Validation of retrofit API facilities


J Robert Adamson, manager compliance & validation, pharmaceutical division at Foster Wheeler Energy, reviews qualification requirements for the introduction of APIs that may be new, or already in production at other sites but may be new to a facility

J Robert Adamson, manager compliance & validation, pharmaceutical division at Foster Wheeler Energy, reviews qualification requirements for the introduction of APIs that may be new, or already in production at other sites but may be new to a facility

The demands of the pharmaceutical industry to both maximise the utilisation and reduce costs for API manufacture has led to an increased focus on the reuse and refurbishment of existing facilities. The drivers for these may arise from:

  • A requirement to expand and provide new capacity for existing products
  • Introduction of a new product into the facility
  • Bring back into service a facility that
  • has been mothballed.
  • The impact of these leads often to;
  • The need to refurbish exiting equipment and utilities
  • Increases or changes to existing facility and equipment to provide new or additional capacity
  • Additional utility infrastructure to meet new manufacturing methods or new legislation
  • Upgrades to meet the latest requirements for GMP operation and validation

This article focuses primarily on the qualification requirements for the introduction of products that may be new or already in production at other sites but that are new to the facility.

Early definition of the scope is critical to the success of these projects. The project sometimes involves facilities that are close to the end of their original design life and a substantial upgrade is required to current Good manufacturing Practices. A good understanding of these factors is essential to developing a successful validation strategy and detailed plan for the facility and equipment. The overall process is shown in figure 1.

initial site investigation

The first step on the process is to clearly define the scope of work. This would involve a detailed survey of the building and equipment to determine both status and suitability for the new processes. Initially this would involve both a physical survey on site and a detailed review of documentation that may or may not be available.

The site survey would typically comprise a complete review of:

  • Equipment, pipework, instruments and electrics
  • Control and automation
  • Process services
  • Utilities including HVAC
  • Building fabric
  • Materials and personnel flows

A review of equipment pipework and E&I would address such questions as:

  • is the equipment vendor still able to support the system?
  • are spares still available?
  • is material certification available for contact parts?
  • are the existing maintenance records up to date?
  • do the drawings reflect the current as built. status?
  • is asbestos present?

Automation systems can present additional problems. These may be no longer supported or may have not been validated to current standards such as GAMP1 especially for older legacy systems. Replacement may well be the best option. Process services and utilities will need examining for capacity and a thorough check on operation and suitability for any new process to be introduced into the facility.

The overall fabric of the facility and its state will depend on its age and the level of maintenance. It is important to review its use in respect to materials and personnel flows, amount of space for storage of working progress, zoning and pressure cascade both in terms of safety and environment to ensure that it meets current standards for both of these.

This review will enable a gap analysis to be completed that will define requirements for the products and processes to be operated in the facility in terms of:

  • status and requirement for upgrade or replacement of existing equipment, pipework and electrics and instrumentation
  • any upgrades that may be required to control and automation systems
  • status of current documentation for the operation and maintenance
  • status of validation documentation

Other factors that may need to be considered are location of the project, and an evaluation of its effects on the surrounding operations and the overall factory supply and logistics chain. A plan will be required to include how to manage interruptions in services, or segregation to avoid contamination to adjoining operation; decontamination may be necessary if changing products.

The status of existing qualification documentation can be critical to the extent of the whole validation exercise. A well maintained set of validation/qualification documents will reduce the effort substantially. However, for such facilities that have been standing idle for a period of time it is likely that the documentation has not been maintained and has limited value. Whichever is the case the expectation of the regulators is that the new validation programme will be prospective not retrospective. This does not mean that previous data is no longer valid but that it must be supported by current information that confirms the suitability and fitness for purpose of the facility for its new operating intent.

validation planning

The overall approach is to develop a Validation Master Plan that is prospective and incorporates the following principles:

  • use of a risk Based Approach typically based on the ISPE Baseline Guide for Commissioning and Qualification2.
  • focus on the critical product quality attributes (CQAs) and critical process parameters (CPPs)
  • development of a systems list and conduct system and Component Impact Assessments
  • maximum use of Good Engineering Practices
  • maximum use of existing corporate and site Validation/ Qualification Procedures and Documentation
  • use of a fully integrated approach with the commissioning

Key assumptions for any plan would be:

  • The existing validation documentation is available but a prospective approach will be required
  • The critical process parameters and critical steps are well characterised and understood.

systems and impact assessment

A comprehensive list of systems should be developed. These would include all process and process services, utilities, electrical, instruments, civils, building services and structural. Whilst the validation would primarily focus on process and process services all these will or may require some engineering design, construction and commissioning.

