Science-Based Technical Report Being Developed to Ensure Effective Use of Blow-Fill-Seal Technology

The Parenteral Drug Association has established a task force to develop a peer- and regulatory agency-reviewed Technical Report that will serve as a science-based industry reference document.

Oct 23, 2013 By: Adeline Siew, PhD Pharmaceutical Sciences, Manufacturing & Marketplace Report

Blow-fill-seal (BFS) aseptic processing in parenteral manufacturing enables the automated formation of a plastic container, aseptic filling of the container with a liquid, and the hermetic sealing of the container, all in a few seconds using one machine. Because packaging of the formulated drug takes place under aseptic conditions without any human intervention, it provides increased product safety. The automated nature of the process leads to lower energy consumption, reduced waste generation, and a lower carbon footprint. In addition, the resins used to form the plastic containers are recyclable, and plastic containers do not shatter like glass. Furthermore, with most advanced BFS systems, numerous different container shapes can be produced, and today premolded, presterilized inserts can be added once the container is filled, allowing for more delivery options. “These advanced aseptic BFS containers and ampuls can deliver precise dosing in disposable formats. The incorporation of a sterile tip-and-cap, a rubber stopper, or a multi-entry insert into the BFS package offers added flexibility in container design and drug delivery methods, as well as enhanced sterility safety,” observes Chuck Reed, director of sales and marketing with Weiler Engineering and leader of the US Parenteral Drug Association (PDA) Blow-Fill-Seal Interest Group.
Today, in fact, FDA characterizes modern BFS technology as an "advanced aseptic process," indicating its use as a preferred technology, according to Reed, director of sales and marketing with Weiler Engineering and leader of the US Parenteral Drug Association (PDA) Blow-Fill-Seal Interest Group. As leader of the PDA BFS Interest Group, and a member of the PDA Task Force, Reed is involved in the development of the BFS Technical Report that will provide science-based support for the use of BFS technology in the pharmaceutical industry.
Cooperation with the BFS International Operators Association (IOA)
The BFS IOA, founded as a meeting forum for users of BFS technology to get together and discuss topics of interest specifically to users, is celebrating its 25th anniversary in 2013.  This group’s BFS Points to Consider is a template and reference document for its members to use when establishing BFS processes for their products. “The BFS IOA and the PDA have signed a memorandum of understanding (MOU) so that the BFS Technical Report Task Force of the PDA can use the BFS Points to Consider as the basis for development of the PDA BFS Technical Report,” Reed explains.
Need for a Technical Report
Interest in the development of a BFS Technical Report was initiated by subject-matter experts on the PDA Science Advisory Board. “Technical Reports have already been developed on filtration and sterilization processes for parenterals, and it was a natural fit to provide the pharmaceutical industry with a similar document on BFS technology since it is increasing in use as its benefits are realized,” Reed says.
The PDA Task Force was created to develop the report and consists of approximately 20 people, most of whom are current active users of the technology. Two of the invited members, however, are representatives from the European Medicines Agency and FDA. “We felt that this size of a group would be able to work effectively and efficiently to develop a first draft. Involving the key regulatory agencies throughout the process ensures that the document will be in accordance with existing regulations,” explains Reed.

Blow–Fill–Seal Technology Meets Challenges of Sterile Packaging

Using blow–fill–seal technology to form and fill a plastic container in a continuous process addresses sterile packaging issues such as package defects, contamination, and process validation.

