Tissue and Cell Processing

An Essential Guide

Deirdre Fehily, Scott A. Brubaker, John N. Kearney, Lloyd Wolfinbarger, Deirdre Fehily, Scott A. Brubaker, John N. Kearney, Lloyd Wolfinbarger

• Publisher: Wiley-Blackwell
• Year: 2012
• ISBN:
  9781118316504
• Edition: 1
• Topic: Medicine
• Subtopic: Hematology

By presenting the latest technological advances and growing national and international regulation, this new book explores state-of-the-art developments in the challenging field of tissue and cell processing. It provides a guide to easier and safer practice in operational principles of preservation, decontamination, and sterilization. Nearly half of the book is devoted completely to tissue- or cell-specific issues relating to processing. With lists of learning points and case studies which consist of sample processing protocols, descriptions of where processing went wrong, sample risk assessments, or validation studies, the authors help you find specific information fast.

1

Regulations and Standards

Michael Cox¹ and Scott A. Brubaker²

¹Danish Medicines Agency, Copenhagen, Denmark

²American Association of Tissue Banks, McLean, VA, USA

Introduction

The primary purpose of statutory regulations is to serve as a common framework for ensuring with confidence the current state of the art on the quality and safety of tissues and cells for therapeutic benefit. Equally, the regulations and linked guidance should be compatible on a wider level to encourage equitable distribution between countries, where regulations may be similar and well established, in early development, or in their infancy. Many countries have implemented or are refining their healthcare services to provide a better standard of care to patients and to enhance the use of tissues and cells for clinical applications. The steps involved in the processing of tissues and cells are critical activities and require the application of specific controls to prevent contamination and cross-contamination, as well as to maintain quality and safety. This chapter gives an overview on the status, history, and scope of key regulations; the practical aspects of implementation; the interface with advanced therapy medicinal products (ATMPs); medical devices; biologics; and some global perspectives.

The therapeutic application of tissues or cells is preceded by a series of complex and inter-related activities, from donor selection and screening, infectious disease testing, tissue and cell recovery, processing, temporary or long-term storage, and distribution for use in the clinical setting. The organization and delivery of healthcare systems are structured and operate quite differently, according to resources and health programs, to address epidemiological characteristics of the endemic population. To encompass these diverse organizations, and their inter-linked activities, a tissue establishment can be defined as:

a tissue bank or a unit of a hospital or another body where the activities of processing, preservation, storage or distribution of human tissues and cells are undertaken. It may also be responsible for the procurement or testing of human tissues and cells [1].

Organizations in healthcare services or the commercial sector performing one or typically more of these activities should be authorized by their national regulating body and are expected to verify compliance with appropriate requirements, so governing the quality and safety of tissues and cells.

Professionals working in the tissues and cells sector have not been wholly amenable to “allografts” being referred to as “products” or “devices;” and some have reservations regarding the use of the term “manufacturing” being applied in the context of human tissues and cells donated altruistically for the benefit of others. However, regulatory preferences and established terminology of other healthcare sectors often over-ride the human dimension in this donation-related work and such terms are commonly applied. This chapter discusses the requirements and language that affect professionals involved in the processing of tissues and cells for transplantation.

To assist all countries where cell and tissue banking activities are developing, and some without regulatory oversight, the World Health Organization (WHO) convened meetings in 2004 and 2005 with the participation of numerous experts and regulators from across all of the WHO regions. Global standards necessary for the development of safe tissues and equitable and ethical access to donation and transplantation of tissues and cells were discussed. This resulted in two useful aide-memoires for use by emerging health authorities, published in 2005 [2] and 2006 [3]. Among other key elements, both documents promote the benefits of quality systems and quality programs. The concept of a supplementary aide-memoire on the generic principles of inspection for tissue and cell establishments, including processing controls, was initiated in late 2009. Following this, in May 2010, the 63rd World Health Assembly endorsed a resolution on the WHO guiding principles for human cell, tissues and organs transplantation [4], which urged Member States to formulate and enforce their own policies, laws and, regulations on this subject.

