1
Challenges to Quality and Regulatory Requirement in the United States—Drugs, Medical Device, and Cell Therapy

Chung Chow Chan, Sultan Ghani, Iain Simpson and James Blakemore

1.1 Overview of Regulatory Requirements for Pharmaceutical, Medical Device, and Cell Therapies

The technologies for the administration of therapeutic agents had been traditionally led by the pharmaceutical industry, which develops small drug molecules into various dosage forms. These developments have been followed by large-molecule pharmaceutical development (proteins, etc.), device development, and the new emerging cellular therapy. Recent breakthroughs in science and technology (ranging from sequencing of the human genome to advances in the application of nanotechnology to new medical products) are transforming the ability to treat diseases and bring with it new challenges in regulatory approval.

This chapter brings together the regulatory requirements for the development of the three platforms of therapeutic delivery solution (pharmaceutical, medical devices, and cellular therapeutic solutions) to illustrate the common/different strategies of regulating these three therapeutic deliveries and the current initiatives initiated in the United States and other countries. Note that the terms “drugs” and “pharmaceuticals” will be used interchangeably in this chapter. The common goal for all three platforms of delivery is current Good Manufacturing Practices (CGMP). The detailed process of achieving the common goal of GMP is different in each therapeutic area. The summary of the common regulatory requirements and the different approaches to reach this goal are presented.

The evaluation and approval processes are being modernized by the Food and Drug Administration (FDA) in the United States and other global regulatory agencies to ensure that innovative products reach the patients who need them and when they need them. In the United States, this is being done through advancing Regulatory science, which is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products [1].

In the United States, drug delivery is regulated by the Code of Federal Regulations (CFR). CFR is the codification of the general and permanent rules and regulations. This is published in the Federal Register by the executive departments and agencies of the Federal Government. It is divided into 50 titles that represent broad areas subject to Federal regulation.

Each title is divided into chapters, which usually bear the name of the issuing agency. Each chapter is further subdivided into parts that cover specific regulatory areas. Large parts may be subdivided into subparts. All parts are organized in sections, and most citations in the CFR are provided at the section level (http://www.gpo.gov/).

Title 21 of the CFR is reserved for Food and Drug under the rules of the FDA, Department of Health and Administrative Services. Title 21 contains the following three chapters:

• Chapter I—Food and Drug Administration, Department of Health and Human Services (Parts 1–1299)
• Chapter II—Drug Enforcement Administration, Department of Justice (Parts 1300–1321)
• Chapter III—Office of National Drug Control Policy (Parts 1400–1499)

1.2 Regulatory Requirements and Challenges for Pharmaceutical, Medical Device, and Cell Therapies

Title 21 Chapter 1 contains Parts 1–1299. The parts that are commonly encountered in the development of the three platforms of therapeutic delivery are listed below:

• Part 3—Product Jurisdiction
• Part 4—Current Good Manufacturing Practice Requirements for Combination Products (effective July 2013)
• Part 11—Electronic Records; Electronic Signatures
• Part 26—Mutual Recognition of Pharmaceutical Good Manufacturing Practice Reports, Medical Device Quality System Audit Reports, and Certain Medical Device Product Evaluation Reports: United States and the European Community
• Part 58—Good Laboratory Practice for Nonclinical Laboratory Studies
• Part 210—Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
• Part 211—Current Good Manufacturing Practice for Finished Pharmaceuticals
• Part 312—Investigational New Drug Application
• Part 600—Biological Products: General
• Part 601—Biologic License Application
• Part 610—General Biological Products Standards
• Part 820—Quality System Regulation (Devices)
• Part 814—Premarket Approval of Medical Devices
• Part 1270—Human Tissue Intended for Transplantation
• Part 1271—Human Cells, Tissues, and Cellular and Tissue-Based Products

In the United States, the regulatory requirements of the three platforms of drug delivery are implemented through three separate Centers in the FDA:

1. Center for Drug Evaluation and Research (CDER) for Pharmaceuticals. CDER’s primary mission is to make certain that safe and effective drugs are available to the American people.
2. Center for Devices and Radiological Health (CDRH) for Medical Devices. CDRH is responsible for ensuring the safety and effectiveness of medical devices and eliminating unnecessary human exposure to man-made radiation from medical, occupational, and consumer products. It will advance public health and facilitate innovation to help bring novel technologies to market and make the medical devices that are already on the market safer and more effective.
3. Center for Biologics Evaluation and Research (CBER) for Cell Therapy. CBER regulates biological products for human use and protects and advances the public health by ensuring that biological products are safe and effective and available to those who need them.

Whether the item is a pharmaceutical agent, cell delivery agent, or medical device, it shares the common criteria in the regulatory approval of intended use of the product and CGMP. Pharmaceutical and cell therapy products share many common processes and techniques to provide relief to disease states of the patient. Device products are more varied and range from simple household products to highly sophisticated imaging products, which may provide other use in addition to providing relief to disease states. However, it still needs to fulfill the common criteria of intended use and be safe to the patients. As an example, a simple device product (Shoulder/Flex Massager) was used to “help relieve muscle pain” (intended use). However, because of incidents related to its safety (report of strangulation and death) at the time of its intended use, the product had been voluntarily recalled by the manufacturer [2].

1.2.1 Center for Drug Evaluation and Research

CDER enforces CGMP through Part 211 by implementing the regulatory sections tabulated in Table 1.1. Section 501(a)(2)(B) of the Food and Drug Act (FD&C Act) requires drugs, which include investigational new drug (IND) products, to comply with CGMP as follows:

A drug…shall be deemed adulterated…if…the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.

Table 1.1 Regulatory sections of Part 211—current good manufacturing practice for finished pharmaceuticals