1.10 DE LA EXPLOTACIÓN DE LAS OBRAS
1.10.2 SERVICIOS BÁSICOS
1.10.2.2 SERVICIOS BÁSICOS COMERCIALES
Wyeth Labs, Pearl River, New York, U.S.A.
Reginald F. Johnson and Paul Von Doehren
Searle & Co., Inc., Skokie, Illinois, U.S.A.
I. INTRODUCTION
Validation is an essential procedure that demonstrates that a manufacturing pro- cess operating under defined standard conditions is capable of consistently pro- ducing a product that meets the established product specifications. In its proposed guidelines, the U.S. Food and Drug Administration (FDA) has offered the following definition for process validation [1].
Process validation is establishing documented evidence that provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics.
Many individuals tend to think of validation as a stand-alone item or an afterthought at the end of the entire product/process development sequence. Some believe that the process can be considered validated if the first two or three batches of product satisfy specifications.
Prospective validation is a requirement (Part 211), and therefore it makes validation an integral part of a carefully planned, logical product/process devel- opmental program. An outline of the development sequence and requirements relevant to process validation is presented inFigure 1. After briefly discussing organizational aspects and documentation, the integration of validation into the product development sequence is discussed. At the end of the chapter there is a
brief discussion of specific ways in which experimental programs can be defined to ensure that critical process development and validation objectives are met.
II. ORGANIZATION
Prospective validation requires a planned program and organization to carry it to successful completion. The organization must have clearly defined areas of responsibility and authority for each of the groups involved in the program so that the objective of validating the process can be met. The structure must be tailored to meet the requirements in the specific organization, and these will vary from company to company. The important point is that a defined structure exists, is accepted, and is in operation. An effective project management struc- ture will have to be established in order to plan, execute, and control the pro- gram. Without clearly defined responsibilities and authority, the outcome of process validation efforts may not be adequate and may not comply with CGMP requirements.
III. MASTER DOCUMENTATION
An effective prospective validation program must be supported by documenta- tion extending from product initiation to full-scale production. The complete documentation package can be referred to as the master documentation file.
It will accumulate as a product concept progresses to the point of being placed in full-scale production, providing as complete a product history as possi- ble. The final package will be the work of many individual groups within the organization. It will consist of reports, procedures, protocols, specifications, ana- lytical methods, and any other critical documents pertaining to the formulation, process, and analytical method development. The package may contain the ac- tual reports, or it may utilize cross-references to formal documentation, both internal and external to the organization.
The ideal documentation package will contain a complete history of the final product that is being manufactured. In retrospect, it would be possible to trace the justification or rationale behind all aspects of the final product, process, and testing.
The complete master documentation file not only provides appropriate rationale for the product, process, and testing, but also becomes the reference source for all questions relating to the manufacture of a product at any plant location. This master documentation file, however, should not be confused with the concept of the master product document, which is essential for routine manu- facturing of the product and is described later in the chapter. The master docu-
mentation file should contain all information that was generated during the en- tire product development sequence to a validation process.
IV. PRODUCT DEVELOPMENT
Product development usually begins when an active chemical entity has been shown to possess the necessary attributes for a commercial product. The product development activities for the active chemical entity, formulation, and process form the foundation upon which the subsequent validation data are built.
Generally, product development activities can be subdivided into formula- tion and process development, along with scale-up development.
A. Formulation Development
Formulation development provides the basic information on the active chemical, the formula, and the impact of raw materials or excipients on the product. Typi- cal supportive data generated during these activities may include the following: 1. Preformulation profile or characterization of the components of the formula, which includes all the basic physical or chemical information about the active pharmaceutical ingredients (API, or the chemical en- tity) and excipients
2. Formulation profile, which consists of physical and chemical charac- teristics required for the products, drug-excipient compatibility stud- ies, and the effect of formulation on in vitro dissolution
3. Effect of formulation variables on the bioavailability of the product 4. Specific test methods
5. Key product attributes and/or specifications 6. Optimum formulation
7. Development of cleaning procedures and test methods
Formulation development should not be considered complete until all those fac- tors that could significantly alter the formulation have been studied. Subsequent minor changes to the formulation, however, may be acceptable, provided they are thoroughly tested and are shown to have no adverse effect on product.
B. Process Development
Even though the process development activities typically begin after the formu- lation has been developed, they may also occur simultaneously. The majority of the process development activities occur either in the pilot plant or in the pro-
posed manufacturing plant. The process development program should meet the following objectives:
1. Develop a suitable process to produce a product that meets all a. Product specifications
b. Economic constraints
c. Current good manufacturing practices (CGMPs)
2. Identify the key process parameters that affect the product attributes 3. Identify in-process specifications and test methods
4. Identify generic and/or specific equipment that may be required It is important to remember that cleaning procedures should at least be in the final stages of development, as equipment and facilities in the pilot or proposed manufacturing plant are involved, and the development of the cleaning verifica- tion test methods must be complete.
Process development can be divided into several stages. Design
Challenging of critical process parameters Verification of the developed process
Typical activities in these areas are illustrated inFigure 2. 1. Design
This is the initial planning stage of process development. The design of the process should start during or at the end of the formulation development to define the process to a large extent. One aspect of the process development to remember is end user (manufacturing site) capabilities. In other words, the practicality and the reality of the manufacturing operation should be kept in perspective. Process must be developed in such a manner that it can easily be transferred to the manufacturing site with minimal issues. During this stage, technical operations in both the manufacturing and quality control departments should be consulted.
