Good Manufacturing Practices for Pharmaceuticals, Seventh Edition

Graham P. Bunn

• Publisher: CRC Press
• Year: 2019
• Print ISBN: 9781498732062
• eBook ISBN: 9781351646994
• Edition: 7
• Topic: Medicine
• Subtopic: Business General

This book provides insight into the world of pharmaceutical quality systems and the key elements that must be in place to change the business and organizational dynamics from task-oriented procedure-based cultures to truly integrated quality business systems that are self-detecting and correcting. Chapter flow has been changed to adopt a quality systems organization approach, and supporting chapters have been updated based on current hot topics including the impact of the worldwide supply chain complexity and current regulatory trends.

Key Features:

• Presents insight into the world of pharmaceutical quality systems
• Analyzes regulatory trends and expectations
• Includes approaches and practices used in the industry to comply with regulatory requirements
• Discusses recent worldwide supply chain issues
• Delivers valuable information to a worldwide audience regarding the current GMP practices in the industry

1	Status and Applicability of U.S. Regulations CGMP Graham P. Bunn

CONTENTS

§ 210.1 Status of Current Good Manufacturing Practice Regulations

§ 210.2 Applicability of Current Good Manufacturing Practice Regulations

§ 210.3 Definitions

What Are CGMPs?

Why Are CGMPs so Important?

How Does FDA Determine if A Company Is Complying with CGMP Regulations?

If a Manufacturer Is Not Following CGMPs, Are Drug Products Safe for Use?

What Can FDA Do to Protect the Public When There Are CGMP Violations?

How Would a New Drug Company Learn about CGMPs and about FDA’s Expectations on Complying with Them?

The Meaning of “Current”

Role and Importance of the United States Pharmocopeia

Specific Drug Categories and Topics

Recent Food and Drug Administration Drug-Related Milestones

Obtaining Food and Drug Administration Regulations

The Federal Register

References

Suggested Readings

The Food and Drug Administration (FDA) is responsible for ensuring the quality of drug products by carefully monitoring drug manufacturers’ compliance with Current Good Manufacturing Practice (CGMP) regulations. The CGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product. The regulations make sure that a product is safe for use, and that it has the ingredients and strength it claims to have. FDA’s portion of the CFR is in Title 21, which interprets the Federal Food, Drug and Cosmetic Act (FD&C Act) and related statutes, including the Public Health Service Act.

The regulations discussed are primarily in Title 21 of the Code of Federal Regulations, which consists of nine volumes. The parts in these volumes are arranged in the following order: Parts 1–99, 100–169, 170–199, 200–299 (containing the bulk of the current good manufacturing practices [CGMPs], 300–499 (containing the bulk of the investigational new drug [IND] application, new drug application [NDA], and abbreviated new drug application [ANDA] materials), 500–599, 600–799, 800–1299, and 1300–end. This last volume addresses matters subject to the Drug Enforcement Administration (DEA), the Department of Justice (DOJ), and the Office of National Drug Control Policy.

The CGMP regulations (21 CFR 210–226) are promulgated by the Commissioner of the FDA under Section 701 (a) of the FD&C Act (21 USC 371 [a]) in furtherance of the requirement of Section 501(a)(2)(B) of the FD&C Act (21 USC 351[a][2][B]), which specifies that a drug is deemed adulterated “if the methods used in, or the facilities or the 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.” The purpose of Section 501(a)(2)(B) is to assure that such drug meets the requirements of the act as to safety and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess. The FDA is, of course, committed to various programs and systems designed to assure the quality of all drug products by careful monitoring of drug manufacturer’s compliance with CGMP regulations. In order to identify their regulatees, Section 510(b) and (c) of the FD&C Act requires the registration of all producers of drugs and devices. Congressional language that accompanied this amendment stated it was “necessary to provide for the registration and inspection of all establishments in which drugs were manufactured, prepared, propagated, compounded, or processed” since these products were likely to enter interstate commerce. Section 510(h) requires that each registrant be inspected for compliance every two years.

