Tobago, Uruguay, and Bolivarian Republic of Venezuela. This survey was targeted toward professionals responsible for the evaluation of biological product licensing applications within the regulatory agency of each country. The survey included a series of questions that allowed establishment of a platform to meet the challenges outlined above. The results of that survey are shown bellow. 3. Survey results The responses from 17 countries (Republic of Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Ecuador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Peru, Dominican Republic, Uruguay and Bolivarian Republic of Venezuela) allowed the identication of the responsible agent for evaluating and granting of the biological product license in each country.

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Most of the countries surveyed (75%) have regulations in place for biological products. However, there are often no differences between documents requested for licensing each product (vaccines, blood derivatives, and/or therapeutic biological medicines). In the case of Bolivia, Colombia, Costa Rica, Ecuador, Peru and Dominican Republic, the documents requested for biological products and for pharmaceutical products are exactly the same. Bolivia, Ecuador, and the Dominican Republic, do however demand additional documents for vaccines that are going to be licensed in their countries. With the exception of Colombia and the Bolivarian Republic of Venezuela, where the duration of the granted license is of 10, and 7 years respectively, for the rest of the surveyed countries the granted license must be renewed every 5 years. In most cases, including Colombia and the Bolivarian Republic of Venezuela, the renewal process involves an exhaustive evaluation of documents. At present, any change in a licensed product must be notied to the NRAs of all the countries surveyed. In most countries there are established procedures for doing so. As shown in Fig. 1, few countries provide specic denitions for vaccines (8), blood derivatives (6), biotechnological products (6), biosimilar products (2) and/or biotherapeutic products (3), respectively, in their local regulations. A total of 12% of the surveyed countries have licensed biosimilar products. The following were licensed under this category of products: recombinant human insulin, coagulation factors (II, VII, VIII, IX, X, XII), plasma activating factor, brinogens, specic immunoglobulins, normal immunoglobulins, human albumin, streptokinase, urokinase, sodium enoxaparine, human recombinant erythropoietin (alpha, beta), lgrastim, lenograstim, interferon (alpha 2a, alpha 2b, beta 1a, beta 1b), niseritide, Saccharomyces sp, Lactobacillus sp, and granulocyte stimulating factor. There are also countries such as the Republic of Argentina, Brazil, the Bolivarian Republic of Venezuela, and soon Costa

Rica, whose regulations treat all biological products as new products, given their nature, and process of manufacture. Therefore, full quality dossier, safety and efcacy studies are requested during their license. Also, comparative studies with the innovating product, including impurity proles of the active principle and nished product, and studies of noninferiority (if applicable) are requested. The Republic of Argentina, Brazil, Chile and the Bolivarian Republic of Venezuela do not support the term of similarity between biological products. Although there is a great interest on the part of the countries surveyed in having harmonized documents for the licensing of biotechnological products, there is no clear trend in the acceptance of mutual recognition mechanisms as an alternative to the licensing of these products, by countries that do not have a strong enough infrastructure for this purpose, without undermining the fact that such recognition must be established by each government and in some cases by the various partnerships between countries such as: Mercosur, the Central American Customs Union, the Andean Community of Nations, and the Alba, among others. At present, countries such as the Republic of Argentina, Brazil, Cuba and the Bolivarian Republic of Venezuela do not use this mechanism. A total of 41% of the countries indicated do not possess legal bases to enable them to identify a mechanism for mutual recognition, indicating that national regulations establish mandatory evaluation of any product that is going to be licensed in the country. Moreover, some surveyed countries (41%) reported conditions for the acceptability of such a mechanism. Among these conditions, they emphasize the importance of: - The harmonization of documents requested during the licensing of biological and biotechnological products in Latin America and the Caribbean. - The granting of recognition by PAHO of the countrys NRA in terms of its regulatory capacity. - The identication of a regional mechanism of biotechnological and biological product certication. Fig. 2, shows the number of countries that use documents of reference issued by international entities considered of reference for the Region, such as the WHO, ICH, EMEA, FDA, etc. With regard to background documents related to vaccines, most countries surveyed indicated the use of WHO Technical Report Series, as well as other general documents regarding the batch release process, and cold chain, in addition to specic pharmacopeial monographs. However, in the case of blood derivatives and biotechnological products, there are many countries that do not mention or are unaware of the existence of reference documents for these products issued by these bodies. In this context, the PAHO is collecting all available information on biotechnological products to distribute among the NRAs of the Region, and place on the website of Vaccines and Biologicals http://new.paho.org/hq/index.php. Also, during

Fig. 1. Number of countries with specic denitions within their local regulation. Answers from a total of 17 Latin American and Caribbean countries were included. Labels indicate how many countries in the PAHO Region do have denitions in their local regulations for vaccines, blood derivatives, biotechnological products, and biotherapeutics.

