Dougals Stockdale

FDA's 2004 aseptic processing guidelines were updated primarily to address six areas of concern: 					

As a result of the new guidelines, contract manufacturing organizations (CMOs) have improved their current good manufacturing practice (cGMP) compliance. If one were to ultra-simplify the guideline, it would say "render everything sterile and then prove that it remains so through aseptic handling in a controlled environment."  

In this article, we will review the six areas of concern and indicate the changes and trends that have occurred. Note that FDA's 2004 aseptic guidance also further aligned the United States regulatory requirements with other global aseptic guidances, such as Annex 1. 

Pre-employment educational requirements have not changed and are minimal. New clean room operators frequently do not have much training prior to the role; although once employed, operator skills are enhanced by a series of steps that include formal company training programmes, off-site aseptic processing courses, cGMP courses and documented on the job training.  

As an example of improvements since the inception of the guidelines, we now see virtually all aseptic CMOs requiring the replacement of casual clothing and shoes by scrubs and clean room shoes prior to sterile gowning. Previously, there was much variance and some aseptic CMOs permitted gowning to go over casual clothing. There is also more emphasis on training employees with respect to air flow; for example, it is routine to see fill equipment that is enclosed by Lexan/acrylic walls, thus physically excluding employees from the critical aseptic fill area. It is now well recognized throughout the industry that employees are the major source of contamination and that air flow is the primary contamination control. If one mixes employees with air flow, then the primary control becomes the major contaminant. 

The concept of multiple levels of protection has taken hold. Critical areas are more often double-protected by low HEPA filters directly over the critical operation while maintaining a Grade A or B background environment. Although isolators are still not the rule in multiproduct facilities, restricted access barriers (RABS) are becoming more prevalent. In addition, there is much greater use of steam-in-place (SIP) and robotics. As more equipment vendors compete with an array of clean room products, initial designs for ease of operation and cleaning have improved. Virtually all aspects of clean room facility equipment (walls, ceilings, floors) are specifically designed and provided by clean room vendors. Special designs also permit room sanitization through the use of vapourized hydrogen peroxide or hydrogen peroxide mist.  

CMOs have become quite sensitized to the issue of room pressurization and product separation. Quality auditors are more sophisticated and may likely ask for mechanical design drawings that clearly state which areas of a facility are controlled by which air handling equipment. They will expect that air from areas with different exposed products is not mixed. Pushing air through a HEPA filter may eliminate dust and microorganisms, but will not reduce potential chemical or submicron biological cross-contamination.  

Clean room air filtration has continued to evolve and some sites have installed differential pressure measurement across every filter to continuously monitor filter status. 

The improvements in processing have been largely automation, particularly SIP. More aseptic fill and finish suites (CMO sites) now have a Grade A aseptic processing area with a clean steam port to allow for flexibility in customer operations. In addition, some sites set up fill and finish, and then steam through the lines — including fill needles, so that the entire product fill train is steam sterilized prior to starting a fill.  

Agency interpretation of the GMP requirements has caused widespread change in the collection, oversight and analysis of data as well as in the thoroughness of sterility testing. All data that is collected from a regulated lot is analysed and presented as part of the official record for that lot. There may not be an increase in the amount of data collected, but there is definitely a greater respect for the analysis and presentation of the data as meaningful to the lot release.  

Sterility testing has seen the greatest change. Previously, sterility testing was not performed in an environment of the same rigour as was manufacturing. This is an area where isolator technology has seen inroads. It is often less expensive to conduct sterility testing in an isolator than it is to build and control a Grade A room used only for sterility testing. Because the sterility isolator is small, it may be purchased as a special item for sterility testing, and meet the requirements of being an environment that is as good or better than the manufacturing site. The sterility test isolator is the most commonly used isolator in an aseptic CMO operation. 

Process analytical technology (PAT) is having substantial impact in the area of environmental monitoring (EM). Perhaps the most promising statement from the 2004 guideline was: "Other suitable microbiological test methods, for example, rapid test methods can be considered for environmental monitoring, in-process control testing, and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods, for example, USP 1" 

We are seeing growth in companies seeking to capitalize on those new techniques. Delayed microbial results coupled with a generally risk-averse industry has resulted in prolonged maintenance shutdowns and increased revalidation activity. New techniques in rapid microbial test methods are permitting greater efficiency within the industry. Although not new, supervisory control and data acquisition (SCADA) systems are being coupled to all of the nonmicrobial monitoring sensors — room pressure, air velocity and nonviable particulates, and these are measured and recorded continuously throughout the validated facility. These systems create vast amounts of data that require validated alarms and human systems to ensure analysis. Some companies have added human tracking reports through the use of electronic access cards. As a consequence, environmental contaminants can often be linked to a specific time and activity. 

Companies are still challenged with the directive to receive and review all records prior to releasing a batch. Technology is far better at collecting data than it is at analysing data to permit decision making; for example, EM data, often massive in quantity, must be reviewed over variable time increments for each batch that is released. While the review of EM data can be performed independently of product release, FDA requires that a link be established to support each specific release. 

An aseptic fill finish operation is a daunting financial investment for an organization, and particularly to an early stage development company where capital is usually scarce. The cost of fill and finish manufacturing in capital dollars expended, lost time, lost focus and increased ongoing operations cost are overwhelming to a small organization.  

