Jeffrey S. Rudolph
St. Augustine, Florida, U.S.A.
Robert J. Sepelyak
AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, U.S.A.
I. INTRODUCTION
In this chapter, emphasis will be placed on the validation of solid dosage forms, from the early stages of product development through pilot scale-up and the commercial manufacturing process. The objective is to present an overview and to discuss aspects of validation in terms of pharmaceutical unit operations; that is, those individual technical operations that comprise the various steps involved in product design and evaluation. The focus of the discussion will be on tablets, but consideration will also be given to hard gelatin capsules. The concept of process validation from its beginnings in the early 1970s through the regulatory aspects associated with current good manufacturing practice (CGMP) regula- tions and the application thereof to various analytical, quality assurance, pilot plant, production, and sterile produce considerations will be discussed elsewhere in this book [1,2].
Although the original focus of validation was directed toward prescription drugs, the FDA Modernization Act of 1997 expanded the agency’s authority to inspect establishments manufacturing over-the-counter (OTC) drugs to ensure compliance with CGMP, thus establishing documented evidence that specific pro- cesses or equipment will consistently, and with a high degree of assurance, pro- duce a product that meets predetermined specifications and quality attributes [3].
All pharmaceutical scientists, whether in development, quality assurance, production, or regulatory affairs, are familiar with the axiom that quality is not
tested into a product but rather is built in. This is an important concept, since it serves to support the underlying definition of validation, which is a systematic approach to identifying, measuring, evaluating, documenting, and re-evaluating a series of critical steps in the manufacturing process that require control to ensure a reproducible final product. Dr. Chao [4] has enumerated four key ele- ments that form the basis of a prospective process validation program.
1. Definition of the desirable attributes of the drug product or compo- nents thereof as well as those characteristics that are not desired 2. Establishment of limitations or constraints for these attributes 3. Determination of the controls or testing parameters that will be mea-
sured or tested
4. Initiation of studies to establish control or boundary limits for those key attributes that influence the product, process, quality, and perfor- mance
These criteria represent a logical progression of activities encompassing the de- velopment of a pharmaceutical product.
There are several important reasons for validating a product and/or process. First, manufacturers are required by law to conform to CGMP regulations. In the early 1990s, the concept of preapproval inspection (PAI) was born and had as one of its basic tenets the assurance that approved validation protocols and schedules were being generated and that comprehensive development, scale-up, and biobatch and commercial batch validation data were required in order to achieve a success- ful regulatory PAI audit [5–9]. Second, good business dictates that a manufacturer avoid the possibility of rejected or recalled batches. Third, validation helps to ensure product uniformity, reproducibility, and quality [10–12].
Most discussions of product and process validation that have been pub- lished [13–15] or that have been the subject of presentations at meetings have concentrated on validation associated with the full-scale manufacture of pharma- ceutical processes and how equipment processing variables affect the overall quality of the finished product. Although this is certainly an important aspect of product validation, validation of numerous earlier aspects of development are critical to the subsequent phases of the process.
Without proper characterization, specification, and control of these earlier development steps, the foundation will be weak and will not support the evolv- ing product when it is challenged during the formal validation of pilot and production batches.
II. VALIDATION OF RAW MATERIALS
The validation process of a solid dosage form begins with a validation of the raw materials, both active pharmaceutical ingredients (APIs) and excipients [16–19].
Variation in raw materials is one of the major causes of product variation or deviation from specification. The API may represent the most uncontrollable component in the complete product/process validation scheme, as key physical properties such as morphology and particle size/surface area may not be com- pletely defined this early in the sequence. Often times the synthesis of the new API (drug substance) is not finalized, and changes occur during the development of the compound.
The preformulation program initiated during the early exploratory phase of product development is rarely considered part of validation, but it represents one of the more critical steps in the development cycle. Chemical characteristics such as drug impurities and impurity levels can affect the stability of the prod- uct. Physical properties such as drug morphology, solubility, and particle size/ surface area are important in assessing drug availability. The particle size, shape, and density of the drug can affect material flow and blend uniformity. The hygroscopic nature of the drug can be important in both the handling the mate- rial and the reproducibility of the manufacturing process [20].
For example, a water-insoluble drug is usually milled or micronized in order to achieve rapid dissolution and in vitro availability [14]. Since particle size is inversely related to surface area, large surface areas (0.5–5 m2/g) are created during a particle reduction process. Particle size is directly interrelated to several key processing variables. Several of the most significant are flow, blend uniformity, granulation solution/binder uptake, compressibility, and lubri- cant efficiency [21]. In order to achieve a uniform blend of active ingredient with other formula components, either for subsequent wet granulation or direct compression processing, it is critical that the active ingredient be compatible with the other ingredients in terms of particle size, density, and shape in order to permit a random distribution of ingredients within the blend prior to compres- sion. If the milling or micronizing process is not controlled and properly vali- dated so as to achieve a reproducible particle size distribution, irregularities in blend distribution will result in content uniformity problems of the final dosage form [22].
Another manufacturing characteristic that may be affected negatively by not validating the active ingredient particle size distribution/surface area is the volume of granulating solution or binder needed to produce a properly agglom- erated mass. A greater volume of granulating agent will be needed to wet-mass a powder bed comprising finely divided particles than is needed for coarser particles of the same substance. If the particle size/surface area ratio is not controlled and a specific amount of granulating solution is not stated in the product manufacturing directions, then in some cases the wet mass will be over- wet, resulting in erratic drying properties (case-hardening, insufficient dried product), or in contrast, it will be too dry and will not form proper granules, resulting in poor granulation flow, poor tablet compressibility, and content uni- formity problems with the final dosage form.