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regulatory process based on a claim of similarity to a reference product (an existing licensed product) [11]. The conict arises when term similarity in itself and the similarity of one biological product to another have to be dened. During the twelfth meeting of the International Conference of Drug Regulatory Authorities, ICDRA, held in Seoul, Republic of Korea in April 2006, a session was dedicated to the global challenges in regulation of vaccines and other biologicals [29]. The following recommendations summarize the requests to WHO: - Facilitate the process through establishment of regional and global networks of regulators. - Develop global regulatory consensus and guidance for biosimilars. - Facilitate the work of the National Laboratories of Control (NLC) through a global review of batch release strategies, and - Ensure sustainability of its international biological reference preparation program, among others. In April 2007, in Geneva, Switzerland, the WHO initiated specic activities related to the regulation of biosimilars, conducting an informal consultation on therapeutic biological medicines regulation. Some of the objectives were to discuss the current status in the regulation of biological (biosimilars) and to review the alternatives and challenges in quality evaluation, safety and efcacy of these products. The consultation recognized the importance of the terminology as well as determining a denition of biosimilars. However, achieving a global consensus on the terminology for these new challenging products was not attempted at the consultation, and it was decided that a future WHO working group should act on this issue as a next step [11]. Also it was agreed that WHO should develop a global regulatory guideline for biosimilar products, including issues of critical importance as principles of evaluation of these products, and regulatory pathways for their licensing oversight. Due to the great interest and the important consequences to the industry and consumers of adopting the concept of biosimilars and its regulation, this document is currently still in development. This publication fullls one of the objectives of the project on biotechnological and biological products started by the PAHO. It presents the results of the review of the regulation of these products in the Region, which is the starting point for any process of harmonization.

Fig. 2. Proportion of countries that use existing documents for the evaluation of biological/biotechnological products. Each bar represents the number of Latin American and Caribbean countries that currently used documents issued by the World Health Organization (WHO), the Food and Drug Administration (FDA), the European Medicines Agency (EMEA), the International Conference on Harmonization (ICH), International and local Pharmacopoeias, and some other documents as guidelines for the regulation of vaccines, blood derivatives and therapeutic biological products respectively.

this review, each country indicated the current, most important needs related to biotechnological product regulation. These needs are mostly oriented toward training in various aspects, harmonization and networking, and to the application of reference documents on biotechnological products. In parallel, the PAHO organized a meeting for the NRAs of the Region, in the Dominican Republic, on June 2008, where a total of 15 countries participated (Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Ecuador, Guatemala, Mexico, Nicaragua, Panama, Peru, Dominican Republic, and Bolivarian Republic of Venezuela). In this meeting the review on biotechnological and biological product regulation in Latin America and the Caribbean described in this article, was presented. Furthermore, updates and the current challenges on biotechnological product regulation, as well as the future activities on this subject to ultimately promote harmonized processes in the Region were discussed. There is particular interest in the use of the term biosimilars, a designation that, until now, has been adopted in an arbitrary manner at the global level. For instance, the EMEA uses the phrase similar biological medicinal products containing biotechnology-derived proteins, in the United States of America and Japan they are referred to as follow-on/protein products, in Canada they are subsequent entry biologics and lastly, in India and Iran these are called biogeneric products. The consensus rests on the fact that the simple term generic does not apply, for biosimilars. These products cannot be regulated in the same way as generic pharmaceuticals due to the complex nature of biologics, their manufacture and additional data, particularly during the evaluation of the toxicological and clinical proles to demonstrate and guarantee the products efcacy and safety. There is also a general agreement that biosimilar products can be approved by an abbreviated

4. Conclusions The regulation of biological/biotechnological products is facing new challenges in comparison with conventional pharmaceutical products. Strong pressure from pharmaceutical companies who recently have incorporated these products into their portfolios, looking for innovation and favorable economic consequences, is making regulators seek for easier and not always adequate pathways to face the new challenges.

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Main regulatory agencies are aware that they are not prepared to regulate properly these products which are invading markets all around the world with a major impact and consequences which could affect negatively mainly developing countries. With the intention to give the rst steps for supporting countries in the Pan American Region, the PAHO has conducted a survey to make a review of the current situation for the regulation of these products. This review gives an overview of the current scene related to the regulation of biological and biotechnological products in 17 Latin American and Caribbean countries, which can be used as an indicator of the current picture at a regional level. This overview indicates that there are preliminary regulatory activities in the Region which can be used as a platform for the establishment of harmonized documents, harmonized procedures and guidelines relating to this subject, which will support the improvement of existing regulatory mechanisms and facilitate the information exchange among the regulators of the Americas. Despite the existing strengths in some countries of the Region regarding regulatory matters, there are also shortcomings, some of which are related to a lack of denitions for each type of product, and/or specic training, not allowing the establishment of harmonized procedures, and also enabling evaluators at the regulatory level to face the specic challenges of biotechnological and biological product regulation. Generally, during the design and development of international reference documents the objective is to resolve precise needs in regulatory matters of countries with strong regulatory agencies. Nevertheless, these proposals of modications are not always applicable to developing countries, because in the majority of the cases these proposals do not consider the existing basic deciencies that span the establishment of denitions and procedures to carry out these proposals. In order to be able to face the challenges posed by the regulation of new biologicals, such as biotechnological products, the regulatory agencies of developing countries should strengthen their regulatory systems through networking work, harmonization of regulations and assessment procedures, among others [30]. Acknowledgments We thank Dr. Michael Corbel, for reviewing this manuscript; Dr. Elwyn Grifths, for providing technical support to the countries in the Region; and Debora Weiss, for providing assistance with the manuscript translation. References
[1] World Health Organization. Training manual: licensing, lot release, laboratory access; 2001. [2] World Health Organization. Annex 1: good manufacturing practices for biological products. Geneva: WHO; 1992. Technical Report Series: 822. [3] World Health Organization [Homepage]. Geneva: The Organization; 2008 [cited on February 10th 2008]. Biologicals, Available from: http:// who.int/biologicals/areas/en.