Apr 18, 2012 By: Ken Muhvich, Hal Baseman

Companies manufacturing sterile drug products using conventional filling and packaging methods continue to face challenges. Prominent among these challenges are component related defects, microbiological contamination control, and aseptic process validation. Blow–fill–seal (B/F/S) is a method for aseptically filling sterile healthcare products, which, if used properly, can help address these challenges.
B/F/S technology is an automated method for forming and filling plastic containers with liquid product in an uninterrupted, continuous process. In the container blowing step, plastic beads are melted at high temperature and formed into a hollow tube or parison, which is cut to the desired length. Two halves of the container mold close around the parison, and air is blown into the parison to expand it into the shape of the container. The partially-cooled container is immediately filled and sealed.
Advantages of B/F/S technology
B/F/S technology offers several advantages for sterile packaging. Product contact surfaces are cleaned and sterilized in place and sterile contact surfaces are protected from environmental contamination with HEPA-filtered or equivalent air. In addition, machine designs create a physical barrier, restricting personnel intervention during the container formation and filling process.
Microbiological contamination control. Operations personnel are the main source of microbiological contamination in the cleanroom and, therefore, represent a potential product contaminant. Automated, well-designed B/F/S operations minimize the need and opportunity for human intervention, thus reducing the risk of microbial contamination. In addition, B/F/S typically involves small container openings and short product exposure times, further lessening the likelihood of microbial ingress.
Reduced container defects. Product seal failures can result from defects in glass and other types of packaging components (e.g., closures). Damage or defects can occur to packaging components during transport and handling, before product filling, or due to variations in the component manufacturing process. Because B/F/S technology does not use supplier-made containers or (in most cases) closures, using B/F/S eliminates shipping and handling damage. In addition, container formation is controlled by the B/F/S product manufacturer as the container is formed immediately before the sterile product is filled and is not affected by flaws in vendor process control.
Easier process validation. B/F/S is a fully automated process that requires little operator involvement, if any. Therefore, its operations are more predictable than manual operations, less variable, and less prone to error. More of the process is controlled by the product manufacturer rather than by component suppliers. This can further reduce process variability, thus resulting in a process which is easier to validate.
Concerns with B/F/S technology
Despite these sound advantages, wider use of B/F/S has been limited by concerns such as:

• nonviable particulate levels in the environment surrounding the B/F/S machine
• exposure of product to the elevated temperature of the formed container
• gas and moisture barrier properties of container plastics.

Particulate control. Relatively high levels of nonviable particulates are generated by the plastic extrusion and cutting process. B/F/S machine manufacturers have taken steps to address the plastic particulate issues by designing better machine enclosures to isolate and protect the product contact surfaces from environmental conditions. Some B/F/S line designs place particle-generating equipment away from the filling zones and isolate with walls and barriers. For some products, closed-parison systems, in which the inside of the parison is continually bathed with sterile air and is not cut, can be used to further protect product contact surfaces.
Temperature effects. B/F/S containers remain at an elevated temperature of up to 60 ºC for several seconds after filling (1). It is speculated that other types of plastic with a lower processing temperature can be used to reduce this temperature. To reduce the effect of exposure to elevated temperature container surfaces, filled product can be cooled soon after filling and sealing.
Oxygen and moisture effects. Plastics typically used for B/F/S containers provide a relatively low barrier to oxygen or moisture, especially as compared to traditional glass containers (i.e., vials and syringes). For oxygen sensitive products, filled units can be placed in foil pouches or other secondary packaging. Inert gases can be used in these secondary packages to lessen risk for oxygen permeation. Process development and product stability studies using products filled using the B/F/S process, container, and packaging can provide evidence of product compatibility. Companies considering the use of B/F/S should take steps to assure that the heat and permeation issues do not have an adverse effect on product quality.
Moving forward
The Blow-Fill-Seal International Operators Association (BFSIOA) and the Parenteral Drug Association (PDA) have been working together to create a comprehensive technical report containing practical and scientific information regarding the use of B/F/S for aseptic manufacturing of sterile products. The report will be based on BFSIOA’s “Points to Consider” document, dialogue with industry, and input from the newly-created PDA B/F/S Industry Group. This guidance on best practices, as well as scientific rationale and data to support those practices, will help the B/F/S industry continue to improve its technology for advanced aseptic processing.
Reference
1. W. Lin, P. Lam, S. Faulhaber, and S. Sane, BioPharm Int’l. 4 (7), 22-29 (2011).
2. Blow Fill Seal International Operators Association, Points to Consider, (Alslev, Denmark, Draft).

