Why Validation is Important!
; 26 August 2010
Validation is a concept that has been evolving continuously since its first formal appearance in United States in 1978. The concept of validation has expanded through the years to encompass a wide range of activities which should take place at the conclusion of product development and at the beginning of commercial production. Validation is confirmation by examination and provision of objective evidence that the particular requirements for a specified intended use are fulfilled.
We all love validation!
Validation is the overall expression for a sequence of activities in order to demonstrate and document that a specific product can be reliably manufactured by the designed process, usually, depending on the complexity of today’s pharmaceutical products, the manufacturer must ensure. Quality cannot be adequately assured merely by in-process and finished product inspection or testing so the firms should employ objective measures (e.g. validation) wherever feasible and meaningful to achieve adequate assurance.
Today we have different definitions of validation, which are as follows-
; Establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a
product meeting its pre-determined specifications and quality
; The collection and evaluation of data, from the process design stage
throughout production, which establishes scientific evidence that
a process is capable of consistently delivering quality products.
; Validation is a process by which a procedure is evaluated to
determine its efficacy and reliability for forensic casework
Why Validation is Important The principles – Quality, Safety and Effectiveness must be designed and built in to the product, quality cannot be inspected or tested in the finished products and each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications. Now let me explain the specific importance of the validation – it is the concept detailed in quality
guidelines of Product Lifecycle and with the help of which we can do the following:
; Determine the process parameters and necessary controls.
; To confirm the process design as capable of reproducible commercial
; Risk/Worst Case assessment. What is Worst Case? It is a set of
conditions encompassing upper and lower limits and circumstances,
including those within standard operating procedures, which pose
the greatest change of process or product failure when compared to
the ideal conditions.
; To provide ongoing assurance that the process remains in a state
of control during routine production through quality procedures and
continuous improvement initiatives.
; Quantitatively determine the variability of a process and its
; The variability within and between batches can be evaluated to
determine the inner and intra-batch variability.
; Greater scrutiny of the process performance for development and
deployment of process controls.
; Scientific study performed prior to implementing a change to a
process can support the implementation of a change without
; Safeguard and process against sources of variation which may not
have been identified during the original process development.
; The most compelling reason to optimize and validate pharmaceutical
productions and supporting processes and cost reduction.
; Control point in the context of preventive maintenance.
; Investigate deviations if any from established parameters. Conclusion
Validation allows us to focus on our everyday business operations of making and selling quality products that also comply with regulatory requirements such as the FDA, Schedule M, etc. The industry which has adopted a lifecycle approach to the product development, validation and modern risk analysis tools can control critical process parameters. The companies can create a new standard of industry best practice by embracing the ability of validation practices which will lead in technological revolution.
Rajkumar P. Patil
Sr. Production Officer
Mobile No. +919945642935
Mail ID. firstname.lastname@example.org
Critical Parameters Affecting Process Validation
; 27 September 2010
Validation is an integral part of quality assurance; it involves systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control. Adequate validation is beneficial to the manufacturer in many ways – It deepens the understanding of processes; decreases the risk of preventing problems, defect costs, regulatory non compliances and thus assures the smooth running of the process.
Process Validation is key to a robust manufacturing process Process validation involves a series of activities taking place over the lifecycle of product and process. Validation requires a meticulous preparation and careful planning of the various steps in the process. All work involved should be carried out in a structured way according to formally authorized standardized working procedures.
What are the Critical Parameters affecting Process Validation? The critical parameters should normally be identified during the development stage or from historical data or during manufacturing and
process control. Process validation involves three stages and now will identify the critical parameters in these stages.
Stage One: Process Design
Process design is the activity of defining the commercial manufacturing process. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its critical quality attributes. A product development activity provides key inputs to the design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. The functionality and limitations of commercial manufacturing equipment should be considered, also contributions of variability by different component lots, production operators, environmental conditions and measurement systems in the production setting.
