Tuesday, 23 April 2013

Validation Guidelines for Pharmaceutical Dosage Forms

1.0 Scope

This guidance document has been prepared to give the pharmaceutical industry guidelines for validation of sterile and non-sterile dosage forms, biologics and radiopharmaceuticals. It should be noted that the additional guidelines for sterile products and not included in this document must also be taken into consideration. These requirements can be found in the validation process presented on the website of the Compliance and Enforcement .

Importers and distributors of pharmaceutical products should prove supporting documents, that their suppliers meet the requirements validation.

2.0 Introduction

This document provides guidance on the issues and problems related to systems, qualification of equipment, validation of products and processes for sterile and non-sterile dosage forms. These issues are a manufacturing of pharmaceuticals, biologics and radiopharmaceuticals that the Inspectorate and the pharmaceutical industry both consider as important. These guidelines were written for inspectors, appraisers and industry, which must deal with issues related to validation. With this information, it should be easier to comply with Title 2 of Part C of the regulation on food and drugs.

The recommendations in these guidelines do not intend to become requirements in all circumstances. The information provided in the Interpretation section, regarding limitations that apply in particular circumstances, as well as the number of lots to be used for validation studies is indicative only. Inspectors, appraisers and industry may consider other measures if they are supported by sound science.
3.0 Purpose

These guidelines describe the general principles that the Inspectorate considers validation elements acceptable for use by manufacturers, packagers and labellers of pharmaceuticals. Guidelines on Good Manufacturing Practices (GMP), Division 2, Part C of the regulation on food and drug state:

    all critical manufacturing processes must be validated;
    validation studies should be carried out according to established protocols. Written reports with summary results and conclusions must be prepared, reviewed, approved and maintained;
    changes in manufacturing processes, operating parameters of the equipment or materials that may affect product quality or reproducibility of the process must be validated prior to implementation.

These guidelines were not meant to define how validation must be done for and are rather an indication of what should be covered by the manufacturers and packagers / labellers.

The validation elements presented in these guidelines are not intended to be exhaustive. The specific requirements validation may vary depending on factors such as the nature of the drug (eg, sterile or non-sterile product, biological product or radiopharmaceutical) and the complexity of the process. The concepts presented in these guidelines have general applicability and provide an acceptable framework to implement a comprehensive approach to validation.

4.0 Definitions

Process capability: Studies conducted to determine the critical process parameters to obtain stable quality as well as their limits of acceptable specifications, based on established sigma deviations of + / - 3 of the process, in extreme conditions, but without being able to assign it causes.

Condition worst case: The highest and lowest value of a parameter that is evaluated in the validation exercise.

Change Control: Written procedure describing the action to be taken in case the proposed change (a) installations, materials, equipment and / or processes used in the manufacture, packaging and drug testing or (b) any changes that may affect the quality or operation of auxiliary systems.

Document-type production documents including specifications for raw materials, packaging materials and packaged dosage form, the standard formula, sampling procedures and standard operating procedures (SOPs) addressing critical processes that reference be made ​​or not to the PONs in the master formula.

Validation team: a multidisciplinary team composed of employees primarily responsible for conducting or overseeing validation studies. These studies can be conducted by a qualified person because of their training or experience in a relevant discipline.

Main equipment: A piece of equipment that performs critical processing steps in the sequence of operations required to manufacture or packaging of pharmaceuticals. Some examples include tablet presses, mills, mixers, fluid bed dryers, heaters, drying ovens, coaters tablet, capsule fitting, fermenters, centrifuges, etc..

Measuring instruments: Equipment used to monitor or measure the parameters of a process.

Critical process parameter: Parameter that contribute to the variability of the final product if it is not controlled.

Master Validation Plan: Written Plan approved specifying the objectives and actions, and establishing when and how a company will comply with the requirements of GMP, with respect to the validation.

Validation protocol: writing specifying how the validation process will be completed Action Plan, the plan establishes that perform the various tasks and defines the test parameters, sampling plans, specifications and analysis methods, product characteristics and equipment to use. It must also specify the minimum number of units to be used in the validation studies must finally define acceptance criteria and specify who will sign / approve / disapprove the findings of such a scientific study.

