The Current State of Aseptic Processing & Fill-finish Manufacturing

What is aseptic processing?

Almost every day, we rely on pharmaceuticals like ear drops, eye drops, nasal sprays, and vaccines to be sterile, hygienic, and free from contamination. Because these parenteral products are injected or introduced to delicate mucus membranes, adding something non-sterile to your eye, nose, or into your vein can have serious adverse effects, such as a fever or infection. This requires a special manufacturing process called aseptic processing, or fill-finish manufacturing, which addresses risks through a range of cleaning, sterilization, and isolation practices.

Aseptic processing is the step-by-step method of making a formulation, filling it into a vial, syringe, ampoule, or cartridge, and then finishing it by inspection, labeling, and packaging—all while keeping it contaminant free. This process is also sometimes referred to as fill-finish manufacturing, but that particular term applies to items that only require an aseptic process at the end steps. Regardless of terms, the goal is the same: safe, effective products that are free of microbial or other contaminants.

Terms to know

• Aseptic 
  • Something has been made contamination-free and will not reproduce or create any harmful living microorganisms (eg. bacteria, viruses and others)
• Bioburden 
  • The number of microorganisms contaminating an object
• Biologics 
  • Products made from living organisms or containing components of living organisms
• Bulk drug substance (BDS) 
  • Materials used in the manufacturing, processing, or packaging of a drug that become an active ingredient or a finished dosage form of the drug
• Cold chain 
  • A temperature-controlled supply chain using thermal and refrigerated packing and storing methods
• Lyophilization 
  • Freeze drying—also called cryodesiccation
• Sterile 
  • Something that is free from contamination caused by harmful bacteria, viruses, or other microorganisms
• Terminal sterilization 
  • The process of sterilizing a product in its final container

Aseptic vs sterile manufacturing

It’s important to differentiate between products produced in an aseptic manner and those that are merely sterilized. Aseptic refers to a process that is orchestrated to make a product without microorganisms present at any point from start to finish. Sterile, however, simply means that the end product is free from living microorganisms.

Regulatory agencies state that terminal sterilization should be used for any product that can withstand it. Aseptic processing is reserved for any filling operation where the drug cannot withstand the heat cycle of terminal sterilization. Why is this? Advanced aseptic techniques require a higher level of engineering and operation to produce safe products. Instead, it is far simpler and less costly to reduce bioburden along the process and then terminally sterilize with heat. There are many drugs that cannot withstand a heat sterilization step including most biologics, vaccines, and cancer drugs.

Terminal sterilization

• IV Bag standard solutions (eg. saline, dextrose, lactated ringers)
• Diluent solutions (eg. WFI [water for injection], simple buffers, simple salts)
• Small molecule drugs not susceptible to heat

Aseptic processing

• Antibiotics
• Biologics
• Vaccines
• Monoclonal antibodies
• Antibody drug conjugates
• Small, medium, and long chain drug products that are susceptible to heat

The challenges of aseptic processing

Aseptic processing hinges on technique, detailed procedures, equipment, and controls. It comes with more risks than non-sterile processes. Therefore, it requires more specialization and analysis than some other pharmaceutical processes such as oral solid dosing.

Failures at the fill-finish stage that introduce microbial contamination and create issues with formulation and dosing can lead to:

• loss of valuable product
• production delays
• potential health risks to patients

An orchestra of operations

Aseptic processing requires close coordination and complex interaction between:

• Personnel
• Pre-sterilized product
• Sterilized product
• Equipment systems
• Cleaning systems
• Cleanroom and support facilities
• Support components
• Transfers

Regulatory scrutiny

Understandably, there are strict regulations regarding anything that is injected, added to the eyes, and to a lesser extent, added to the nose. Because of the potential risks to patients of contamination or drug degradation, as well as their highly technical nature, fill-finish operations are the subject of significant regulatory scrutiny.

5 aseptic processing must-dos

1. Control the contamination in the space (both viable and non-viable)
2. Protect the product by controlling the bioburden
3. Utilize cleaning to continually control particulates (both viable and non-viable)
4. Maintain Good Manufacturing Practices (GMP) by utilizing a focused risk-based approach to protect the critical areas
5. Train and adhere to procedures and follow good aseptic practices

Handling sensitive biologics

There is a growing diversity of biologic drugs as small, medium, and long molecule API drug products expand to meet patient needs. Here are five unique challenges that come when working with biologics.

