Employing QbD to mitigate risk in aseptic parenteral fill and finish

Blow/fill/seal technology, used widely for ophthalmic, respiratory and parenterals, has been slow to make an impact in the US injectables market. Bill Hartzel, Director, Strategic Execution, Advanced Delivery Technologies, Catalent Pharma Solutions, reviews how its potential advantages meet QbD principles and mitigate the risk in parenteral filling applications

Blow/fill/seal (BFS) technology has been used for decades to provide sterile products in the ophthalmic and respiratory markets

It will probably come as something of a surprise to European biopharmaceutical manufacturers that few injectable drug products are packaged using blow/fill/seal (BFS) technology in the US. This advanced aseptic process has been used for decades to provide sterile products in the ophthalmic and respiratory markets and is extremely well understood in those sectors. Additionally, it is commonly employed by pharma companies in Europe, Asia and South America for injectables. Yet in the US, despite its many benefits over traditional aseptic filling techniques, it has thus far had limited use in the injectables market.

BFS technology provides a significant advantage by drastically reducing the risk of microbial and particulate contamination. BFS is classified as an ‘advanced aseptic’ technique and meets the demands of the FDA’s 2004 cGMP guidance, ‘Sterile drug products produced by aseptic processing’, in terms of equipment, controls and microbial challenge test results. The process has no direct interventions made by operators and there are no open product containers or exposed product outside of the controlled class A space within the machine. Finally, the time and exposure in the class A environment is only seconds. This technology is fast, automated, and operates in a robustly controlled environment, with all parameters machine set and remotely monitored.

If microbial contamination does enter the room, then every single piece of equipment, including all the vials and stoppers, may no longer be sterile

There are many risks associated with traditional aseptic manufacturing. As might be expected, the regulator’s guidance drives toward the avoidance of human contact. The biggest risk to a product’s sterility comes from human operators present within the filling suite. Additional risks come from components of the filling line that must be cleaned and sterilised before they are assembled, as well as both containers and stoppers that are open to the atmosphere after cleaning, sterilisation and depyrogenation. The vagaries of the turntable and stopper bowl mean operator intervention to ensure vials and stoppers do not get overturned or jammed is common. If microbial contamination does enter the room, then every single piece of equipment, including all the vials and stoppers, may no longer be sterile. This creates significant risks to product integrity, plus the impact on productivity is obvious.

BFS filling process

It is very different in a BFS line. This process is highly automated and removes the need for operators in the filling process. Even if something does go awry and the fill has to be stopped, the product loss is minimised because only a small amount of product is ever exposed to the air at any one time, with the remainder protected from the atmosphere.

The premise behind BFS is the forming of the primary container, the filling of the product and sealing to create the finished container closure in a controlled process. Even though there are different forming techniques in the BFS market, the principles are all the same. The filling process takes place within an ISO 4.8, or Class A, environment, and the whole operation from container formation through filling to final seal takes place in seconds. At the heart of this advanced aseptic designation for BFS are the fundamental principles of Quality by Design (QbD) and the microbial challenge data.

There has been a significant amount of data generated on this technology to understand the critical control parameters to ensure product sterility

There has been a significant amount of data generated on this technology to understand the critical control parameters to ensure product sterility. Fundamentally, the fact that the material flows for both container formation and product are virtually closed in a simplified automated process results in an advanced aseptic process.

To describe the process, the first consideration is the polymer pathway. A vacuum feeds virgin polymer pellets into a plastic extruder, where the pellets are processed with both heat and pressure (typically around 180°C and 200atm) to form a molten parison. The parisons are extruded into an ISO 4.8 space, where a maximum of 3,520 particles 0.5µm in size are permitted in a cubic metre of air, and just 20 5.0µm particles.

The next step involves a brass and steel two-stage mould, in which the first stage closes around the parison to create the body of the primary container. With the top of the container open, fill nozzles are activated and the product is filled. The second stage of the mould then closes around the container to seal it. This process takes a matter of seconds and is always contained in the ISO 4.8/Class A environment. The product filled container is now ready for the secondary handling processes.

Another important part of the aseptic nature of the process is the continuous monitoring of both viable and non-viable airborne particles and the level of control in the filling area. If the levels within the fill zone exceed those that are permitted, the run will automatically be stopped so that no further containers are filled while the air is out of spec. Additionally, because there are no containers produced while the machine is stopped, it eliminates the potential of contamination to the container and product.

In a BFS line, everything is cleaned and sterilised in situ within a closed system

The product pathway is also closed. In a traditional filling line, all the components through which the product passes, including tank, filter housings, hoses and filling system, must be sterilised ahead of time and stored, then assembled and aseptically connected by human operators immediately before the filling starts, increasing the potential of contamination.

