Validating a pharmaceutical manufacturing operation is an essential aspect of the production of quality pharmaceutical products in accordance with predetermined quality criteria. One of the most essential types of validation is prospective validation, as it provides documented evidence enabling a pharmaceutical company to commence commercial production prior to the commencement of normal commercial production.
A pharmaceutical company will typically conduct prospective validation during the product development phase or prior to beginning production using a new manufacturing process. Through prospective validation, the pharmaceutical manufacturer can identify variation in the manufacturing process, establish parameters for the manufacturing process and ensure that the physical product meets predetermined quality criteria prior to being released to the marketplace. Regulatory agencies have placed strong emphasis on prospective validation through Good Manufacturing Practices (GMP) due to the fact that prospective validation reduces the potential risk of manufacturing failures and defective products.
- Selecting the specific manufacturing parameters
- Conducting formulation studies
- Selecting the appropriate equipment
- Conducting an initial risk assessment
This stage establishes the basis for all subsequent validation activities.
- Qualification of the equipment
- Qualification of all utilities
- Conducting specific manufacturing trials
The process is qualified after obtaining three consecutive successful batches.
- Trend analysis
- Monitoring during processing
- Quality review
If the process continues to be monitored, it will be maintained in a validated condition.
- The purpose and scope of validation
- Responsible parties
- How the process works
- What parameters are to be monitored
- How samples will be selected
- Criteria to evaluate the success of the validation process
The protocol must be approved prior to the initiation of the validation process.
- A Failure Modes and Effects Analysis (FMEA)
- A risk ranking
- A Hazard Analysis
These tools can be used to help define the scope of validation efforts.
- Installation Qualification (IQ)
- Operational Qualification (OQ)
- Performance Qualification (PQ)
Equipment qualification verifies the dependability of the process.
- Size of batches
- Variability in beginning materials
- Conditions under which the process will be performed
Typically, three consecutive validation batches will be assessed for validation.
All critical parameters will be evaluated during the entirety of the manufacturing process. Examples include:
- Time for mixing
- Amount of force applied for compression
- Temperature during drying process
All observations made will be documented thoroughly.
- While in production
- Once finished
- Continuously during the stability study
Comparison of test results against pre-established specifications will begin at this point.
- Variability of processes
- Uniformity of processes
- Reproducibility of processes
If there are any deviations, they must be investigated thoroughly.
- An overview of all validation activities
- All test results
- Any deviations or investigations performed
- Final conclusion regarding whether validation was successful
The manufacturer will require Quality Assurance (QA) signature as part of the validation approval process for all validations.
Most pharmaceutical companies prefer to perform prospective validation because this reduces the risk to the company and helps them with the release of their products.
- Approving protocols/reports
- Reviewing deviations
- Verifying compliance with all Good Manufacturing Practice requirements
- Overseeing that documentation practices comply with Good Manufacturing Practice requirements.
Regulatory Expectations from the Pharmaceutical Industry
In order to comply with regulatory agencies, pharmaceutical companies must:
In pharmaceutical manufacturing, prospective validation is considered one of the critical methods of validation. It provides written evidence of the ability of a process to consistently produce items meeting specified quality standards prior to starting commercial distribution.
Pharmaceutical manufacturers can use a structured procedure for validation as well as proper documentation and risk-based controls to help ensure compliance with applicable regulations, reliability of processes and quality of products. Today’s pharmaceutical manufacturing uses prospective validation as a significant basis to assure quality and safety for all customers.
What is Prospective Validation?
Prospective Validation shows valid and reliable evidence (i.e. objective evidence) that a specific manufacturing process can manufacture products consistently to meet the established predetermined specifications for quality (standard). This validation of a manufacturing process is done:- Before a process is in routine production
- Before a product is released to the market
- Before a new process/system is implemented
Importance of Prospective Validation
The preferred method of validating manufacturing processes is through prospective validation as this method evaluates how well the process will perform before products are manufactured (distributed to the market). Positive outcomes of prospective validation include:- Assurance that all products will be consistently produced with good quality.
- Identification of critical parameters in a manufacturing process.
