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Drug Regulations and the Pharmaceutical Laboratories

Kim Huynh-Ba

Pharmalytik LLC, Newark, DE, USAUSA

TABLE OF CONTENTS

• 1.1 Introduction
• 1.2 Food and Drug Administration: Roles and Its Regulations
• 1.2.1 Code of Federation Regulations
• 1.2.2 FDA Guidance Documents
• 1.2.3 FDA Manual of Policies and Procedures
• 1.3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Its Role
• 1.3.1 ICH Background
• 1.3.2 ICH Structure
• 1.3.3 ICH Organization
• 1.3.3.1 Steering Committee
• 1.3.3.2 Global Cooperation Group
• 1.3.3.3 MedDRA Management Board
• 1.3.3.4 Working Groups
• 1.3.3.5 Secretariat
• 1.3.3.6 Coordinators
• 1.3.4 ICH Topics
• 1.3.4.1 Quality Guidelines
• 1.3.4.2 Safety Guidelines
• 1.3.4.3 Efficacy Guidelines
• 1.3.4.4 Multidisciplinary Guidelines
• 1.4 Pharmaceutical Analysis
• 1.4.1 Analytical Testing
• 1.4.2 Interaction of the Analytical Development Department and Other Functional Areas
• 1.4.3 Drug Development Process
• 1.4.3.1 Toxicological Phase
• 1.4.3.2 Investigational New Drug
• 1.4.3.3 Clinical Phase
• 1.4.3.4 Registration Phase
• 1.4.3.5 New Drug Application
• 1.4.3.6 Post-Approval Phase
• 1.5 Summary
• List of Abbreviations
• References

1.1 Introduction

The pharmaceutical industry is a complex business in the global economy. As well as having to meet profit margins, issues such as safety considerations, effectiveness assurance, regulatory compliance, patent protection, labeling, and the supply chain, can significantly affect the development and commercialization of pharmaceutical products. Regulatory agencies define testing requirements, and these requirements vary from country to country where the products are marketed. This chapter explains different regulatory bodies and how they affect the testing of pharmaceutical products.

1.2 Food and Drug Administration: Roles and Its Regulations

The regulatory body in the United States (US), the Food and Drug Administration (FDA) (www.fda.gov), is within the Department of Health and Human Services (HHS). The primary responsibility of the FDA is to protect the public health, and pharmaceutical companies must maintain the quality of the drug products through their shelf life based on current regulations. The FDA consists of the Office of the Commissioner and four Directorates overseeing the core functions of the agency: Medical Products and Tobacco, Foods, Global Regulatory Operations and Policy, and Operations. Each of these offices has numerous centers and offices with the goal of protecting public health. Figure 1.1 shows a few centers that interact closely with the pharmaceutical industry.

The Center for Drug Evaluation and Research (CDER) ensures that safe and effective drugs are available to improve the health of people in the United States. This center regulates over the counter (OTC) and prescription drugs, including biological therapeutics, brand drugs, and generic drugs. The Center for Biologics Evaluation and Research (CBER) regulates biological products for human use. The Center for Devices and Radiological Health (CDRH) oversees the medical devices and radiation-emitting products. The Center for Veterinary Medicine (CVM) regulates the manufacture and distribution of drugs, devices, and food additives that will be given to animals, including animals from which human foods are derived, as well as food additives and drugs that are given to companion animals. The Center for Food Safety and Applied Nutrition (CFSAN) provides support for safety and labeling issues relating to food and cosmetics. For additional information, visit the FDA webpage at www.fda.gov/ [1, 2].

Although residing under the same umbrella, these FDA centers may have different policies specific to the products they review, and pharmaceutical laboratories interact with the different centers based on their products. Since FDA issues regulations that are legally enforced, the agency works closely with the industry to develop various guidances and initiatives that support the development of new medicines for US consumers. For the past several years, the FDA has gone through many reforms to be more effective in providing support to the industry (Figure 1.2).

Figure 1.1 FDA offices that interact closely with the pharmaceutical industry.

Figure 1.2 FDA offices overseeing the development of policies and guidelines.

1.2.1 Code of Federation Regulations

The code of federal regulations (CFR) is the set of final regulations that are published in the federal register, which companies must comply with while distributing their products in the United States [1]. The CFR encompasses 50 broad areas subject to federal regulations. Section 21 of the CFR contains regulations pertaining to food and drug products. The federal law governing pharmaceutical labs can be found in 21 CFR Part 210 - Current Good Manufacturing Practices (CGMP) in Manufacturing Process, Packing, or Holding of Drug; General, and 21 CFR Part 211 - CGMP for Finished Pharmaceuticals [2].

Given these regulations are written into law and are legally enforceable, the FDA audits manufacturers and laboratories and conducts inspections of total quality systems. When a manufacturer fails to meet CGMP requirements, its products are considered adulterated and FDA can take legal action without proving that the product is contaminated. Any violations in CGMPs can result in observations, warning letters, consent decree, or criminal prosecution. These regulations also include the requirement that manufacturers wanting to market a prescription product in the United States submit an appropriate application to the FDA.

1.2.2 FDA Guidance Documents

In addition to the CFR, the FDA also issues guidances to introduce current views of the agencies on different subjects. FDA guidance documents provide additional guidelines for the operation of manufacturing facilities, laboratories, etc., and the format and content of the application that is not included in the CFR, helping to maintain consistency among agency reviewers or application owners. The guidance documents are not laws and thus are not enforceable; however, many find that these documents provide more specific details and better clarity than the requirements listed in the regulations. Scientific justifications are necessary if the application does not follow this guidance. The FDA typically issues these guidelines after they collaborate with other regulatory agencies, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and industry [3-5].

1.2.3 FDA Manual of Policies and Procedures

The FDA creates operating manuals listing internal policies and procedures to assist in achieving consistency in application review and operational activities. These documents are publicly available to provide transparency and a better understanding of regulatory policies and agency responsibilities.

When a pharmaceutical manufacturer develops a new drug, it must understand the regulations of quality systems supporting their processes. The manufacturer must conduct its work correctly the first time, as the cost of noncompliance can be enormous. A manufacturer can request meetings with the appropriate center to discuss various scientific and regulatory aspects of their application prior to submission to assure that their development strategy is acceptable. Since 2016, the FDA has required all regulatory submissions to be filed electronically for ease of review and communication [4, 6, 7].

1.3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Its Role

In the late 1980s, to harmonize regional regulatory requirements, many industry expert groups collaborated with regional agencies to discuss technical requirements for drug submissions. This section goes into further detail on the collaboration within the global pharmaceutical industry [6].

1.3.1 ICH Background

The fundamental purpose of a regulatory agency is to protect public health; therefore, it can deny market access to pharmaceutical products if the product's development does not meet the agency's requirements. These requirements usually vary from country to country and often with similar but slight, and sometimes significant, variations in registration requirements. This key factor drives up the cost of development, expands resources, and delays market access to high-quality medicines. Recognizing this problem, in the early 1990s, regulators and industry representatives from the European Union (EU), Japan, and the United States formed a group called the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (www.ich.org) [5, 6, 8]. On 23 October 2015, this...