• Stability: Many biopharmaceuticals are fragile in nature and their protein structure, function, and stability can be negatively affected during processing and filling. For example, most biopharmaceutical formulations are aqueous. Proteins have limited stability in their liquid state so special care must be taken to preserve a protein’s three-dimensional (3D) structure during the entire aseptic process. Temperature control plays an important role in maintaining stability.
• Risk of loss: There is huge potential for loss of valuable product. By the time a drug is filled into the final container, a significant amount of time, effort, materials, and labor has been invested in drug production. Any bacterial or human contamination at the final step could lead to safety issues for patients and significant economic losses for manufacturers.
• Filling: Every biologic dose should be filled with precision to present the appropriate dose to the patient and reduce risk of contamination at every stage of manufacturing, storage, shipping and delivery.
• Inspection: Inspection challenges with biologics include the visual inspection of clear and opaque suspensions in amber vials, distinguishing between foreign and product-related particulates, and determining if there’s any microbial contamination despite a clean or sterile appearance. Strong QA measures are necessary to prevent contaminated products from reaching patients.
• Shipping: The cold chain aspects of storing and shipping parenteral formulations are among the most expensive steps. This is driving the industry to innovate at the final drug filling step to reduce cold chain storage and shipping needs. Lyophilization of filled vials is becoming a popular method to stabilize the product and reduce cold chain costs.

Step-by-step aseptic processing

Aseptic processing requires specialized capabilities and equipment, as well as close coordination between personnel, equipment, and facilities. Here’s how it’s done.

1) Bulk drug substance prep

After the bulk drug substance (BDS) arrives at a manufacturing facility and is accepted by the quality control team, it is transferred into storage until its scheduled filling date. The quality of a biologic BDS is ensured through traceability and end-to-end cold-chain infrastructure. Intermediate storage—used for extended hold times or multiple-day filling processes—also requires appropriate transfer and storage procedures to maintain sterility and optimal temperature of BDS. Safety measures should include 24-hour temperature monitoring, notification procedures in case of failure, and redundant refrigeration systems and emergency power.

2) Pooling/formulation

In an ideal setup, thawing steps are performed in closed systems to prevent exposure of BDS to outside air, reducing potential microbial contamination. Next, pooling and formulation of the final medication takes place in a compounding and formulation suite in either small or large tanks. Typically, a facility requires between one and six rooms of equipment for this step of aseptic processing. Engineering measures such as temperature control and monitoring of particulate exposure are used to ensure the product’s efficacy and value is maintained.

3) Component preparation

Not only does aseptic fill-finish need to be performed in a sterile environment, but all equipment and components must also be sterile and free of pyrogens (fever-causing microorganisms). This includes:

• Tools going into the filling line and isolator
• Vial preparations
• Syringe preparations
• Stopper or crimp cap preparations

There are several systems available to sterilize equipment. Each method has a different impact on processes, packaging materials, and possible contaminants. The correct method must be chosen to achieve sterilization.

• Autoclaving (steam):  Steam autoclaving is the most conventional sterilization technique as it effectively eliminates many pathogens. This method is a trusted standby for sterilizing fill-finish equipment, and/or connections between equipment. However, it can break down fragile components and can also be detrimental to tools and packaging that are highly sensitive to heat and moisture. Any items that need to be sterilized periodically or regularly need to be made of a material that is suitable for sterilization via steam.
• Depyrogenation tunnel (dry heat): Dry heat sterilization in a depyrogenation tunnel completely destroys pyrogens through controlled temperature for a controlled period of time. This method can sterilize equipment in a continuous feed to the fill line.
• Fumigation: Fumigation allows manufacturers to decontaminate large areas and reach difficult equipment arrangements more successfully than other methods. The process uses vapor phase hydrogen peroxide (VPHP), ionized hydrogen peroxide (iHP), or chlorine dioxide (CD) gas to kill microorganisms. While the technique is consistent and repeatable, all fumigants are considered health-hazardous materials—corrosive, and toxic or highly toxic. There are many facility integration issues that must be taken into consideration when planning to fumigate rooms.
• Radiation technology: Radiation is a supplemental technique that can be used in conjunction with traditional techniques. Radiation is usually used to sterilize items that are manufactured in a package that keeps the material inside of the package sterile during transport. Many single-use components are sterilized by radiation.
• E-beam: E-beam inactivates microorganisms by causing microbial death as a direct effect of the destruction of a vital molecule or by an indirect chemical reaction. It can penetrate medical devices and pharmaceutical products in their final shipping containers. E-beam is also used for surface decontamination for the entry of syringes in a container to be brought into the aseptic filling environment.