Designing an efficient process with an effective process control approach is dependent on the process knowledge. Use of risk analysis tools to screen potential variables for Design of Experiment (DOE) studies to minimize the total number of experiments. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment parameters and in-process material quality attributes. Manufactures should document the variables studied for a unit operation and the rationale for those variables identified as significant. This information is useful during the process qualification and continued process verification stages, including the design is revised or strategy for control is refined.
Process control addresses the variability to assure quality of the product. Controls can consists of material analysis and equipment monitoring at significant processing points designed to assure that the operation remains on target and in control with respect to output quality. Timely analysis, control and adjust the processing conditions so that the output remains constant.
Stage Two: Process Qualification During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. It confirms that all established limits of the critical parameters are valid and that satisfactory products can be produced even under worst case condition. This stage has following elements –Qualification of Utilities and Equipment.
Installation Qualification is an essential step preceding the Process Validation exercise which is normally executed by Engineering group. The installation of equipment should follow well defined plans which is developed and finalized following progression through a number of design stages. This stage of validation includes examination of Equipment Design, Determination of Calibration, Maintenance and Adjustment Requirements. Consider the following Equipment Calibration Requirements
1. Confirmation of calibration of calibrating equipment with reference to the appropriate national standard.
2. Calibration of measuring devices utilized in the Operational Qualification stage.
3. Identification of calibration requirements for measuring devices for the future use of the equipment. At the Installation Qualification stage the company should document preventive maintenance requirements for installed equipment.
Operational Qualification is an exercise oriented to engineering function referred as commissioning. It is important stage to assure all operational test data conform with pre-determined acceptance criteria and manufacturer should develop draft standard operating procedures for the equipment, service operation, cleaning activities, maintenance requirements and calibration schedules.
The critical operating parameters for the equipment or the plant should be identified at the Operational Qualification stage. Critical variables should incorporate specific details and tests that have been developed. The completion of a successful Operational Qualification should include the finalization of operating procedures and operator instructions documentation for the equipment.
Performance Qualification combines the actual facility, utilities, equipment, trained personnel, control procedures and components to produce commercial batches. Performance qualification will have a higher level of sampling, additional testing and greater scrutiny of process performance. The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch during process. Stage Three: Continued Process Verification
Continually assure that the process remains in a state of control during commercial manufacturing. A system or systems for detecting unplanned departures from the process as designed is essential. The following points to be considered in Continued Process Verification.
Collection and evaluation of information and data about the performance of the process will allow detection of process drift. Evaluation should determine whether action must be taken to prevent the process from drifting out of control.
An ongoing program to collect and analyze product and process data that relate to product quality must be established to verify the critical quality attributes are being controlled throughout the process. Process variation also can be detected by assessment of defect complaints, out of specifications finding, process deviation reports, process yield variations, batch records, incoming raw material records and adverse event reports.
Operator’s errors should be tracked to measure the quality of the training program.
Maintenance of the facility, utilities and equipment is an important aspect of ensuring that a process remains in control.
Process validation is a mean of ensuring and documenting that the processes are capable of producing a finished product of the required quality consistently and should cover all the critical elements of the manufacturing process. The process design stage and the process qualification stage should have as a focus the measurement system and control loop establishing scientific evidence that the process is reproducible and will consistently deliver quality products. Good process design and development should anticipate significant sources of variability and establish appropriate detection, control, appropriate alert and action limits. Process variability should be periodically assessed. It is the responsibility of the manufacturer to judge and provide evidence of a high degree of assurance in its manufacturing process.
; Guidance for Industry Process Validation: General Principles and
Practices – US Dept. of Health and Human Services, Food and Drug
Administration. Nov. 2008 Current Good Manufacturing Practices.
; ANNEX 15. Validation Master Plan, Design Qualification,
Installation and Operational Qualification, Non Sterile Process
Validation, Cleaning Validation. 17th Sep. 1999.
Process Robustness in
; 4 November 2010
The objective of this study is to unify understanding of the current concepts of process robustness and application of robustness principles to non-sterile solid dosage form manufacturing. Process robustness
start at the earliest stages of process design and continue activities
throughout the life of the product, it suggests greater process certainty in terms of yields, cycle times and level of discards.
