Process Validation is a requirement of:
- Current Good Manufacturing Practices (cGMP) Regulations for Finished Pharmaceuticals, 21 CFR Part 210 and 211.
- Good Manufacturing Practice (GMP) Regulations for Medical Devices, 21 CFR Part 820, Quality System Regulation.
- Medical Devices – Quality Management Systems – Requirements for Regulatory Purposes, ISO 13485:2016.
Hence, they become applicable to the manufacturing of pharmaceutical products and medical devices. FDA now aligns the activities of process validation with product life-cycle aspects. We’ll see further those activities effortlessly and will also open out other commonly practiced validation aspects and tools. This way, you can keep this article handy. This is going to be a bit long yet interesting, so sit back and stay focused.
Following factors assures the product quality;
- Sufficient Product and Process Design
- Overall Process Control
- In-Process Controls
- Final Product Testing
- Selection of Quality Components and Materials
- Destructive Testing as applicable
Besides, the following fundamentals represent the goal of quality assurance to show the materials manufactured to result in being fit for their intended applications;
- Quality, Safety, Potency, Purity, and Efficacy
- Quality in every process step. Remember? We defined this in our previous article Difference Between Qualification and Validation.
- Ensuring process optimization at every step for the finished product to meet all quality and design specifications.
The difference between Potency and Efficacy: Amount of drug required to produce the desired effect termed as Potency, while Efficacy defines the actual effect of a drug in therapeutic use.
To address these, process validation come out as a mechanism to measure that these goals meet.
The 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 a quality product.FDA definition of Process Validation
Why Process Validation Required?
Process validation required to confirm that “Whether your process is effective enough in controlling the quality of your final product“. Once the process validation completes, it shows that your process is consistent to produce a quality product batch to batch and unit to unit.
Therefore, the manufacturer must write a validation protocol, clearly laying down the requirements for test procedures and data collection including but not limited to:
- A number of process runs to ensure the process shows the reproducibility and consistency. Though, this approach now becoming an old way to validate a process and FDA now recommends the product life-cycle approach.
- Bracketing for test parameters performed in such a way that upper and lower process limits challenged to show the worst-case conditions
- Evidence of suitability of materials and the performance and reliability of equipment and systems
- Documenting and monitoring key process variables
Test data including In-Process and Finished product has its own value during process validation. This becomes more relevant in the tedious measurement of quality attributes and variables. In these conditions, the qualification of each system in production along with the communication with other systems establish a process validation approach.
Going along with Good Documentation Practices also becomes a requirement while executing all the documentation activities.
Approach to Process Validation
As per product life-cycle approach, process validation activities broken down in three stages.
- Process Design (Development and Scale-up)
- Process Qualification (Challenge Reproducibility)
- Continuous Process Verification (Periodic Verification)
Product and process development data serves as a ground to pass the process validation successfully. Based on this data, a control philosophy built to ensure that it achieves the desired product quality attributes. Variations can severely affect the product quality if not performed the following checks.
- Identify the variations
- Analyze the magnitude of the variations
- Perform impact assessment
- Control the variations
- Build confidence in process performance
For already established product footprints, only considering stage 3 would be sufficient. Further, let us understand the general aspects, recommended stages, and micro-activities in process validation.
General Considerations in Process Validation
To complete process validation successfully, proper planning and documentation of project activities is the key throughout the product life-cycle. Planning and conducting sound scientific studies help in identifying, monitoring, and co-relating the gathered product and process information. Process validation assures the protection of the process against the variabilities, to achieve the desired product output.
Another aspect deals with handling critical quality attributes. Considering risk-based decision making throughout the product life-cycle, the term “critical” should show a continuous approach and not an intermittent one. Therefore, all such attributes should readily be available along with the well-plotted control measures.
There are in general 3 stages and 4 types of process validation and they are quite correlative by principles detailed further.
3 Stages of Process Validation
- Process Design
- Process Qualification
- Continuous Process Verification
4 Types of Process Validation
- Prospective Validation
- Concurrent Validation
- Retrospective Validation
Overall Scheme for Process Validation
When it comes to process validation, understanding an overall scheme helps in visualizing a whole picture. Let’s see the scheme first as per the product life-cycle approach and then we’ll see each concept in detail.
