FDA has given certain guidelines for the manufacturers to validate the manufacturing process. The guidelines are given in accordance with pharmaceutical development, pharmaceutical quality system and quality risk management and interlinking ICH guidelines to product life cycle. Keeping in tune in with present scenario FDA underlines that the concepts of modern pharmaceutical development need to be followed at all stages of product life cycle.
Categories of drugs included:
Active pharmaceutical ingredients & finished products, veterinary drugs, human drugs, drug constituent of combination of drug and medical device product and biotechnology and biological products.
Categories of product excluded:
Medical devices, Human tissues for transplantation, Type A medicated article and medicated feed, Dietary supplements.
These guidelines apply to validation process in automated equipment used in processing but not to the modern manufacturing equipment like computer hardware and software interfaces.
Process validation- Drug quality
Effective process validation assures significant drug quality with the ultimate aim of making the product perform its intended action. This can be ensured when certain criteria within the product are fulfilled like:
1. Efficacy, safety and quality should be ensured in a product.
2. Quality should not be determined based on the product during the process or a finished product.
3. Every step in the manufacturing process should be monitored so all the attributes of quality are attained in the product.
Approach
Process validation is defined as the evaluation of the collected data from the design stage of the process through its commercial production by establishing the scientific basis that a process should deliver a consistent quality product.
Process validation is given in three different stages:
1) Process design
2) Process qualification
3) Continued process verification
Success of a validation process is attained by the knowledge and information taken from process and product development.
To deliver a consistent product relating to identity, quality, purity, and strength and potency manufacturers should bear in mind the following:
1) Understanding the sources and detecting the presence & degree of variation.
2) Understanding the impact made by the variation and controlling it so it doesn’t cause any risk to product.
General considerations for process validation:
To ensure an effective process validation program at all stages of product life cycle, good project management and scientific knowledge should be followed and maintained throughout the life cycle.
Project plans should be made with the involvement of the entire team and experts across various departments like analytical chemistry, industrial pharmacy, quality assurance, statistics, manufacturing, industrial pharmacy, microbiology and process engineering. At various stages of product lifecycle taking information from any studies to understand or correlate or confirm the process and the product then it should be done in accordance with the scientific principles.
All parameters and attributes should be evaluated in terms of their roles and impacts of the products. Attributes and parameters should be controlled in accordance with the risk to the process outcome.
Between the batches of the process validation homogeneity should be maintained throughout the manufacturing process. Validation assures that a process is protected against various sources of variations which may affect problems in supply or production or alter public health.
Stages of Process Validation
I) Process design
At this stage a suitable process is designed so that a consistent product is produced meeting the attributes of quality. Process design defines the process in commercial manufacturing which is further documented in control records and master production.
Understanding and building of Process knowledge
Previously for the products for commercial distribution which are manufactured during process qualification and verification only required to be formed under good documentation practices with sound scientific knowledge but did not mandate to be under CGMP requirements. But still they should be documented for future quality review.
Impurity clearance and viral inactivation studies are often done in small scale laboratories but aren’t considered in early process design experiments.
Product development activities provide inputs on quality parameters, dosage form and manufacturing pathway in this stage along with process information.
There may be limitations or variations in commercial manufacturing related to measurement systems, environmental conditions and production operators in the production setting. However few pilot studies can be done to measure the variability.
Design of experimentation (DOE) studies help in attaining efficient process by building multivariate interactions between component characteristics or process parameters (inputs) and (outputs) materials during in process, intermediates and finished products. The results from DOE studies help in providing range over component quality, equipment attributes and quality of in process materials and also provide information & predict the performance of commercial process.
The outcome of the studies can be used to in further build a model or simulate the process.
The activities done and information obtained should be documented which should reflect the basis for making such decisions.
Strategy for Process control
To device an approach for process control knowledge and understanding of process should form the base for each unit individually and the overall process. Strategies are designed to decrease and adjust variations in the input parameters during the manufacturing.
The variables like in materials, equipment are monitored and controlled in this step to ensure product quality. Risk analysis helps in combating the variability in the process
Special caution should be taken in conditions where the attributes of the products and intermediates are not characterized or can’t be measured. In such situations process control should be done by setting operational limits and in process monitoring.
To ensure that output remains constant throughout strategy like process analytical technology (PAT) are implemented with time analysis which gives a more process control than non PAT systems.
The planned commercial production and records with all strategy and operational limits should be carried to next stage.
II) Process Qualification
In this stage process design is evaluated if it is able to replicate commercial manufacture. It comprises of two elements: facility design and qualification of utilities and equipment, process performance qualification (PPQ)
If the products in this stage are acceptable then they can be handled for distribution. CGMP procedures must be followed and it should be completed before commercial distribution.
Facility design and qualification of utilities and equipment
Manufacture facility should be designed according to part 211 of subpart C of CGMP regulations on buildings and facilities.
Process Performance Qualification
PPQ covers facility, equipment and utilities along with trained personnel and also control procedures, commercial manufacturing process and other components to produce commercial batches.
Data from previous studies and experiments and with scientific knowledge approach to process performance qualification should be done.
Using PAT systems can demand a different PPQ approach rather than traditional approach.
PPQ protocol
A Protocol should be prepared specifying the conditions, controls, testing and outcomes in manufacturing.
PPQ protocol should include the following:
Execution of PPQ protocol and reporting
After the protocol has been reviewed and approved by each and every department then it has to be implemented.
During the execution of PPQ protocol normal conditions should be maintained in terms of commercial manufacturing process and routine procedures like operating conditions.
A report should be prepared after completing the protocol. It should
III) Continued process verification
This stage verifies that process remains in the same state of control during the commercial manufacture.
Any undesired process or variations should be detected which on evaluating helps in identifying problems and the necessary steps taken to correct and prevent the problems.
A continuous ongoing program should be implemented to collect, evaluate and process data relating to quality of the product. The data should be statistically trended and reviewed by skilled personnel and ensure the quality parameters are controlled properly.
To evaluate process capability and process stability a trained statistician should be employed with adequate knowledge on statistical methods.
By good process design and development any variations encountered should be detected and solved.
To generate significant estimates on variations monitoring and sampling of process and quality parameters should be done.
By periodic assessments of defect complaints, reports on process deviation, adverse events & incoming raw material, batch records, process yield variations, out of specification findings variations can be easily identified.
Gathering the data from such events helps in improving the process.
Based on this data sometimes requalification can be intended for equipment’s and utilities.
Process validation, process design, process qualification, continued process verification
