CFR21/11 brings significant benefits to pharmaceutical companies by encouraging better electronic record keeping in good manufacturing practice (GMP) and good laboratory practice (GLP) environments. Furthermore, CFR21/11 welcomes, but doesn’t enforce, electronic submissions in new drug applications and updates, promoting the introduction of new technology which can prevent fraudulent changes being made to electronic records.
The regulations also mean that significant cost reductions can be achieved through standardisation, increased use of electronic transactions and automation. This translates to simplified exchanges between industry players and helps improve public perception, which enhances the pharma industry’s credibility.
CFR21/11 focuses on the impact that manufacturing and packing processes have on product quality and data integrity. Adequacy and timeliness of planned corrective measures is also high on the agenda. Another key aspect of the new set of regulations is tracing the compliance history of a pharmaceutical company, especially with respect to data integrity.
To put things into context, CFR21/11 is vital for UK manufacturers, because we are part of a truly global market which demands product standardisation. In today’s economy you can’t guarantee products will stay in their country of origin; they can be traded all over the globe, changing hands multiple times. For this reason, recording information about all transactions involving the drug by using a unique number stamped on to the blister has become compulsory in the US.
In 2007 the FDA lobbied for a law to be passed which states that prescription medicine should use a serialised National Drug Code (NDC) which contains a unique numeric or alphanumeric code no longer than twenty characters. This number allows for the creation of an electronic pedigree, which is a documented history of product custody through the supply chain. In essence, the NDC helps trace the product’s journey from the point of manufacture to the point of dispensing.
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| Perscription medicine contains unique serialised National Drug Code |
Following the American model, the European Federation of Pharmaceutical Industries and Associations (EFPIA) recommends the use of 2D data Matrix including unique serialisation numbers for each secondary packaging unit distributed and sold in Europe. Furthermore, recent EU directives regarding pharmaceutical packaging have suggested the implementation of individual product codes and tamper evident package seals that only manufacturers, or those authorised by manufacturers, apply.
CFR21/11 has triggered a move towards more streamlined manufacturing across the world. This means that the pharmaceutical industry has had to keep up with the times by adopting more traditional manufacturing practices and standards which have long been used in other sectors such as food and beverage. Such considerations can no longer be ignored by the pharmaceutical industry.
Hence, manufacturers need to be flexible enough to modify their methodology and become leaner. This involves adopting the technology which allows them to serialize and then track, trace and manage manufacturing for different types of drugs and various kinds of packaging.
Serialisation has emerged as a means of identifying and tracking unique items throughout the global supply chain. The need for more precise product identification has driven the development of item-level serialisation as a logical response to FDA safety initiatives.
Most markets are interested in tracking unique items to fight counterfeiting and unauthorised diversion, or simply to improve efficiencies within the supply chain.
Currently, there is an emphasis on the use of information technology so that item level serialisation can be achieved. This requires secure and reliable computer systems at all stages of manufacturing.
“Operating processes are being automated and key decisions are being made based on electronically recorded data. Implementation of such systems should include configurable, scalable global solutions that can be deployed on high available appliances companywide; without requiring custom coding, one off architectures or 24/7 administration oversight,” explained Stephen Lisa, director of product marketing at Systech International.
The records collected are used during the authentication stage, where the authenticity of a product or a number in the supply chain is verified. This way stakeholders can track and trace where a drug is currently located and most importantly, where it came from.
Authentication, track and trace and electronic pedigree all require watertight processes that work smoothly. The best way to achieve this is through high availability computing systems which strengthen the platform from which that process is drawn.
High availability is a system design approach and associated service implementation that ensures a prearranged level of operational performance will be met during a contractual measurement period. Availability in an industrial context refers to the ability of the user community to access the system, whether to submit new data, update or alter existing data, or collect the results of previous work. If a user cannot access the system, it is said to be unavailable.
In order for manufacturers to comply with CFR21/11 regulations and provide accurate traceability, all systems need to function at all times. Failing that, the data recorded becomes unreliable, thus defeating the purpose of quality checks.