Regulating the Environmental Impact of Pharmaceuticals

Pressure is mounting on European legislators to introduce tighter regulations at both the European Union (EU) and national levels on the potentially harmful impact of pharmaceuticals on the environment. Politicians, environmentalists and even medicines regulators are calling for action in the face of increasing evidence that pharmaceutical chemicals used through the whole lifecycle of medicines from production through to disposal are posing a bigger than previously anticipated threat to the environment.
There are, however, divided opinions on what needs to be done. Some groups want stricter regulation of production processes, more consideration of environmental issues when market authorisations are granted and more rigorous rules on disposal of pharmaceuticals. Some regulators, environmentalists and fine-chemical producers support suggestions that tougher environmental standards should be applied to imported APIs. This increase in standards could be done by extending rules on GMPs to environmental protection. Others, particularly most parts of the pharmaceutical industry, believe that voluntary initiatives should be sufficient to eliminate the dangers of medicines in the environment.
The European Federation of Pharmaceutical Industries and Associations (EFPIA), representing research-based companies, concedes that the public wants more information about the risks from concentrations of certain medicines in the environment. “We believe that voluntary initiatives might be a relatively fast and flexible way (of dealing with this issue),” says an EFPIA spokesperson.
European countries concerned
The European Commission appears to be taking its time on the issue. The Commission is expected to release shortly a study it has funded on the environmental risks of pharmaceuticals after its publication was postponed last year (1). In 2015, the Commission is scheduled to issue a strategy document outlining ideas for new regulatory measures after which it will have the option to draw up a draft legislation.
Some countries may not wait for specific proposals by the European Commission. Instead they could enact their own regulatory schemes. This effort could happen among groups of states. Countries bordering the Rhine have, for example, already put forward ideas for international regulations to protect the river from pollutants such as pharmaceuticals.
The countries most concerned about pharmaceutical environmental threats are the Scandinavian states, Germany and its German-speaking neighbours. Sweden has been particularly active in lobbying other EU states for new EU regulations to ensure all risks associated with environmentally harmful chemicals are controlled at their source. “This should also, as far as possible, be a principle underpinning the management of environmentally harmful chemicals in medicinal products for human use,” claimed the Swedish Environment Ministry in a policy communication last year.
The Swedish government has also been taking a global perspective on environmental standards in the pharmaceuticals sector. It first proposed several years ago that the EU should move to extend the scope of GMPs to cover environmental protection in the production outside Europe of both finished medicines and APIs.
Environmental research
A lot of the latest research in Europe on the dangers of some pharmaceuticals, including APIs, to the environment has been done in Germany. With the encouragement of Germany’s Environment Ministry (BUMB), the country’s environment agency (UBA) has been conducting or funding studies in areas such as the contamination by pharmaceuticals of soil and sludge through emissions from production processes, sewage and waste-water treatment plants.
In research funded jointly by the UBA and BUMB, IWW Water Centre at Duisberg-Essen University found in an extensive literature investigation a total of 123,761 incidents of measured environmental concentrations (MECs) of pharmaceuticals across the world, according to the results of the study revealed at a workshop in Geneva in April (2). The majority of these were in concentrations in sewage, waste-water treatment effluent and surface water. Only a small minority were found in soil, sediment and slurry.
Altogether, 559 different pharmaceuticals or their derivatives such as metabolites were found in waste-water treatment influent, effluent and sludge, according to IWW. Another 38 different pharmaceuticals were found in surface, ground and drinking waters. The greatest concentration tended to be in Europe and North America. Among the 16 pharmaceuticals most frequently detected in surface, ground and drinking waters, the majority were in Europe, headed by the analgesic diclofenac and the anti-epileptic carbamazepine. With diclofenac, for example, 36 of the 50 detections were in Europe, most of which were in Western Europe.