Stage 1 – Process Design (~Prospective Validation)
This stage helps in designing a process suitable for routine commercial manufacturing that fulfills the pre-determined quality attributes. Performing process development activities in this stage help to identify the key process inputs including the route of drug administration and critical quality attributes. Information gathered through these activities supports the process design stage.
Because of the insufficient availability of process variables, using lab-scale or exhibit scale data would support and represent the overall variations for the time being. Effective Process Design and Control relies on the knowledge and understanding gathered through the Design of Experiment (DOE) studies. This will build relationships between different process parameters and outputs. DOE, therefore, helps the industries in bracketing the upper and lower process limits to which we call operating ranges. Process dynamics and simulation testing may help in identifying potential risks before commercial manufacturing, avoiding potential damages.
Importantly, documentation of all the above activities should reflect the rationale for any relevant decision making for the process validation. The best example to elaborate this: Determining the number of temperature probes in a sterilization system and rationale for finalizing those numbers. This then becomes a supporting document during the next stages of the product life-cycle approach in process validation.
Building Process Control Strategy
Variations in the input can damage the process output if not addressed at the right time. Therefore, it becomes important to build a control strategy that will ensure the process output remains unaffected. These controls may include monitoring and maintaining critical process parameters and material attributes. One of the crucial aspects to identify these parameters involves proper risk assessment and mitigation.
While building up a control strategy, the process sometimes imposes limitations on the sampling and product uncertainties. Then, FDA recommends conducting material inspection and equipment monitoring especially using in-process monitoring and operations limits respectively, which gets included in BMR (Batch Manufacturing Records).
For additional and in-depth analysis of materials and designing control loops, the use of proper guides such as Process Analytical Technology (PAT) can help in optimizing the process conditions for constant outputs. This will ensure more confidence in process performance. However, it then requires a fresh approach for process qualification outlined in FDA’s guidance, A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.
Process design activities are performed during the development stage and prior to commercial manufacturing. It is a key stage in process validation for new products. This includes drawing up the schedule for trial plans, performing risk analysis, and establishing the required control strategy.
Summing up the Stage 1 – Process Design highlights;
- Define the commercial production process
- Define CQAs and CPPs through pilot and exhibit batches
- Risk Assessment, pFMEA (process Failure Mode Effect Analysis)
- Plan the controls to mitigate the risks
Stage 2 – Process Qualification (~Concurrent Validation)
Now that we have complete documentation describing the process design evaluations that show how the process is capable to reproduce the desired outcomes. The next stage deals with the two critical aspects for further development, i.e. Design of a Facility and Qualification of Equipment, Utilities, and Process Qualification. This stage requires the manufacturers to follow all the associated cGMP procedures. Also requires the manufactured product to remain in quarantine until successful completion of this stage, after which the products can undergo commercial distribution if found acceptable.
Facility Design and Equipment and Utilities Qualification
Before moving on to Process Performance Qualification, we must perform the activities assuring suitable facility design and commissioning. Therefore, it is required to design the facility per Subpart C – Buildings and Facilities of 21 CFR Part 211.
For equipment and utilities, following activities commonly considered:
- Chalking out Project Plan with Change Control procedures, Qualification timelines, and Risk assessments.
- Appropriate selection of MOC for equipment and utility systems, including operation mechanism and performance attributes.
- Verification of equipment and utility systems built in accordance with the design specifications.
- Verification of equipment and utility systems operation in peak load consumptions throughout their operating range.
- Documentation activities with Protocols. Also, Reports with clear conclusions addressing requirement criteria outlined in the protocol and approved from the respective Quality unit.
Process Performance Qualification (PPQ)
Performing this activity successfully shows that the elements covered in the Process Design stage conform to actual scenarios. It also shows the commercial manufacturing process performs as intended. Unless they (manufacturers) comply with this activity, they can’t distribute the drug product commercially. Wherever possible, lab and pilot-scale data shall be used to support the commercial process for additional assurance.
