Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics

Carmen Medina

• Publisher: CRC Press
• Year: 2003
• Print ISBN: 9780367247416
• eBook ISBN: 9781135520465
• Topic: Medicine
• Subtopic: Pharmacology

This text lists the necessary steps for meeting compliance requirements during the drug development process. It presents comprehensive approaches for validating analytical methods for pharmaceutical applications.

1
Regulatory Submissions

Patricia Fritz and Anisa Dhalla
UCB Pharma, Inc., Smyrna, Georgia, U.S.A.

Regulatory submissions refers to applications providing data or information to the Food and Drug Administration (FDA) related to the development, approval, or postapproval reporting for prescription drugs, biologics, and medical device products. Regulatory submissions are the primary means by which the pharmaceutical and the medical device industry communicate product-specific information to the FDA. Submissions of applications for either premarket investigations or market authorization are generally a series of submissions reflecting product or applicant information from the development stage throughout the marketing life cycle of a product.

The FDA is responsible for the review and market approval of new drugs, biologics, and medical devices in the United States under the authority of the Federal Food Drug and Cosmetic Act (the Act) and Section 351 of the Public Health Service Act (the PHS Act). The FDA defines “premarket review” as the examination of data and information in an application as described in Sections 505, 510 (k), 513 (f), 515, or 520 (g) or 520 (I) of the Act or Section 351 of the PHS Act. This refers to the premarket review of data and information contained in any Investigational New Drug application (IND), Investigational Device Exemption (IDE), New Drug Application (NDA), Abbreviated New Drug Application (ANDA), Biologics License Application (BLA), device premarket notification [510 (k)], or device Premarket Approval Application (PMA).

The review of these applications is performed by three major program centers in the FDA organization: the Center for Drug Evaluation and Research (CDER), with responsibility for drug products, the Center for Biologics Evaluation and Research (CBER), with responsibility for biologic products, and the Center for Devices and Radiological Health (CDRH), with responsibility for medical devices. Each center is organized into scientific review divisions and also includes divisions responsible for quality and compliance aspects.

Applications to gain marketing authorization for new prescription drugs, biologics, or medical devices generally fall within one of the following: NDAs for new prescription drug products, BLAs for new biologic products, and PMAs for certain new medical device products. These marketing applications require the inclusion of the results of human testing to support the safe and effective use of the new product. In order to ship investigational products to the investigators for the required clinical testing, applicants must submit either an IND for a new drug or a biologic product or an IDE for new medical device products.

Abbreviated new drug applications are submitted to gain approval of generic versions of already approved drug products. Premarket notification [510 (k)] applications are the mechanisms for marketing medical devices that are substantially equivalent to already marketed device products. Both of these applications are based on approved similar product information.

There are numerous other regulatory submissions, including product listings and establishment registrations and modifications or changes to already submitted applications, as well as routine periodic reporting. While each of these applications is not discussed in detail, the overall philosophical approach for the preparation of regulatory submissions across these product categories is similar. A tabular summary of the major applications is provided in Appendix A.

The submission of an application conveys an acceptance of certain responsibilities, including the accuracy and the quality of the data as well as the required subsequent reporting and technical commitments for the product and its intended use. To assure the accuracy and quality of the data and information provided in applications, the Act gives the FDA broad authority to inspect pharmaceutical and medical device establishments, including manufacturers and other research testing facilities from which data are derived. Applicants therefore must have documented systems in place for all processes from which data are derived and included in regulatory submissions. These systems should also assure the required reporting, including the reporting of changes after the submission of an application.

1 CRITICAL ELEMENTS OF REGULATORY SUBMISSIONS

Regulatory citations in Title 21 of the Code of Federal Regulations (CFR) and FDA guidance documents provide the content requirements for all required applications. While these references discuss the content and format of regulatory submissions, they are not rich in detail and often do not specifically address an applicant’s specific product concerns. Outlines of the required elements of INDs, NDAs or BLAs, ANDAs, IDEs, PMAs, and 510 (k)s are included in Appendix B. The data and information required in these applications encompass a wide range of disciplines, including medical, pharmacology, toxicology, microbiology, biopharmaceutics, statistics and chemistry, manufacturing, and controls.

There are some common administrative elements for all applications. For example, a cover letter should address the purpose of the submission and make reference to any relevant previous submissions or previous agreements with FDA. To the extent possible, a summary of the information provided in the submission should be included. Cover letters should also include, if applicable, the assigned application or serial number, user fee information, contact persons, a description of the sections being submitted on paper and being submitted electronically, and an antivirus statement for electronic submissions.

Nearly every application has a required FDA transmittal form. Transmittal forms are primarily screening tools and are used to identify the information required and also provide administrative information for the application. Electronically generated forms may be used, provided the FDA approves the form prior to its initial use. A copy of FDA’s approval letter should accompany the form the first time it is submitted. In some instances in which there are no transmittal forms, specific cover sheets or checklists are recommended. These are found within the guidance documents specific to the application type.

