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If an inspection reveals any shortcomings ... a manufacturer may be warned, fined, or its facility closed down until full control can be demonstrated to the satisfaction of the authorities ....
Both active pharmaceutical ingredient (API) primary facilities and manufacturing plants are critical company assets — essential for the efficient production of a pharmaceutical product to quality and regulatory standards. They reflect the final investment phase in the development of products that may take many years and hundreds of millions of dollars to bring to market.
A vast amount of information is generated during the design of facilities — information that is required for downstream activities in construction, commissioning and qualification (C&Q), operations and maintenance (Figure 1). Experience shows that the key to making the best use of plant information is to understand how, where and why business processes use that information; to improve communications across the supply chain; and to reuse plant information throughout the life cycle of the facility. Keeping the information up to date with the evolving configuration of the plant is also vital.
Regulatory issues often determine areas of primary focus. In an industry survey
(www.accenture.com) of leading pharmaceutical companies' approaches to US Food and Drug Administration (FDA) compliance, respondents had placed the total cost to meet the requirements for 21 CFR Part 11 at approximately $100 million (E83 million) — excluding maintenance. The good news is that since the survey was conducted, FDA has narrowed the compliance scope of Part 11, believing that the original, broader interpretation would "lead to unnecessary controls and costs [and] discourage innovation and technological advances."
So Part 11 does not apply "when persons use computers to generate paper printouts of electronic records, and those paper records meet all the requirements of the applicable predicate rules .." In addition, FDA now intends to exercise "enforcement discretion" in the case of legacy systems, validation, audit trails, record retention and record copying requirements.
However, Part 11 does still apply in all those cases when (as FDA puts it) "persons choose to use records in electronic format in place of paper format." Also, "records must still be maintained or submitted in accordance with the underlying predicate rules." In addition, FDA has made it clear that it "still intend[s] to enforce" system access control; operational system checks; authority checks; policies that hold individuals accountable; controls over systems documentation; controls for open systems; and electronic signature requirements.
So while there has been a constructive response to the earlier concerns expressed by the industry, the Part 11 challenge should not be underestimated. Given the potential investment needed to respond, the role of new technology — and in particular, the adoption of a plant information management (PIM) policy and systems to optimize a company's response to Part 11 requirements — is critical.
Figure 1 The pharmaceutical workflow.
During the pharmaceutical life cycle, many parties are involved in generating plant information. Part 11 primarily focusses on those electronic records that are required to fulfil existing regulations, for example, good manufacturing practices (GMPs) and good laboratory practices. They state that where electronic records are used, they should have the same auditable integrity as paper records with revision management and history, and that electronic signatures should be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures. The essential elements needed to meet 21 CFR Part 11 are security, traceability, auditability, work flow and data integration.
Establishing and maintaining the documented efficacy of plant processes and products is critical to generating expected revenue and upholding corporate and regulatory quality standards during the life of a facility. Performed effectively, management of this critical information helps the manufacturer improve time-to-market and sustain regulatory compliance, as well as operating GMPs. It enables auditors who want to see inspection information on a particular asset, go to any computer and access accurate information immediately.
In the event of an FDA inspection, it is of course essential for plant managers to be able to demonstrate that they are in control of their facility and its procedures, to comply with legislative regulations. FDA's emphasis on individual responsibility has not lessened. If an inspection reveals any shortcomings in either area, the manufacturer may be warned, fined or its facility closed down until full control can be demonstrated to the satisfaction of the authorities — with well publicized and devastating consequences for the company's share price, not to mention a serious dip in production revenues.
As explained in the introduction, while Part 11 has pushed PIM into the spotlight, the benefits of having an effective PIM policy do not only address Part 11 compliance. Taking advantage of the data set used in the creation of a facility throughout its operating life is a new and vital step in addressing the shifting pharmaceutical business model. It ensures that information is available across the organization for C&Q, operations and maintenance activities. In this scenario, the physical plant is managed as a core company asset.
The early process adopters of a life cycle approach to plant asset management (such as the oil, gas, chemical and power industries) have reaped rewards from their investment in this area during the last 5 years. Their industry drivers have included their lack of control over the price of oil, deregulation, regulatory and safety requirements, and mergers and acquisitions.
Automotive, aerospace and electronics industries have derived benefits from the same approach during the last 10 years. This is an established approach with established enabling technologies.
New pharmaceutical industry-oriented solutions are now emerging that help plant operators to manage their 'physical plant asset.' Asset information management solutions use specialized software to create, manage and reuse engineering information during the design, build and operation of facilities.
When designing, building and revamping plant facilities, the use of intelligent design and engineering tools, with inherent rules, reduces the need for rework and enables consistent design, faster project execution and earlier time-to-market. Intelligent tools also generate intelligent information for reuse.
