FDA Process Validation 101 – A Complete Guide

It is common knowledge that any company within the Food and Drug industry has to maintain certain sets of standard of their products. They cannot create benchmarks unique to themselves and compare the results with those individual standards. Food and Drug Administration state this would cause disparity in composition of similar products, compromise their quality and threaten the health of its users. To address this issue, FDA Process Validation is implemented in every food and drug manufacturing unit.

Food and Drug Administration aims at standardizing processes in every manufacturing unit through process validation to ensure that every product that is produced comply with prerequisite standards while maintaining high quality. Read on to know more about FDA Process Validation and all you need to know about it.

What is FDA Process Validation

FDA Process Validation is universally defined as collection and evaluation of data, from the process design stage through commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product. It promotes a ‘lifecycle’ approach that is comprised of reliable design practices, qualifications and process verification. The lifecycle approach is an on-going validation process that necessitates comprehensive process design to understand sources of variability and achieve process understanding. It incorporates risk management while recognizing that additional knowledge will be gained during commercial production.

The lifecycle approach of FDA process validation links product and process development to commercial manufacturing process. It also maintains the process in a state-of-control during routine production. Process validation indicates that every process in manufacturing has been subjected to high levels of scrutiny and analysis that the final result at the end of each process, either a product or service, can be guaranteed. This is achieved by controlling each step of a manufacturing process to assure that the finished product meets all design characteristics and quality attributes that include specifications as well. The knowledge gained at every step should be reviewed, analyzed and documented without fail.

Why FDA Process Validation Is Required

FDA process validation guidance enlists various elements and concepts that are considered as acceptable components of validation program by FDA. This guidance play a key role in assisting manufacturers in the understanding of requirements for quality management system of food, and human and veterinary medicinal products. Furthermore, it provides them suggestions on the different ways that manufacturers may prepare and carry out process validations.

It is crucial to remember that requirements of process validation will vary across different factors based on the nature of food and drug products, complexity of the process involved, technology involved etc. However, this guidance provides a framework that manufacturers can work with to achieve the desired results. Process validation assures that product performance and quality remains consistent through all the batches and units.

FDA Approval Process

The FDA approval process consists of three stages:

  • Stage 1: Process Design – This stage defines a commercial process based on knowledge gained through developmental procedures and scale-up activities.
  • Stage 2: Process Qualification – This stage is responsible for evaluating and assessing if the concerned process is capable of commercial manufacturing that can be reproduced over a period of time, across all the batches.
  • Stage 3: Continued Process Verification – In this stage, one can gain assurance that all the processes remain in a state of control through the routine production.

Each of these stages is responsible for creating an approach that delivers products ranking high on quality and consistencies across all the batches. Different activities and tools are observed in each stage, some which are unique to them. It is highly recommended that relevant documentation and analytical methods are used through all the stages to maximize the benefits and results of process validation.

FDA Process Chart

Let us see each of these stages in detail.

Stage 1: Process Design

This is where it all starts. This stage focuses on developing methods to build and capture process knowledge, which can be used to assess the success of final results. Process design stage aims at designing a process that is applicable for routine commercial manufacturing with an ability to consistently deliver products that meets Critical Quality Attribute (CQAs). Every process and unit operation is broken into different, smaller segments which makes studying and analyzing them easier. This scientific knowledge is then used as the basis for establishing an approach to effective process control.

Significant variables affecting process’s unit operations are identified and categorized. Each variable’s operating limits and related monitoring requirements/ techniques is defined critically and is quite context-specific. All significant variables and related attributes should be linked suitably, which can be derived empirically. It can be said that Process Design is the beginning of a structured and interconnected chain of validation evidence. Design of Experiment (DOE) studies greatly help in developing process knowledge by displaying relationships and interactions between variable inputs and corresponding outputs. Extensive experiments are conducted to maximize the knowledge; however risk analysis tools can be utilized to minimize the number of conducted experiments.

The results at the end of DOE studies should be used for establishing equipment parameters, incoming component quality range, and attributes required for process material quality. Process Analytical Technology (PAT) may be used for real time analysis, facilitating control loops to adjust processing conditions to keep the output reproducible and constant. It is advised that the process design team takes early consideration of functionality and limitations of commercial manufacturing equipment.