A table of contents should accompany all submissions and specify the volume and page number for each item included. This is a critical navigation tool to orient the reviewer to the information provided in the application.

Most applications require that certifications be included with the submission, either in the administrative section of the application or within reports of specific types of data included in the application. These include field copy certifications, debarment certifications, current good manufacturing practice (cGMP) certifications, current good laboratory practice (cGLP) certifications, current good clinical practice (cGCP) certifications, patent certifications, and financial disclosure certifications.

Field-copy certification—a certification, as stated in 21 CFR 314.94, that a true third field copy of the technical sections (chemistry, manufacturing, and controls) of the application has been submitted to the appropriate FDA district office. The district office should also receive a certification with the submission that it is a true copy of the information submitted to the reviewing division.

Debarment certification—a certification that the applicant did not and will not use in any capacity the services of any debarred persons in connection with a drug product application. If the application is an ANDA, it must also include a list of all convictions described under the Act that occurred within the previous 5 years and were committed by the applicant or affiliated persons responsible for the development or submission of the ANDA.

cGMP certification—a statement that facilities and controls used in the manufacture of the product comply with the applicable GMP regulations.

cGLP certification—a statement for each nonclinical laboratory study. A statement that the study was conducted in compliance with the requirements set forth in 21 CFR Part 58, or, if the study was not conducted in compliance, it should include a brief statement justifying the noncompliance.

cGCP certification—a statement with regard to each clinical investigation involving human subjects that it either was conducted in compliance with the requirements in 21 CFR 56 or was not subject to such requirements in accordance with 21 CFR 56.104 and 56.105 and was conducted in compliance with the requirements for informed consent in 21 CFR Part 50.

Patent certification—a certification regarding “any patents that claim the listed drug or that claim any other drugs on which investigations relied on by the applicant for approval of the application were conducted, or that claim a use for the listed or other drug.”

Financial disclosure certification—(1) A financial statement for any clinical investigator conducting any clinical study submitted in a marketing application that the applicant or FDA relies on to establish that the product is effective; (2) additionally, any study in which a single investigator makes a significant contribution to the demonstration of safety. This applies to marketing applications for drugs, biologics, and medical devices. The applicant is required to submit as part of this certification a list of investigators who conducted applicable clinical studies and certify or disclose certain financial arrangements as follows:

TABLE 1 Some of the More Common Certifications Included in Applications and Supplements

Certification that no financial arrangements have been made with an investigator where by the study outcome could affect compensation, that the investigator has no proprietary interest in the product of interest, that the investigator does not have a significant equity interest in the study; and that there were no significant payments.

Disclosure of financial arrangements and steps to minimize the potential bias on the study of interest.

Failure to include the required certifications in submissions can result in an application being refused for filing. In addition, NDAs and BLAs require the submission of a user fee form 3397 indicating that the fee has be...

Table of contents

• COVER PAGE
• TITLE PAGE
• COPYRIGHT PAGE
• DRUGS AND THE PHARMACEUTICAL SCIENCES
• PREFACE
• ACKNOWLEDGMENTS
• INTRODUCTION
• CONTRIBUTORS
• 1: REGULATORY SUBMISSIONS
• 2: COMPLIANCE REQUIREMENTS DURING THE DRUG DEVELOPMENT PROCESS
• 3: VALIDATION: A NEW PERSPECTIVE
• 4: VALIDATING ANALYTICAL METHODS FOR PHARMACEUTICAL APPLICATIONS: A COMPREHENSIVE APPROACH
• 5: THE STABILITY TESTING PROGRAM
• 6: COMPUTER VALIDATION: A COMPLIANCE FOCUS
• 7: COMPLIANCE ISSUES ASSOCIATED WITH CLEANING IN THE PHARMACEUTICAL INDUSTRY
• 8: THE BATCH RECORD: A BLUEPRINT FOR QUALITY AND COMPLIANCE
• 9: CHANGE MANAGEMENT: A FAR-REACHING, COMPREHENSIVE, AND INTEGRATED SYSTEM
• 10: THE VENDOR QUALIFICATION PROGRAM
• 11: HANDLING LABORATORY AND MANUFACTURING DEVIATIONS
• 12: THE INTERNAL AUDIT PROGRAM: A QUALITY ASSESSMENT
• 13: PREAPPROVAL INSPECTIONS: THE CRITICAL COMPLIANCE PATH TO SUCCESS
• 14: THE IMPACT OF TOTAL QUALITY PERFORMANCE ON COMPLIANCE
• 15: INTERNATIONAL COMPLIANCE ISSUES AND TRENDS
• 16: STRATEGIC PLANNING FOR COMPLIANCE AND REGULATORY DEFENSIVENESS
• 17: UNIQUE AND UNPRECEDENTED COMPLIANCE CHALLENGES IN THE BIOLOGICS ARENA