Victor Bornsztejn, global growth director, and Brian Collins, validation programme director, both of GE Healthcare Services, explore a new modular, more cost-effective approach to facility validation
RRegulatory compliance remains one of the greatest issues pharmaceutical manufacturers face. Poorly or incorrectly validated facilities and processes cost manufacturers millions of pounds in lost product and time, and companies regularly receive citations and warnings that are linked to their validation, or lack thereof, often for reasons that are easily avoidable.
Planning, designing, constructing and validating a new facility, or remodelling an existing one, are significant projects that are subject to budgets and timelines, but that, in reality, are often significantly more expensive and take much longer than originally expected.
With global regulations becoming increasingly stringent, manufacturing costs rising and product pipelines shrinking, it is important that manufacturers achieve regulatory compliance of facilities, labs, processes and equipment more effectively. That means optimising time to go-live, use of standardised documentation, using risk-based strategies to minimise non-value added work, reduction of errors etc., to remain competitive in the market.
Facility validation programmes are currently based on traditional and somewhat complex models, where validation planning and execution is often started too late in the project process (see Figure 1). Not agreeing the validation strategy early enough can lead to projects running over-budget and over-time - facilities simply do not go on-line as scheduled.
One of the reasons this occurs is because the major components of any facility validation project, such as documentation, protocols, standard operating procedures (SOPs), critical utilities, equipment and automated manufacturing systems, are detailed and mapped out from the beginning in a large and complicated site validation master plan (VMP) without engaging the validation department, which has the detailed compliance understanding to ensure the project will deliver the necessary evidence to support facility and process approval. Currently, this level of detail and assumption comes too early.
Once this approach to validation of using the VMP as a repository for all information affecting validation has been adopted, it is hard to compile, and difficult to control and maintain - and subsequently to complete projects. Critically, this VMP is not a flexible document and usually needs revisions and rewrites as the facility's construction progresses. The impact can be significant; delays in the go-live date can lead to delays in product manufacture with additional costs and loss of revenue.
process involvement
Another important consideration is that there is usually little or no link to process development and process understanding. This means that important validation decisions are not based on the critical quality attributes of the product to be manufactured, resulting in unnecessary validation effort, missing required work or both.
Currently, there remains a disconnect between drug/process development, facility validation and ongoing facility compliance management. For this reason GE Healthcare has launched a global service for complete facility validation (for new or existing builds) including all facilities, utilities, equipment, computer systems etc. The objective is to improve the efficiency of achieving regulatory approval of a facility by using a new approach to validation that improves the ability to complete projects on-time, assists the containment of cost and supports the use of standardised methods that improve the accuracy of documentation.
Ultimately, manufacturers will benefit from more efficient and comprehensive compliance of their facilities and manufacturing systems when compared with complex traditional approaches.
Manufacturers work against a background of high activity with a proportionate level of supporting documentation. GE Healthcare's Modular Validation Platform (MVP) is designed to minimise the exposure of surplus information, while optimising the level of control and ease of managing the compliance inspection process; for existing builds it minimises the impact of change. Additionally, it provides a springboard for future validation programmes.
The ideal approach is for planning to start early (Figure 2) before the facility has been designed to facilitate an early agreement between all parties on the validation strategy. It involves thinking about validation holistically and not developing a detailed VMP too early, because invariably it will be modified as the validation programme progresses. The VMP must also satisfy a number of objectives:
Leverage process knowledge as a basis for all decisions
Facilitate continuity into routine operations once the facility has achieved regulatory approval
Ensure complete buy-in from all employees
Be manageable, transparent and maintainable
Comply with all current regulatory legislation and requirements
Be flexible and adaptable to comply with foreseeable industry trends and regulations.
Industry standards and directives such as the FDA's report, "Pharmaceutical cGMPS for the 21st Century - A Risk Based Approach", and the ICH Q8, Q9 and Q10 guidelines indicate the desire of the regulators to change the way in which product development, quality management and validation processes are carried out, using risk management strategies to support all manufacturing and control activities. In fact, the recent ASTM 2500 guideline is already taking this a step further by steering the validation effort towards a continuous verification process that is inherently risk-based, underpinning all decisions with detailed process and product knowledge.