4) Sterile filtration

Sterile filtration is used in aseptic processing to remove microorganisms. It’s important to use accurately sized filters to reduce hold-up and loss of high-value biologics. Of note, peristaltic pumps (versus piston pumps) have become the standard for many biologics filling processes. It is easier to adjust flow speed with peristaltic pumps, thereby preventing foaming and splashing.

5) Aseptic filling

Accurate filling methodologies prevent underfills (which causes rejects) or overfills (which increase costs). The tolerance of the filling methodologies are easier to adjust than in the past. As servo motors have increased the variability of the movements of a filling machine, facilities have been able to lose less units to rejects, therefore increasing the number of acceptable units from each batch. Filling types include time pressure fills, peristaltic pumps, and diaphragm pumps.

6) Lyophilization

Lyophilization, or freeze drying, is used to stabilize formulations of sensitive parenteral drugs, especially biologics. Maintaining aseptic conditions during lyophilization is a technical challenge for manufacturers because it involves complex heat and mass transfer processes. It also requires sterile procedures to prevent contamination while loading and unloading the sterile dryer.

Step 1: Fill
The liquid is filled into vials or bulk trays, which are then loaded into the lyophilizer.

Step 2: Freeze
The temperature is lowered in the lyophilizer and the liquid freezes into a solid.

Step 3: Sublimate from frozen to dry
In the final optional step, a vacuum is created in the chamber to create a phase change. The frozen medication becomes a powder, making it easier to store and ship. It also increases shelf life, lowers cost, and allows drug products to ship at room temperature.

Step 4: Stopper
For glass vials, the shelves are used with a ram to depress the stoppers into the vial. Although the vials are not stoppered; the industry does not consider them closed until they have a cap crimped onto the system to make an integral container closure.

Step 5: Unload
The stoppered vials are then singulated out of the lyophilizer to the downstream capping and crimping operations. It is at this point that the industry considers the container closed—once the vial, stopper, and crimp are all integral within the performance specifications of the container closure.

For bulk lyophilization that is not in vials: many times this bulk lyophilization is performed in trays. Those trays then need to be unloaded and the powder transferred for use in the next step. Sometimes that lyophilized powder is filled into vials or bottles. Sometimes that lyophilized powder is added to an inhaler, and sometimes that lyophilized powder is loaded into a container for further processing.

7) Inspection

Product and container inspection is a critical part of the filling process. Inspection can be manual, semi-automatic, or fully automatic. Inspection processes typically are used to identify any non-conformities in the batch such as cosmetic defects, container closure defects, or particulates within the container.

8) Packaging

Finally, once the product is filled, finished, and inspected, it needs to be packaged for shipping. Packaging must label, identify, and protect the container for shipment. All products have some form of packaging and each package is specially designed for the container within. Examples of final packaging forms include:

• Vials
• Bottles
• Syringes
• Ampoules/or cartridges
• IV bags
• Microneedles
• Injectable medical devices
• Ophthalmic drops
• Otic (ear drops)
• Inhalation (puffers)

Getting the right scale

To maximize efficiency, a fill line needs to be right-sized. Each facility—depending on scale, risk, and costs of goods—will need a different solution and each business case is different. A facility needs to factor in the speed at which the lines run, transfer time, and even the way cleaning occurs. To arrive at the best solution, it’s important to conduct a cost-of-goods analysis and a risk assessment with the goal of determining how to reduce risks and costs of failures.