[4] World Health Organization. Annex 2: guidelines for national authorities on quality assurance for biological products. Geneva: WHO; 1992. Technical Report Series: 822. n Panamericana de la Salud. Mo dulos I y II: Vacunas de [5] Organizacio Calidad, Washington: OPS; 2004. [6] World Health Organization. Annex 3: guidelines for assuring the quality of pharmaceutical and biological products prepared by recombinant DNA technology. Geneva: WHO; 1991. Technical Report Series: 814. [7] World Health Organization. Annex 3: requirements for human interferons prepared from lymphoblastoid cells. Geneva: WHO; 1989. Technical Report Series: 786. [8] World Health Organization. Annex 7: requirements for human interferons made by recombinant DNA techniques. Geneva: WHO; 1988. Technical Report Series: 771. [9] World Health Organization. Annex 3: guidelines for assuring the quality of monoclonal antibodies for use in humans. Geneva: WHO; 1992. Technical Report Series: 822. Monoclonal antibodies. [10] World Health Organization. WHO Informal Consultation on International Nonproprietary Names (INN) Policy for Biosimilar Products. Geneva; September 2006. [11] World Health Organization. Meeting report of WHO informal consultation on regulatory evaluation of therapeutic biological medicinal products; 2007. [12] World Health Organization. WHO International biological reference preparations held and distributed by the WHO International laboratories for biological standards cytokines/growth factors http://www.who.int/ bloodproducts/catalogue/en/index.html; 2007. [13] European Medicines Agency. Guideline on similar biological medicinal products. CHMP/437/04; 2005. [14] European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. EMEA/CHMP/BWP/49348/2005. [15] European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005. [16] European Medicines Agency. Concept paper on similar biological medicinal products containing low molecular weight heparins-non-clinical issues. EMEA/CHMP/BMWP/496286/2006. [17] European Medicines Agency. Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor. EMEA/CHMP/BMWP/31329/2005. [18] European Medicines Agency. Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant human soluble insulin. EMEA/CHMP/BMWP/32775/2005. [19] European Medicines Agency. Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant erythropoietin. EMEA/CHMP/BMWP/94526/2005. [20] European Medicines Agency. Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing somatropin. EMEA/CHMP/BMWP/94528/2005. [21] European Medicines Agency. Guideline on comparability of biotechnology-derived therapeutic products after a change in the manufacturing process. Non-clinical and clinical issues. EMEA/CHMP/BMPW/101695/2006. [22] European Medicines Agency. Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006. [23] European Medicines Agency. Guidance on comparability of medicinal products containing biotechnology-derived proteins as active substance. Non-clinical and clinical issues. EMEA/CPMP/3097/02/2003.

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M.L. Pombo et al. / Biologicals 37 (2009) 271e276 procedures and acceptance criteria for biotechnological/biological products Q6B; 1999. [28] International Conference on Harmonization of Technical Requirements for registration of pharmaceuticals for human use. Preclinical safety evaluation of biotechnology-derived pharmaceuticals S6; 1997. [29] ICDRA. 12th International Conference of Drug Regulatory Authorities, Recommendations http://www.who.int/medicines/areas/quality_safety/ regulation_legislation/icdra/recc_nal; 2006. s M, Di Fabio J. Regulation of small-molecule drugs versus bio[30] Corte logicals versus biotech products. In: Gad Shayne Cox, editor. Handbook of pharmaceutical biotechnology; 2007. p. 1373e90.

[24] European Medicines Agency. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: quality issues. EMEA/CPMP/BWP/3207/00/2003. [25] International Conference on Harmonization of Technical Requirements for registration of pharmaceuticals for human use. Comparability of biotechnological/biological products subject to changes in their manufacturing process Q5E; 2004. [26] International Conference on Harmonization of Technical Requirements for registration of pharmaceuticals for human use. Quality of biotechnological products: stability testing of biotechnological/biological products Q5C; 1995. [27] International Conference on Harmonization of Technical Requirements for registration of pharmaceuticals for human use. Specications: Test