Regulations – Development, Scope, and Principles

Europe

The forerunner to the Tissue and Cell Directives (see below) was a comprehensive guidance document published by the European Health Committee of the Council of Europe which defined the standards required, and quality assurances to be achieved, for the transplantation of organs, tissues, and cells. It was updated again in 2010 [5] and is a valuable source of scientific information and clinical practice guidance. The first legislative proposal to set binding requirements on the quality and safety of human tissues and cells by the European Commission was presented in 2002. Its objective was to facilitate the cooperation and collaborative activities between the healthcare systems of the Member States. The regulation of substances of human origin, such as blood, tissues, cells, and organs, at a European Union (EU) level became legally possible when the Treaty of the EU was amended in 1995 by Article 152 of the Treaty of Amsterdam. This article extended the legal competence of the EU to certain aspects of healthcare stating that “Measures setting high standards of quality and safety of organs and substances of human origin, blood and blood derivatives” would be adopted. The legal basis would allow individual Member States to adopt more stringent requirements if they considered it appropriate. National representatives of the Member States, together with their experts, then negotiated a technical and political approach for the regulatory framework to control these activities for the greater protection of public health.

The entry into force for the principal Directive 2004/23/EC [1] was April 2006, which preceded Directive 2006/17/EC [6] in November 2006 and Directive 2006/86/EC [7] in September 2007. Collectively these are the “Tissue and Cell Directives” which address the standards of quality and safety for the donation, procurement, testing, processing, preservation, storage, distribution, and import/export of human tissues and cells. Since then the Member States have transposed the Directives into national laws and put in place the implementation measures for their application. Aspects of these Directives apply also to other manufactured products that are regulated as medicines but are wholly or partially derived from human tissues and cells. Specifically, donation, procurement and testing of the tissues and cells used for the manufacture of such products are regulated by the Tissue and Cell Directives. Tissues and cells used as an autologous graft in the same surgical procedure and those used for research studies not involving application to the human body, are excluded, as are organs, blood, and blood products. The Tissue and Cell Directives therefore regulate tissues for transplantation such as bone, skin, heart valves and corneas, cells such as hematopoietic stem cells from bone marrow, peripheral blood, or cord blood as well as other cells that are not extensively manipulated, plus gametes and embryos.

United States

As a comparison, tissue regulations in the USA were first introduced in the 1980s and aimed at processing requirements for the manufacture of two specific human tissue types, corneal lenticules and, separately, human dura mater. By mid-1991, cryopreserved allograft (replacement) heart valves were singled out as a “product,” like man-made replacement heart valves, requiring data submission to demonstrate safety and effectiveness. These allografts were classified as medical devices by the Food and Drug Administration (FDA) and regulated by their Center for Devices and Radiological Health (CDRH). Although enforcement of requirements related to the Class III medical device designation for allograft heart valves was rescinded due to a decision in late 1994 [8], other federal regulations were published in 1993 and were applicable to a variety of conventional tissue allografts. This federal oversight of human tissues for transplantation advanced further after two specific events. In 1991, there was realization of HIV transmissions from the transplantation of human tissue from one donor reported by the Centers for Disease Control and Prevention (CDC). Soon thereafter, the FDA received reports from US tissue banks of brokers selling unprocessed tissue from improperly screened and tested donors from Russia, eastern Europe, and Central and South America [9]. In response to the concern for public health, the FDA published an Interim Final Rule entitled “Human Tissue Intended for Transplantation” [10]. With this publication, the FDA’s Center for Biologics Evaluation and Research (CBER) was assigned responsibility for oversight of tissue establishments that screen donors, and recover, process, store, and/or distribute tissue for transplantation. This Interim Rule, codified in 21 CFR Part 1270, included minimum requirements for screening and testing tissue donors, and maintaining procedures and records with specific emphasis on preventing the transmission of viral hepatitis and HIV. The American Association of Tissue Banks (AATB) and the Eye Bank Association of America (EBAA) actively promoted communication between industry professionals and CBER to ensure further development of regulations would be effective. Various public workshops and meetings were held and in June 1997 the FDA published a Final Rule and Guidance Document that amended parts of the Interim Rule. These focused on considerations involving the eligibility of deceased donors such as criteria to be used when screening, infectious disease tests that must be performed, plasma dilution evaluation of the blood sample used for testing, and the physical assessment of the donor.