Sterilization of Blow-Fill-Seal Equipment for Aseptic Filling

Pharmaceutical Technology spoke with experts from Noxilizer and Weiler Engineering about using nitrogen dioxide to sterilize and depyrogenate the aseptic fill area in a blow-fill-seal process.

Jul 2, 2014 By: Jennifer Markarian

STEVE GSCHMEISSNER/getty images

Blow-fill-seal (BFS) technology—in which a polymeric container is formed, filled, and sealed in one continuous process--has been used for more than 40 years to aseptically package parenteral pharmaceutical products, such as ophthalmic solutions. Use of BFS technology is expected to increase for packaging biologics, such as vaccines and protein-based materials. BFS is an automated system that minimizes human contact. Typically, the product-contact path of the BFS process is sterilized with steam, and the entire process takes place in a cleanroom environment. Noxilizer, which supplies nitrogen dioxide (NO₂) sterilization systems, and BFS equipment supplier Weiler Engineering recently presented research on NO₂sterilization and depyrogenation of the fill area in Weiler’s ASEP-TECH BFS systems using a Noxilizer NOX FLEX Rapid Biodecontamination System (1). Pharmaceutical Technology spoke with David Opie, PhD, senior vice-president of R&D at Noxilizer, and Chuck Reed, director of sales and marketing at Weiler Engineering, about this sterilization and depyrogenation method.
Sterilization and depyrogenation
PharmTech: What are some of the concerns for sterilizing BFS equipment?
Opie (Noxilizer): Aseptic processing requires rigorous and careful manufacturing practices due to the potential adverse effect on the healthcare consumer. Regulatory agencies are placing greater focus on improved patient safety and are developing standards to ensure sterile, contamination-free products. In particular, regulatory standards increasingly state that pharmaceutical manufacturers should be aware of new procedures designed to reduce risk to the product through the use of enhanced technology. One such procedure is the reduction of pyrogens during the decontamination process.
Pyrogenic contamination comes from endotoxins, which are mainly lipopolysaccharide components of Gram-negative bacterial cell walls that can cause acute febrile reactions. These endotoxins are heat stable and may be present even when viable organisms are no longer detectable. Endotoxins are impossible to eliminate from filled containers; thus, procedures are generally directed at eliminating endotoxins during the preparation process.
Reed (Weiler): The entire BFS process takes place in a cleanroom environment, and the product-contact path is sterilized in place with steam. The fill area of a BFS system is much different from the fill area of a conventional aseptic filling system, because the product is filled as soon as the container is formed, which reduces the opportunity for contamination. The critical filling zone area of a BFS machine is the area comprising the fill system shroud, which typically encompasses the fill needles and electronic modular dosing system. This enclosed area has typically been manually sanitized prior to the start of a production batch, and during production is supplied by HEPA-filtered air. We wanted to provide additional assurance for our customers of the decontamination of the fill area. The NO2 process offers a new procedure for depyrogenation and decontamination of the fill area in a BFS system to give that additional assurance.
Advantages of NO₂
PharmTech: What are the advantages of using NO2 to sterilize the BFS fill area?
Opie (Noxilizer): The room-temperature process combines decontamination of exposed critical zone surfaces with the potential for depyrogenation of these surfaces. The Noxilizer process is a fast (less than one hour), automated process that yields more than a six-log reduction in biological indicator organisms and more than a three-log endotoxin reduction (1). The NO2 process is a true gaseous process that has more uniform distribution than vapor processes. Another feature of the NOX FLEX system verified in this study was the remote operation of the decontamination process with up to 50 meters of conduit between the NOX FLEX unit and the ASEP-TECH system, which permits the location of the Noxilizer equipment outside of the cleanroom in which the BFS machine is installed.
Reed (Weiler): BFS technology is well suited for aseptic processing of biologics, such as vaccines and protein-based materials, which are particularly sensitive to residual sterilant in the filling environment. NO₂ has been demonstrated to have a fast aeration rate that results in low residual sterilant. In addition, the automated NO₂ system eliminates the human interaction required in the manual sanitization method. Finally, the integrated system is an efficient process that can be more easily validated than the manual process.
Cycle parameters
PharmTech: What are the critical parameters of the sterilization cycle?
Reed (Weiler): The cycle parameters were developed to coincide with the normal cycle time of the clean-in-place/sterilize-in-place process for sterilizing of the product path in the BFS machine. The BFS cycle parameters for the study were 30 mg of concentrated NO2, 55% relative humidity, a 40-minute decontamination time and 30-minute aeration time (1).      
Reference
1. C. Reed, et al., “Decontamination and depyrogenation of an Asep-Tech Blow/Fill/Seal system,” poster presented at the PDA Annual Meeting (San Antonio, TX, 2014).