In a BFS line, everything is cleaned and sterilised in situ within a closed system. Therefore the sterility boundary is never reached and this potential for contamination is removed.

Challenge tests

The design of a BFS line and the process controls that are in place form the basis for the advanced aseptic designation that this technology has been afforded. This was achieved through a whole host of challenge tests run by various experts in the industry, including Automated Liquid Packaging Inc, which is now part of Catalent. These tests were designed to investigate how a range of different microbial challenges would affect the sterility and integrity of the final filled vials.

A specific test facility was designed at Catalent to carry out these microbial challenges. Essentially, this was a room within a room, with its own dedicated HVAC introduction and exhaust systems to ensure no cross-contamination or false readings were possible. The only contamination that would be present during the test would be those carefully measured amounts that had been deliberately introduced, whether via fogging or the surface contamination of equipment and components.

Of the many studies that were run, three examples show just how safe and effective this process is. All of these tests involved introducing a specific form of microbial challenge, followed by a normal filling run being carried out, and the contamination levels of the final containers evaluated.

The first of these tests looked at the air quality of the room. The test room was fogged with a 102–108m3 aerosolised suspension of Bacillus subtilis, with aerosolisation continuing throughout the test period.

Multiple filling runs were carried out, with challenges including the activity of the HEPA air shower in the ISO 4.8 space, the most critical part of the filling line. The contamination fraction was established at 10–3, representing a substantial reduction from those much higher levels of contamination that had been introduced into the room. It was also directly proportional to the microbial load that had been applied. These results identified the critical control parameters that enabled operating and environmental conditions for BFS filling lines to meet the sterility assurance level of 10–6 that is required for terminal sterilisation.

Next, challenges to the raw plastic resin pellets were undertaken. The resin was loaded with up to 108 spore suspension of B. subtilis, which is drastically higher than anything that has been seen for incoming material. The plastic resin was then processed through the typical temperatures and pressures involved in the extrusion process to create the primary containers. It was shown that the extrusion process provided 10–3 reduction in bioburden and provided the basis for control of incoming material.

Equipment tests

Finally, the effect of contaminated equipment and components was investigated. With the exception of the filling nozzle, all surfaces of the BFS equipment were coated with up to 108 spore suspension of B. subtilis. Even though the surfaces were loaded with microbial contamination, the only surface that created a media failure was the fill nozzle that comes in direct contact with the product. This proves that even if the equipment itself is extremely contaminated, the final product remains safe.

One does not need even to run similar tests on a traditional filling line using pre-formed vials and stoppers to know that the results would not look good. An aerosolised 107 spore suspension within the filling suite would cover absolutely everything – from equipment to containers – with a layer of microbial contamination that could be removed only by dismantling the line and re-sterilising every single component, and repeating the cleaning, sterilisation and depyrogenation process for the vials and stoppers. Without that re-sterilisation, virtually every single vial of product that was filled would surely be contaminated. This contrasts sharply with the advanced aseptic process of BFS.

ADVASEPT technology, for the advanced aseptic filling of injectable drugs was launched at Interphex this year. It employs an ultrapure plastic design that eliminates the risk of glass particulate contamination, significantly reduces the risk of breakages and minimises container weight

The future

There are significant advantages in employing the advanced aseptic process in comparison with traditional glass filling and it would seem unlikely that the US parenterals market will lag behind the rest of the world for much longer in terms of implementing this advanced aseptic technique in the filling of parenteral products. This is not new technology; on the contrary, it has been used to fill products for the ophthalmic and respiratory markets for decades, and is already well established for parenteral products in other major world markets. It is not that the FDA does not accept the technique, either – the 2004 guidance shows that it is well aware of the advantages of advanced aseptic processes like BFS.

It would seem unlikely that the US parenterals market will lag behind the rest of the world for much longer in terms of implementing this advanced aseptic technique

In recent years, the heightened challenges that occur in the aseptic manufacturing space have led to product recalls and drug shortages which have provided the market with a new vigour in finding a better way to manufacture. An advanced aseptic solution such as BFS could drive a significant change in product supply and decrease the potential risk associated with aseptic manufacturing.

Additionally, this process creates a glass-free container closure system that provides advantages compared with glass in the reduction of breakage, elimination of glass delamination and safety for practitioners.

While there are economic and reputational impacts for recalls due to contamination and sterility issues, the real losers are the patients, who may find the drugs they rely on are unavailable because of drug shortages or their safety at risk due to contamination. The implementation of an advanced aseptic process such as BFS is one way to reduce the risk of contamination and the subsequent consequences.

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