spacer
home > pmps > summer 2012 > contained solutions
PUBLICATIONS
Pharmaceutical Manufacturing and Packing Sourcer

Contained Solutions


Containment of potent pharmaceutical compounds has been a continuous challenge for the industry, but help is at hand from a range of specialised devices and technologies.

Over the last 20 years, the containment of pharmaceutical potent compounds has been an on-going challenge for a large number of associated equipment manufacturers. Just as the industry meets these demands with successful containment technology, chemists have developed increasingly potent cytotoxic drug formulations and consequently raised the containment performance bar.

Generally, global drug manufacturers require containment solutions to achieve an acceptable level of operator protection, reduce the threat to the environment and to maintain product sanitisation without the risk of cross contamination. While maintaining the above criteria, the solutions developed would also need to be cost effective, operator friendly and adaptable to a wide variety of processes.

A containment device widely used within the pharmaceutical industry to achieve product transfer is the Split Butterfly Valve (SBV) (see Figure 1). Developed over 20 years ago, the utilisation of SBVs within manufacturing processes has evolved from its role in the transfer of low potent powders to highly toxic compounds. This achievement has been the result of a small number of established and specialised organisations, which have developed their own unique range of SBVs to meet the demands of the industry. The challenges these companies have had to face are generally common to all; however, the solutions offered in return have been rather varied. A number of key aspects have been identified below with a brief outline of construction options and applied solutions to meet the varying level of exposure limits.

Design Concepts

At each process step within a typical manufacturing or formulation phase, there exists the associated containment level, commonly referred to as the ‘Process OEL’. In order to successfully achieve these levels of containment, the split valve manufacturers have progressively developed a range of design concepts, which are applied to the defined containment categories, and also in conjunction with the specific process application. These take into account: the total volume of batch or batches being transferred; the bulk density on the material; the flow characteristics; and cohesivity. These are key factors which determine the methods that should be used

Fundamentally, the requirement of any SBV is to achieve an appropriate level of containment, both during product conveying and also after the active and passive parts are being and have been separated. A significant element of the valve design that can dictate this containment efficiency is the method by which the active and passive disc halves form a seal when they are docked together, and are opened to allow product flow through (see Figure 2).

In some cases, elastomer seals are utilised to provide a ‘gasket’ joint between the mating discs. Some designs offer inflatable seal technology combined with this methodology, while other less common designs offer a metal to metal disc interface. The performance results for each method can be quite similar; however, overall performance should be gauged on repeatability and the cost of consumables over a running period.

Equally important, the elastomer seals within the valves have a particular influence on both containment achievement and valve operability. The commonly termed ‘seat’ component serves as an interface between active and passive body parts, and also provides the critical seal around the disc perimeter. These seats are often manufactured from various grades of elastomer material, selected on suitable compatibility with the process chemicals.

Essentially, it is the dimensional accuracy of this seat and the effect when exposed to the process that will dictate the containment performance and the operability of the valve. In some cases, special machining techniques are adopted on post moulded seats, resulting in precision and continuity between each manufactured seat.

Cytotoxic Products

Where cytotoxic products are being manipulated, the SBV design takes on a critical level of responsibility. Here, the higher level containment requirements are met with a variety of techniques. Quite often, an extraction arrangement will be applied to the valve. This is adopted in various forms, with the ultimate goal of recovering any potentially airborne particulates, during and after passive and active separation (see Figure 3).

In some cases, this methodology can be combined with a ‘wet flushing’ sequence between the discs. This can be an effective method of achieving high containment, as it has the ability to potentially dissolve exposed residue and recover this within the flushing stream. Furthermore, it can be less difficult with this method to remove compacted particulates once dissolved or suspended within a flushing solution stream. However, one drawback to this is the fact that it utilises a liquid – commonly a solvent – to achieve this flushing process. This can present a risk to the downstream process if, at any stage during this cleaning sequence, there is a breach within the valve sealing, creating a leak path for the cleaning solution. In some cases, this may not be a problem, particularly when the fluid is compatible with the downstream process. However, this can have a detrimental effect when the process step is dry and must not be exposed to any moisture.

Large volumes of solvent consumption can also present a high running cost for this method and requires appropriate solvent recovery and recirculation equipment. In general, for this approach, the balance associated with the cost and potential process risk should be considered alongside the benefits of achieving high level containment.

