Validation for Contract Manufacturing Organizations

Carrying out validation in Contract Manufacturing Organizations (CMOs) is more complicated than doing validation in a single-site pharmaceutical company. Product quality is the responsibility of two entities: the contract giver (the entity that owns the marketing authorization or the product) and the contract manufacturer (the entity responsible for production and compliance with GMP).

The validation program should guarantee an appropriate scientific justification for the processes, equipment, analytical methods, cleaning procedures and documentation while indicating who is responsible for their execution. Whenever regulatory inspections are conducted, this is typically one of the first fields inspected, as if responsibilities are not distinct, this can lead to severe compliance issues.

In my practice, I check that the technical agreement, validation approach and responsibilities in regard to quality are in correspondence with one another. Otherwise, it will be hard to justify the validation program.

Start With a Clear Technical Agreement

Prior to the commencement of process validation, it is necessary for the two parties to come up with a thorough quality or technical agreement. Such an agreement should be able to specify the ownership of the activities related to validation instead of relying on presumptions.

Some of the responsibilities include:

• Taking charge of process validation
• Performing qualification of equipment
• Conducting cleaning validation
• Validating or transferring analytical methods
• Giving approval for change control
• Investigating deviations
• Executing CAPA
• Establishing responsibilities for stability
• Supporting batch release
• Communicating with regulatory institutions

In addition, the agreement must clearly specify how the data related to validation would be shared and examined.

Technology Transfer Comes Before Process Validation

There are many difficulties in validation that come from the technology transfer as opposed to the validation stage itself.

The receiving plant must have a clear sense of product formulation, important process parameters, production procedure, in-process controls, equipment difference, analytical approaches and quality characteristics before the commercial validation.

One of the common mistakes I notice is that people sometimes think that having a successful development batch gives people automatic results of the commercial process in another plant. Equipment geometry, blending efficiency, heating properties, as well as automation and scale are factors that can have an effect on the process outcome.

Being structured in the technology transfer means that it allows creating a good basis for the successful process validation.

Structuring the Risk-Based Validation Strategy

Validation for Contract Manufacturing Organizations (CMOs) must start with the formulation of a written quality risk evaluation. The importance of factors that may impact product quality should be recognized first, rather than testing all factors equally.

This assessment must include:

Validation Area	Risk Considerations
Manufacturing Processes	Key Process Parameters
Equipment	Scale and Design Variations
Cleaning	Symptoms of Carryover and Worst-Case Approach
Utilities	Water Supply, Heating Ventilation and Air Conditioning (HVAC) System and Compressed Gases
Analytical Techniques	Transfer and Verification of Analytical Techniques
Packaging	Risks Related to Line Set-Up and Changeover
Computerized Systems	Data Integrity and Control of Access

A crucial takeaway from the quality assurance perspective regarding the risk evaluation process is the need to have it as a living document that needs updates whenever there are any changes in related processes.

Process Validation Requires Joint Scientific Review

It is important to consider that although the contract manufacturing organization (CMO) carries out the production of validation runs, the owner of the product will have to be involved in assessing the scientific justification behind the process in question.

A complete package for process validation includes:

• A protocol approved by the relevant parties
• Documentation about the manufacturing processes
• Monitoring of process parameters
• Conducting testing of the intermediary products
• The rationale for sampling
• Statistical analysis in relevant cases
• Any deviations
• Corrective and preventive actions
• The report on validation results

When I am examining an investigation, I look for evidence of both companies' assessment of the surprising findings instead of focusing solely on whether one of the companies produced the report.

Cleaning Validation Often Becomes the Highest Risk

Most of the time CMOs fabricate a variety of products on the same equipment, so cleaning validation is very important.

The validation plan should provide justification for:

• Worst-case products selection
• Equipment grouping
• Places for sampling
• Recovery studies
• Acceptance criteria
• Maximal holding times
• Manufacturing campaigns

One thing I have always paid attention to is whether new products are still included in the original worst-case analysis. Potency, solubility, toxicity and cleanability of new product classes would need fresh validation, not thinking that previous validation is still applicable.

Cleaning validation should change with the product portfolio and not remain unchanged after the first study.

Managing Changes Across Two Organizations

Controlling changes becomes much tougher in contract manufacturing because one alteration can influence numerous verification and regulatory obligations.

The following are examples:

• Replacement of equipment
• Change of the supplier of raw materials
• Change of manufacturing parameters
• Adjustment of analytical techniques
• Change of utilities
• Upgrade of software
• Modification of packaging machines

Each important change must be validated before its implementation through a particular document.

Questions to ask:

• Is the validated status going to be affected by the change?
• Is there a need for revalidation, either full or partial?
• Should the approval of the change by the product owner be sought?
• Do regulatory papers need to be changed after the change?
• Is there a need for modifications of already-existing documentation?

The efficient communication of QA departments is of immense importance in terms of appropriate change management.

Continued Process Verification After Commercialization

Just because three commercial batches have been successfully validated doesn't mean the validation process is over.

CMOs need to implement continued process verification. This means monitoring process trends, critical quality attributes, nonconformities, conditions of production environment, complaints and OOS/OOT results, equipment performance and periodic data from product quality reviews.

In many cases, regular trend analyses help detect gradual process changes before they become serious validation issues.

For instance, gradual increase of variability of mixing time or hardness of tablets might point to emerging changes in the processes that need further investigation, although the batches might still be within the specification limits.

This way of thinking is in line with modern GMP requirements.

Documentation That Should Always Be Inspection Ready

Inspections are often done by the authorities to cross-check that the supporting documents are available and linked to the final report.

The validation documents must provide complete traceability from performance to conclusion.

The list of important documents includes the following:

• Technical or Quality transfer agreement
• Validation master plan
• Technology transfer documents
• Risk analysis
• Qualification documents (IQ/OQ/PQ)
• Process validation protocol and report.
• Cleaning validation certificates
• Analytical methods transfer documentation.
• Deviation and CAPA
• Change management process.
• Ongoing process verification documentation

In other words, I would consider a validation process inspection-ready only when it can link all findings to supporting evidence.

Common Validation Gaps in Contract Manufacturing

1. There are a few common failures in any auditing process relevant to contract manufacturers.
2. Lack of clear accountability on both the part of contract giver and contract manufacturer
3. Incomplete documents regarding technology transfer
4. Deficient impact validation assessments whenever any changes occur
5. Old rationale for conducting worst-case cleaning validation
6. Insufficient checking for continued process verification
7. Inconsistencies in record-keeping between quality control systems
8. Delays in reporting of failures with regard to validated processes

Many such problems can be avoided by increases in governance, not by performing additional tests.

For Contract Manufacturing Organizations, validation is principally about the corporate role shared by both parties . The CMO helps develop the validation methods and conducts testing of the validated process, but both parties ensure that the validated process is executed under controlled conditions characterized by a thorough documentation.

A successful program combines technology transfer with the approaches to validation that are based on risk assessment, cleaning validation methodologies and strict procedures for change management and process verification along with open communications between the parties.

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