Key documents for the technical definition of the process are the flow diagram, the cause-and-effect diagram, and the influence matrix. The details of the cause-and-effect diagram and the influence matrix will be discussed under experimental approach in a later section.
The flow diagram identifies all the unit operations, the equipment used, and the stages at which the various raw materials are added. The flow diagram
inFigure 3outlines the sequence of process steps and specific equipment to be
used during development for a typical granulation solid dosage from product. The flow diagram provides a convenient basis on which to develop a detailed list of variables and responses.
Figure 2 Product development flow.
Preliminary working documents are critical, but they should never be cast in stone, since new experimental data may drastically alter them. The final ver- sion will eventually be an essential part of the process characterization and technical transfer documents.
Regardless of the stage of formulation/process development being consid- ered, a detailed identification of variables and responses is necessary for early program planning. Typical variables and responses that could be expected in a granulated solid dosage form are listed in Table 1. This list is by no means complete and is intended only as an example.
Table 1 Typical Variables and Responses: Granulated Product
Process step Control variables Measured responses
Preblending Blending time Blend uniformity
rpm Load size Order of addition
Granulating Load size Density
Amount of granulating agent Yield Solvent addition rate
rpm
Granulation time
Drying Initial temperature Density
Load size Moisture content
Drying temperature program Yield Air flow program
Drying time Cooling time
Sizing Screen type Granule size distribution
Screen size Loose density
Feed rate Packed density
Blending Load size Blend uniformity
rpm Flow characteristics
Blending time Particle size distribution
Tableting Compression rate Weight variation
Granule feed rate Friability Precompression force Hardness Compression force Thickness
Disintegration time Dissolution
As the developmental program progresses, new discoveries will provide an update of the variables and responses. It is important that current knowledge be adequately summarized for the particular process being considered. It should be pointed out, however, that common sense and experience must be used in evaluating the variables during process design and development. An early trans- fer of the preliminary documentation to the manufacturing and quality control departments is essential, so that they can begin to prepare for any new equip- ment or facilities that may be required.
2. Challenging of Process Parameters
Challenging of process parameters (also called process ranging) will test whether or not all of the identified process parameters are critical to the product and process being developed. These studies determine:
The feasibility of the designed process The criticality of the parameters
This is usually a transition stage between the laboratory and the projected final process.Figure 4also shows typical responses that may have to be evalu- ated during the ranging studies on the tableted product.
3. Challenging of Critical Process Parameters or Characterization of the Process
Process characterization provides a systematic examination of critical variables found during process ranging. The objectives of these studies are
Confirm critical process parameters and determine their effects on product quality attributes.
Establish process conditions for each unit operation.
Determine in-process operating limits to guarantee acceptable finished product and yield.
Confirm the validity of the test methods.
A carefully planned and coordinated experimental program is essential in order to achieve each of these objectives. Techniques to assist in defining experimental programs are mentioned later in the chapter.
The information summarized in the process characterization report pro- vides a basis for defining the full-scale process.
4. Verification
Verification is required before a process is scaled up and transferred to produc- tion. The timing of this verification may be critical from a regulatory point of view, as the there is little or no room for modifying the parameter values and
specifications, particularly shifting or expanding after the regulatory submission is made. This ensures that it behaves as designed under simulated production conditions and determines its reproducibility. Key elements of the process verifi- cation runs should be evaluated using a well-designed in-process sampling pro- cedure. These should be focused on potentially critical unit operations. Vali- dated in-process and final-product analytical procedures should always be used. Sufficient replicate batches should be produced to determine between- and within-batch variations.
Testing during these verification runs will be more frequent and cover more variables than would be typical during routine production. Typically the testing requirements at the verification stage should be the same or more than the proposed testing for process validation runs. The typical process verification analysis of tabulated product includes the following:
Unit operation Analysis
Preblending Potency (if required) Granulation Potency (if required) Sizing Particle size distribution
Loss on drying (LOD) Blending Uniformity
Particle size distribution Tableting Weight
Hardness Thickness
Disintegration and/or dissolution Friability
Potency
Dosage uniformity Degradants
For maximum information, the process should not be altered during the verifica- tion trials.
5. Development Documentation
The developmental documentation to support the validation of the process may contain the following:
Process challenging and characterization reports that contain a full de- scription of the studies performed
Development batch record
Equipment list and qualification and calibration status Process flow diagram
Process variable tolerances
Operating instructions for equipment (where necessary) In-process quality control program, including:
Sampling intervals Test methods Finished Product Stability
Critical unit operation Final product specifications Safety evaluation
Chemical Process
Special production facility requirements Cleaning
Procedure for equipment and facilities Test methods
Stability profile of the product Produced during process development Primary packaging specification
V. DEVELOPMENT OF MANUFACTURING CAPABILITY
There must be a suitable production facility for every manufacturing process that is developed. This facility includes buildings, equipment, staff, and support- ing functions.
As development activities progress and the process becomes more clearly defined, there must be a parallel assessment of the capability to manufacture the product. The scope and timing of the development of manufacturing capability will be dependent on the process and the need to utilize or modify existing facilities or establish new ones.
VI. FULL-SCALE PRODUCT/PROCESS DEVELOPMENT
The development of the final full-scale production process proceeds through the following steps:
Process scale-up studies Qualification trials Process validation runs