- Reduction of the risk of manufacturing failures.
- Reduction of the risk of product failures at the end of the product.
- Supporting compliance with regulations.
When is Prospective Validation Required?
There are many scenarios where prospective validation is commonly needed. Some scenarios include:- New product introduction
- Installing new equipment
- Transferring a manufacturing process
- Modifying an existing process significantly
- Starting up a new manufacturing facility
Key Objectives of Prospective Validation
The main objective of prospective validation is to demonstrate that the process can produce a consistent output result for all batches of product produced using the process. The other objectives of prospective validation include:- Establishing critical parameters for the process
- Defining acceptable limits for operating conditions
- Determining the ability of the process to produce the same output from batch to batch (reproducibility)
- Assessing the ability of the process to achieve its desired end result (capability)
- Assisting in obtaining regulatory approval for the product being produced (confirmation)
Stages of Prospective Validation
The stages of prospective validation are systematic and scientific by nature.1. Development of the Manufacturing Process
At this stage, the manufacturing process is designed and optimized. Preparation for Manufacturing will include:- Selecting the specific manufacturing parameters
- Conducting formulation studies
- Selecting the appropriate equipment
- Conducting an initial risk assessment
This stage establishes the basis for all subsequent validation activities.
2. Qualification of the Manufacturing Process
Qualification of the manufacturing process demonstrates that the system is operating properly under the actual conditions stipulated for use. It entails:- Qualification of the equipment
- Qualification of all utilities
- Conducting specific manufacturing trials
The process is qualified after obtaining three consecutive successful batches.
3. Continued Monitoring of the Manufacturing Process
After the manufacturing process has been validated, it will be routinely monitored to ensure that it continues to meet the manufacturer's specifications. Continued monitoring will include:- Trend analysis
- Monitoring during processing
- Quality review
If the process continues to be monitored, it will be maintained in a validated condition.
Procedure for Prospective Validation
There are a number of steps involved in carrying out a successful prospective validation.Step 1. Validation Protocol
The validation protocol is an important document to comply with when performing prospective validation; it establishes the framework for conducting the process. The protocol must contain:- The purpose and scope of validation
- Responsible parties
- How the process works
- What parameters are to be monitored
- How samples will be selected
- Criteria to evaluate the success of the validation process
The protocol must be approved prior to the initiation of the validation process.
Step 2. Risk Assessment
The risk assessment identifies the process variables that could affect product quality. Commonly used tools used for this purpose are:- A Failure Modes and Effects Analysis (FMEA)
- A risk ranking
- A Hazard Analysis
These tools can be used to help define the scope of validation efforts.
Step 3. Qualification of Equipment and Utilities
All associated equipment and systems must be qualified prior to performing process validations. Equipment must undergo:- Installation Qualification (IQ)
- Operational Qualification (OQ)
- Performance Qualification (PQ)
Equipment qualification verifies the dependability of the process.
Step 4. Selection of Validation Batches
Validation batches must represent production conditions that resemble those under which routine production occurs. Areas of consideration include:- Size of batches
- Variability in beginning materials
- Conditions under which the process will be performed
Typically, three consecutive validation batches will be assessed for validation.
Step 5. Execution of Validation Batches
All manufacturing will take place per established procedures.All critical parameters will be evaluated during the entirety of the manufacturing process. Examples include:
- Time for mixing
- Amount of force applied for compression
- Temperature during drying process
All observations made will be documented thoroughly.
Step 6: Sampling and Testing
Sample collection occurs at multiple points throughout production. Testing may be performed:- While in production
- Once finished
- Continuously during the stability study
Comparison of test results against pre-established specifications will begin at this point.
Step 7: Analysis of data
The analysis of collected data begins to ascertain if manufacturing processes are consistent and capable. Statistical analysis may be done on the following types of data:- Variability of processes
- Uniformity of processes
- Reproducibility of processes
If there are any deviations, they must be investigated thoroughly.
Step 8: Validation Report Preparation
Upon successful validation completion a validation report is prepared by the manufacturer. The report will include:- An overview of all validation activities
- All test results
- Any deviations or investigations performed
- Final conclusion regarding whether validation was successful
The manufacturer will require Quality Assurance (QA) signature as part of the validation approval process for all validations.