Entering this phase shows that the process specifications have been established and equipment installation considered acceptable. It is unnecessary to expedite the overall operating range if process design data seems sufficient in assuring the performance. If the product and/or process is not new, historical analytics can also be helpful, provided that they are supported by a sound statistical approach and calculations (described further in this article). Heightened sampling and monitoring plans should also be on the checklist as and when necessary to confirm uniform product quality.
Reusing process consumables such as filters or resins should show through relevant lab studies that they don’t degrade the product quality and integrity. If this condition seems applicable, PPQ protocol should cover this approach too.
A written document covering the following specifications termed a PPQ Protocol. A simple way to understand which portions should get a space in the PPQ protocol described below hierarchically.
- Process control
- Process description
- Sound process limits
- Control methods
- Impact assessment
- Personnel training and qualification
- Manufacturing conditions like;
- Raw materials
- Operating ranges
- Process limits
- Testing instructions and acceptance criteria for;
- Process characterization
- Sound sampling plan
- No. and location of sampling points
- No. of samples
- Sampling frequency
- In-process testing
- Final testing
- Process indicators
- Process variability
- Deviation handling and CAPA procedure as per applicable SOP
- Non-coformance management
- Expected outcome
Upon review and approval from all the stakeholders, including the quality unit, execution of the protocol should begin as per BMR and SOPs under normal operating conditions. All the observed deviations during execution must justify the rationale and approval prior to implementation, including the quality unit.
Report preparation can begin contemporaneously unless otherwise justifiable, documenting and examining the outcomes with PPQ protocol. Report contents should include the following things at a minimum.
- Summary and analysis of the data collected during the execution, including non-conformances
- Missing data from protocol, if any, should be part of the report
- Unexpected observations should also get tested in the report
- Review of all the protocol references
- Discussion and summary of the observed deviations such as failed test results, OOS. This should also propose a CAPA strategy to either modify the process or controls
- An explicit statement of PASS or FAIL based on the requirements outlined in the PPQ protocol. Otherwise, the report should mention the expected condition to consider as PASS or FAIL backed by documented evidence or justification as appropriate.
Once all the above aspects accomplished, the report can then route for review and approval, including the quality unit.
Process Qualification activities are performed during commercial manufacturing to demonstrate and assure that the process will remain in a state of control during commercial manufacturing. Stage 1 and 2 should involve measurement systems and control loops for the identified attribute/s.
Summing up the Stage 2 – Process Qualification highlights;
- Conduct enough commercial-scale production batches consecutively (generally 3 consecutive batches) to qualify the process designed in Stage-1
- Closely monitor all the process parameters
- Detail out the collected data for assessing CQAs and CPPs for consistency and variabilities
- Design the facility
- Perform equipment and process performance qualification
Stage 3 – Continued Process Verification (~Retrospective Validation)
This stage aimed to assure the reproducibility of process performance in all expected conditions. To achieve this, ensuring system design as per worst-case scenarios is the key. This means the system should detect any unplanned deviations from established parameters from previous stages.
Apart from system design, cGMP aspects such as collection and evaluation of process performance-related data will also enable the firms to detect and address the variations. Also, enabling to implement CAPA and controlling quality attributes appropriately through-out the process. This data may include trends, charts, material inspection reports, etc. Firms may also involve the application of statistical tools such as process capability studies to ensure the process remains stable and consistent. Use of quantitative and statistical tools encouraged as workable to examine both intra-batch and inter-batch variations and confirm the continued process verification approach.
These estimates can help in establishing heightened sampling and monitoring adjustments periodically. Performing additional checks to detect the process variations and assure continued process verification may include;
- Out-of-Specification (OOS)
- Market Complaints
- Yield fluctuations
- Deviation reports
- Analyzing raw material inspection reports
- IPQA inspections
- Preventive maintenance and calibration schedules
- Re-qualification based on periodic assessment
This gathered data helps in optimizing the process by adjusting and documenting the operating conditions or other process control measures with appropriate rationale.