Reaction Vessel

Within a chemical development phase or primary manufacturing stage of a compound, the most frequently adopted process technology is the reaction vessel. The conditions within the majority of reactor processes can be chemically aggressive and are typically operated at elevated pressure and temperature conditions. Commonly inerted with a nitrogen purge, the conditions within these process vessels are hazardous and regularly require a method of contained charging of ingredients.

Once again, the SBV offers such a service, and does so quite effectively, achieving it with a minimal footprint, resulting in reduced obstruction to other process instrumentation or drive systems mounted upon the vessel, and also with limited or no utility service requirements. It is vital in this situation that the SBV maintains a pressure seal. A design trend followed by the majority of SBV manufacturers has involved a thicker active disc profile.

This offers a secure pressure seal, but only when the active valve is closed. Alternatively, a pressure sealing plug component fitted within the active body will provide a seal between this plug and the active body, removing the need for a thicker disc profile.

While this second option does require an additional component, the design feature also presents benefits. As this method does not utilise the active disc to achieve a pressure seal, the valve can remain open during a pressure or vacuum condition when fitted with appropriate ancillary components, such as a sightglass or a pressure rated container. Indeed, another benefit of this feature is that it can be utilised for processes where low volumes or cohesive products can be charged by means of a pressure transfer.

Cleaning

Cleaning and decontamination is particularly important and presents challenges to not only the SBV manufacturers but also the end user with respect to achieving a suitably validated cleaning and decontamination procedure. Essentially, SBVs must be designed with GMP standards in mind and would ideally offer simple dismantling methods with a limited number of breakdown parts. Common design arrangements applied to WIP and CIP systems include strategically positioned spray heads, located within the process. More effective is the traversing spray lance, which enables the CIP heads to be manoeuvred through the valve and potentially into the process itself (see Figure 5). The most effective method, however, for the removal of all product residue and to avoid any potential cross contamination risks, is to carry out a complete dismantling procedure and place these components in a parts washing machine. Although this can be procedurally complex, it does prevent cross-contamination risks within multipurpose manufacturing facilities. In the case of single product processes, it is normal to carry out a clean-in-place procedure, especially where the SBV is of a large diameter, fully automated and may even be presented with accessibility issues. These local cleaning solutions can be in the form of the methods previously mentioned, or even as a recirculation cleaning procedure, where the detergent or dilute solvent is pumped through the SBV and back round through the process. Of course, with this method, it is essential that the SBV design should maintain a secure, liquid-tight seal with the valve open at the pressure at which it is carried out.

Classical formulation and final processing facilities are designed to accommodate large volumes of blended product and are contained within commonly adopted stainless steel intermediate bulk containers (IBCs). With these large containers, the cleaning methodology becomes somewhat more complex. The IBCs normally fitted with the passive halves would ultimately require a contained method of cleaning. Once again, the industry has designed and developed complete IBC wash stations. Within the IBC wash station, the SBV manufacturer would provide a specific ‘Wash Active’ arrangement, allowing automated docking and opening of the passive halves, giving access to the traversing wash head arrangements. These wash actives come with a further challenge, with higher level IP rating requirements and elevated temperatures of cleaning solutions, for items such as the actuators and proximity sensors identifying the status of the valve, which must resist these conditions. Upon satisfactory SBV integration, these IBC wash stations provide an effective and repeatable approach towards cleaning of large volume containers.

For smaller batch transfers, normally weighing less than 100kg, there is a wider variety of manually handled rigid containers and flexible bags, which can be transferred by hand. Containers are usually offered in FDA-compliant plastic materials, such as polypropylene or polyethylene, and can commonly be re-used after appropriate cleaning (see Figure 6). The advantages of plastic containers are their lightweight nature, a degree of translucency and generally their low cost. Overall, plastic containers are favoured within the industry for these benefits; however, one major drawback is the nature of plastic and its inherent static properties, which can present hazardous risks with certain products with characteristically high ignition energy levels. The alternative option to this is the adoption of stainless steel containers. Where this is able to overcome the static issue and also has the added potential benefit of being pressure rated, it is no longer a lightweight and inexpensive option and does not enable visual intervention.