The impact assessment process will identify those systems that do have a direct impact on product quality attributes (CQAs) and critical process parameters (CPPs). These are designated as direct impact systems and would define those systems that have an impact on CQAs and CPPS. These direct impact systems will require qualification systems. The remaining systems are designated as having indirect or no impact. All systems will be subject to Good Engineering Practices (GEP)2. This process must be documented and approved by the quality group as it defines the extent and scope of the qualification.

The gap analysis that as been conducted can now be used to complete the extent of the qualification activity.

A typical focus of the assessment will identify materials of construction as a key requirement for the process. Providing the equipment and instrumentation details have been maintained there should be records from the original documentation to confirm the materials of construction. Any items that are new or sent for refurbishment can be provided with new certification. Clearly the greatest effort from a GMP perspective would be the process and process utility piping. The question is how much inspection and testing is required. The approach to this should be risk based and consider such factors as:

  • Age of the system and level of maintenance record
  • The duty and any proposed change in duty
  • Risk of contamination from the piping and fitting
  • Cleaning especially if a multiproduct and multipurpose use

Early site inspection should have included a visual check on the piping and fittings. A level of further inspection and testing would then be set based on the evaluated risks and set some predetermined acceptance criteria. This may comprise a visible check externally and internally, and/or some level of testing for materials of construction. Failure to meet the acceptance criteria should be included in the plan. For example an initial 10% check on the visual state of pipework may find an unacceptable level of issues. The plan would allow for this and perhaps state that additional inspections be carried out and including an increased percentage of materials of construction testing.

commissioning plan

A commissioning plan should be prepared to cover all the systems that require commissioning. These are likely to be the utilities, process services and process systems. There is some merit in commencing the commissioning of those systems that do not require any or limited modification as soon as they are available. If the overall project schedule is such that they are not required immediately they can be put into a planned preservation programme. This approach minimises the overall risk and allows increased focus on those systems that are product critical. Quality should review this plan but approval is not a regulatory requirement.

The overall construction and commissioning should be an integrated schedule and take full account of validation requirements. Commissioning should be to GEP and be documented with relevant test documents and certification of completion. This is especially important where commissioning test results are being use in support of qualification. Where the tests are recorded and conducted to GEP there is no requirement to repeat this work for regulatory reasons. This is completely consistent with the principles detailed in the ISPE Baseline Guide for Commissioning and Qualification reference1.

engineering design and DQ

Where there is new design or the design purpose has changed there should be a review to ensure that the design meets all user requirements including those for product quality and process. This would be executed through a series of design reviews typically: HAZOP, Constructability, Maintenance, and Materials of Construction, (Note for safe design and operation it would be normal practice to revisit the earlier HAZOP for the whole facility to confirm that there was no change).The GMP and quality requirements are often covered in a GMP and Compliance review which would be attended by the client quality representative. This reviews the design to ensure that it meets regulatory requirements and is suitable a fit for purpose and will meet the requirement for CQAs and CPPs. Where design qualification is a client requirement these reviews can form the basis of the DQ.

IQ and OQ

IQ and OQ protocols would be prepared for the direct impact systems. The acceptance criteria will have been determined though knowledge of the CQAs and CPPs and the system and component impact assessment. Approvals will be required as a minimum for IQ by both QA and Engineering and plus Operations for OQ. Others groups may be required to approve these documents as laid down in site and corporate procedures.

Where existing documentation for IQ and OQ is good and well maintained the qualification can be simply an addendum to the existing. However for older facilities, and especially those that have lain idle, it is more likely that there is no or limited reliable qualification data. In these cases a more comprehensive protocol is required.


Similarly to that for the facility and equipment the process control and automation systems will require to be assessed for suitability and fitness for purpose. The assessment should typically cover:

  • Age of the system and level of current support that is available
  • Is there sufficient capacity in the system for the new activities
  • Level of knowledge of support personnel
  • Is current validation documentation upto date and support current standards

Should any of these items not have an adequate answer then the most likely option will be to provide a new system which based on the projected new extended life of the facility is likely to be the most cost effective and least risk option


Validation of retrofit facilities should always be based on a detailed review and assessment of the facility and equipment. This ensures a clearly defined scope. Use of risk-based approaches provides focus on those areas that have greatest impact on product quality and process control. The process needs to be prospective in order to meet current regulatory expectations.