Summing up the Stage 3 – Continued Process Verification highlights:
- Qualify the process by evaluating and collecting historical information of previous batches and analyze how well process parameters remain in the acceptable range.
- Perform periodic analysis of data to conclude the requirement of re-qualification of process
Type 1 – Prospective Validation
Prospective Validation is conducted before the distribution of a new product. Prospective Validation and Stage 1 – Process Design mostly include considerations that deal with an entirely new product introduction. Therefore, it becomes a completely planned program to design and validate a process, including a fundamental document like Validation Master Plan (VMP) and Strategy Protocol. The VMP may include the following:
- Planning and Scheduling
- Summary and current status of a facility, systems, equipment, and/or process
- Change control procedures required to follow
- Reference of this VMP to execute the validation activities
While elements of Prospective Validation would include; Equipment and Process qualifications like Installation Qualification, Process Performance Qualification, Product Performance Qualification, and associated documentation. Also, revalidation assessment becomes important for the timely validated state of product and process. Remember, the aim is to establish documented evidence before commercial manufacturing that the process will perform as intended.
Type 2 – Concurrent Validation
Unlike Prospective Validation, Concurrent Validation occurs parallel to product manufacturing. This means firms can distribute the batches commercially before the approval of validation activities whereas; the product must meet pre-defined quality specifications. Till then, it should be quarantined.
The rationale for this distribution should include documentation with supporting data according to which the decision is made. All the documentation requirements remain as per Prospective Validation, yet this approach decided based on product or market limitations. This includes issues like short shelf-life, high demand short supply, etc.
Involvement of all the stakeholders for review and approval of concurrent validation including regulatory bodies as FDA consider this way of validation as rare condition. Assessment and conclusion of performing this type of process validation should be documented with justification.
FDA outlines the several expectations for concurrent release of PPQ batches;
- Prior to commercial distribution of the PPQ batch, expect preparing a dedicated protocol mentioning this special case.
- Potential situations and rationale should be part of PPQ protocol. Also, the complete execution of the PPQ protocol and data evaluation is a must before drawing any conclusions.
- Additional process design and qualification become necessary when Stage 2 – Process Qualification fails.
- A lot released concurrently must comply with cGMP and other regulatory requirements despite the pending clearance on PPQ batches. Also, it must pass all the acceptance criteria outlined in the PPQ protocol.
- Firms can release a lot when met the required confidence levels for quality attributes applicable to that product.
- Fast-track assessment of market complaints or feedback is expected when a lot released concurrently.
Type 3 – Retrospective Validation
Retrospective Validation is based on historic control, testing, and production data for a product that is already in commercial distribution.
Performing this validation does not demand special requirements as such. In fact, this type of process validation may or may not require the firms to reperform all the validation activities previously executed. Sometimes, a conclusive summary of not performing validation may be provided showing how the system working in its desired state flawlessly since commissioned. In some cases, validating only specific parts would bring confidence to the process performance. To support such a decision, data and statistics should be attached.
As the system is already setup and running, Design Qualification deemed unnecessary for retrospective validation whereas; all the other documentation activities remain identical to the Prospective and Concurrent Validation.
Type 4 – Re-Validation
Re-validating the existing process becomes essential, especially when any changes made in the process or its environment including but not limited to changes in:
- Raw material
- Raw material supplier
- Product formulation
- Packaging material MOC
- Packaging material supplier
- BMR step modifications
- Change outside the established process range
- Transfer from one site to other
- Relocation (Major change)
- Major modifications (Through proper assessment)
- Product changeover
- Software upgrade
- Change in the area (HVAC Changes)
Re-validation therefore should start based on the established procedures outlining such specific instances. The extent of this re-validation depends on the nature of the change and the potential impact on product quality assured in previous validation stages. This means, for example, a material change in product packaging would not require complete process validation and only focusing on packing operation would suffice the requirement. However, it becomes essential to determine the effects and start and endpoint of re-validation based on the nature of change. Change control will establish the extent of re-validation.
V Model for Validation
Another term we generally come across is V-Model for validation. This is more of a simple presentation than a requirement for a quick understanding of the overall validation cycle. You can consider it as either equipment or process validation.
