Prospective Process Validation
Validation is an essential procedure that demonstrates that a manufacturing process operating under defined standard conditions is capable of consistently producing a product that meets the established product specifications.
Process validation is establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
Prospective validation is a requirement (Part 211), and therefore it makes validation an integral part of a carefully planned, logical product/process developmental program.
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.
III. MASTER DOCUMENTATION
An effective prospective validation program must be supported by documentation extending from product initiation to full-scale production. The complete documentation 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 possible.
It will consist of reports, procedures, protocols, specifications, analytical methods, and any other critical documents pertaining to the formulation,process, and analytical method development. The Master Documentation may contain the actual reports, or it may utilize cross-references to formal documentation, both internal and external to the organization.
The ideal documentation 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,
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. The master documentation file should contain all information that was generated during the entire 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 formulation 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. Typical 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 entity)
2. Formulation profile, which consists of physical and chemical characteristics required for the products, drug-excipient compatibility studies,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 factors 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 formulation 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
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 verification test methods must be complete.
Process development can be divided into several stages.
Challenging of critical process parameters
Verification of the developed process
Typical activities in these areas are illustrated in Figure 2.
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 in Figure 3 outlines 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.
Preliminary working documents are critical, but they should never be cast in stone, since new experimental data may drastically alter them. The final version will eventually be an essential part of the process characterization and
technical transfer documents.
Regardless of the stage of formulation/process development being considered,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.
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 transfer of the preliminary documentation to the manufacturing and quality control departments is essential, so that they can begin to prepare for any new equipment
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 4 also shows typical responses that may have to be evaluated 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 uality 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 provides a basis for defining the full-scale process.
Verification is required before a process is scaled up and transferred to production.
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 verification runs should be evaluated using a well-designed in-process sampling procedure.
These should be focused on potentially critical unit operations. Validated 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:
For maximum information, the process should not be altered during the verification 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 description of the studies performed
Development batch record
Raw material test methods and specifications
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:
Critical unit operation
Final product specifications
Special production facility requirements
Procedure for equipment and facilities
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 supporting 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
Process validation runs
A. Scale-Up Studies
The transition from a successful pilot-scale process or research scale to a full scale process requires careful planning and implementation. Although a large amount of information has been gathered during the development of the process (i.e., process characterization and process verification studies), it does not necessarily
follow that the full-scale process can be completely predicted.
Many scale-up parameters are nonlinear. In fact, scale-up factors can be quite complex and difficult to predict, based only on experience with smaller scale equipment. In general, the more complex the process, the more complex
the scale-up effect.
For some processes, the transition from pilot scale or research scale to full scale is relatively easy and orderly. For others the transition is less predictable.
More often than not there will be no serious surprises, but this cannot be guaranteed.
Individuals conducting the transfer into production should be thoroughly qualified on both small- and large-scale equipment.
The planning for scale-up should follow the same general outline followed for process characterization and verification. It usually begins when process development studies in the laboratory have successfully shown that a product can be produced within specification limits for defined ranges of process parameters.
Frequently, because of economic constraints, a carefully selected excipient may be used as a substitute for the expensive active chemical in conducting initial scale-up studies. Eventually, the active chemical will have to be used to complete the scale-up studies, however.
It is common sense that every effort will be made to conduct the final scale-up studies under CGMP conditions, thus any product produced with specifications can be considered for release as a finished salable product (for overthe-
counter products only).
B. Qualification Trials
Once the scale-up studies have been completed, it may be necessary to manufacture one or more batches at full scale to confirm that the entire manufacturing process, comprising several different unit operations, can be carried out
smoothly. This may occur prior to or after the regulatory submission, depending on the strategy used in filing.
C. Process Validation Runs
After the qualification trials have been completed, the protocol for the full-scale process validation runs can be written. Current industry standard for the validation batches is to attempt to manufacture them at target values for both process parameters and specifications. The validation protocol is usually the joint effort of the following groups:
Research and development
Pharmaceutical technology or technical services
Quality control (quality assurance)
One of these groups usually coordinates the activities.