Equipment Qualification: Studies to determine with confidence that the equipment and auxiliary processing systems can operate consistently within the limits and tolerances. These studies should focus on the technical characteristics of the equipment, as well as validation of the installation and operation of all major pieces of equipment used in the manufacture of commercial scale batches. The equipment qualification should simulate actual production conditions, including those of the "worst case" and functioning under stress.

Qualification Process: The validation phase on sampling and analysis at various stages of the manufacturing process to ensure compliance with product specifications.

Installation Qualification (IQ): Demonstration, supporting documentation, that the equipment used for the treatment and were well chosen and installed auxiliary systems.

Operational Qualification (OQ): Demonstration, supporting documentation, that the equipment used for processing and auxiliary systems are working well and according to specifications.

Revalidation process: Required when changing one or more of the critical process parameters, formulation, primary packaging components, manufacturers of raw materials, major equipment or premises. Non-compliance with the specifications of process and product in sequential batches also would require revalidation process.

Validation: An operation to demonstrate supporting documents, a procedure, process or activity will lead to the expected results. It includes the qualification of systems and equipment.

Concurrent Validation: Process where current production batches are used to control the process parameters. This process provides a guarantee for the lot to study, but can only provide a limited guarantee of consistent quality from one batch to another.

Validation of cleaning processes: Demonstration documented the methods of cleaning of equipment used in the manufacture and packaging reduce to an acceptable level all residues (products and cleaning agents) and cleaning and storage normal equipment does not result in microbial growth.

Process Validation: Develop, with a high level of assurance, documented proof that a particular process will consistently produce a product meeting its specifications and quality characteristics predetermined. The validation process can take the form of a prospective, concurrent or retrospective validation or certification or revalidation process.

Prospective Validation: Validation conducted prior to the distribution or a new product or a product manufactured using a modified production process, where changes are important and can affect the characteristics of the product. This is a scientific approach, planned in advance, which includes the initial stages of developing the formulation, method and process specifications, development of analytical methods during manufacture and plans sampling, the creation of batch files, defining the specifications of the raw materials, the startup batch of pre-production, transfer of technology lots of scaling to lots in commercial scale and list applicable to major equipment and environmental controls.

Retrospective Validation: Validation was performed for a product already on the market and based on a wealth of data collected over several batches over time. Retrospective validation can be used for older products that the manufacturer has not validated when they were put on the market, but which must now be validated to conform to the requirements of Division 2, Part C of Regulation Food and Drugs.

5.0 Phases of the validation

Activities related to validation studies can be grouped into three phases:

Phase 1 Phase-validation or qualification which covers all activities related to research and product development, formulation, pilot studies in developing lots, studies of scaling, the transfer of technology for commercial scale batches, establishing stability conditions, storage and handling of finished dosage forms and during manufacture, equipment qualification, qualification of installation, production documents, operational qualification and process capability.

Phase 2 Phase Process Validation (qualifying process) aims to ensure that all limits of critical process parameters are valid and that it is possible to produce satisfactory products, even in the most adverse conditions.

Phase 3 Phase keeping validation requires frequent review of all documents related to the process, including reports of hearing on the validation check to ensure that there is no change, apart , failure or modification of the production process and that all SOPs have been met, including change control procedures.

At this stage, the validation team also ensures that there has been no change or difference, which would have resulted in requalification and revalidation.
6.0 Interpretation
General concepts

Quality, safety and efficacy should be an integral part of the product. To this end, we must pay particular attention to a number of factors, such as the selection of materials and components of good quality, product design and process, process control, the control process and Analysis of the finished product.

Due to the complexity of pharmaceuticals, current tests on the finished product are not sufficient for several reasons. In addition, the quality can not be analyzed from the finished pharmaceutical product, because it is rather an integral part of manufacturing processes, and these processes must be controlled so that the finished product meets all quality specifications. The design and rigorous validation of systems and process controls used to establish a high degree of all batches produced will comply with the specifications trust.