Implications of the Classification System

Over the past few years there has been an increasing trend to change from previous classification systems used to the ISO classification systems in ISO 14644-1. However, many companies have continued to use the traditional Class 100, 10,000, 100,000 room classification system from Federal Standard 209-e. In Europe, the GMPs utilize another system—Grades A through D.

Many global companies choose to use this classification system. All of these systems are acceptable for use. However, we have also tended to link the systems together, e.g., ISO 5/Class 100/Grade A. This type of linkage is seen in the FDA’s Guidance for Aseptic Processing (2004). If you are manufacturing an aseptic product and use this linked classification system it is not likely to be an issue. However, if you are not manufacturing an aseptically processed product, choosing to link the classification systems together may lead to other consequences.

The ISO 14644-1 classification system, which replaced Federal Standard 209e, establishes the certification requirements for air cleanliness areas. Within this document the various classification systems are based upon the requirements for counts associated with non-viable particulates. In the FDA’s Guidance for Industry—Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice (2004)—which is limited in scope to the manufacture of medicinal products using aseptic processing—there is a similar chart which includes the requirements for both viable and non-viable microbial counts as part of the classification system.

Numerical Simulations for Tableting and Coating

Solid dose tablet manufacturing processes often lack reliability and robustness as a result of errors in production and a shortfall in process control. Facing unprecedented economic pressures, pharmaceutical manufacturing companies are continuously looking to improve on the quality of their products and the productivity of their processes. Multi-physics numerical simulation is emerging as game-changing technology to help step up efficiency, enhance quality, and shorten time-to-market through virtual prototyping and optimization.

Challenges of Solid Dose Tablet Manufacturing
Tableting (compression from a powder into a solid dose tablet) and tablet coating are two vitally important steps in the tablet manufacturing process that ultimately determine the weight, thickness, density, hardness and coating of the final solid dosage form. Variability in any of these attributes not only negatively impacts the release profile and therapeutic efficacy of the medicine, it alters the disintegration and dissolution properties of the tablet, leads to tablet defects and causes breakage during bulk packaging and transport.
With the adoption of novel manufacturing processes such as non-stop end-to-end processing, and the push to build quality and efficiency into production, solid dose tablet manufacturers have a challenging road ahead of them because they must pinpoint the key factors and requirements that will lead to robust and repeatable processes, resulting in superior products.

Why Numerical Simulations?
Multi-physics Computational Fluid Dynamics (CFD) is a numerical method for predicting the coupled behavior of fluid, gas and particulate flows including heat and mass transport. A significant advantage of using numerical simulations is that it allows for the validation of a design or process before physical tests need to be carried out.  For example, the development of a new tablet shape or coating material calls for performing an extensive number of costly and time-consuming experiments to avoid unexpected variations, identify unpredictable process parameters and address scale-up problems. Studying these effects through numerical simulations can greatly reduce time, material and development costs. In addition, numerical visualization tools offer a wealth of detailed information, not always readily available from experimental tests. This not only results in an increased level of insight into the details of what is going on inside the processes, it enables innovation.