A complete qualification protocol will contain specific sections; however,there can be considerable variation in individual protocol. Section content typical validation protocol may consist of the following:
Gas or liquid discharge limitations
Solid or scrap disposal instructions
Packaging and storage
Process flow chart
Critical parameters and related means of controls
Responsibilities of each of the groups participating
Cleaning validation/verification requirements
Master batch components (percentage by weight)
Production batch component (by weight)
Process batch record
In-process testing and acceptance criteria
Finished product testing and acceptance criteria
Test method references ,
Validation sampling and testing
Definition of validation criteria
Lower and upper acceptance limits
Cleaning sampling plan (locations, type, and number of samples)
It is expected that acceptable, salable products will be produced, since all qualification batches will be produced using a defined process under CGMP conditions with production personnel.
A question that always arises is how many replicate batches or lots must be produced for a validation protocol to be valid or correct. There is no absolute answer. Obviously, a single batch will provide the minimum amount of data.
As the number of replicated batches increases, the information increases. The FDA, however, has determined that the minimum number of validation batches should be three.
D. Master Product Document
An extensive quantity of documents is generated at each stage of the development and validation of the final production process. Some of these documents will be directly related to the manufacture of the final products. Others may provide the basis for decisions that ultimately result in the final process.
The documents that are required for manufacturing the product then become the master product document. This document must be capable of providing all of the information necessary to set up the process to produce a product
consistently and one that meets specifications in any location.
Items that will normally be included in the master product document are Batch manufacturing record
Process flow diagram
Master manufacturing instructions
Master packaging instructions
Sampling (location and frequency)
Process validation data
Each of the above items must contain sufficient detailed information to permit the complete master product document to become an independent, single package that will provide all information necessary to set up and produce a product.
VII. DEFINING EXPERIMENTAL PROGRAMS
The objective in this section is to examine experiments or combinations of related experiments that make up development programs so that adequate justification can be developed for the formulation, process, and specifications. The emphasis will be on techniques to increase developmental program effectiveness.
A logical and systematic approach to each experimental situation is essential.
Any experiment that is performed without first defining a logical approach is certain to waste resources. The right balance between overplanning and underplanning should always be sought.
It is usually impossible to define a substantial experimental effort at the beginning and then execute it in every detail without modification. To overcome this, it is convenient to split the program into a number of stages.
Each stage will normally consist of several specific experiments. The earlier experiments tend to supply initial data concerning the process and define preliminary operating ranges for important variables. As results become available
from each stage, they can be used to assist in defining subsequent stages in the experimental program. In some cases it may be necessary to redefine completely the remainder of the experimental program on the basis of earlier
The following discussion describes some techniques to help improve experimental program effectiveness. A logical and systematic approach coupled with effective communication among individuals associated with the program is
emphasized. Topics to be discussed include Defining program scope
Experimental design and analysis
A. Program Scope
Defining a clear and detailed set of objectives is a necessary first step in any experimental program. Some similarity exists between objectives for different products and processes using similar existing technology. For products and processes at the forefront of technology, the definition of specific experimental objectives can be a continuing activity throughout product development.
Constraints on planning experimental programs can be classified according to their impact on time, resources, and budget. The effect and impact of these should be incorporated into the experimental program early to avoid compromising critical program objectives.
B. Process Summary
An initial clear understanding of the formulation and/or process is important.
The following techniques can assist in summarizing current process knowledge.
1. Flow Diagram
A process flow diagram (Fig. 3) can often provide a focal point of early program planning activities. This diagram outlines the sequence of process steps and specific equipment to be used during development for a typical granulated product.
Flow diagram complexity will depend on the particular product and process.
The flow diagram provides a convenient basis on which to develop a detailed list of variables and responses.
2. Variables and Responses
For process using existing technology, many of the potential variables and responses may have already been identified in previous product-development studies or in the pharmaceutical literature. Once properly identified, the list of variables and responses for the process is not likely to change appreciably. Typical variables and responses that could be expected in a granulated solid dosage form are listed in Table 1.
In addition, the relative importance of variables and responses already identified will likely shift during development activities.
3. Cause-and-Effect Diagram
An efficient representation of complex relationships between many process and formulation variables (causes), and a single response (effect) can be shown by using a cause-and-effect diagram . Figure 4 is a simple example.
A central arrow in Figure 4 points to a particular single effect. Branches off the central arrow lead to boxes representing specific process steps. Next,principle factors of each process step that can cause or influence the effect are drawn as subbranches of each branch, until a complete cause-and-effect diagram is developed. This should be as detailed a summary as possible. An example of a more complex cause-and-effect diagram is illustrated in Figure 5. A separate summary for each critical product characteristic (e.g., weight variation, dissolution,friability) should be made.
