Demonstrating compliance in a complex landscape
Pharmaceutical contract manufacturers need to be able to demonstrate compliance throughout the whole manufacturing process. The quality of drug products is ensured by careful monitoring of the manufacturer’s compliance with the relevant regulations. These include minimum requirements for the methods, facilities and controls used in drug manufacturing, processing and packaging. Of course, regulations not only ensure that a product is safe for use, but that it has the ingredients and properties claimed by the manufacturer.
Traditional paper-based monitoring and reporting systems have created a number of challenges for manufacturers in the pharmaceutical space. In practice, compliance can require extremely high levels of paper and hybrid systems in order to perform a number of functions; documenting procedures and work instructions, creating paper files of batch records or device history records at the material preparation phase, and throughout the whole manufacturing process, and reviewing, correcting, approving and storing batch records or device history records for each release.
It is estimated that a batch record requires 16 hours to create and can take up to 48 hours to review. On top of this, it is estimated that 10 percent of all entries contain errors, which need to be rectified by the quality team before the batch can be released.1 As a result, the process of ensuring and demonstrating compliance can be both timely and costly.
The power of technology in compliance
In recent years, the industry has experienced greater adoption of manufacturing execution system (MES) technology, as companies in the contract manufacturing space and their vendors realize the benefits of managing and monitoring operations in real-time. In fact, MES solutions are being adopted by the life sciences industry at a faster rate than any other vertical market.2
MES describes a class of software used to manage all aspects of production. The wide-ranging functions typically include the ability to schedule activity, deliver instructions to operators, synchronize manual activities with automated processes and integrate with manufacturing computer systems. This allows contract manufacturing organizations (CMOs) to ensure quality control, deviation management and effective enterprise resource planning (ERP), as well as enabling users to document floor activities for monitoring and reporting purposes.
Advances in MES technology have prompted a shift in the industry, allowing paper documentation, which can be labor intensive and error prone, to be replaced by computerized records, known as electronic device history records (EDHRs) and electronic batch records (EBRs). As they can be accessed in real-time by all users, this helps to simplify compliance and improve transparency throughout manufacturing. They also provide a tool for risk management, helping to identify potential errors in real-time, and ideally before, they occur.
Put simply, MES is concerned with providing the right information, at the right time, to the right party, whether this is a human operator or an automated system, to achieve ‘right first time’ production.
While automation systems are responsible for controlling the manufacturing process and ERP systems focus on managing the entire supply chain, there is an information and/or time lag between these two automation layers, often addressed within the manufacturing department using spreadsheets or word documents. MES focuses on plant operations to address this gap, so that materials and information flow smoothly through the plant to produce quality products, while maintaining low levels of inventory.
A shifting mind-set
Compliance with Food and Drug Administration (FDA) or other local regulations underline the specific requirements of any MES system for the life science sector. The benefits of MES to reduce FDA compliance costs have been well established for over 10 years. This has led all large pharmaceutical companies to undertake global MES deployment programs, with many of them in a standard maintenance mode today.
With the establishment of clear guidance documents on validation of these systems by industry groups such as the International Society for Pharmaceutical Engineering (ISPE) Good Automated Manufacturing Practice (GAMP), the deployment of such systems on the manufacturing floor no longer causes concerns. Even more significant is the fact that MES is now occasionally deployed to remediation production problems listed in warning letters.
Although the IT landscape is now shifted towards a cloud-based model for many domains, the pharmaceutical industry has been reluctant to embrace this approach at first, for several reasons, the most important being security, or how to protect the intellectual property and safeguard mission critical systems. Performance—how to ensure low response time—is another issue, as is availability—how to ensure that a remote system and all communication infrastructure are available 24/7. But with other industries demonstrating the viability of cloud-based approaches, the mind-set has changed and cloud-based solutions are now considered by the largest organizations as part of their upgrade strategies.
The ISPE GAMP community of practice is now developing guidelines to validate cloud-based solutions; evidence that the next generation of MES solutions will be cloud-based.3,4
This leads to a more technologically oriented mind-set from a larger number of companies in the contract manufacturing space that are eager to use the automation they are accustomed to in their daily lives.
Considerations when implementing MES technology
Both CMOs and vendors have a number of specific requirements when selecting and implementing MES technology. For an MES solution to be viable in the pharmaceutical industry it must first meet all of the compliance requirements in terms of current good manufacturing practices (cGMP), the FDA’s 21 CFR 11 rule on electronic records and signatures or other local regulations.
The MES solution must also enforce standard operating procedures (SOPs), ensuring that the manufacturing process adheres to a workflow or recipe. A library of master recipes relating to all products and processes must be created before implementation.
The solution must also be able to validate that the materials being used are correct as defined in the bill of materials (BOM) and are within their use-by/ expiry dates, as well as validating that equipment is ready for use and has been through the proper cleaning cycle and/or is within calibration windows.
All production records including EDHRs and EBRs should be available electronically at the click of a button. The MES should also allow real-time visibility on operations and processes to enable the elimination of errors and tracking of work in progress (WIP). In summary, it is critical that an MES provides complete two-way traceability of raw materials, semi-finished and finished goods.
While performing all of the above functions, it must maintain a level of flexibility similar to paper processes, with the ability to adapt to changes throughout the manufacturing process.
Driving down costs
Cost is always a huge driver when implementing new processes and systems. Will the long-term benefits outweigh any upfront investment? Will the new technology deliver cost savings for both the CMO and its vendor by improving efficiencies and eliminating errors and downtime? These are the questions that are often asked in the early stages.
Introducing new technology is often associated with a large upfront investment, which has meant that larger companies have found implementation more feasible. The industry is facing greater scrutiny on IT spending, which again has created a barrier for many small and medium-sized contract pharmaceutical manufacturers looking to implement MES.
New, flexible ways of introducing the technology, such as modular licensing structures that can be scaled up or down to meet changing needs, have opened MES up to a wider part of the industry. A web-based architecture, which is possible in today’s environment, also removes the need for a heavy IT footprint.
When implementing a flexible and scalable MES solution, ROI is feasible within 12-months. It can be achieved by a combination of reducing working capital such as materials and inventory, lowering direct costs, increasing reliability and therefore reducing downtime, improving operational efficiencies and reducing manufacturing operation and supply chain risk.
In any contract manufacturing environment, time is money, and therefore opportunities to improve efficiencies and increase productivity must be explored. The pharmaceutical industry faces increasingly stringent regulations, making compliance a priority when implementing new technology. By creating a centralized point of information in line with GMP standards and allowing real-time production visibility and instant reporting, MES can help to simplify the compliance process. Those companies that embrace new technologies can be both compliant and competitive in an extremely fast-moving and continually evolving environment.
- Figures from LZ Lifescience analysis, industry estimates and MESA (Manufacturing Enterprise Solutions Association) International.
- Strategic Analysis of the Global MES Market, Frost & Sullivan (Sept 2014).
- Compliant Cloud Computing – Managing The Risks, David Stokes, Pharmaceutical Engineering (July/Aug 2013).
- Cloud Computing in a GxP Environment: The promise, the reality and the path to clarity, GAMP Cloud Computing SIG, Pharmaceutical Engineering (Jan/Feb 2014).
Christian Fortunel is vice president at LZ Lifescience Inc. (USA). He is responsible for operations management and the successful financial running of the U.S. business, as well as bringing a wealth of MES deployment expertise to his role.