A Solution
With its automated polyhedral meshing technology and comprehensive range of physics models, STAR-CCM+ is a complete multi-disciplinary simulation toolkit to tackle a wide range of applications in the pharmaceutical industry. One capability in STAR-CCM+ that is particularly well-suited for the simulation of tablet manufacturing processes is Discrete Element Modeling (DEM), fully coupled with numerical flow simulations and delivered in a single software environment.
Tableting and coating involve a large number of discrete particles that interact with each other and the fluids surrounding them. DEM accurately tracks these interactions and models contact forces and energy transfer due to collision and heat transfer between particles and fluids. The DEM capability in STAR-CCM+ can predict dense particle flows with more than one million particles in a reasonable time, making it practical for analyzing real-world tablet manufacturing processes such as filling, compressing/compacting, coating and drying.

Figure 1 shows the results obtained from a STAR-CCM+ simulation of pre-compression in a tablet press to determine how to overcome common tablet defects such as capping (splitting of the tablet’s upper cap) that often occur as a result of entrapment of air and migration of fine particles during the compression process. DEM is used to track the interaction of the particles with each other and with the die as they are re-arranged and move into the empty spaces during pre-compression.  This simulation offers a detailed look at the uniformity of the granule distribution and can help determine the optimal pre-compression force and dwell time required to ensure that fine particles will be locked in place before compression starts, greatly reducing the risk of incurring common tablet defects during production.

DEM simulations with particle-fluid interactions also provide realistic solutions to assess uniformity of film coating thickness, a critical parameter for tablet quality.  Figure 2 depicts a simulation performed with STAR-CCM+ for the coating process in a fluidized bed where DEM is used to analyze the random movement of particles as their trajectories change while layers of coating are applied. Parameters such as particle velocities, residence time and coating thickness are monitored during the simulation. These can be fed as objective functions into Optimate, a module in STAR-CCM+ that enables intelligent design, to help identify the important factors for equipment design (e.g. nozzle spacing) and to determine optimal equipment operating conditions. In future releases, STAR-CCM+ will also have a novel Lagrangian passive scalar capability, enabling the user to easily monitor the coating thickness and other features of tablets. Figure 3 illustrates a case where 70,000+ tablets are tumbled in industrial coater. The goal of the study is to improve on inter-particle coating uniformity by determining optimal spraying equipment settings in the tumbler.  Two Lagrangian passive scalars representing coating thickness are defined: one with source volume confined to one cone above surface, another with source volume confined to two cone volumes and with an effective spray area identical as for the first passive scalar. Using this approach, a single simulation allows for a comparison of the inter-particle coating uniformity for two different spray zones and the result indicates that the two sprays configuration provides a more uniform coating distribution.

Conclusion
In today’s competitive climate, manufacturing of solid dose tablets must have a focus on building quality and efficiency into processes and multi-physics CFD simulations offer a cost-effective way to achieve this through rapid prototyping and optimization. The complex flow-fields associated with tableting and coating can be addressed with ease by using the high-end physics models delivered by STAR-CCM+, including the powerful DEM and novel passive scalar capabilities. Users in the pharmaceutical industry are fully leveraging these state-of-the art technologies as it opens the door to explore innovative ways to improve quality, reduce cost and shorten time-to-market.

Cleanroom design concepts

Contamination control is the primary consideration in cleanroom design; however, the relationships between contamination control and airflow are not always well understood.¹

As a first step towards design and construction of the cleanroom and air handling systems, a basic specification must be developed. For this the following factors must be accounted for:²