FDA also announced their “Proposed Approach to the Regulation of Cellular and Tissue-based Products” which outlined a tiered, risk-based strategy for regulating traditional tissues as well as new cell/tissue allograft products. This oversight was aimed at the control of contamination and cross-contamination throughout all manufacturing steps. The “Tissue Action Plan” (TAP) was developed to guide this proposal to fruition. Soon after the start of the new millennium, the FDA described a more comprehensive regulatory framework, codified it in 21 CFR Part 1271, and promoted regulations via final rules that encompass registration of tissue establishments and listing of products (2001) [11], donor eligibility requirements (2004) [12], expectations for maintaining Current Good Tissue Practice (2004) [13], and reporting, inspection, and enforcement regulations. The last of the final rules published in 2004 became effective for cells and tissues recovered from donors after May 25, 2005. The regulations in 21 CFR 1271 describe the scope of the expanded oversight to be applicable to human cells, tissues, and cellular and tissue-based products (HCT/Ps). These are described as conventional tissue (e.g., bone, including demineralized bone, skin, tendons, ligaments, fascia, pericardium, dura mater, cartilage, heart valves, veins/arteries, amniotic membrane), ocular tissue (i.e., corneas, sclera), reproductive tissue (i.e., semen, oocytes, embryos), and hematopoietic stem/progenitor cells (including cells derived from peripheral or cord blood). Federal regulations have matured to include a wide variety of allograft cell/tissue products intended for implantation, transplantation, infusion, or transfer into human recipients, whether sourced from living or deceased donors.

21 CFR 1271 is not applicable to some human-derived therapeutic products, such as solid organs used for transplantation; blood or blood components; minimally manipulated bone marrow; secreted or extracted human products such as milk, collagen, and cell factors; and products derived from or exposed to cells, tissues, or organs from non-human animals. In addition, exemptions include autologous tissue re-implanted within the “same surgical procedure.” A regulatory ladder (tiered, risk-based approach) was created to address nuances if HCT/Ps are combined with other materials or whose use and effect on the body become complicated after further manipulation. In a number of ways, HCT/Ps may be elevated to a higher regulatory scheme that encompasses requirements for medicinal products, specifically those attributable to FDA designation as a “biologic” or a “medical device.”

Australia

In the Therapeutic Goods Act 1989 and subsequent amendments, human organs, tissue, and cellular products, as well as tissue- and cell-based derivates, are regulated by several different routes. The related Australian Code of Good Manufacturing Practice (GMP) [14] is applicable to human tissue for transplantation when procured, stored, and supplied without deliberate alteration to its biological and mechanical properties (e.g., dura mater, heart valves, skin, corneas, and bone). It was published by the Therapeutic Goods Administration (TGA) in 2000 and adopts GMP expectations for tissue establishments. The quality system requirements include quality objectives, organizational structure, monitoring systems, and management review. It incorporates many quality systems elements from the ISO 9000 series of standards and equally applies these principles for the control of blood products. Similar to the regulatory designations for human tissues and cells in Europe and the Americas, these allografts may be regulated as medicines or therapeutic devices, depending on their biological/mechanical properties or their therapeutic purpose. The regulation of viable human and animal tissues that undergo processing and modification prior to implantation or infusion to patients have yet to be fully addressed in the current legislation. In July 2002, the Australian Health Ministers supported the TGA for a regulatory framework for human tissues and emerging biological therapies. The ensuing Human Cellular and Tissue therapies (HCT) framework was originally planned as a part of the regulatory partnership between Australia and New Zealand, but its postponement in July 2007 meant the HCT framework was delayed. In July 2009 the Australian Government moved forward independently with this framework, which excludes assisted reproductive tissues and solid organs. Hematopoietic progenitor cells are envisaged to be part of the framework, after a public consultation phase with that profession’s stakeholders. Recently, amendments to the Therapeutic Goods Regulations 1990 that create a new regulatory framework for biologicals were passed by Executive Council on March 10, 2011. The biologicals framework commenced on May 31, 2011. After this date, all products within the scope of the framework will need to comply with the requirements made under the new legislation, but a three-year transition period is provided for establishments to come into compliance. Four classes of biologicals have been developed, based upon risk, extent of manipulation applied, and whether use is homologous or not. In this regard, similarities exist with the European and US perspective but a major difference is that the submission of an extensive dossier for products is required for not only Class 3 and 4 biologicals, but also for Class 2. A dossier of information on a product is akin to a “device history file,” so requiring this extensive compilation to characterize a Class 2 biological, which is equivalent to a conventional tissue allograft in the USA, is an onerous task for tissue banks. Guidance documents are being developed to assist stakeholders to better understand the TGAs expectations. It is also interesting to note that these biological products (of any class), once reviewed and approved by the TGA, become officially listed on the Australian Registry of Therapeutic Goods (ARTG) and a reimbursement fee is assigned to each one. This i...