Ahhh, the weather! We have sure have had our fair share over the course of the summer. Mother Nature threw everything and the kitchen sink at us collectively. But that is nature we are talking about, a force that no one can predict and ready itself for. A force that, no matter how ready you seem to be, can overcome you as quickly as it comes and goes. We can all agree that this unpredictable nature will really never allow us to be fully ready to withstand its wrath. In the contract pharmaceutical space, we feel the same pressure from the regulatory agencies that we are regulated by. The regulations are the forecast of the weather and we perform due diligence to make sure we are compliant, yet when the regulatory agency swoops in, we find that we may not be withstanding the regulatory storm because the storm type changes. However, we must give the FDA kudos on their recent inspection of several aseptic fill/finish houses.

Aseptic fill/finish manufacturers are held to the highest standard and regulation. Rightly so, as parenteral products go from the dock to the clinic, to be used for clinical trials on patients, or into the commercial market. Any deviation to the tried and true methods of aseptic filling can have a tremendous effect on final product safety. However, we become so focused on the regulatory requirements set forth by the regulatory bodies that we sometimes overlook the best scientific approach to these requirements. This is really where aseptic technique came from: science (specifically, microbiology). We as an industry have become very adept at these techniques and we also have the ability to quantify that these techniques really work.

In the past few months, several aseptic fill/finish providers were not in line with best aseptic fill/finish practices. It was evident by reading the warning letters that these entrusted scientific aseptic practices were not being utilized. It wasn’t so much the regulations per se that were not being followed; it was the activities surrounding and monitoring them. It is one thing to have the system in theory and another to actually employ the system.

These violations were environmental excursions that were not properly addressed, facility maintenance that can affect aseptic manufacture and a litany of other microbiological issues. What is hard to understand is how these sites could get into this type of trouble. “Aseptic” is as clean of a word as you can get, so the idea of having these environmental, facility and microbiological issues in this day and age is clearly stunning.

In the aseptic business, it is all or nothing. If any of the building blocks are not in place to perform aseptic manufacturing, then it all falls. This certainly fits in the risk assessment model. If one system cannot meet the demand of the environment needed for aseptic filling, then having the other 1,001 controls/systems in place do not matter. All of the systems need to be firing top notch in order for the system to work. The FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing¹ states that we have to have all these systems in place, but if they are poorly designed, not utilized or deviated from again and again, the aseptic manufacturing becomes questionable. This means that the checks and balances of a quality system need to help with making sure that the sterile environments and surrounding support SOPs truly are working and show no signs of trending towards failure.

Procedures in place allow us to be proactive with environmental excursions, facility problems and microbiological issues. Policies can be put into place to discuss best aseptic practices, and several steps can be taken to eliminate the chance of contamination. In doing so, we can add several items to the list:

• Personnel training
• Environmental Monitoring (EM) Procedures
• The use of single-use technology (e.g. needle/tubing sets)
• Facility design and maintenance
• Process Simulations
• Raw Material control, preparation, sterilization

Personnel Training

Personnel background, education, experience and training supports the aseptic process. As we all know, these personnel must have these aseptic skills in order to process the runs in a sterile fashion. Education should include not only conventional schooling in a science-related field but may include further certificate education practices. Training should be specific enough in aseptic practices as well as on company SOPs on how to perform these tasks. This includes gowning, proper aseptic technique, cleanroom training and all other specific clean space training. Personnel are the core to an aseptic facility because they have the most impact, positive and negative. FDA has indicated to companies that it is important to create an environment that encourages employees and makes them responsible to report quality issues when observed. This includes if there is any breakdown of the current aseptic practices.

Environmental Monitoring (EM) Procedures

I mentioned the science-based approach to best practices, which include not only the aseptic training of operators but also the surrounding work necessary to capture data to prove that these systems are working. This is where the environmental monitoring program comes in. We will not get into too much detail about these systems; the point is that the data must be utilized effectively. Does the system allow for trending not only excursions but “out of trend” situations? Is it reviewed on a regular basis to see if there are any breakdowns in the system or potential failures in the aseptic suite areas? Does it show you that there may be areas of improvement?

The environmental program does include the gowning procedures and processes². These are qualified procedures that the operators need to be challenged against. In addition, FDA often sites companies that do not perform root cause analysis (this includes investigation and identity) of environmental monitoring data that exceeds documented action limits. This includes all looking at proper disinfectant use, proper cleaning, poor environmental control practices and to provide a plan of action to effectively evaluate any of these factors.