• Defining the area of the clean space
• Establishing the correct cleanliness level (in relation to the international cleanroom standards)
• Establishing the optimal air change rate and determination of the supply airflow rate. (There should be not less than 20 hourly air changes in the controlled area.)
• Establishing requirements for positive pressure differentials (normally 10-15 Pascals between adjacent cleanrooms). This range allows doors to be opened and overcomes problems for cleanroom operators in relation to the high pressure difference, which arises due to air leakage.
• Considering use of mini-environments for additional air cleanliness (such as localized unidirectional airflow or isolators)
• Optimizing ceiling coverage in relation to air filters. With HEPA filters, the design should seek to include: HEPA filters with differential pressures (P); adequate space for low pressure drop air flow; low face velocity; fan design; motor efficiency; variable speed fans.
• Minimizing the pressure drop (air flow resistance)
• Adequate sizing and minimizing the length of ductwork
• Optimizing pressurization
• Reducing air flow when the cleanroom is unoccupied (to save energy consumption)
• Efficient use of components
• Defining the electrical systems that power air systems

Qualification and validation are undertaken in order to prove that equipment and processes consistently do what they are supposed to do.The performance of a cleanroom is defined by a set of complex interactions between the airflow, sources of contamination and heat, position of vents, exhausts, and any objects occupying the space. Consequently, changes to any of these elements will potentially affect the operation of the cleanroom and could invalidate aspects of the room design.

With cleanrooms used in the pharmaceutical industry, there are additional considerations aimed at minimizing contamination. These are centered on the idea that cleanrooms should be constructed in a way which makes them easy to clean and disinfect. It’s important that such cleanrooms have:

• A smooth and cleanable finish
• A final coating which is impervious to detergents and disinfectants
• No uncleanable recesses
• Very few projecting ledges
• Very few electrical sockets
• Pipes and conduits are appropriately boxed in

Qualification and validation The design, building, and certification of a new cleanroom is covered by a formal and documented qualification and validation process. Qualification and validation is undertaken in order to prove that equipment and processes consistently do what they are supposed to do.

It is a Good Manufacturing Practice (GMP) requirement to prove control of the critical aspects of certain operations. For this, testing and documentation is required (GMP refers to a set of regulations specific to the production of medicinal products). The aim is to ensure that the device meets its specification or process parameters and that it is capable of a consistent performance.

All validation activities should be well planned and clearly defined. This is usually through a validation master plan. In establishing a validation plan, all critical parameters that may be affected and impact product quality must be identified. Validation typically consists of the following steps:

• User requirement specification, where the user outlines the objective for the project
• Design qualification (DQ), where the finalized design is compared with applicable national and international standards
• Factory acceptance testing (FAT). The FAT is undertaken by executing a suite of documented tests on a completed system or item of equipment—for example, cleanroom control systems.
• Installation qualification (IQ), which is testing to verify that the equipment is installed correctly
• Operational qualification (OQ), which is testing to verify that the equipment operates correctly
• Performance qualification (PQ), which is testing to verify that product can be consistently be produced to specification

A protocol describing each test and the acceptance criteria must be prepared, and once the testing is complete, a validation report should be written.

Design process

Prior to the construction of a cleanroom or the modification of an existing cleanroom, a design must be produced together within working drawings. The design is a set of documents containing explanatory notes (texts) and drawings. This will take the form of a design specification, and the produced document should be checked against industry standards.

With the PQ phase, the cleanroom is tested to ensure that it meets accepted standards in the “in operation” state—where personnel are present. The design process has been enhanced in recent years by the use of computer models, in particular computational fluid dynamics (CFD).³ CFD is a branch of fluid mechanics that uses numerical methods and algorithms to solve and analyze problems that involve fluid flows. Computers are used to perform the calculations required to simulate the interaction of liquids or gases within defined boundary conditions. With cleanrooms, this involves studying the way that air behaves within the clean zone. Here, numerical simulation results in velocity, pressure, and temperature values to be calculated for each of the individual cleanroom air volumes. The combination of these factors provides for a detailed airflow distribution.

CFD, therefore, enables cleanrooms and the equipment within the cleanroom to be accurately designed at the early stage of the design process. CFD models are not only used to visualize airflow patterns in cleanrooms but are also working to analyze particle migration paths.