Process Robustness in Pharmaceutical Manufacturing
An assessment of process robustness can be useful in risk assessment, reduction, potentially be used to support future manufacturing and process optimization. Robustness cannot be tested into a product; rather it must be incorporated into the design and development of the product. Performance of the product and process must be monitored throughout scale up, introduction and routine manufacturing to ensure robustness is maintained.
Principles Of Process Robustness Definition of Robustness –
“The ability of a process to demonstrate acceptable quality and
performance while tolerating variability.”
Process performance and variability may be managed through the choice of manufacturing technology. Well designed processes reduce the potential for human mistakes, thereby contributing to increased robustness. During product and process development both the inputs and outputs of the process are studied to determine the critical parameters and attributes for the process, the tolerances for those parameters and how best to control them. Critical Quality Attributes, Process Parameters, Process Capability, Manufacturing and Process Control Technologies and Quality System Infrastructure are referred as Manufacturing Science underlying a product and process. Principles of process robustness are as follows –
(A) Critical Quality Attributes (CQAs) – The identified measured
attributes that are deemed critical to ensure the quality requirements – intended purity, efficacy and safety of an intermediate or final product, termed as Critical Quality Attributes.
(B) Critical Process Parameters (CPPs) – Is a process input that, when
varied beyond a limited range has a direct and significant influence on a Critical Quality Attribute. It is important to distinguish between parameters that affect critical quality attributes and parameters that affect efficiency, yield, worker safety or other business objectives. Most processes are required to report an overall yield from bulk to semi-finished or finished product. It is important to have an understanding of the impact of raw materials, manufacturing equipment control, degree of automation or prescriptive procedure necessary to assure adequate control.
(C) Normal Operating Range (NOR) and Proven Acceptable Range (PAR) –
In developing the manufacturing science a body of experimental data is obtained and the initially selected parameter tolerances are confirmed or adjusted to reflect the data. This becomes the Proven Acceptable Range for the parameter, and within the PAR an operating range is set based on the Normal Operating Range for the given parameter. In a robust process, critical process parameters have been identified and characterized so the process can be controlled within defined limits for those CPPs. A process that operates consistently in a narrow NOR demonstrates low process variability and good process control. The ability to operate in NOR is
a function of the process equipment, defined process controls and process capability.
(D) Variability: Source and Control – Typical sources of variability
includes process equipment capabilities, calibration limits, testing method variability, raw materials, human factors for non automated processes, sampling variability and environment factors within the plant facility.
(E) Setting Tolerance Limits – Upper and lower tolerances around a
midpoint within the PAR of a parameter should be established to provide acceptable attributes. The defined limits should be practical and selected to accommodate the expected variability of parameters while confirming to the quality attribute acceptance criteria.
Development Of A Robust Process A systematic team-based approach to development is one way to gain process understanding and to ensure that a robust process is developed. The following are the steps for the development of a robust process –
(1) Form the Team – Development of a robust process should involve a team of technical experts from R&D, technology transfer, manufacturing, statistical science and other appropriate disciplines. This team approach to jointly develop the dosage form eliminates the virtual walls between functions, improves collaboration and allows early alignment around technical decisions leading to a more robust product. This team should be formed before optimization and scale-up.
(2) Define the Process – A typical process consists of a series of unit operations. Before the team can proceed with development of a robust process they must agree on the unit operations they are studying and define the process parameters and attributes. Defining the process is to list all possible product attributes and agree on potential Critical Quality Attributes. The final step in defining the process is determining process parameters. Categorizations of parameters to consider are materials, methods, machines, people, measurement and environment.
(3) Prioritize Experiments – It is recommended that the team initially
use a structured analysis method such as a prioritization matrix to identify and prioritize both process parameters and attributes for further study. A ranking of parameters of importance is calculated by considering the expected impact of a parameter on attributes as well as the relative importance of the attributes.