Validation Protocol

Writing stating how validation will be conducted and specifying particular test parameters level, product characteristics, production equipment and packaging and decision points constitute acceptable test results. This document must contain details of the critical steps of the manufacturing process to be measured, the acceptable limits of variability and how the system should be tested.

The validation protocol is a summary of what you want to achieve. The protocol should list the process parameters and control parameters selected, indicate the number of items to be included in the study and how the data, once gathered, will be processed in order to verify their relevance. The date of approval by the validation team should also be recorded.

In the case where a protocol is altered or modified after approval must document the rationale for the change.

The validation protocol must be numbered, signed and dated, and must contain at least the following information:

    the objectives, scope and content of the validation study
    members of the validation team, qualifications and responsibilities
    the type of validation: prospective, concurrent, retrospective re-validation
    the number and selection of consignments to be in the validation study
    a list of all equipment to be used, their operating parameters in normal operating conditions and worst case
    the results of the IQ, OQ for critical equipment
    the requirements for calibration of measuring apparatus
    the critical process parameters and their tolerances
    description of manufacturing steps: a copy of the master of production of
    points, levels, methods and sampling plans
    statistical tools to be used in data analysis
    training requirements for personnel involved in the manufacture
    the validated analytical methods to be used in the analysis of the products being manufactured and finished products
    specifications for raw materials, packaging materials and methods of analysis
    forms, tables and graphs to be used for recording results
    format for the presentation of results, documentation of findings and approving the results of the study.

Validation Master Plan

A validation master plan is a document that summarizes the overall philosophy and intentions of the company, and approaches it will use to determine the adequacy of the performance. The validation master plan must be approved by the management of the company.

Validation typically requires meticulous preparation and careful planning of the various process steps. All work must also be done in a structured way, in accordance with standard operating procedures that are officially authorized. All submissions must be documented and, to the extent possible, be recorded as actual numerical results.

The validation master plan should provide an overview of the whole validation exercise of its organizational structure, its content and planning. Key elements of this plan are the list or inventory of items to be validated and the planning calendar. All validation activities related to critical technical operations, with respect to control of product and process within a company should be included in the master plan validation. This plan should include all prospective validation, concurrent and retrospective as well as revalidation.

The master validation plan should be a summary document and should therefore be brief, concise, and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOPs, validation protocols and validation reports.

The format and content should include:

    an introduction: policy validation, scope, location and schedule
    Organizational structure: staff responsibilities
    the description of the plant / process / product: the reason for inclusion or exclusion and the extent of validation
    special consideration for processes that are critical and those that require further attention
    a list of products / processes / systems to validate, summarized in the matrix format, the validation approach
    rehabilitation activities, the current status and plans for the future
    the main criterion of acceptability
    format for documentation
    reference to SOPs required
    schedule for each project and sub-project validation.

Installation qualification and operational qualification

The level of detail and scope of the exercise of qualification are in many ways related to the complexity of the equipment involved and the critical nature of the equipment in terms of the quality of the finished product.

Exercises installation qualification and operational qualification is to ensure, through appropriate performance tests and related materials, the equipment, systems and accessories subsystems have been commissioned properly. The final results are to the effect that all future operations will be reliable and will respect the limits prescribed performance.

The basic principles are:

    Equipment are installed in accordance with an installation plan
    The requirements of calibration, maintenance and cleaning are covered in SOPs approved
    The tests are made to ensure that the equipment is working properly in normal conditions of use or worst case
    Requirements for operator training new equipment are met and documented.

The various stages of the validation exercise must have protocols, documentation, procedures, equipment, specifications and acceptance criteria for the test results. All these aspects must be examined, verified and authorized. There should be representatives of relevant professional disciplines (eg., Engineering, research and development, manufacturing, quality control and quality assurance) are actively involved in these activities, and the final approval is given by a validation team or the representative of quality assurance.
Installation Qualification (IQ)

The IQ is a method to determine with confidence that all major processing equipment, packaging and all accessories are manufactured in accordance with the specifications of the installation, equipment manuals, layout and technical drawings. This validation step includes a review of the requirements for the design, the determination of the calibration, maintenance and adjustment of the equipment.