Flexible Bag Technology

One further method of handling powder product in conjunction with the SBV, is in the form of the flexible liner or bag technology. Rapidly increasing in popularity, the flexible bag has numerous benefits over its rigid container counterparts. Primarily, it offers a disposable option, which removes the costly and time consuming need for cleaning and the validation procedures commonly associated with the conventional bottle technology. It provides the operator with full visual capability and the ability to manipulate, manually de-agglomerate and vitally be able to ‘feed’ the product through the SBV – all of which cannot be achieved with a rigid container. This feeding process is especially advantageous when attempting to transfer larger than normal batch volumes through a small diameter SBV. Almost unachievable with a rigid container, powder material with lower bulk densities would generally remain within the bottle and require additional methods such as vibration to assist with flow through the SBV. The majority of bag systems that are provided are manufactured from low density polyethylene (LDPE) and some ranges boast a high level of anti-static properties. Unfortunately, the bag option is not a superior offering and has the disadvantage of not having a pressure rating capability and also has a limited load capacity.

The evolution of the SBV over the last 20 years has been rather impressive. It was once considered as a general dust control transfer device with the ability to contain down to levels of under 10μg/m3. Today, it has developed into a high containment concept achieving nanogram levels of containment. Furthermore, system integration has been a key factor of the SBV’s success, providing complete turnkey solutions for contained milling, sieving, isolator dispensing and interfacing between each process step within tableting or capsule filling facilities.

Conclusion

The materials of construction from which the SBV product contact parts are constructed remains a substantial progressive challenge. New product developments also bring with them a wide-ranging chemical cocktail. These are typically aggressive to the common elastomer components, and in some chemical development facilities they would also be corrosive to the metals used to manufacture the SBVs. Often, 316 stainless steel is widely accepted and compatible, but where this is not suitable, owing to corrosion issues, a popular alternative is Hastelloy or Alloy 22. In most cases, this offers excellent chemical resistance – but generally at a higher price. Attempts have been made to offer a less expensive and nonresistant base metal material, bonded to a coating of superior material. This can either be a PFA or PTFE coating. Although there has been some progress with this technology in both metal and sealing parts, the reliability and security of these options remains a concern in the majority of cases. The risk of damaging the fine coating can lead to potential corrosion of the base metal or degradation of the coated elastomer, resulting in a severe compromise of the process.

The next 20 years will certainly present greater challenges to SBV designers. Today there is an increasing need for aseptic technology transfers, and while this has been addressed and continually developed by a limited number of organisations, it needs to progress at the same growth rate as the pharmaceutical industry itself.

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer
Michael Avraam has a mechanical engineering background, with 20 years of experience within the pharmaceutical and process containment industry. He has project managed, designed and engineered glovebox isolator and filtration and drying systems within the pharmaceutical industry. Michael has specialised in the development of split butterfly valves, offering design solutions to a wide range of industry sectors. As a Senior Manager within ChargePoint Technology he currently provides training, technical advice and process support to a global sales management team, while developing across the global industry.
spacer
Michael Avraam
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

PCI Pharma Services Announces Organization Updates

Philadelphia, PA – May 20, 2019 – PCI Pharma Services, a leading biopharmaceutical outsourcing services provider, is pleased to announce the following management updates to help drive the company’s future vision, strategy and growth.
More info >>

White Papers

Life Cycle of an Analytical Method - a Case Study on the Monocyte Activation Test

Wickham Laboratories Limited

Pyrogens, a heterogeneous group of fever inducing contaminants, are comprised of microbial and non-microbial compounds; e.g. endotoxin (lipopolysaccharide, LPS) produced by Gram-negative bacteria, lipoteichoic acid (LTA) from Gram-positive bacteria, bacterial DNA (CpG-motive), endogenous pyrogens, virus and fungi particles or even fragments of packaging materials, plastic and dust. Contaminat ion wi th pyrogens in pharmaceutical products, biotherapeutics and on medical devices can lead to life threatening fever reactions. To ensure consumer safety, pyrogen testing is mandatory for parenteral products and medical devices.
More info >>

 
Industry Events

World Pharma Week 2019

17-20 June 2019, Seaport World Trade Center, Boston

World Pharma Week will bring together a unique and international mix of large and medium pharmaceutical and biotech companies, CROs, leading universities and clinical research institutions, emerging companies and tool providers—making it a perfect meeting-place to share experience, foster collaborations across industry and academia, and evaluate emerging technologies.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement