Validation Strategy for Contract Manufactured Products

The decision to outsource pharmaceutical manufacturing is an important aspect in the operations of many businesses. Contract Manufacturing Organizations (CMOs) offer extra advantages, such as manufacturing capacity and technological capabilities and allow Marketing Authorization Holders (MAHs) to concentrate on development and commercialization. Nevertheless, it is crucial to keep in mind that regulatory requirements need to be met independently from outsourcing. In this respect, regulatory bodies state that product owners are responsible for ensuring the product is manufactured in compliance with necessary regulations.

Nevertheless, the key issue of technology transfer to the contractor is the successful development of a validation strategy. In the absence of it, companies face delays in commercialization, inconsistencies in the manufacturing process, regulatory problems and constant validation. In order to avoid the above-mentioned issues, the validation plan ought to define responsibilities, requirements of validation and control over the process in the course of the product lifecycle.

My experience with similar projects has taught me that validation failure is hardly ever caused by poor testing; rather, it is result of the lack of clarity regarding the obligations of those involved, the absence of the complete transfer of technology, or the manufacturing site specifications differing from those at the pilot production. A good validation plan takes care of the aforementioned problems even before commercial production starts.

What is a Validation Strategy?

A validation strategy is simply a plan a manufacturer has documented that describes the validation process in detail.

The following components (for contract manufacturing) should be included in the strategy:
- Validation of the manufacturing process
- Qualification of the equipment
- Qualification of the utilities
- Cleaning validation
- Transfer and validation of analytical methods
- Validation of the computerized systems
- Validation of packaging
- Validation of the transport
- Continued process verification (CPV)
- Change management after commercialization
The intention of these activities is to create a cohesive plan rather than to simply carry out the processes independently.

Reasons to Have a Separate Validation Approach for Contract Manufacturing

Making a product at a contract facility brings in many new variables that do not exist in a self-manufacturing facility.

These can include:

• Different types of machines
• Different automation processes
• Different local procedures
• Different utility make-ups
• Different environments
• Different experiences of staff
• Different sources of raw materials
• Different packaging processes

Even when the production process is similar, these differences can impact the operation of the process. Thus, the validation method should take into consideration site-specific characteristics that influence the quality of the product.

Define Roles and Responsibilities Early

The first important step should be clarifying who is responsible for validation.
The Marketing Authorization Holder has various responsibilities, including the following:

• Defining the required quality attributes of the product
• Supplying necessary expertise on development and validation
• Signing validation plans and reports
• Investigating non-compliance issues
• Interacting with the regulators
• Approving important changes in the process.

The Contract Manufacturer's job includes the following:

• Conducting the validation tests
• Keeping the manufacturing system compliant and efficient
• Hiring trained personnel
• Managing manufacturing
• Implementing necessary calibrations and maintenance activities
• Keeping records of all validation processes.

These responsibilities must be written down in a Quality Agreement prior to starting validation.br />

Perform a Gap Assessment Before Validation

A gap assessment is necessary before writing validation plans by comparing both parties involved in production and analyzing aspects such as:

• Collection of equipment abilities
• Availability of different utilities
• Manufacturing process flow
• Site layout
• Environmental classification
• Automation processes
• Cleaning process performed
• Process control

The gaps identified must get corrected before proceeding with commercial validation.

Use Risk Assessment to Build the Validation Strategy

The validation strategy ought to be based on risk assessment.
A cross-functional team ought to identify the following:

• Critical Quality Attributes (CQAs)
• Critical Process Parameters (CPPs)
• Critical Material Attributes (CMAs)
• Possible failure modes
• Worst-case operating situations
• High-risk manufacturing processes

Risk assessment methods such as Failure Mode and Effects Analysis (FMEA) could prioritize the validation process and identify the need for further testing. It’s necessary to revise the risk assessment whenever there are significant changes in the process.

Develop a Comprehensive Technology Transfer Package

The process of technology transfer must involve a lot more than just the instructions for manufacturing.
An ideal kit should have such elements as:

• Reports on the product development
• Data regarding the development of the process
• Manufacturing instructions
• Records of the manufacturing processes
• Diagrams of the processes
• Information about validation
• Main process parameters
• Key features of the quality
• Stability information
• Information regarding cleaning validation
• Details regarding the methods of analysis
• Plans of sampling
• Data about deviations

Absence of some information during technology transfer can lead to many unnecessary failures.

Equipment and Utility Qualification

Prior to the start of the process validation process, all of the support systems must have satisfactory qualification.

The normal qualification steps are as follows:

• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Performance Qualification (PQ)

Additionally, the possible support utilities consist of:

• Purified water systems
• Water for Injection (WFI)
• Compressed air
• Clean steam
• HVAC systems
• Nitrogen supply
• Process gas

It would not be correct to say that the manufacturing process is accurately validated without the qualifying of support infrastructure.

Process Validation Strategy

The validation procedure should be descriptive as far as the conducting of PPQ batches is concerned.

Elements of consideration include:

• Number of validation batches
• Size of a batch
• Where to sample
• How often to sample
• Criteria of acceptance
• The worst-case scenario
• How to evaluate data statistically
• How to handle deviations

Validation processes should confirm that the site can produce an exact product as the site of origin does.

Cleaning Validation

It is important to focus on cleaning validation since the equipment design varies from one manufacturing location to another.

The strategy must cover the following aspects:

• Grouping of products
• Selection of the worst-case product
• The process of cleaning
• Sampling techniques
• Recovery tests
• Acceptance criteria
• Criteria for visual inspection
• Cleaning schedule

When cleaning processes are considerably different, earlier validation results might not apply directly.

Analytical Method Transfer

The quality of a product cannot be ensured unless the analytical methods used in the new laboratory work reliably

Analytical method transfer must involve:

• Accuracy
• Precision
• Repeatability
• Intermediate precision
• Suitability for use qualifications
• Operator-to-operator variability
• Instrument equivalency

The source of any identified discrepancies needs to be understood before normal laboratory testing can commence.

Validation of Packaging Process

When CMO handles the packaging, validation is supposed to include:

• Clearance verification of the packaging line
• Label reconciliation
• Qualification of the vision system
• Verification of serialization
• Testing of packaging integrity
• Verification of printing
• Verification of parameters of the barcode

Errors in packaging can lead to serious regulatory implications even if manufacturing is managed properly.

Managing Deviations During Validation

Validation can be done through a predefined course of action with regards to errors that have occurred.
In particular the kind of dangers that happened should determine:

• Root cause
• Impact of the product
• Impact of validation
• Corrective action to be performed
• Preventive action to be taken
• Need for modification of protocol
• Need for another validation

The results of validation should always take into account the results of the investigation of the errors that occurred.

Continued Process Verification

Continued Process Verification must not finish with the last PPQ run of batches.
The validation approach must comprise continuous verification of:

• Important Process Attributes
• Important Quality Characteristics
• Process efficiency
• Yield fluctuations over time
• Frequency of deviations
• Customer feedback
• Chemical stability behavior
• Annual Product Quality Assessment reports

Ongoing Process Verification allows us to secure that the supplied technology keeps working correctly during the production.

Common Challenges During Contract Manufacturing Validation

The factors making validation problematic for contract manufacturers include the following:

• Lack of complete tech transfer
• Different specifications of equipment
• Discrepancies in documentation
• Lack of communication between companies
• Delays in deviations investigations
• Different interpretations of validation process
• Poor management of change

All of the above problems may be solved with proper planning and cooperation.

Best Practices for a Successful Validation Strategy

The most effective contract manufacturing campaigns have a few important things in common.

• Prepare a comprehensive Quality Agreement before the transfer.
• Make sure to involve both parties in the validation planning stage.
• Conduct detailed risk and gap analysis.
• Transfer the full process knowledge, not just the production process instructions.
• Use a multidisciplinary review team.
• Establish the acceptance criteria before the start of validation.
• Review validation study results together.
• Keep in touch throughout the project.
• Conduct routine analysis of process performance after commercialization.

These practices reduce validation delays and improve long-term manufacturing consistency.

In order to create a validation strategy for contract manufactured products, it goes far beyond simply handing over batch records and performing validation runs. The process should feature a roadmap that combines technology transfer, risk management, qualification, process validation, analytical method transfer as well as continued process verification into one comprehensive lifecycle plan. A clear division of roles and responsibility, scientific decision making and effective communication between product owner and contract manufacturer are crucial for ensuring product quality and adherence to regulatory requirements.

One of the consistently observed conclusions from successful technology transfer projects is that companies that spend time on thorough planning face significantly lower validation problems during commercial production. A properly planned validation strategy is the basis for not only ensuring regulatory approval but also establishing successful mobile cooperation between Marketing Authorization Holder and Contract Manufacturing Organization throughout the whole life cycle of the product.

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