In the case of complex equipment or large pieces of equipment, a pharmaceutical manufacturer may decide before delivery to verification of equipment made to assembly supplier facilities. This check before delivery does not replace the installation qualification. It is recognized, however, that the audits performed and documented at this stage can overlap with a number of audits conducted at the stage of IQ, which helps to reduce the scope of audits at the IQ

All equipment, all gauges and all services should be clearly identified and have a serial number or other reference number. This number should be included in the records relating to validation studies on equipment.

The installation qualification requires a formal and systematic check of all equipment installed under the specifications of the equipment supplier and additional criteria identified by the user as part of the purchase specifications. These checks, tests and challenges should be repeated several times to ensure the reliability and significance of the results.

At the stage of the IQ, the company should document preventive maintenance applicable to existing equipment requirements. The preventive maintenance schedule should be integrated into the current preventive maintenance.

It may be that the installation of the equipment has not been subject to an initial qualification and technical drawings and equipment manuals are no longer available in the manufacturer's plant. However, the existing equipment works for a long time without problems or without modifications have been made to the design since the initial installation. In these circumstances, the Inspectorate considers that it might be advisable to check a few of the most critical parameters showing that the equipment has been properly installed. The company can then go directly to step operational qualification (OQ) there is documented evidence sufficient to conclude that these elements have always been well maintained and calibrated in accordance with a predetermined schedule.

Operational Qualification (OQ)

Exercise operational qualification must be made according to an approved protocol. Critical parameters for the functioning of the equipment and systems should be developed to the stage of operational qualification. Plans for operational qualification should specify the studies to be undertaken on critical variables, the sequence of these studies and measuring instruments to use and acceptance criteria to meet.

Studies on critical variables should include a condition or set of conditions encompassing upper and lower processing and operating limitations, which is designated by the term "extreme cases." After a year of successful operation qualification, it should be possible to develop the final version of the documentation for the operating mode of the equipment and instructions to operators. This documentation should be used for operator training.

After a year of installation qualification and operational qualification duly made, it should be issued a license in good and due form, so that the equipment is subject to the next step of the validation exercise process, provided that the requirements for calibration, cleaning, preventative maintenance and operator training are met and the results of this exercise are documented.

Changes to equipment or moving should be done after a satisfactory review and prior approval of the change request in accordance with a procedure change control. This formal review should include considerations for the re-qualification of equipment. Minor changes or those who have no direct impact on the quality of the final product or the product being manufactured should be made through a system of documentation of a preventative maintenance program.
Process validation

In principle, the validation stage of the process must be completed before delivery of a finished product for sale (prospective validation), otherwise, it may be necessary to validate processes during the normal production (concurrent validation). The methods used for some time and have not undergone any significant change could also be validated by an approved protocol (retrospective validation).

What analytical characteristics apply in a particular case?

