Victor Bornsztejn is Global Growth Director - Life Science Services, Ge Healthcare (USA).

Victor Bornsztejn

Despite the fact that regulatory compliance is fundamental to the pharmaceutical industry, too many manufacturers lose millions of euro in revenue because of poorly or incorrectly validated facilities. With increasingly demanding global regulations and guidance, rising manufacturing costs and dwindling product portfolios, it is vital to achieve efficient and effective compliance of facilities, processes and equipment to retain market competitiveness.    

Enhanced facility compliance (e.g., optimizing go-live dates, implementing standardized documentation, reducing errors and using risk-based strategies to minimize non-valueadded work) can be achieved by switching from the traditional method of validation to a modern modular approach that helps complete projects on time, assists the containment of cost, and supports the use of standardized methods that improve the accuracy of documentation. 

Currently, traditional facility validation programmes are complex, and the planning and execution phases are often initiated too late in the process (

). If the validation strategy is not agreed early enough (a common issue), it can contribute to projects running over budget and over time, which means facilities do not go live as scheduled and product manufacture is delayed.  

Under the traditional method, major facility components (e.g., process descriptions, documentation standards, protocols, standard operating procedures [SOPs], critical utilities, process equipment, automated manufacturing systems, validation programming information and validation status information) are detailed and mapped out from the start of the validation phase in a large and intricate site validation master plan (VMP). This approach does not necessarily employ a validation team, which would help ensure the planned project delivers the necessary evidence to support facility and process approval. Additionally, because the VMP is used as a repository for all validation-impacting information, it is hard to compile, control and maintain, making it difficult to complete projects. Critically, the VMP is not a flexible document and needs constant revisions as the construction of the facility progresses, which can lead to delays in golive dates and product manufacture. There is usually little or no link to process development and process understanding; because important validation decisions are not necessarily based on the critical quality attributes of the product to be manufactured in the facility. This can result in non-valueadded validation effort and missing required work. 

The drawbacks of traditional facility validation methods result from a disparity between drug/process development, facility validation and ongoing facility compliance management. A carefully planned modular approach, however, can avoid these issues and increase the efficiency of achieving regulatory approval, thus improving the ability to complete projects on time, as well as assisting cost containment and supporting the use of standardized methods for enhanced documentation accuracy. A modular approach will also help minimize exposure to surplus information, while optimizing the level of control and ease of managing the compliance inspection process; for existing facilities, it minimizes the impact of change. 

Figure 1: Traditional facility validation programmes.			

Implementing a modular validation platform results in a validation process that is compliant with all current regulations, and provides a springboard for future-orientated regulatory initiatives. This includes standards and directives such as the FDA's 

Pharmaceutical cGMPS for the 21st Century — A RiskBased Approach

 and the ICH Q8, Q9 and Q10 guidelines, which demonstrate regulators' desire to use risk-management strategies to support all manufacturing and control activities.The ASTM E2500 guideline is already taking this a step further by steering validation towards a continuous verification process that is inherently risk-based, underpinning all decisions with detailed process and product knowledge.

Planning should begin before the facility has been designed (

) and all the parties involved should agree on the validation strategy. This requires a holistic approach to validation and not developing a detailed VMP too early for the reasons discussed earlier. It is, however, essential that the VMP is manageable, transparent and maintainable. 

Figure 2: Validation planning should begin earlier in the facility design/build project.			

A modularized document/ masterplan should be put together that begins with the high-level detail (e.g., setting out intent and broad observations) and building in the specific details

). Overall, this provides more efficient compliance with full traceability.    

Figure 3: Modular validation strategy.			

Starting with the activities highlighted in the top left hand corner of 

, the deliverables are mapped through to the end via traceability matrices.

  The production/process rationale drives the validation effort and clarifies what needs to be validated and what does not; dividing the facility into logical chunks minimizes the risk of doing unnecessary work.  

The process rationale, which evaluates the risks to product quality and formally documents the process-critical parameters, is the starting point for the validation programme and forms a platform for a series of risk assessments that are performed while the user requirement specifications (URSs) and detail of the fullscale production model are being developed. This provides a step-by-step analysis of the proposed production process and all the parameters that may have an impact on finished product quality. It also identifies non-critical parameters and justifies their lack of criticality. 

The benefits are that protocols and reports are developed in a way that each series of prerequisites, checks and tests has its own objective, methodology and acceptance criteria selection — with the detail (such as test scripts) and record sheets separated from the protocol to reduce review and approval times. Additionally, system definitions, which identify the physical boundaries of a system(s) and describe its complete set of attributes, enable descriptions in validation plans to be minimized, but supported by cross-referencing; for example, a complex automated cleaninplace (CIP) system linked to a variety of other systems would have a system definition that would be precise and information-heavy, whereas a vendor user's guide may be adequate for a simple pH meter. 

URSs hold all the known requirements of all stakeholders and are prepared before buying utilities, equipment and operating systems. Within a modular validation project, non-detailed and flexible URSs act as a 'master control' for more detailed system URSs. This ensures that, while there is enough information for prospective vendors to satisfy all necessary requirements, the URSs are flexible enough to allow more cost-effective and compliant solutions to be put forward. Because all validation protocols import their acceptance criteria via the URSs, a site project or operational change management system ensures that any modifications are recorded and that the validation programme is updated accordingly. 

Also, as discussed earlier, the validation plans (facility, manufacturing and cleaning) for a site do not need to be highly detailed and inflexible documents. System descriptions in VMPs and validation plans can simply be crossreferenced to system definition documents, which allows changes (other than to a critical parameter) to be easily added without revisions to plan(s).  

Essentially, the VMPs and validation plans serve as highlevel documents that refer back to specific and appropriate plans. This helps minimize the impact of any site changes, and specific changes can be recorded and documented in the most appropriate plan. For a new or existing facility, it is important that the level of detail in VMPs and validation plans is suitable to the knowledge and information available at the time it is generated, and then to build in details as the validation project develops. This saves time and money from not having to rewrite, revise and reissue the plan(s). 

Effective validation ensures better commissioning, good engineering practice, a higher standard of documentation, a platform and reference for future validation programmes, better employee appreciation of the process and, ultimately, increases the likelihood of success. Current, traditional methods to facility validation are complex and expensive, whereas a modular approach can help establish more effective validation platforms for both the short- and longterm, accelerating the time taken to bring a facility online and removing unnecessary validation work. Ultimately, more efficient compliance of facilities and manufacturing systems can be achieved compared with complex traditional approaches. 			

is Validation Program Director — Life Science Services, GE Healthcare (UK).			

is Global Growth Director — Life Science Services, GE Healthcare (USA).			

For more insight into efficient facility validation, read our exclusive interview with Victor Bornsztejn available at: 

1. ASTM, E2500 — 07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, May 2007. 

Articles

Despite the fact that regulatory compliance is fundamental to the pharmaceutical industry, too many manufacturers lose millions of euro in revenue because of poorly or incorrectly validated facilities. With increasingly demanding global regulations and guidance, rising manufacturing costs and dwindling product portfolios, it is vital to achieve efficient and effective compliance of facilities, processes and equipment to retain market competitiveness.