The first requirement for high availability in the pharma industry is robust hardware that will work to a highly reliable standard. Fault tolerance at hardware level means that preventative action can be taken before the problem affects the process. As a result, the manufacturer is informed of any potential downtime long before it occurs, so that precautionary maintenance activities can be undertaken.
The traditional view in IT is that uptime, continuous availability and failover are crucial to the smooth running of a manufacturing or packaging plant. But perhaps the semantics should focus on the actual systems that provide all this? This would mean a robust computing solution that can continue the service even when there are faults in hardware, ensuring the correct recording of data to comply with CFR21/11.
As a result, it’s essential that pharmaceutical companies need to invest in a fault tolerant machine which delivers at least 99.99% uptime. Such a system would be down for only five minutes in the year, and then as part of scheduled downtime.
At HardwarePT, a division of the automation and industrial computing expert, SolutionsPT, these concepts are taken to the next level and plant activity is viewed holistically. This can mean applying everything from traditional high technology fault tolerance software to something as simple as a ruggedized industrial keyboard or even a support contract. Between them they represent a form of insurance. Their role is to guarantee production does not come to a grinding halt when something unexpected happens.
Furthermore, for optimal performance in a serialization packaging environment, it is imperative that you have the proper depth of data integrity. This may call for server level applications and databases that provide manufacturers with the peace of mind that drugs can be easily traced afterwards, in compliance with CFR21/11.
To ensure the quality of the data, best practice is to have an appliance or black box environment where mission critical data is kept independent from other business applications in production. The serialised application will not require constant attention and will take on the bulk of the network responsibility and allow IT operations to run without daily support. The application should be flexible enough to solve complex packaging needs.
Systech, an innovator of packaging executions systems (PES), has developed, in partnership with HardwarePT, a series of applications that support a wide range of packaging operations, many of which require 100% server access.
“Assuming your solution has the ability to keep the packaging line running during server or network interruptions, you must consider the impacts for post lot and centralized operations. Rework and quality assurance operations that take place outside of the packaging line require data that is stored on the site server. Any downtime, latency or interruptions within the site serialization server will have negative impact on these operations. When considering pallet building operations where multiple packaging lines feed a single palletizing area, the uptime of the site server is critical to complete the packaging process,” added Systech’s Lisa.
Balancing between site performance demands and IT site support is challenging. Deploying a combination of a PES solution with a high available appliance helps reduce the need for local onsite IT support while providing the background performance required to meet packaging operations.
Fault tolerant servers, which are built by doubling up of all the components, help avoid unplanned downtime. They provide a backup for everything; from the power supply, to the interfaces and even the server. The server has a software layer which makes the connection between hardware components and makes all the elements of the backup system function as one, unitary machine.
As well as increased plant security, this ‘two-in-one’ box system has the additional advantage that only one licence is needed for both computers.
Furthermore, as the software runs ongoing diagnostics for the hardware inside the machines, the system is constantly checking itself to make sure that the hardware is behaving as it should. For example if a processor is underperforming or is performing irregularly, the system would pick up on it and react accordingly.
But perhaps the most important characteristic of this sort of availability solution is its ability to communicate and provide updates to the hardware manufacturer. The system is configured to feed back information to the headquarters of the company who produced the server, which can offer 24/7 support.
This feedback allows the support team to work on a pre-emptive basis and act before something is about to go wrong. If, for example, the memory is about to fail, under the support contract conditions the company responsible for monitoring the system will despatch a replacement for the faulty component. Unlike a server farm which would involve a high level of IT competence in-house, this kind of support is just a matter of plug and play.
Due to its unparalleled reliability, this technology is employed by the emergency services and used in banking operations systems. The railway networks in the UK also use this type of machine for reliable signalling and communications. These examples are illustrative of the level of availability and uptime such a package can provide.
For a pharmaceutical company where system failure is not an option, this totally proactive maintenance solution offers security and peace of mind. Furthermore, it gives companies the perfect instrument for packaging lines to comply with traceability regulation enforced by the FDA.