All the features mentioned in Section 3 does not have to be taken into account in all cases, it is necessary to determine in each case the important ones. However, the following principles are generally applicable.
The methods used to examine pharmaceutical products can be classified into four broad categories:
• Class A: Tests for establishing the identity of pharmaceutical substances in bulk or a component of a finished pharmaceutical preparation.
• Class B: Methods for detecting and assaying of impurities in a bulk material or a complete preparation.
• Class C: Methods used to quantitatively determine the concentration of a substance in bulk or a major component of a finished pharmaceutical preparation.
• Class D: Methods used to determine the characteristics of finished pharmaceutical preparations, such as the dissolution profile and the uniformity of the active ingredient content.
Table 1 provides a guide to determine the relevant features in each case. Despite these generalizations, there are clearly cases where certain features that are not mentioned may be necessary, and vice versa. In addition, the goal may influence the choice of features and the importance that should be accorded. For example, Table 1 lists the characteristics required precision among the methods of class B, C and D, but this can be done more or less appropriate. Ainsi, il n'est peut-être pas nécessaire que l'estimation d'une impureté soit aussi précise que le dosage quantitatif d'une substance en vrac. De même, la précision d'une méthode de contrôle de l'uniformité de la teneur (classe D) pourrait être acceptable malgré une certaine erreur systématique, alors qu'une telle erreur serait inadmissible dans le dosage quantitatif d'une préparation pharmaceutique (classe C). Autre exemple: les caractéristiques exigées d'une méthode destinée à établir l'identité d'une nouvelle molécule active pour laquelle aucune donnée n'a encore été présentée devront probablement être beaucoup plus strictes que pour une méthode servant à vérifier l'identité d'une substance connue depuis longtemps en vue de son inclusion dans une pharmacopée.
L'importance des différentes caractéristiques n'est pas nécessairement la même selon qu'une méthode est destinée à figurer dans une pharmacopée ou à appuyer une demande d'homologation. Par exemple, la robustesse est une caractéristique essentielle des méthodes de la pharmacopée, mais elle peut être moins importante dans les spécifications établies par un fabricant pour le contrôle d'un de ses produits.
Tableau 1 Caractéristiques à prendre en compte pour les différents types de méthodes analytiques

Classe A
Classe B
Classe C
Classe D

Méthodes quantitatives
Méthodes qualitatives


X a

Linéarité et domaine d'utilisation

Limite de détection


Limite de dosage

Characteristics of analytical methods

Below we list and the definition (in this context) features that can be specified for an analytical method with guidance on how to determine.
All these characteristics are not applicable to all test methods or all analytes. It depends largely on the purpose of the analysis. This aspect of validation is discussed in section 4.
The accuracy of a method is the degree of concordance between the results and the true value of the measured quantity, the accuracy can be determined by applying the method to analyze samples of the product prepared by an accurate quantitative method. Whenever possible, these samples must contain all components of the product, including the analyte. It is also necessary to prepare samples which have been incorporated in amounts of analyte upper and lower by about 10% in the range of expected results. Accuracy can also be determined by comparing the results of the method with those obtained using another method already validated.
The accuracy of a method is the degree of agreement between the results obtained in different tests. It is measured by the dispersion of individual results of each side of the middle and is generally represented by the standard deviation or the coefficient of variation (relative standard deviation) calculated after applying the full method so repeated a number of identical samples from the same homogeneous batch of material to be analyzed.
This variation results in a single laboratory characterizes the precision obtained when the method is repeated by the same analyst, under the same conditions (reagents, equipment, timing, laboratory) in a short time interval. The repeatability of a method is evaluated by performing complete and separate determinations on the same samples from the same homogeneous batch of material. This allows to assess the accuracy of the method under normal operating conditions.
It is the accuracy of the method when applied in different circumstances - usually in different laboratories - in separate samples, nominally identical, taken from the same homogeneous batch of material to be analyzed. The comparison of results obtained by different analysts, with different hardware, or on different dates, can also provide valuable information in this regard.
Robustness is the quality of a method capable of giving results of acceptable accuracy and precision in a variety of conditions. It assesses the extent to which the results of separate samples, nominally identical, taken from the same homogeneous batch of material to be analyzed, are influenced by changes in operational or environmental conditions within the specifications for method.
Linearity and field of use
Linearity of an analytical method is its ability to produce results directly proportional to the concentration of analyte in the samples. The area of ​​application is the interval between the lowest concentration and the highest that has been shown that they can be determined with precision, accuracy and linearity acceptable concentration. These characteristics are determined by applying the method to a series of samples with analyte concentrations cover the entire area of ​​proposed use. When the relationship between the concentration and the response is not linear, the method can be calibrated using a calibration curve.
The selectivity or specificity of a method is its ability to measure the concentration of the analyte without interference from the other constituents of the sample (for example, impurities resulting from the production or degradation of the product, or other components the analyte, that these substances are pharmacologically active or inert). The selectivity (or lack of selectivity) can be expressed by the systematic error found in the results obtained with the analyte in the presence of other components of the expected concentrations, compared with the results obtained in the absence of these substances . When all other components are known and available, selectivity can be determined by comparing the results obtained with the analyte alone and with the analyte added substances suspected of causing interference. When these substances have not been identified or are not available, it can often assess the selectivity by adding known pure analyte sample quantities in which the concentration of other components is kept constant and determining the amount of analyte found.
Sensitivity is the ability of the method to detect small variations in concentration. It is represented by the slope of the calibration curve. We must avoid giving the term a broader sense encompassing the limit of detection and / or quantitation limit.
Detection limit
The detection limit is the lowest concentration of analyte that can be detected, but not necessarily measured, using a specific method, under the experimental conditions imposed. This limit is usually expressed as a concentration (eg in micrograms per liter). When the final measurement is based on the reading of an instrument, it should take into account the background noise (characteristics of signal / noise ratio of the observed responses).
The LOQ is the lowest concentration of analyte that can be determined in a sample with acceptable accuracy and precision when applying the method indicated. To set this limit, we analyze samples containing decreasing amounts and determining the lowest level for which the accuracy and precision are acceptable. When the final evaluation is based on playing an instrument, it may be necessary to determine the background noise (signal / noise ratio) and taken into account. In many cases, the limit of determination is approximately twice the detection limit.