FD&C Act Section Number	Title
Sec. 501	Sec. 351—Adulterated drugs and devices
Sec. 502	Sec. 352—Misbranded drugs and devices
Sec. 503	Sec. 353—Exemptions and consideration for certain drugs, devices, and biological products
Sec. 503A	Sec. 353a—Pharmacy compounding
Sec. 503A-1	Sec. 353a-1—Enhanced Communication
Sec. 503B	Sec. 353b—Outsourcing facilities
Sec. 505	Sec. 355—New drugs
	Sec. 355-1—Risk evaluation and mitigation strategies
Sec. 505D	Sec. 355e—Pharmaceutical security
Sec. 506A	Sec. 356a—Manufacturing changes
Sec. 510	Sec. 360—Registration of producers of drugs or devices
Sec. 511	Sec. 360a—Clinical trial guidance for antibiotic drugs
	Sec. 360a-1—Clinical trials

In recent years, the FDA has assumed additional roles for assurance to vendees through programs like the Government-Wide Quality Assurance Programs for drug purchase contracts by the Department of Defense and Veterans Affairs and the MAC program (Maximum Allowable Cost), a program that became seminal to the manufacture of generics. Their policy is outlined in the ORA (Office of Regulatory Affairs) Compliance Document Sec. 400.200 Consistent Application of CGMP Determinations (CPG 7132.12).

Decisions regarding compliance with CGMP regulations are based on inspection of the facilities, sample analysis, and compliance history of the firm. These data are summarized in profiles that represent several years of history of the firms.

The CGMP deficiencies supporting regulatory action by the FDA also support decisions regarding nonapproval of NDA Supplements, as well as the purchasing contracts and candidacy for MAC; hence, some FDA expanded action is likely. Therefore, issuance of a “warning” letter or other regulatory action based on discovery of CGMP deficiencies must be accompanied by disapproval of any pending NDA, ANDA, or Supplement, or any government contract produced under the same deficiencies.

The FD&C Act applies to drugs introduced into interstate commerce in the United States, including drugs exported to or imported from other countries. Manufacturers in other countries who export to the United States are inspected either by the FDA or under reciprocal inspection agreements as part of the NDA approval process and antibiotic drug certification. Individual drug products are subjected to extensive examination, including laboratory testing, before being allowed into the United States.

On 1 November 2017, further aspects of the mutual recognition agreement between the European Union (EU) and the United States (US) was initiated to recognize inspections of manufacturing sites for human medicines conducted in their respective territories. This agreement, which updates the agreement from 1998, allows for recognition of each other’s inspection outcomes and hence for better use of inspection expertise and resources. In June 2017, the European Commission confirmed that the US FDA had the capability, capacity, and procedures in place to carry out good manufacturing practice (GMP) inspections at a level equivalent to the EU. The FDA confirmed the capability of eight EU Member States (Austria, Croatia, France, Italy, Malta, Spain, Sweden, and United Kingdom). The remaining inspectorates will continue to be assessed until 15 July 2019.

The following was published on the FDA website in June 2018²:

The Mutual Recognition Agreement (MRA) between FDA and European Union allows drug inspectors to rely upon information from drug inspections conducted within each other’s borders. Under the Food and Drug Administration Safety and Innovation Act, enacted in 2012, FDA has the authority to enter into agreements to recognize drug inspections conducted by foreign regulatory authorities if the FDA determined those authorities are capable of conducting inspections that met US requirements. FDA and the EU have collaborated since May 2014 to evaluate the way they each inspect drug manufacturers and assess the risk and benefits of mutual recognition of drug inspections.

MRA

• Yields greater efficiencies for US and EU regulatory systems by avoiding duplication of inspections

• Enables reallocation of resources towards inspection of drug manufacturing facilities with potentially higher public health risks across the globe

FDA will continue to perform some inspections in EU countries with capable inspectorates, such as product manufacturing assessment inspections to support marketing approval decisions. However, FDA expects to perform fewer routine surveillance inspections in EU countries with a capable inspectorate.

The FDA has the authority to deny entry to any drug if there is a question regarding its safety, identity, strength, quality, or purity. This authority is exercised unless factory inspection is permitted or inspection information is available concerning nondomestic firms, in lieu of conducting foreign inspections. Although this authority is exercised more rarely and tempered by Chapter 8 of the Act, the FDA also has the authority to deny exit to questionable drugs.