Stage 2: Process Qualification

Process qualification is a seamless extension of process design. This stage comprises of defining and executing testing strategy of all variables that have been quantified and categorized in the previous stage. It has its own internal cycle that approximates the acceptance criteria, protocol preparation and execution, and related events. The primary goal of process qualification is to confirm that the process design is capable of producing reproducible and consistent commercial manufacturing process. This stage is further divided into 2 segments:

  1. Designing the facility and qualification of the equipment and utilities: Ensuring that all processes are executed in the right manner and steps isn’t enough. It is equally important to note the role of proper facility design and qualification of equipment/utilities used in the processes. Until their qualification is confirmed, it is unadvisable to carry on with succeeding steps. This can be achieved through following qualification activities:
    • Selecting appropriate utilities and equipment based on their specific use
    • Confirming that compliance and design specifications of utility system and equipment are built/installed are maintained in accordance with process requirements throughout the processes
    • Challenging existing equipment and system functions under several loads comparable to that expected during routine production
    • Analyzing performance of interventions, stoppage, and start-up as expected during routine production

    These qualification activities can be executed as individual plans or overall project plan. Risk management should be pursued diligently so that performance isn’t compromised at any stage. All findings and knowledge should be reviewed, approved and documented properly for future references.

  2. Performance Qualification (PQ): This step is responsible for confirming the success of process design and demonstrating that commercial manufacturing processes perform as expected. It combines the qualified equipments, facilities and utilities with trained personnel using compliant control procedures (SOPs). Further, it also connects all raw materials and components necessary to produce commercial batches. In short, it can be said that two efforts are combined in this stage to achieve the desired goal of Performance Qualification. Success at the PQ stage is considered as a crucial milestone in any product lifecycle. This stage should be executed and finished successfully before commercial distribution of the products start.

Stage 3: Continued Process Verification

This stage focuses on continually assuring that concerned processes remain in a state of control throughout commercial manufacture. To achieve this, robust systems are implemented that can detect any unplanned distraction, diverting the designed process from desired results. Reliance on data is evident in this stage of continued process verification, which makes data collection extremely important. Trained personnel should be a part of this team who can review the available data and assess it suitably. Adequate training should be provided to them in statistical process control techniques.

The collected data should evaluate a process’s stability and capability through the manufacture. It should verify that all critical quality attributes (CQAs) are being controlled suitably. All intra-batch and inter-batch variables of the processes should be considered. Based on the available data, insights should be gathered which may indicate possible drifts in the process, which can further help in organizing correctional procedures to negate the drift. If no drift is detected, the gathered data can also be used for further optimizing the existing processes. Till sufficient data is available, all processes will have to be sampled, enhanced and monitored constantly to generate significant variability estimates and justification using statistical metrics. All concerned procedures can be controlled and managed in highly efficient manner based on the provided data. This stage indicates that maintaining the facility, equipments and corresponding utilities is extremely important to ensure smooth and controlled ensuring processes.

At this stage, it becomes critical that all information/data is accessible and transparent across all organizational units. This assists concerned teams in making informed, quick and data-based decisions that may greatly affect final outputs and products.

FDA Process Validation Frequency

FDA process validation relies heavily on documentation of every element and steps that comprise various manufacturing processes. It is important to keep the documents up-to date, which is possible only through conducting the validation tests frequently. Re-validation frequency depends upon the following factors:

  • Any change in the main raw materials
  • Changes in physical properties of existing raw materials that may affect the process or final product. Physical properties include viscosity, density, particle size distribution etc.
  • Changes in the equipment and facilities being used, such as addition of automated system or removal of non-functioning system
  • Changes in process, such as temperatures, mixing conditions, required pressure etc
  • Changes in production area and support system changes such as flow meter calibration and similar calibration services
  • Transfer of processes to another site
  • On observing sudden, unexpected changes in the process at any stage of manufacturing

Neglecting any of these changes will create havoc in existing processes which will be manifested in the final output. The risk also lies in the fact that quality of products will be heavily compromised and inconsistencies will be observed across them. This will make reproducible and consistent manufacturing impossible. Conducting FDA audits at regular intervals is highly recommended to keep processes smooth, efficient, up-to date and at par with existing technology.

FDA Process Validation Guidelines promote the following:

  • Process improvement
  • Modern manufacturing principles
  • Innovation
  • Risk Assessment and mitigation

FDA regulations ties qualities across various products rolling out of various food and drug industries. The regulations are very strict and adhering to them will not only in FDA approval of the products but also ensures that the health and well-being of the consumers is prioritized over anything else. If you are a part of the Food and Drug industry, implement process validation in all your processes and you will be guaranteed of getting desired results by improving process performance and quality. It will also eliminate the chances of your products getting rejected based on several conditions. As manufacturers, you will have a thorough understanding of your processes and platforms, how they are interconnected and applying a systematic approach for streamlining the processes, thus elevating your outputs.

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