What analytical validation?

The analytical control of a drug or some of its components is essential to ensure that the drug in question will remain safe and effective throughout its proposed shelf life, that is to say, during the phases of storage, distribution and Usage. This check should be carried out as much as possible to specifications developed and validated during the development of the product. Thus, we will have the assurance that quality specifications are applicable not only to the pharmaceutical preparation was used to determine the biological characteristics of the active ingredients, but also the dosage forms placed on the market. From the moment the biomedical product evaluation is completed, the specifications are the only acceptable basis for all subsequent batches.
Validation of analytical methods has as main objective to ensure that an analytical method given will sufficiently reliable and reproducible results, given the purpose of the analysis. It should therefore correctly identify both the conditions under which the method will be used and the purpose for which it will be used. These principles apply to all methods used by a manufacturer of pharmaceutical products, whether or not described in a pharmacopoeia.
These guidelines apply to the methods used to examine the chemical and physico-chemical characteristics of a product, but most of them are also applicable to microbiological and biological methods.


Many different experimental designs and analysis methods can be used in devel-
opment activities

 Indeed, the possibilities could fill several books. For-
tunately, 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 effi-
ciency, 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
Specific objectives
Available resources
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 experi-
mental 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 avail-
able. 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 communica-
tion becomes important for larger complex programs, especially when con-
ducted under severe constraints on time and resources. Documentation can con-
sist 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 be-
ing performed
b. A detailed description of the steps necessary to obtain a valid
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 afore-
mentioned experimental documentation in a manner suitable for re-
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 measure-
ments 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 fa-
cilitated 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.

Master Product Document

An extensive quantity of documents is generated at each stage of the develop-
ment 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 be-
come the master product document. This document must be capable of provid-
ing 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
Master formulation
Process flow diagram
Master manufacturing instructions
Master packaging instructions
Sampling (location and frequency)
Test methods
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 pack-
age that will provide all information necessary to set up and produce a product.

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 valida-
tion batches is to attempt to manufacture them at target values for both process
parameters and specifications. The validation protocol is usually the joint
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; how
there can be considerable variation in individual protocol. Section content
cal validation protocol may consist of the following:
Safety instructions
Environmental restrictions
Gas or liquid discharge limitations
Solid or scrap disposal instructions
Raw materials
Pertinent characteristics
Acceptance limits
Analytical methods
Packaging and storage
Handling precautions
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
Process sequence
Process instructions
Material usage
Product testing
In-process testing and acceptance criteria
Finished product testing and acceptance criteria
Test method references
Validation sampling and testing
Finished product
Definition of validation criteria
Lower and upper acceptance limits
Acceptable variation
Cleaning sampling plan (locations, type, and number of samples)
It is expected that acceptable, salable products will be produced, since all quali-
fication batches will be produced using a defined process under CGMP condi-
tions 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.

