Gone are the days of outsourcing the production of aseptic products based only on the cost per unit. With manufacturers entering into consent decrees and closing key facilities, pharma companies are looking for contract manufacturing organizations (CMOs) with more robust product delivery systems that adhere to current good manufacturing practices (cGMPs), have validatable cleaning and decontaminations methods, and comply with global regulatory requirements.

For many years pharma companies have been leveraging CMOs to support their business initiatives. Big pharma companies contracted with CMOs for redundancy and to increase production capacity on well established drug products. Today, with the lack of blockbuster drugs in their pipelines and a drive to minimize internal costs, big pharma is also looking to CMOs to produce their products instead of spending more capital on expanding their own facilities. Traditionally, the design and construction of a facility to support a new product would have to start well in advance of the completion of clinical trials in order to be first to the market. If the product didn’t make it through the trials, the company would be stuck having already paid for a facility it could not use until it could be re-tooled for another product or sold off. In an effort to reduce this risk and respond to initiatives to drive down the cost of medicine, big pharma companies are now utilizing CMOs to help with the development of new drugs and to ultimately manufacture them.

Medium-sized pharma companies are also sourcing CMOs for the development and production of their products. Because of their size, their core business usually revolves around sales and marketing with a focus on R&D for creating new drugs or products. These companies do not have the infrastructure for production and distribution and so they rely on the capabilities of well established CMOs.

CMOs have been around for many years, providing lower cost production to their clients. Since they have historically been evaluated based on their ability to manufacture cheaply, many CMOs have not been able to reinvest in the improvement of their own facilities the way larger pharma companies have. They have outdated equipment and facilities that no longer comply with industry cGMPs and regulatory guidelines. Often these facilities find themselves at a point where simple equipment upgrades and basic facility renovations can no longer address legacy issues. Such facilities often end up in a consent decree and must be shut down to avoid risk to patients. The FDA is well aware of these issues and is now paying extra regulatory attention to these older facilities because they simply do not have the modern systems in place to ensure the safe production of sterile products. They know that the greatest source of risk during sterile manufacturing is personnel-related contamination, and they are driving aseptic processing facilities to apply principles of separation and automation. Separation refers to removing the operator from the sterile environment through the use of an isolator or RABS (Restricted Access Barrier System). Automation is meant in terms of continuous processing to minimize manual interventions during aseptic operations, which again reduces the risk of operators as vectors of contamination. For example, facilities should be moving away from batch processing and implementing equipment that provides continuous washing and depyrogenation of glass and automated loading/unloading systems for lyophilizers.

Pharma companies are now looking for the next generation of CMOs. They are looking for facilities that employ the latest technology and demonstrate an understanding of cGMPs. CMOs must be able to respond to a global market with facilities that comply with global regulatory requirements and are flexible enough to produce various product types. They must have design solutions in place that address the risks pharma companies have been mitigating for years. Some of these risks include:

• Lot mix-up and cross-contamination in multiproduct facilities
• Contamination of the sterile environment during aseptic processing
• Containment for potent, biological or cytotoxic products
• Cleaning and decontamination of equipment

Lot Mix-up and Cross-contamination
Regulatory inspectors and pharma companies want to see measures in place that prevent the possibility of lot mix-up and cross-contamination. Many modern facilities address this through the use of unidirectional flows for both materials and personnel. Throughout processing, materials dedicated to different lots of product should be kept in segregated areas, with their status controlled electronically throughout the formulation, filling, inspection and packaging processes. For personnel, procedures should be in place requiring gowning and degowning steps when entering and leaving productions suites containing different products.

Aseptic Processing
When it comes to advanced aseptic processing, the industry is continuing its trend towards barrier technology. Isolators and RABS provide a tremendous advantage at minimizing contamination risk to the aseptic environment. Isolators have the added advantage of not only protecting the product from contamination, but also protecting the operator from exposure to the product as well. Recent advancements in VHP (vaporized hydrogen peroxide) technology have reduced the isolator decontamination times down to as little as two hours, which in turn decreases the total time it takes to turn around a production suite and improves the overall efficiency of the facility. Utilization of isolators has also been seen to reduce both capital and operational costs in new facilities. They can be placed within an ISO 8 environment, which reduces the complexity and total number of rooms that are typically required for conventional and RABS-based aseptic facilities required to be in ISO 5/7 environments. The reduction of airlocks and separate rooms reduces the size of the building as well as the operating costs associated with the mechanical systems and gowning requirements typically found in conventional aseptic facilities.

Containment
A containment strategy must be established at the start of the facility design. This will involve the definition of a containment boundary and providing measures for air containment and decontamination. Wherever possible, equipment should provide primary containment with the use of isolators and closed systems. The facility should provide secondary containment through the use of monolithic architectural finished, pressurized airlocking schemes and filtered air systems capable of room decontamination if necessary.

Cleaning Validation
A CMO must be able to demonstrate that it can completely clean and decontaminate its facilities as well as the equipment inside them. The cleaning processes must be repeatable and validatable. This is best achieved through the use of automated systems. Pass-through equipment washers and autoclaves should be used wherever possible to not only provide reproducible cleaning cycles, but to also segregate equip that has been washed or sterilized from equipment that is dirty or only clean. Isolators benefit from automated VHP cycles for interior decontamination, while RABS and conventional filling lines have to be decontaminated manually along with the entire filling room, which relies heavily on procedures and operator training.

Above all CMO facilities must be flexible. The business plan should determine the range of products that will be made in a given facility. Because the complete process for future products is often not known during the design of the facility, assumptions should be made based on common process steps for specific product types. Some additional space and utility capacity should be provided to accommodate additional steps and equipment that were not foreseen at the time of the initial design. The facilities should also be expandable to grow as capacity requirements and market forecasts increase.

The role of the CMO is becoming more and more important in supporting the increased demand for pharma products. As pharma companies look to the CMO to help them reduce risk, delivery times and costs, so too will the regulatory agencies be watching and inspecting to ensure patients are receiving the same safe, high-quality products they’ve come to expect from big pharma production facilities.

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Jason S. Collins, RA, NCARB is director, Process Architecture, at IPS-Integrated Project Services. He can be reached at jcollins@ipsdb.com