The MVP is compatible with this industry direction, both through its flexible structure and GE Healthcare's knowledge of biopharmaceutical process development and manufacturing. The company's approach is to put together a modularised document/master plan that begins with the high level detail (e.g. setting out intent and broad observations) and building in the details as the facility design progresses (Figure 3). Additionally, automated document generation software that is supported by a regulatory database provides a more efficient compliance status capability with full traceability.
modular validation
A modular validation effort starts with the activities in the top left hand corner of Fig. 3:
process and production rationales
user requirement specifications
compliance reviews
system definitions
system impact assessments.
The deliverables are then determined and mapped through to the end via traceability matrices.1 With this approach, the production/ process rationales drive the validation effort and provide clarity on what does and does not need to be validated; dividing the facility into logical chunks avoids the risk of unnecessary work.
The process rationale, which evaluates the risks to product quality and formally documents the process critical parameters, is the starting point for a modular validation programme and forms a platform for a series of risk assessments that are performed while the user requirement specification (URS) and detail of the full-scale production model are being developed. This provides a step-by-step analysis of the proposed production process and all the parameters that may impact on finished product quality. It will also identify non-critical parameters and justify their lack of criticality. A number of major components of the modular validation approach are described here:
User requirement specifications (URS). It is crucial to highlight the importance of the URSs, which hold all the known requirements of all stakeholders and are prepared before buying all facilities, utilities, equipment and operating systems. Within a modular validation project, non-detailed and flexible URSs act as a "master control" over more detailed system URSs.
This approach ensures that product impacting requirements are automatically extracted from the process and production rationales and compliance information from the regulatory database, meaning 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 the validation programme is updated accordingly.
System definitions. Another key component of the MVP is a system definition document, which identifies the physical boundaries of systems and describes its complete set of attributes. Prepared prior to a system impact assessment, it enables descriptions in validation plans to be minimised, but supported by cross-referencing. For example a complex automated clean-in-place system linked to other systems would have a system definition that would be precise and information-heavy, whereas for a simple pH meter a vendor brochure may be adequate.
Validation plans. The validation plans (facility, manufacturing and cleaning) for a site need not be detailed and inflexible documents. Rather, system descriptions in VMPs and validation plans can simply be cross-referenced to system definition documents. This enables changes (other than to a critical parameter) to be easily added without revisions to plans. Essentially, the VMPs and validation plans serve as high-level documents that refer back to specific and appropriate plans. This approach helps to minimise the impact of any site changes, and specific changes can be recorded and documented in the most appropriate plan. It is important that the level of detail in VMPs and VPs is consistent with the knowledge and information available at the time it is generated, and details are added as the validation project develops. This saves time and money in not having to rewrite, revise and reissue plans.
Protocols and reports. These also benefit from a modular approach because they are developed such 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.
Automated documentation. User-friendly automated document templates are an important facet of the new approach, allowing authors to select the most appropriate document from a menu that includes site validation policy, traceability matrix and compliance review. The software then guides authors to the correct part of the document and any changes/additions are automatically fed consistently throughout the document where required. Each template also contains all the relevant and latest acceptance criteria to fulfil FDA and EMEA requirements.
Considering the increasing industry cost and competitive pressures, and a changing regulatory environment, now is an ideal time to review facility validation procedures. Traditional approaches to validation are often complex, and time- and cost-intensive. GE Healthcare's research shows that implementing a modular approach accelerates the time taken to bring a facility on-line and produces better quality medicines quicker, while ensuring that the work that is required is performed and documented correctly and accurately.
Effective validation leads to 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.
Looking ahead, the industry continues to discuss "risk-based" validation, something that regulatory authorities are advocating. However, we are still some way from implementing successful "risk-based" approaches to facility validation. This will ultimately be driven by the increasing importance of process understanding, which will in turn accelerate the adoption of risk-based approaches such as PAT. This, combined with a vast potential to leverage IT and systems will elevate the science of validation to a new status, removing much of the fear associated with regulatory compliance.