Thursday, 18 April 2013

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 neces-
sarily 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 guaran-
teed. 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 param-
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 speci-
fications can be considered for release as a finished salable product (for over-
the-counter products only).

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
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:
Sampling intervals
Test methods
Finished Product
Critical unit operation
Final product specifications
Safety evaluation
Special production facility requirements
Procedure for equipment and facilities
Test methods
Stability profile of the product
Produced during process development
Primary packaging specification

Thursday, 4 April 2013

Process Development 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 sucha 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 ina 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 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.
 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.

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. Developa suitable process to producea 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.
Challenging of critical process parameters
Verification of the developed process
Typical activities in these areas are illustrated in Figure 2

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.


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.

Prospective Process Validation-INTRODUCTION

Validation is an essential procedure that demonstrates thata manufacturing pro-
cess operating under defined standard conditions is capable of consistently pro-
ducinga 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 .
Process validation is establishing documented evidence that provides a
high degree of assurance thata 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 isa requirement (Part 211), and therefore it makes
validation an integral part ofa carefully planned, logical product/process devel-
opmental program. An outline of the development sequence and requirements
relevant to process validation is presented in Figure 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.


Although the emphasis on validation began in the late 1970s, the requirement
has been around since at least the 1963 CGMP regulations for finished pharma-
ceuticals. The Kefauver-Harris Amendments to the FD&C Act were approved in 1962 with Section 501(a)(2)(B) as an amendment. Prior to then, CGMP and
process validation were not required by law. The FDA had the burden of prov-
ing that a drug was adulterated by collecting and analyzing samples. This was
a significant regulatory burden and restricted the value of factory inspections of
pharmaceutical manufacturers. It took injuries and deaths, mostly involving
cross-contamination problems, to convince Congress and the FDA that a revi-
sion of the law was needed. The result was the Kefauver–Harris drug amend-
ments, which provided the additional powerful regulatory tool that FDA re-
quired to deem a drug product adulterated if the manufacturing process was not
acceptable. The first CGMP regulations, based largely on the Pharmaceutical
Manufacturers Association’s manufacturing control guidelines, were then pub-
lished and became effective in 1963. This change allowed FDA to expect a
preventative approach rather than a reactive approach to quality control. Section
505(d)(3) is also important in the implementation of process validation require-
ments because it gives the agency the authority to withhold approval of a new
drug application if the “methods used in, and the facilities and controls used
for, the manufacture, processing, and packing of such drug are inadequate to
preserve its identity, strength, quality, and purity.”
Another requirement of the same amendments was the requirement that
FDA must inspect every drug manufacturing establishment at least once every
2 years [6]. At first, FDA did this with great diligence, but after the worst
CGMP manufacturing situations had been dealt with and violations of the law
became less obvious, FDA eased up its pharmaceutical plant inspection activi-
ties and turned its resources to more important problems.
The Drug Product Quality Assurance Program of the 1960s and 1970s
involved first conducting a massive sampling and testing program of finished
batches of particularly important drugs in terms of clinical significance and
dollar volume, then taking legal action against violative batches and inspecting
the manufacturers until they were proven to be in compliance. This approach
was not entirely satisfactory because samples are not necessarily representative
of all batches. Finished product testing for sterility, for example, does not assure
that the lot is sterile. Several incidents refocused FDA’s attention to process
inspections. The investigation of complaints of clinical failures of several prod-
ucts (including digoxin, digitoxin, prednisolone, and prednisone) by FDA found
significant content uniformity problems that were the result of poorly controlled
manufacturing processes. Also, two large-volume parenteral manufacturers ex-
perienced complaints despite quality control programs and negative sterility test-
ing. Although the cause of the microbiological contamination was never proven,
FDA inspections did find deficiencies in the manufacturing process and it be-
came evident that there was no real proof that the products were sterile.
What became evident in these cases was that FDA had not looked at the
process itself—certainly not the entire process—in its regulatory activities; it
was quality control- rather than quality assurance-oriented. The compliance offi-cials were not thinking in terms of process validation. One of the first entries
into process validation was a 1974 paper presented by Ted Byers, entitled “De-
sign for Quality” [7]. The term validation was not used, but the paper described
an increased attention to adequacy of processes for the production of pharma-
ceuticals. Another paper—by Bernard Loftus before the Parenteral Drug Associ-
ation in 1978 entitled “Validation and Stability” [8]—discussed the legal basis
for the requirement that processes be validated.
The May 1987 Guideline on General Principles of Process Validation was written for the pharmaceutical, device, and veterinary medicine industries.
It has been effective in standardizing the approach by the different parts of the
agency and in communicating that approach to manufacturers in each industry.
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Once the concept of being able to predict process performance to meet user
requirements evolved, FDA regulatory officials established that there was a le-
gal basis for requiring process validation. The ultimate legal authority is Section
501(a)(2)(B) of the FD&C Act [4], which states that a drug is deemed to be
adulterated if the methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform to or were not
operated or administrated in conformity with CGMP. Assurance must be given
that the drug would meet the requirements of the act as to safety and would
have the identity and strength and meet the quality and purity characteristics
that it purported or was represented to possess. That section of the act sets the
premise for process validation requirements for both finished pharmaceuticals
and active pharmaceutical ingredients, because active pharmaceutical ingredi-
ents are also deemed to be drugs under the act.
The CGMP regulations for finished pharmaceuticals, 21 CFR 210 and
211, were promulgated to enforce the requirements of the act. Although these
regulations do not include a definition for process validation, the requirement is
implicit in the language of 21 CFR 211.100 , which states: “There shall be
written procedures for production and process control designed to assure that
the drug products have the identity, strength, quality, and purity they purport or
are represented to possess.”