In 1994, GAMP 1st Edition, ISPE introduced this model which shows how and where a validation phase starts and ends, including the correlation between them. Don’t get confused with the V-Model in software validation, it provides a common ground for a basic understanding of pharmaceutical aspects as well.
Left-arm of V represents the planning stage or specification phase, while the right arm of V represents the actually obtained results. The point of convergence represents the system as-built.
- 1st correlation shows that the system installed as per design specification.
- 2nd correlation shows that the system operates as per functional specification.
- 3rd correlation shows that the system performs as per user requirement specifications.
- The start point of the V-Model is Validation Master Plan and the endpoint is maintaining a validated state.
The V-Model exhibits a reasonable pattern that assists to order the activities defining project scope and execution.
Validation Master Plan (VMP)
Process Validation Master Plan summarizes overall validation strategy across the organization containing documentation for validation life-cycle components right from commissioning till decommissioning. These components include Process, Equipment, Utilities, Cleaning Procedures, Computer Systems, Test Methods, etc. VMP also captures the validation status of each component to evaluate the impacts on product quality, efficacy, or even identity.
It is basically a list (controlled document) of the reference numbers related to all the validation activities such as Protocols, Final Reports in the organization. This log maintained to support the validation status of each applicable and not applicable component.
Following items considered to be the part of VMP at-least;
- Product Name
- Validation Reference Number
- System Details
- System ID
- Review Date
- Re-validation Date (if required)
- Deviation, Non-conformance Reference Numbers (if applicable)
VMP Process Flow
Below mentioned is the simple process flow chart for different activities covered under VMP.
Following components considered essential to capture under Validation Master Plan.
- Drug Product
- Manufacturing Process
- Utilities in direct contact with product or process
- Validation Strategies or Plans
- Validation Protocols and Reports
- Relevant SOPs
- Roles and Responsibilities
- The flow of planned activities
- Equipment and ancillary systems that must be validated
- Periodic Review Program
- Any other component dealing as per validation requirements
VMP must address the following aspects to ensure its completeness, accuracy, and frequency.
- Changes in:
- Ancillary Systems
- Responsible Functions
- Validation Plans, Protocols and Reports
- Any additional validations other than proposed in strategies
- Updating VMP log for any addition, removal or modification of validation component
The purpose of performing periodic reviews deals with the concern – “whether the cumulative changes have affected the manufacturing process performance”. Supporting data to conclude periodic reviews can be collected from various sources such as:
- Environment Monitoring
- Test Reports
- Market Complaints
- Calibration Records
- Preventive Maintenance Records
- Quality Audit Records
- Process Monitoring and Control
Once all the events gathered and ready, periodic reviews shall be documented as per applicable templates to deem the component status as validated OR not-validated OR validation not required with ready justifications. At the same time, update the VMP log for the made decisions. This way the firm can perform effectively in terms of managing process validation cycles.
Process Validation Life-Cycle Documents
Documents that broadly considered as Validation Life-Cycle mentioned below, however, different organizations may include more additional requirements per their site policy.
Tools To Improve Effectiveness of Process Validation
Apart from regular manufacturing activities, the following tools are also used to improve the effectiveness of process validation. These tools help in monitoring and optimizing the process variables that bring out the desired result.
- Lean and 6 Sigma
- Process Capability
- 5 Why Analysis
- Fault Tree Analysis
- Fish Bone Diagram / Ishikawa Diagram / Cause and Effect Diagram
- Quality by Design (QbD)
- Design of Experiments (DOE)
- Process Analytical Technology (PAT)
- Gage R&R Study
You can read this article for more information on these tools, Quality by Design and 9 Allied Tools To Thrive Productivity.
When it comes to process validation, every step you take is counted reasonably and in a very common sense whether you are working from scratch or re-validating your existing processes. It is management’s responsibility to come up with a sound and scientific strategy and ensuring that actually execute on the ground.
Hope you find this guide insightful and valuable for your Process Validation know-how. The aim of this article was to put process validation in a single picture rather than different pieces the learner needs to understand separately.