Acceptance Criteria in Prospective Validation
Acceptance Criteria for Prospective Validation must be based on scientific justification and be predetermined. Some common examples are:- Due to product assay limits
- Dissolution specifications
- Weight variation limits
- Microbial limitation
Documentation Requirements
Documentation is necessary to meet regulatory requirements. Key documents include:- Validation master plan
- Validation protocol
- Batch manufacturing records
- Test reports
- Validation report
Advantages of Prospective Validation
There are many advantages associated with Prospective Validation. Some major advantages are:- Identify process issues early on
- Clearer understanding of how the process works
- Less likely to experience product failure
- More likely to meet regulatory requirements
- Higher quality products
Challenges with Prospective Validation
Despite these advantages; many companies will have realistic challenges. Examples of these types are:- High level of resources
- Longer time to complete studies
- Some variation in process
- Incomplete data collection
Difference Between Prospective and Concurrent Validation
One primary difference between prospective and concurrent validation is the "timing" of when these validations take place.Prospective Validation
Prospective Validation is performed before the final product will be sold.Concurrent Validation
Concurrent Validation is performed while the routine production run of a product is released to the market.Most pharmaceutical companies prefer to perform prospective validation because this reduces the risk to the company and helps them with the release of their products.
Quality Assurance Contribution Towards Validation Process
Quality Assurance plays an important role in all aspects of the validation process. Quality Assurance is responsible for:- Approving protocols/reports
- Reviewing deviations
- Verifying compliance with all Good Manufacturing Practice requirements
- Overseeing that documentation practices comply with Good Manufacturing Practice requirements.
Regulatory Expectations from the Pharmaceutical Industry
In order to comply with regulatory agencies, pharmaceutical companies must:
- Have a scientifically sound validation approach
- Identify critical process parameters
- Properly keep records of all validations
- Perform ongoing process monitoring
Best Practices for Prospective Validation
Some of the best practices for prospective validation are:- Utilize a risk-based approach
- Use clearly defined acceptance criteria
- Properly train personnel
- Maintain comprehensive documentation
- Perform a statistical review of all validating data
When Does a Validation Require Revalidation?
A validation may require a re-validation under the following circumstances:- Modification of an existing process
- Change of an existing piece of equipment associated with the validation
- Deviation from the validation results
- Changing the batch size of a product
- Using a different raw material in the manufacturing process
In pharmaceutical manufacturing, prospective validation is considered one of the critical methods of validation. It provides written evidence of the ability of a process to consistently produce items meeting specified quality standards prior to starting commercial distribution.
Pharmaceutical manufacturers can use a structured procedure for validation as well as proper documentation and risk-based controls to help ensure compliance with applicable regulations, reliability of processes and quality of products. Today’s pharmaceutical manufacturing uses prospective validation as a significant basis to assure quality and safety for all customers.
Frequently Asked Questions (FAQs) on Prospective Validation
Q1. What is prospective validation?
Answer: Prospective validation is a record of how a process can always produce products of high quality prior to marketing.Q2. Why prospective validation is needed?
Answer: To provide proof of consistency of product quality, consistency of the process and compliance with regulations prior to starting normal manufacturing activities.Q3. When is prospective validation performed?
Answer: Prior to launching a new product, process or manufacturing system.Q4. What is the average number of batches that are validated?
Answer: Three successful consecutive batches from the same lot.Q5. What is in a validation protocol?
Answer: A validation protocol includes scope, responsibilities, sampling plans, acceptance criteria and testing methods.Q6. What is the purpose of a risk assessment in prospective validation?
Answer: A risk assessment will identify critical parameters relating to how a process will produce a quality product.Q7. What is the primary difference between prospective validation and concurrent validation?
Answer: Prospective validation occurs prior to release of a product, while concurrent validation occurs during normal production.Q8. What are the expectations of regulators regarding prospective validation?
Answer: Scientific evidence of product consistency, process consistency and adherence to Good Manufacturing Practices.
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