Chapter 1
Drug Approval Process and Regulatory Requirements

1.1 Introduction

The role of the Food and Drugs Administration (FDA) in the review and approval of pharmaceutical products is divided into two broad categories. Each of the categories has its own set of regulations and issues, but regardless, they are designed to protect patients against harm and ensure the effectiveness of the medical products. These medical products include drugs from animals, plants, or human origin and products obtained via synthetic pathways, medical devices, and combination products

The two categories are as follows:

1. 1. Analytics in the discovery process (R&D) of pharmaceutical products
2. 2. Analytics in the compliance of products to their standards in the marketplace

Broadly speaking, the first category is a proactive approach while the second category is reactive. The first category ensures the safety and effectiveness of the products via the requirements for new drug applications (NDAs) and biologic license application (BLA) and occurs in the R&D phase of development of products, while the second category ensures that the manufacture of these products follows the NDA/BLA when they reach patients. The quality, safety, and effectiveness of pharmaceutical products are indicated via analysis of products that act as surrogates for these characteristics.

The nature of pharmaceutical products is their uniqueness that creates problems, issues, as well as challenges. A validated analytical procedure that works for one product might not provide for validation of the method for other products. The concept of validation must be applied in a flexible way to allow for changes due to the nature of a product, its chemical pathway, its origin and the nature of the APIs and inert ingredients (excipients) used for its manufacture. These issues will occur in both categories, and attempts to provide guidelines should include a more flexible approach that is not used presently.

The increase in regulatory requirements, often as a reaction to some perceived, potential, or real problems has increased the cost of development and compliance of pharmaceutical products. This is compounded by an adversary relationship among the regulatory agencies and pharmaceutical/biotech industry. In a perfect world, they should work in tandem in a win-win approach on scientific requirements and methodologies since they both have the same purpose, to ensure safety and effectiveness of pharmaceutical products.

However, before reviewing the role of FDA in the analytic areas, it would be of interest to briefly describe the FDA role by which a new drug entity is developed and approved.

In this chapter, we review in more detail the role of analytics required by FDA to approved products, to approve changes in products and to ensure through compliance that manufacture done according to NDAs will yield a quality product that is safe and effective. However, it is also important to discuss in some detail the good laboratory practices (GLPs) in 21CFR 58.

1.2 The Regulatory Process for New Drug Entity

A simplified schematic description of the overall FDA process [1] is shown in Figure 1.1.

Figure 1.1 Schematic high-level representation of the overall FDA review process [1].

1.2.1 Preclinical Studies

The organization will perform animal- or cell-based tests to determine if the drug is preliminarily safe and could become a candidate for human clinical trial. General guidance for these studies is provided by FDA, but must be adapted to the nature of the tested product. This is followed by one or more meetings with FDA, which reviews the data and, if necessary, requests additional data or clarifications. You can obtain guidances through the FDA website or through the Government Printing Office website.

1.2.2 Investigational New Drug Application (INDA)

The next step is to complete an INDA (21 CFR 312). Various "guidance for industry," some based on ICH, are available from the FDA website. Following review by FDA of the INDA and approval, clinical trials are conducted in Phase 1, Phase 2, and Phase 3

1.2.2.1 Phase 1 Clinical

Initial introduction of the investigational drug to 20-30 patients or normal volunteers to determine safety, pharmacologic actions, side effects associated with increased doses, and mechanism of action.

1.2.2.2 Phase 2 Clinical

Controlled clinical study to evaluate effectiveness and risks using hundreds of patients.

1.2.2.3 Phase 3 Clinical

Expanded trials to show effectiveness in several thousand patients.

1.2.3 New Drug Application (NDA)

1.2.3.1 NDA Review by FDA

For NDA with a high urgent priority, the review of the application will take about 6 months on average. For other NDAs, the target is to complete the review in 22 months.

1.2.3.2 NDA Review Process

See in Figure 1.2, a generalized NDA review process that was adapted by Dabbah [1] based on Mathieu [2].

Figure 1.2 Generalized NDA review process from Dabbah [1], which was adapted from Mathieu [2].

1.3 Good Laboratory Practice for Nonclinical Laboratory Studies

The intent of this section is not to reproduce the 21CFR-58 that one can obtain easily through the Internet, on the FDA website. The intent is to extract items that relate directly or indirectly to the analysis of pharmaceutical products, that would be applicable to products in development as well as to products that are on the marketplace. The scope of the regulation is large, but we will confine our discussion to human and animal drugs, medical devices for human use, and biological products. We will not discuss the animal facilities or the electronic products used [3].

The term of analytics applies to analysis of products using methods and procedures that have been validated for each of the products in question, and these tests are conducted according to protocols also called standard operating procedure (SOP) that would allow a consistent analysis of products. The results of analysis should ensure that the quality of the products fulfills the requirements of the NDAs for these products. If a test procedure has been validated, but the application of the test to the products is not done under a strict protocol, the credibility of the results will be in question, and the release of products to the marketplace will be harmful to patients and will also be illegal. The SOPs will include the environment of the laboratory where testing is being done. It goes without saying that an analysis must be performed by trained and skilled personnel under the supervision of the testing facility management or its delegate.

A requirement of GLPs is that there is a Quality Assurance Unit in the organization that will approve developed protocols designed to ensure the credibility of the results of analysis. Deviations in protocols must be approved by the Quality Assurance Unit before they are implemented.

Perhaps, one of the most important factors in assessing the credibility of analysis is the calibration of equipment for the purpose intended [4]. A credible analysis starts with the choice of a test article that should be representative of the tested system or the production batch. For example, in microbiological testing, microorganisms are not homogeneously distributed, thus representative sampling is a must. The use of control articles or reference standards is indicated in protocols to ensure that the tested article has the appropriate quality, strength, identity, purity, and composition to ensure the efficacy of the products.

The reporting of results of analysis must be based on the actual analysis of a product that is documented, archived, and retrievable.

1.4 Validation of Analytical Procedures: Methodology

Every analytical procedure must be validated. Guidance and recommendation are shown in Guidance for Industry: Q2B Validation of Analytical Procedures: Methodology, which was developed by the International Congress on Harmonization (ICH) and adopted by FDA in November 1996 [5]. Since these are guidelines, other approaches to validation may be acceptable.

The main objective of validation of an analytical procedure is to demonstrate that the test is suitable for its intended purpose. In general, one wants to determine the capability of the procedure in terms of specificity, linearity, range, accuracy, precision, detection, and quantitation limits. In Chapter 5, there is an extensive discussion of these characteristics applicable to most analytical procedures but might require some modifications due to the nature of the procedure and its applicability.

In the Guidelines for Industry on Validation of Analytical Procedures [6] (ICH-Q2A, which was also adopted by FDA (March 1995)), there is a general discussion of the seven characteristics shown earlier It also adds a section on the revalidation of the validation of analytical procedures. It should occur when there are changes in the synthesis of the drug substance, changes in the composition of the finished product, and changes in the analytical procedure.

The US Pharmacopeia information on the validation of analytical procedures should be consulted, inasmuch as that they are cited and applicable for products that are approved by FDA. These US Pharmacopeia (USP) chapters are <1223> Validation of Alternative Microbiological Methods [7]; <1225> Validation of Compendial...