The smallest Phase I aseptic processing area (APA) that could hope to be compliant, including the necessary support areas, will require an investment of at least $3 million dollars. Add in the capital investments for component preparation, sterilization equipment and the aseptic processing equipment, and your investment may double prior to the required qualifications and validation investments. 

Installation, qualification, and validating a new clean room and aseptic fill and finish operation to meet US, European and Japanese regulatory requirements may cost as much as the capital equipment investment. 

Beyond the facilities and process setup, there are the on-going operating expenses to maintain your validated APA. It quickly becomes evident that significant money and time are being spent into an activity that will be used sparingly. At an early-stage development company, investment would be better spent in research or upstream manufacturing operations. 

After initial capital, another business issue is the organizational infrastructure to maintain and support aseptic fill and finish. The technical and operational expertise for aseptic processing may not currently reside within the organization. That is readily resolved by hiring the necessary staff with the required training and experience. But since the APA operation cannot regularly utilize the fill and finish operation, staff training and proficiency in aseptic technique will become an issue. 

Another issue for the organization is operational focus. To build and maintain an aseptic fill and finish operation is to further dilute time and energy away from the key R&D. Companies frequently have to make decisions about core competencies that deserve investment, whereas aseptic fill and finish can be readily outsourced. 

A further issue is the strict regulatory requirement for an asepticly filled product. Aseptic fill and finish is a unique process requiring full validation, even at the beginning of Phase I clinical trials. The major global regulatory agencies are clear about the need for a safe product being administered to humans, and they are equally clear that implementation requires a fully validated aseptic processing facility. Complete validation of aseptic fill and finish is capital- and time-intensive, and, most significantly, it is an ongoing operation for the life of the facility.  

There are reasons that companies set up their own APA and fill finish operation; for example, the need for timely clinical trial product(s) is critical and control over a CMO may never be sufficient (there is no guarantee that they actually get a product for their money! If a CMO drops a bottle of the product, you my still pay the fees and have no product). There may also be aseptic processing steps in the manufacture of active pharmaceutical ingredients (APIs) that are unique and must be performed by company personnel. Fill and finish might be a small addition to capital and operations. However, it should always be weighted as significant. 

When a decision has been made to outsource aseptic fill and finish operation to a CMO, there are still many decisions to be made — selecting the right CMO partner; obtaining an equitable contract; transferring the technology; start-up; and managing the on-going relationship. 

You want to find a compatible organization that is suitable with your corporate culture. Finding a CMO partner will take time and an incorrect choice that leads to changing the CMO is financially very painful.  

The process to select, complete the necessary audits, contractual agreements, technology transfer and startup can take more than 9 months, depending on what activities need to be accomplished. If you do not have the necessary process information, the start-up period can extend to more than a year. 

You will need to identify your specific aseptic CMO activities. Different CMOs will request different information from you to perform your compounding and fill and finish manufacturing. Are you going to deliver a complete sterile bulk for filling or a concentrated non-sterile API that will require formulation and sterile filtration? Do you need an aseptic CMO with extensive process engineering capabilities, analytical laboratories, or a development lyophilizer for cycle development? What do you want the deliverable from the CMO to look like?  

The CMO will want to have product-specific questions such as do you have the necessary assays for technology transfer? What safety precautions to take. Do you have a material safety data summary (MSDS)? Have you completed any toxicology studies? For biological-derived products, they will want statements that the source was free of transmissible spongioform encephalopathies (TSE) and that viral clearance studies have been satisfactorily completed.  

There are many technical questions that must be addressed for the CMO to perform your work. Concurrently, there is a need to develop a CMO supply contract and a CMO quality agreement. To successfully employ a CMO, you should have a multidisciplinary team from your side. We recommend developing a user requirements specification (URS checklist) that can then be adapted to become your request for quotation (RFQ) to potential vendors. 

After determining what you need your aseptic CMO to do and what not to do, you can complete a very quick supplier survey. With the CMO requirements identified, you can sift through the various CMOs that are available and narrow the choices to a manageable number. From the URS, you should now be able to finalize a RFQ for the final CMO selection. It is a good practice to ensure that a confidentiality disclosure agreement (CDA) is completed with the final CMO firms before sending out a detailed RFQ. Prior to the CDA and technical discussion, most CMO firms will only give a ballpark budgetary figure for fill and finish. 

It is also useful to use a balanced scorecard for making a decision about the final CMO. This involves listing the required attributes that are necessary and weight-critical requirements. Cost per vial is one of many attributes evaluated. Of course, outsourcing fill and finish should not be based on the lowest cost per vial. An on-site supplier visit must be made for a final assessment, and we recommend that this be reserved until the suppliers are narrowed to the final three that are under consideration. 

When the potential CMOs have been identified and the CDAs are in effect, then the detailed RFQ should be sent. It is best that there be a single point of contact during this phase, and since most of the questions will probably be technical, we would recommend that the single point of contact be the project engineer. Purchasing and legal should not begin work until the final CMO is chosen. It may be prudent in larger organizations to consult with purchasing and legal in the beginning to see if there are constraints that may impact how business will be conducted.  

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Finding a CMO partner will take time and an incorrect choice that leads to changing the CMO is financially very painful.