Oral Solid Dosage Forms Pre Approval Issues.

BACKGROUND

Two common complaints regarding validation issues frequently have been raised. The first concerns the misconception that the 1987 validation guide represents a new requirement. The second concerns the lack of specificity in the agency's guides. In 1978, the Current Good Manufacturing Practice Regulations were revised and provided for process validation. Therefore, this guideline does not represent a new requirement. The regulation is nearly 15 years old.

Both the agency and the industry have recognized the need to establish general guidance for the validation of manufacturing processes, and the agency published a draft guideline in March, 1983. However, this draft guideline was a very general document addressing general principles and was applicable to sterile and non-sterile drugs and devices. In March, 1984, it was reissued as a draft guideline, and was finalized in May, 1987.

The 1987 validation guideline merely points out the need to adequately develop and control manufacturing processes. It discusses microbiological issues and provides few specific an practical applications for the validation of manufacturing processes for a marketed solid oral dosage form.

The issue of retrospective validation, and its application to marketed products, is frequently encountered. This concept of using historical data (test results), along with process control and process specificity was of value until more scientific methods for demonstrating process validation evolved. It should be pointed out that retrospective validation is not merely the review of test results. It also requires that the manufacturing process be specific and the same each time a batch is manufactured. Thus, specific raw material specifications (including particle size when necessary), in-process specifications (tablet hardness, etc.), and specific manufacturing directions are required. Obviously, any failing batches attributed to the process would necessitate the conclusion that the process is not validated and is inadequate.

Prospective process validation is required, particularly for those products introduced in the last 7 to 8 years, or those for which manufacturing changes have been made. However, in some cases where older products have been on the market without sufficient pre-market process validation, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used.

PRE-APPROVAL INSPECTIONS

Validation of three full size commercial lots is not required for approval of the application, however the firm must have data that justifies the full-scale commercial process filed in the NDA/ANDA or NADA/ANADA application. In other words, the firm should have sufficient research on the test batches to establish specifications for the manufacturing and control procedures listed in the application. These data and specifications form the basis for the validation protocol which may be developed following approval of the application. The final step in the process is the demonstration (validation) runs proving that the process will perform consistently. Firms should validate the process using the specifications listed in the filing.

Master Formula

This document must include specific manufacturing directions for the full scale commercial process including in-process and finished product specifications.

Compare the process filed in the application to the process used to manufacturer the bio/clinical batch. In some cases the process may be different after scale-up. This is acceptable if the firm has data showing the product produced by this process will be equivalent. Data such as granulation studies, finished product test results, and dissolution profiles are used to document that the two processes are equivalent.

History Section of the Application

This section of the application is used to identify the bio batch or batches used for pivotal clinical studies. It is also useful for review of the correspondence between the firm and CDER/CVM. One of the basic objectives of our review is to identify the bio batch. Also, any batches in which in-vivo studies were carried out, and particularly those which in-vivo studies showed inequivalence should be reviewed.

Development Data (Product Development Report)

The firm cannot logically proceed to the validation step without some prior evaluation of the process. During the development phase the critical process parameters must be identified and specifications established. These predetermined specifications must be established during the development of the process, with the bio batch or pivotal clinical batch serving as the reference batch.

Development of a solid dosage form will vary from firm to firm and will be dependent upon the specific product and process. However, the formula ranges, physical and chemical specifications of the drug substance and excipients, in-process variables, interaction effects of the dosage form ingredients under normal and stress aging conditions, should be confirmed by limited challenge in pilot-scale and production-size batches.

This development data serves as the foundation for the manufacturing procedures, specifications and validation of the commercial process. In some cases, manufacturers have attempted to establish specifications such as hardness and particle size during validation. However, as the validation definition states, specifications must be determined prior to validation of the process.

When a manufacturer files a manufacturing process in an application, we expect that the process will yield a product which is equivalent to the product on which the biostudy or pivotal clinical study was conducted. Therefore, it is important that the development and scale-up of the process be well documented so that a link between the bio/clinical batches and the commercial process can be established. The firm should have data such as granulation studies, finished product test results, and dissolution profiles which may be used to document that the two processes are equivalent.

In most cases in vitro data alone will not be sufficient to document equivalency. Determine if an equivalency evaluation has been made. This bioequivalency evaluation must be made by qualified individuals, and the firm should have a signed statement documenting that the processes are equivalent. Therefore, in many cases you may see an in-vivo bioequivalency study performed. Obviously, the firm cannot provide this type of data if the have not manufactured pilot or test batches using the types of equipment an controls specified in the proposed master formula.

 Inspection of the Facilities

It is important that you physically inspect the facility to assure that the area and the ancillary equipment such as air handling and water systems are suitable for the proposed manufacturing process. Construction of new walls, installation of new equipment, and other significant changes must be evaluated for their impact on the overall compliance with GMP requirements. This includes facilities used for development batches and to be used for full-scale production batches.

Raw Materials

Review the information contained in the Raw Material section under Product Development Report above. Inventory records are a good source for the identification of batches used for product development and biostudies.

Laboratory

The inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with GMP's and to specifically carry out the commitments in an application or DMF.

Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipment, and methods validation data to determine the overall quality of the laboratory operation and the ability to comply with GMP regulations. (Refer to the Laboratory Inspection Guide for additional discussion).

Many of our inspection have identified foreign peaks and impurities not filed or discussed in applications. Also, many of our inspections have shown laboratory test methods not to be validated. The transfer of laboratory methods and technology from the Research and Development Department to the Quality Control Department should be reviewed.

 Equipment

At the time of the pre-approval inspection we expect that the equipment is in place and qualified. New products, particularly potent drug products, can present cleaning problems in existing equipment. Manufacturers must validate their cleaning processes for the new drug/dosage form. (Refer to the Cleaning Validation Inspection Guide for additional discussion).