Single-Use Technology

With the industry moving away from novel multi-use equipment to single-use equipment we do need to mention the benefit of using single use technology. Single-use technology is critical in the aseptic fill/finish arena. We utilize this technology because it gives us cleanliness, safety and aseptic assurance, as the system has not come in contact with the outside environment. There is always a risk with multi-use materials because of manual/automated cleaning and sterilization of the materials which, even with costly cleaning/sterilization validations, pose a potential cross contamination situation. It becomes easier to use materials once and discard and is a great contamination control effort.

Facility Design and Maintenance

Another specific area of FDA focus on is facility maintenance used for the aseptic manufacture of drug products. Citations recently point to facilities not having proper preventive maintenance but also to programs that often don’t include routine up-keep. These rooms are used many times over the course of the year and will require not only scheduled maintenance, but also as necessary. These “use related” facility items are wear-and-tear-related and may include cracks, holes, peeling paint, and chipping paint, all of which could lead to areas of contamination. It is best practice to perform a walkthrough of the areas on a regular basis using a defined list of inspection activities and document what needs to be done in order to address these issues. Lastly, the facility maintenance program should allow for preventive action activities to prevent reoccurrence of the facility wear and tear.

Process Simulations

Another supporting program is the Process Simulation (or media fills). These should include interventions that are both determined scientifically as well as practically and it must support your practice. FDA has been looking at these closely to make sure that adequate aseptic technique is being used. Interventions are determined by activities that do or can occur during an aseptic run. These are added to the process simulation protocol. Listed below are some of the common interventions:

• Change out of the fill head/pump mechanism
• Simulation of a stopper jam by removing a stopper from the stopper bowl track with non-sharp utensils
• Aseptic connection to a break vessel

Several recent FDA citations include witnessing practices such as using scalpels to move stoppers through the feed line and stopper feed removal. These interventions were not simulated during the process simulation and therefore cannot be used as validated aseptic practices. Secondly, use of sharp objects and stabbing at stoppers may prove to be particulate generating (again, this would be evaluated during the EM of the process simulation).

Raw Material Control, Preparation, Sterilization

Another area of microbiological control starts with materials. Materials used in manufacturing are stored in a controlled environment so that there is no microbial contamination. Material such as components (stoppers/vials and caps) are sterilized/depyrogenated respectively using validated sterilization cycles. If there are changes to these cycles then the load must be revalidated.
Fill/finish manufacturing companies must maintain the highest level of microbiological control. Many types of product come through the doors of aseptic fill/finish CMOs, including:

• Small molecule pharmaceuticals
• Oligonucleotides
• Natural Products
• Large Molecules
• Combination Products
• Drug Delivery
• In-vitro diagnostics
• Medical devices

All of these industries require the GMP controls mentioned in this article. As I’ve stated, if the controls are in place, the provider needs the best way to keep the control from failing. It is what we do with this data that makes the systems robust. The failure of the aseptic manufacturing companies the have had recent regulatory actions against them is that the systems that were in place were not designed to be monitored correctly. If no CAPA is derived from an environmental excursion, then there is no way to correctly monitor the system. If there are multiple gowning failures by operators, then does the quality or support system allow for the proper investigation into root cause?

We can talk about validated systems and monitoring data and how these data are utilized in your contamination control system, but we cannot forget to talk about the trigger for change in a validated system: Change Control. Change control must be used for any change of any validated system to be able to determine the overall impact of the change to the original validation, allows the company to determine the future impact and as a vehicle to capture what kind of changes are occurring. Without an effective change control program proper impact assessment/risk assessment cannot be performed.

Keeping with the contamination control systems are critical in maintaining the level of environment that is required for aseptic manufacturing of final drug product. Overall impact to changes due to excursions or failures must be resolved through an impact/risk assessment approach in order to assess how the other supporting system will be affected and how the overall monitoring of the environment will change. FDA has been very critical of aseptic fill/finish companies as it pertains to environments and investigations of any item that is out of trend or outside of specifications. The importance of system monitoring through data generation and analysis will pave the way for all of us to keep on the path of best aseptic practices.

References
1    FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, September 2004 Pharmaceutical CGMPs
2    ISO 14644-1: Cleanrooms and Associated Controlled Environments, Classification of Air Cleanliness.

Alexander (Alex) Mello, M.S., SM (NRCM) is the director of Project Management, Manufacturing at MicroTest Laboratories, Inc. in Agawam, MA. He can be reached at 800-631-1680, Ext 121 or at anmello@microtestlabs.com.