With or without the aid of computer design, the design process should contain the following steps:

• Design: basic design; working drawings
• Design specification
• Construction: installation drawings; executing of construction/installation; field supervision; executive drawings
• Start-up
• Testing
• Commissioning
• Operation

In relation to the construction process detailed plans are required. The issues that require addressing, through documentation, include:

• Process flow charts
• Cleanroom or separation concept
• Layouts of premises with room specifications
• Specifications for control equipment
• Personnel (number and qualification) for each room
• Utilities (electricity)
• Waste disposal
• Safety requirements

These various factors must relate to the main elements of the installation such as air handling units, air ducts, cleanroom construction, connections to dynamic pass-through hatches, dampers and control valves, measurement sensors, and so on.

Risk assessment

A relatively new dimension to modern cleanroom design is the formal adoption of quality risk management. This is now a regulatory expectation. In applying risk assessment to the design process, the most important guidance document is ICH Q9.4 ICH Q9 was adopted as part of EU GMP in 2008 and by the FDA in 2010.

Qualification steps

Once construction is complete and initial qualifications completed, the performance qualification is performed. With the PQ phase the cleanroom is tested to ensure that it meets accepted standards in the “in operation” state, as defined by ISO 14644 which is where personnel are present. The tests required include:

• Airborne particle count for classification and test measurement of cleanrooms and clean air devices
• Air pressure difference test
• Installed filter system leakage test
• Airflow direction test and visualization
• Temperature test
• Humidity test
• Recovery test (to show that the cleanroom can recovery to its expected level of airborne particulates after an elevated rise in airborne particulates)

Of the above tests, the most important of all tests is the particle counting test given that this is a direct measure of contamination. The particle count test is used for proving that the cleanroom functions in conformity with the requirements and that it fulfils the set standards in terms of meeting its required classification. For this test, ISO 14644-1 provides a formula for calculating the minimum number of sample locations based on the room size. ISO 14644-1 also requires the volume of the air sample to be sufficient to count 20 particles from the biggest particle defined for a given class.

Ongoing compliance

For a new facility, each phase is tested. For an established cleanroom, the operational state is verified on a six-month or annual basis, as per ISO 14644-2: Specifications for testing and monitoring to prove continued compliance.⁵ Cleanroom verification is performed in either the “at rest” or “in operation” occupancy state and should address the following parameters:

• Air cleanliness class
• Pressure differences between rooms
• Air velocity (for unidirectional airflow) or the air flow rate (for turbulent airflow)
• Installed filter leak test of HEPA filters

Conclusion

Cleanroom design, construction, and certification can represent a challenging area. For the pharmaceutical sector, these challenges center on the avoidance of high levels contamination that might present a risk to the medicinal product processed within the cleanroom. Modern approaches to cleanroom design can help to minimize the contamination risks.⁶

These approaches include the adherence to quality risk management to identify sources of contamination; the utilization of validation phases, which ensures rigorous testing; and the application of computer aided design, such as computational fluid dynamics, which allow for predictive models to be used to help identify contamination sources relating to unwanted air movement.

References

1. Houten, J. Containment: Comprehensive Assessment and Integrated Control. PDA J Parenteral Sci Tech. 46:22-24; 1992.
2. Ljungqvist B., ReinmüllerBerit. Cleanroom design - Minimizing contamination through proper design. Interpharm Press, Buffalo Grove IL/USA; 1997.
3. Gafford, J., Roberts, J. and Sullivan, J. Computational fluid dynamics as a tool for designing quality into the pharmaceutical cleanroom. Pharmaceutical Engineering 30 (4): 54-60; 2010.
4. ICH Q9: Quality risk management. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH, Geneva; January 2006.
5. ISO 14644-2, Cleanrooms and associated controlled environments – Part 1: specifications for testing and monitoring to prove continued compliance with ISO14644-1, ISO, Geneva, Switzerland; 2000.
6. Sandle, T. and Saghee, M.R. Cleanroom management in pharmaceuticals and healthcare, Euromed Communications: UK; 2013.