Another factor to consider is the desired flexibility of fill lines. Fill line flexibility can be measured by product profile, value, or container type. For example, one facility may find it valuable to accommodate vials, syringes, and cartridges all on one line. Another facility may want the flexibility to run multiple types of products such as monoclonal antibodies, cell therapies, and gene therapies on one line. Achieving the correct amount and type of flexibility will be dictated by what a company hopes to achieve with its fill lines.

Small line

• 20 to 20,000 units
• Up to 50 units/minute
• Used for:
  • speciality products
  • biologics and therapeutics (smaller batches, high-value product, more protection)
  • cell and gene therapy (very small patient population)
  • oncology drugs (hazardous compounds that could harm the operator)

Medium line

• Up to 200 units/minute
• Used for:
  • high-value products
  • pain medicines
  • Rheumatoid arthritis meds (e.g. Remicade, Enbrel)

High-speed line

• Up to 300 to 600 units/minute
• Used for:
  • blockbuster drugs for large populations
  • vaccines
  • insulins

Current trends in aseptic processing

Even prior to the pharmaceutical demands brought on by the pandemic, there was tremendous pressure within the aseptic processing industry. The availability of aseptic processing for new products was already limited as CDMOs were at 95 to 98% capacity. If a company had a new drug, they had to get in line with a significantly delayed timeline. Many drugmakers were already preparing new manufacturing space to be able to final-fill their product.

When COVID-19 vaccines were ready for manufacture, a significant amount of CDMO capacity was instantly redirected. This has meant that most ATMP companies need to plan on providing their own fill-finish capacity. For biologics, biosimilars, and generics, there are significant concerns about fill-finish availability, timeliness, and drug shortages.

The challenges of aseptic processing will continue to grow in complexity as more small-batch targeted biologics enter the market. The transition to flexible and multi-product fill-finish operations will be made possible through advances in automation and cleanroom technology, including isolators and restricted access barrier systems (RABS).

Automation

Facilities will continue to see increased automation ranging from simple robots to fully automatic processes. Robotics reduces many of the past sources of contamination risk and makes the fill-finish process consistent and endlessly repeatable. It therefore increases a manufacturer’s ability to meet production quotas on tight deadlines.

Although it may be controversial, automation allows for a decrease in the number of operators required to complete a batch. The goal of future facilities is to employ as few operators as possible. This isn’t just about the bottom line, but also because operators tend to be a major source of contamination of any clean room process. Additionally, automation eliminates human error and can significantly boost the number of batches a facility produces each day.

Automation at work: It is possible to have a completely automated aseptic fill-finish process without ever removing a drug product from the lyophilization environment. Vials are automatically filled and loaded into a lyophilizer. Next, the lyophilizer shelves are automatically lowered, causing stoppers to attach to vials. The entire operation happens under isolation in a barrier system and calls for an extraordinarily precise setup as vials must be prepared in batches with their stoppers resting on vial edges.

One of the challenges of automated systems is that it requires extensive programming to perform fill-finish steps in a specific way until instructed to perform a different process. Automated systems are also not fully equipped to respond to unexpected events or variations in an operation. Human oversight will always be required to some degree in even the most automated aseptic processing facility. Another aspect of automation to keep a close eye on is data integrity. For example, the FDA demands control over logins and passwords to prevent data breaches. Just like online banking info, online data must be protected. Potential data breaches are under heavy scrutiny and have resulted in citations.

Facilities of the future

The fill-finish industry is expanding quickly and aseptic processing will continue to require coordination, risk management, and regulatory compliance. Meeting this growing demand for fill-finish services requires:

• specialized expertise
• appropriate equipment
• innovations in both emerging technology and business models

Expect to see continued innovation in single-use technologies. It seems unlikely, however, that single-use systems will ever replace stainless steel equipment entirely.

Facility owners should expect to flex to keep up with changing, patient-centric demands for new drug-delivery systems that can better fit patient lifestyles and increase convenience and adherence. The broader shift in the pharmaceutical market from blockbuster drugs to specialized, targeted therapies intended for small patient populations is creating a need for fill-finish operations with flexible capabilities. The growing global biopharmaceutical industry is likely to drive the fill-finish manufacturing market in the future.

No matter what the future brings, the core demands of fill-finish processes remain the same: to provide patients with contaminant-free drug products that are as effective and safe as possible.