Integrating design tasks in this way meets or exceeds industry quality goals as well as allowing modular repeatable, standard plant configurations. These can be adopted as company best practice — boosting efficiency, shortening schedules and providing more accurate deliverables for the construction process. These tools form part of a wider approach, centred on the overall management of plant information in which an information management system manages engineering data and documents. Plant information can be collated and made available to all authorized parties, for downstream activities such as C&Q, and handover of the accurate 'as-built' plant information to operations and maintenance.
Traditionally, C&Q can be a bottleneck when bringing a new or revamped facility online, threatening time-to-market, patent window and market share. More than 90% of the information needed to complete C&Q activities is associated with the piping and instrumentation diagram, instrumentation and electrical information. Capturing this information from the design environment and applying it to the business processes undertaken from mechanical completion to preapproval inspection enables significant time savings during C&Q, and consequently time-to-market.
This does require advance planning to set expectations and guidelines for contractors, module builders and suppliers who all contribute design information. But a new business model that can reduce C&Q timescales by even 10% would bring the industry enormous benefits.
With the correct information required for C&Q available earlier, electronically, and from one managed source, the problems inherent from inaccurate and incomplete information are removed. This also avoids delays that traditionally occur when contractors or suppliers have already moved on to other projects.
C&Q protocols, for example, installation qualification and operational qualification, can now be executed electronically, under electronic records and signature controls. Information technology (IT) systems not only electronically drive through the agreed work process, but also record who executed what, when and why. All records are retained; higher quality assurance and control is achieved; and quality assured information is available electronically for loading into operations and maintenance systems. Vitally, this approach helps the manufacturer achieve faster validation and shorter time to production, so maximizing patent lifespan, ensures product safety and efficacy, and reduces costs.
Taking this life cycle approach, production commences with a 100% accurate view of the plant integrity, inherited from C&Q. This good grasp of the entire technical baseline for an existing facility delivers the basis from which to sustain regulatory compliance. Engineering information is in a constant state of flux, so it is vital to be able to track past and present plant configurations, and plan for future options.
An incremental benefit is gained from managing engineering change every time an alteration to a validated process is undertaken, or rework is undertaken on an existing facility for new drug production. Managing change in operations is not only important for regulatory compliance. Asset management solutions can manage plant engineering change procedures, from planning though approval to implementation and maintaining an audit trail of activities undertaken. The solution retains all historical information and configurations, enabling 'rollback' to 'as was' plant information at earlier dates and times — a true and accurate, historically valid picture of plant operations.
The solution models the physical plant breakdown structure. It encompasses engineering information for all components, including buildings, systems, areas, lines, equipment and instrumentation. It is not often realized that engineering can generate at least 40% of the information needed to analyse the integrity of the plant, for example, in the case of a product deviation or product recall.
Implementing systems of this kind guarantees a permanency to engineering information as changes are never deleted, but simply marked as obsolete information. Importantly, it ensures that historic records are preserved intact, to provide valuable traceability and audit trails. It provides an accurate 'as built' electronic data source from which detailed and thorough integrity validations can be performed by the plant operator.
Clearly, Part 11 compliance — and (despite a narrowing of the scope) the potentially high cost of non-compliance — is a big driver for the industry. Effective PIM systems help pharmaceutical companies to meet FDA requirements. They also reduce the risk and cost of change control, through better management of the work processes that in turn automate and audit change procedures in the physical plant. This supports the FDA requirement for consistency and uniformity of procedures, from plant to plant.
Systems of this kind map work processes and drive electronic delivery of work tasks, auditing all actions undertaken, together with date, time and user information — providing vital support for Part 11 in all those cases where the organization is using records in electronic format in place of paper. A lower risk of plant shutdown is a major motivator for any manufacturer, along with reduced liability for plant managers through improved work process audit trails.
Other measurable benefits of having a plant asset information management policy and enabling IT environment include reduced cost and cycle time for planning and executing routine plant changes; reduced plant downtime through improved planning for plant turnaround activities; and better response times for emergency repairs. Additional benefits include reduced insurance premiums, both for liability, because of improved safety, and comprehensive cover, because of the availability of current asset inventory records. Critically, this environment also enables faster return to production following unplanned downtime through better, quicker access to the information required to recover the plant.
By establishing an overall management approach for Part 11, pharma companies can utilize electronic information more efficiently and effectively. Their strategy should
It is important to draw up a clear requirements specification before implementing a technology-supported policy of this kind, including core system functionality requirements for creating, storing, managing and accessing engineering information, as well as those for interfacing with existing systems.
A PIM solution should also provide supporting engineering information to plant maintenance systems to assist with planned and unplanned maintenance — and should be able to interface to other manufacturing systems. In this way pharmaceutical companies will achieve sustainable compliance by
At the same time, they will gain competitive advantage through more effective information management that