4. Influence Matrix
Once the variables and responses have been identified, it is useful to summarize their relationships in an influence matrix format, as shown in Figure 6. Based on the available knowledge, each process variable is evaluated for its potential
effects on each of the process responses or product characteristics. The strength of the relationship between variables and responses can be indicated by some appropriate notation, such as strong (S), moderate (M), weak (W), or none (N),together with special classifications such as unknown (?).
Construction of the influence matrix assists in identifying those variables with the greatest influence on key process or product characteristics. These variables are potentially the most critical for maintaining process control and should be included in the earliest experiments. Some may continue to be investigated during development and scale-up.
VIII. EXPERIMENTAL DESIGN AND ANALYSIS
Many different experimental designs and analysis methods can be used in development activities (Fig. 7). Indeed, the possibilities could fill several books. Fortunately,in any given situation, it is not necessary to search for that single design or analysis method that absolutely must be used; there are usually many possibilities. In general, designs that are usable offer different levels of efficiency,complexity, and effectiveness in achieving experimental objectives.
A. Types of Design
It is not possible to list specific designs that will always be appropriate for general occasions. Any attempt to do so would be sure to be ineffective, and the uniqueness of individual experimental situation carefully, including
Availability of previous theoretical results
Relevant variables and responses
Qualifications and experience of research team members
Cost of experimentation
It should also be determined which design is appropriate. A statistician who is experienced in development applications can assist in suggesting and evaluating candidate designs. In some cases, the statistician should be a full-time member of the research team.
B. Data Analysis
The appropriate analysis of the experimental results will depend on the experimental objectives, the design used, and the characteristics of the data collected during the experiment. In many cases, a simple examination of a tabular or
graphical presentation of the data will be sufficient. In other cases, a formal statistical analysis may be required in order to draw any conclusions at all. It depends on the particular experimental situation. No rules of thumb are available.
In general, the simplest analysis consistent with experimental objectives and conditions is the most appropriate.
C. Experiment Documentation Documentation is essential to program planning and coordination, in addition to
the obvious use for the summary of activities and results. Written communication becomes important for larger complex programs, especially when conducted under severe constraints on time and resources. Documentation can consist of some or all of the following items:
1. Objectives; an exact statement of quantifiable results expected from the experiment
2. Experimental design; a detailed list of the experimental conditions to be studied and the order of investigation
3. Proposed/alternate test methods
a. A list of test methods consistent with the type of experiment being performed
b. A detailed description of the steps necessary to obtain a valid measurement
c. Documentation supporting the accuracy, precision, sensitivity,and so on of the test methods
4. Equipment procedures; documentation of safety precautions and step by-step methods for equipment setup, operation, and cleanup
5. Sampling plans; the type, number, location, and purpose of samples to be taken during the experiment; in addition, the type and number of all measurements to be performed on each sample
6. Protocol; a formal written experimental plan that presents the aforementioned experimental documentation in a manner suitable for review
7. Data records
a. Experiment log; details of events in the experiment noting process adjustments and any unusual occurrences
b. In-process measurements; records of the magnitude of critical process parameters during the experimental sequence Sample measurements; recorded values of particular measurements on each sample
8. Report; documentation of experiment implementation, exceptions/modifications to the protocol, results, and conclusion
D. Program Organization
Throughout the experimental phases of the development program, it is essential to maintain effective communication among various team members. This is facilitated by having one individual with the necessary technical and managerial skills assume responsibility for the experimental program, including procuring
resources and informing management of progress.
In a large experimental program, the responsible individual may serve as a project leader or manager with little or no technical involvement.
Prospective validation of a production process utilizes information generated during the entire development sequence that produced the final process.
Validation is supported by all phases of development from the product concept.
As a potential product moves through the various developmental stages,information is continually generated and incorporated into a master documentation file. When the validation runs are planned for the final process, they will
be based on the master documentation file contents.
Prospective Process Validation
Allen Y. Chao
Watson Labs, Carona, California, U.S.A.
F. St. John Forbes
Wyeth Labs, Pearl River, New York, U.S.A.
Reginald F. Johnson and Paul Von Doehren
Searle & Co., Inc., Skokie, Illinois, U.S.A.