Early aseptic filling was primitive by today’s standards. It was in the 1930s and afterwards that glove boxes came into use for similar purposes. Glove boxes continued to be used with modifications that eventually included some form of air filtration. It was not until after World War II that HEPA filters became available and the traditional cleanroom concept emerged.
The cleanrooms were based upon unidirectional airflow over the filling area and have remained so ever since. Improvements to avoid the effect of air displacement by operator movements led to screening with sheets of hanging flexible plastic.
There was much hesitation in the industry to move to isolators fixed onto a filling machine. The move was largely driven by the need to aseptically fill products that were heat labile such as vaccines and blood products. Another consideration was the preparation of certain products that were hazardous to operators such as hormones or cytotoxic preparations. The dilemma was that nobody wanted to be first but nobody wanted to be third!
Parallel with these moves, filling instrument manufacturers also viewed the use of isolators as part of the development of their equipment and gradually filling lines became more ‘isolator friendly’. Air leakage was viewed as a problem when using positive pressures due to the design of early fillers and also the escape of decontaminating agent into the surrounding environment, but gradually these problems were addressed by the equipment manufacturers and most of the modern isolator/filler combinations showed very little leakage of air or decontaminating agent when sealed.
Isolator manufacturers also looked at the requirements of placing an isolator onto a filling machine and developed the typical (as seen today) stainless steel shell with doors. Windows in the doors and in other panels surrounding the filling machine were equipped with sleeves and gloves for handling purposes. These were suitably placed for appropriate manipulations within the enclosure.
Other rigid models appeared using plastic materials moulded and shaped, with typical window and glove fixtures. Many had attached pass-throughs that could be ‘sterilised’, either together with the isolator or separately. The use of the term ‘sterilised’ is for simplicity. In practice a sporicidally active chemical decontaminant is normally used.
As aseptic filling processes had, by tradition, been carried out under unidirectional (laminar) airflow which was the only real protective mode for such a process (Grade A conditions), it followed that for particle control and for microbiological purposes the rigid isolators had to be built to use the same principle. This type of design became the conventional isolator for aseptic filling and processing the active principles
into finished product.
In parallel with these developments, due to the cost of some of the isolator systems and the size and complexity of filling machines at that time, a new concept of a barrier system evolved. Rigid sheets of plastic fitted with gloves were suspended around the critical filling area as it was the operating personnel who posed the greatest risk of generating airborne contamination in the critical filling area.
Further development led to a variety of RABS used for aseptic filling which closely resembled conventional isolators. It is important to note that the main protective mode of the RABS is still the use of unidirectional airflow with a barrier to prevent intrusion by the process operators during the filling process.
Further developments were made so as to be able to biologically decontaminate a RABS in a similar way to a conventional isolator. In nearly all cases, with the design of a conventional isolator or a RABS, the HEPA filters, in essence, became the ‘ceiling’ of the isolator. In the early days this type of design using unidirectional airflow became the norm for filler/isolator combinations and has continued but there are now debates about the use of turbulent airflow as another method.
In the case of isolators used to transfer sterile product or equipment into the filler/isolator, then in many cases turbulent airflow was and is used, either with cartridge or with box type filters. The debate has largely centred on the microbiological aspects of conventional isolators as it has been confirmed that the status of the isolator, after a suitable validated biological decontamination process, showed no microorganisms present on all of the surfaces exposed to the chemical agent used. This led PIC/S inside a recommendation to state the isolation of one colony forming unit inside a ‘sterilised’ isolator indicated the failure of the system and a thorough investigation should take place. PIC/S also made recommendations regarding assaying the microbial status of the ‘sterilised’ isolator without placing any bacteriological test equipment inside the unit.
With the use of unidirectional airflow within a ‘sealed box’ it was necessary to have the larger part of the airflow return back to above the HEPA filters with a little make up air from the surrounding environment. The return systems varied in shape, size and complexity and were, in some cases, demountable for ease of cleaning. Air return ducts with slotted apertures on the edge of the floor of the filling machine were common with associated pipe work outside the enclosure returning air to the plenum above the HEPA filters.
Later developments for air return included the sophisticated design of a double window where the small space between the windows in the isolator or on the isolator doors allowed for the return air to the plenum. This technique largely removed the need for external air return systems and was much more elegant.
Cleaning was obviously essential especially with the use of decontaminating or sanitising agents such as peracetic acid/hydrogen peroxide mixtures and later hydrogen peroxide either as a vapour, aerosol or ultra-sonic mist.
As with the early flexible film isolators other process equipment was added onto the rigid type isolators to
enable a continuous flow of product in a sterile environment. Examples include:
• Freeze dryers, attached to the filling machine isolator for the aseptic transfer of partially stoppered vials into the lyophilizer and also recovering the stoppered vials back out of the freeze dryer for capping to seal etc. This form of the technology involved resolving issues of reach for the operators. Some systems were made to work automatically (loading and unloading) but for manual work it was usual to employ a half suit.
Freeze dryer interfaces with filling isolators have become very sophisticated and in some cases fully automatic by way of loading and unloading.
• Dry heat tunnels to deliver sterile endotoxin free containers direct onto the filling line. These could be bottles, vials and syringe barrels.
• E-beam tunnels to deliver tubs of sterile syringes directly into the filling zone. The e-beam system is used to decontaminate the external surfaces of the syringe tub.
• Autoclaves for delivering sterile media into sterility test isolators, duct contact components of a
filling line into the isolator or sterile containers for filling.
Downstream from the filling isolator, depending on the product, other units could be and were added including particle inspection, labelling and packing into primary cartons. In the case of syringes also a unit for plunger insertion.
Original text: Clean Air and Containment Review - Issue 20- October 2014
Comments