1936345048 Process Validation Principles, Practices and Strategies for Medical Devices: Process Validation Standard Operation Procedure
Robert K Mitu

145284318X Principles of Process validation: A handbook for professionals in Medical Device,Pharmaceutical,and Biomedical Industries.
David N Muchemu

1439850933 Process Validation in Manufacturing of Biopharmaceuticals, Third Edition (Biotechnology and Bioprocessing)
Anurag S. Rathore

B007LQ7ZI6 Process Validation for Medical Devices - DOCUMENT BUNDLE
Robert Mitu


The term process validation is not defined in the Food, Drug, and Cosmetic Act
(FD&C) Act or in FDA’s CGMP regulations. Many definitions have been of-
fered that in general express the same idea—that a process will do what it
purports to do, or that the process works and the proof is documented. A June
1978 FDA compliance program on drug process inspections [2] contained the
following definition:
A validated manufacturing process is one which has been proved to do what
it purports or is represented to do. The proof of validation is obtained
through the collection and evaluation of data, preferably, beginning from
the process development phase and continuing through the production
phase. Validation necessarily includes process qualification (the qualifica-
tion of materials, equipment, systems, buildings, personnel), but it also in-
cludes the control on the entire process for repeated batches or runs.
The first drafts of the May 1987 Guideline on General Principles of Process
Validation [3] contained a similar definition, which has frequently been used in
FDA speeches since 1978, and is still used today: “A documented program which
provides a high degree of assurance that a specific process will consistently pro-
duce a product meeting its pre-determined specifications and quality attributes.”

1936345048 Process Validation Principles, Practices and Strategies for Medical Devices: Process Validation Standard Operation Procedure
Robert K Mitu

145284318X Principles of Process validation: A handbook for professionals in Medical Device,Pharmaceutical,and Biomedical Industries.
David N Muchemu

1439850933 Process Validation in Manufacturing of Biopharmaceuticals, Third Edition (Biotechnology and Bioprocessing)
Anurag S. Rathore

B007LQ7ZI6 Process Validation for Medical Devices - DOCUMENT BUNDLE
Robert Mitu