Since the inception of the GMPs, the FDA strived to ensure that the regulated industries comply with a total control of product quality concept through its factory inspection programs and through participation in voluntary CGMP compliance seminars and workshops sponsored jointly with the industries or with educational institutions. As part of the FDA’s Pharmaceutical CGMPs for the 21st Century Initiative, they have introduced quality systems and risk management approaches into existing programs. Regardless of the approaches used, the FDA wants the industry to prevent a drug product from being deemed adulterated under Section 501(a)(2)(B) and violative of Section 301(b) of the Food, Drug, and Cosmetic Act as is indicated by 21 CFR 211, Current Good Manufacturing Practice for Finished Pharmaceuticals.

§ 210.1 STATUS OF CURRENT GOOD MANUFACTURING PRACTICE REGULATIONS

a. The regulations set forth in this part and in parts 211, 225, and 226 of this chapter contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess.

b. The failure to comply with any regulation set forth in this part and in parts 211, 225, and 226 of this chapter in the manufacture, processing, packing, or holding of a drug shall render such drug to be adulterated under section 501(a)(2)(B) of the act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action.

c. Owners and operators of establishments engaged in the recovery, donor screening, testing (including donor testing), processing, storage, labeling, packaging, or distribution of human cells, tissues, and cellular and tissue-based products (HCT/Ps), as defined in §1271.3(d) of this chapter, that are drugs (subject to review under an application submitted under section 505 of the act or under a biological product license application under section 351 of the Public Health Service Act), are subject to the donor-eligibility and applicable current good tissue practice procedures set forth in part 1271 subparts C and D of this chapter, in addition to the regulations in this part and in parts 211, 225, and 226 of this chapter. Failure to comply with any applicable regulation set forth in this part, in parts 211, 225, and 226 of this chapter, in part 1271 subpart C of this chapter, or in part 1271 subpart D of this chapter with respect to the manufacture, processing, packing, or holding of a drug, renders an HCT/P adulterated under section 501(a)(2)(B) of the act. Such HCT/P, as well as the person who is responsible for the failure to comply, is subject to regulatory action.

[43 FR 45076, Sept. 29, 1978, as amended at 69 FR 29828, May 25, 2004; 74 FR 65431, Dec. 10, 2009]

§ 210.2 APPLICABILITY OF CURRENT GOOD MANUFACTURING PRACTICE REGULATIONS

a. The regulations in this part and in parts 211, 225, and 226 of this chapter as they may pertain to a drug; in parts 600 through 680 of this chapter as they may pertain to a biological product for human use; and in part 1271 of this chapter as they are applicable to a human cell, tissue, or cellular or tissue-based product (HCT/P) that is a drug (subject to review under an application submitted under section 505 of the act or under a biological pro...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface
• Editor
• Contributors
• Chapter 1 Status and Applicability of U.S. Regulations: CGMP
• Chapter 2 Quality Management Systems and Risk Management
• Chapter 3 Management Responsibility and Control
• Chapter 4 Organization and Personnel
• Chapter 5 Finished Pharmaceuticals: General Provisions
• Chapter 6 Production and Process Controls
• Chapter 7 Records and Reports
• Chapter 8 Clinical Trial Supplies
• Chapter 9 Contracting and Outsourcing
• Chapter 10 Buildings and Facilities
• Chapter 11 Equipment
• Chapter 12 Control of Components and Drug Product Containers and Closures
• Chapter 13 Holding and Distribution
• Chapter 14 Returned and Salvaged Drug Products
• Chapter 15 Active Pharmaceutical Ingredients
• Chapter 16 Pharmaceutical Excipient Good Manufacturing Practices
• Chapter 17 Packaging and Labeling Control
• Chapter 18 Laboratory Controls
• Chapter 19 Microbiological Aspects of Pharmaceutical Aseptic Processing in the Compounding Pharmacy
• Chapter 20 CGMP Enforcement Alternatives in the United States
• Chapter 21 FDA Inspection Process
• Chapter 22 FDA Pre-approval Inspections
• Chapter 23 Worldwide Good Manufacturing Practices
• Chapter 24 Data Integrity and Fundamental Responsibilities
• Index