A good uptime solution should include alongside reliable software and hardware, a tailored support contract. The support contract represents the administration of the proactive maintenance system and responds to replacement parts requests. No matter how intelligent a system is, without constant monitoring and interpreting of data, it would most certainly fail on its own. In essence, the support agreement is crucial because it ensures that the system works to its maximum potential in terms of uptime, whilst providing a means of controlling costs.
The performance of computer hardware will be negatively affected by moisture, dust and temperature variances and any outages or failures will have some kind of impact on the overall performance of the line. As a result, IT hardware for the industrial sector is ruggedized and built to cope with the harsher environments of various kinds of plant floor.
Specifying the right kind of industrial hardware, from PCs, monitors and thin clients to networking equipment or Industrial Servers is crucial. It can make a significant difference to the performance of a manufacturing line over its entire lifecycle.
One of the non-traditional issues which can slow production is the existing contingency plan for incidents. The IT world is a place where things fail; processors, motherboards and memory all have a MTBF (Mean Time Before Failure). This fact needs to be considered and adequate provision put in place to deal with failures when they inevitably occur.
Typically provision for failure involves some kind of support contract, but increasingly a more bespoke service, where specific requirements and support for customer installations can be accommodated, is needed. Pre-agreed stock quotas for necessary equipment which provide a suitable amount of available spares to deal with any anticipated problems are also in high demand.
Unfortunately, all too often the one machine that no-one understands, or the server that is not on support is the one that fails, dragging an entire production line down with it. Such a crisis situation is often followed by a frantic scrambling of resources to fix the problem and it ultimately ends up costing the business a significant sum, in terms of lost man hours and the price of securing replacements at short notice.
If the machine that fails is critical, but there is not sufficient knowledge on site to fix the problem, then the costs to restore the system can quickly escalate. Bringing in hardware manufacturers’ technical staff at short notice in an effort to promptly rectify the problem and limit downtime can quickly become expensive. In addition to these costs, other consequences need to be considered including the price of lost stock and production delays which can often lead to additional fines from customers and partners.
Keeping a lid on these kinds of expenses is the Promised Land for IT managers and the availability solutions offered by HardwarePT deliver that for the serialisation market. The starting point is to encourage manufacturers to sit down and think about the consequences of losing a particular machine or process. Understanding the complex implications this can have is the first step to developing a working solution or a plan.
The plan of action needs to offer an answer for when failures happen, as well as to limit the impact on production or more appropriately, the overall cost of the failure to the company.
The use of a fault-tolerant server is ideal for the serialisation process in the pharma sector because it offers a shortcut to fixing potential downtime. The machine offers full hardware redundancy through a doubling of all system components and then pro-actively monitors itself with the help of the manufacturer through the internet connection back home.
Another added benefit is that all hardware replacements are included within this price, which prevents budgets being stretched. Having a fixed cost for dealing with all problems is very attractive to those in charge of managing operations budgets. As an added bonus, servers are incredibly simple to maintain using plug and play hardware components, which means that the in-house IT knowledge required to keeping things running is also minimised.
These so called ‘soft costs’ are often not taken into consideration when evaluating the business case for availability systems. Even though the base price for a continuous availability solution may appear to be higher in the beginning, at least plant managers know exactly what to budget for, with no hidden extras. By contrast, leaving things to chance, without any backup, may prove to be a lot more expensive.
But perhaps the most important lesson is to make sure that crucial packaging systems are protected and backup is available at all times. This issue becomes even more important if pharmaceuticals manufacturers are standardizing and automating their processes as indicated by the FDA.
Ultimately, patient safety and multi billion pound life-saving drugs are at stake. This should prompt companies to invest in robust, failover systems that work. Availability is a concept that should be taken seriously, as it represents the ultimate insurance against failure and costly downtime. Skilful use of reliable hardware and software can guarantee compliance with FDA regulation and avoidance of costly errors.
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