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Integrity testing of HEPA filters: A practical approach

Filtering the air in aseptic process areas is critical to maintaining the cleanliness of the production environment. Jesus Casas provides tips to ensure HEPA filters are fit for purpose once installed in your facility.

Manufacturers of high-efficiency particulate air (HEPA) filters for cleanrooms and controlled environments test their products for particle removal efficiency. Equally, once the unit is installed in the user’s production site, the test should be performed promptly to verify the integrity of the filter as well as the installation. Typically, HEPA filters capture up to 99.97% of particles as small as 0.3 microns.

The dispersed oil particulate (DOP) scan testing, also known as filter integrity testing, or leak testing, is one of the most quoted methods by industry standards. The test is recommended to be repeated at regular time intervals to verify the continued efficiency of the filter. During the test, the filter is challenged by introducing particulates and measuring the output.

The HEPA filter leak test is mandated in various international standards, including the FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – cGMP and the World Health Organization Technical Report Series, No. 961. For cleanrooms, the ISO 14644-3 standard provides further guidance.

The traditional aerosol photometry test method, used since the 1950s, is adequate for measurements to 0.003% by DOP scan testing. To perform an accurate filter leak test, it is necessary to make sure the challenge aerosol concentration is uniform over the entire upstream face of the filter(s) being tested; this is called spatial uniformity. Otherwise, high or low local concentration may cause the filter to incorrectly fail or pass the test. The ISO 14644-3 suggests that the variation in test aerosol concentration through time should not exceed ±15%. The uniformity of the challenge upstream of the filter should be verified.

If a cleanroom suite is the target of a test, the challenge aerosol is injected just after the air handling unit (AHU). By the time the air gets to the filters, the test particles are well mixed within the air ducts leading to an even concentration across the back of each terminal filter.

If the aerosol cannot be injected just after the AHU, it must be introduced into the ductwork system at least 15 to 20 duct diameters from the filter.

Flow rate for the test

It is important that the proper flow rate through the filters is established prior to testing. When checking for filter leaks onsite, the system should be checked following tests described in ISO 14644-3 to verify that airflow volume, velocity tests balancing and, if appropriate, the uniformity of these parameters are within specified limits. These tests should precede the challenge uniformity test and leak test.

The standard ISO 14664-3 suggests a penetration of 0.01% of the test challenge concentration but allows alternative criteria to be agreed between customer and supplier. The FDA Guidance, however, indicates that 0.01% penetration is a leak.

It is best to start scanning at the gasket area, rather than the filter face, so that any problem with spillage of test particles from the gasket area and onto the filter face do not cause false reports of leaks in the medium. After checking the gasket, it is probably best to move on to the sealing between the filter medium and the casing, and then on to the filter face.

Choosing the aerosol

There are three types of aerosol that can be used for testing filter installations in a cleanroom. These are:

  • Cold generated aerosol
  • Hot generated aerosol
  • Microspheres

The first two are formed from oil-type liquids. Polystyrene latex (PSL) spheres are most commonly used in microelectronic applications, while polyalphaolefin (PAO) in life sciences. The information in Table 1 describes the typical challenge aerosols used for HEPA testing.

Before starting the filter scan, it is necessary to set the concentration of test aerosol particles upstream of the filter. The ISO 14644-3 standard suggests a concentration ranging 10µg/l and 100µg/l should be used for the photometry test method. It also suggests that concentrations lower than 20µg/l reduces sensitivity, and concentrations over 80µg/l give filter fouling. It is best to use the lower recommended concentration to minimise the potential for blockage or a bleed-through event.

What is a leak?

Also important to understand is the scanning velocity of the probe across the filter face. If it is done quickly over a filter leak, there may be insufficient time for it to pick up some of the aerosol challenge coming from the leak and this will cause the value to drop below the designated rate.

Figure 1: Example of a sampling probe. W is the width and D is the depth

Figure 1: Example of a sampling probe. W is the width and D is the depth

The scanning velocity is associated with the depth of the probe size (see Figure 1). The smaller the depth of the probe, the less time it is over the leak and therefore insufficient; fewer leaks will be found in comparison with a deeper probe.

Following the ISO 14644-3, the scanning velocity is calculated by the following equation:

Scanning velocity (cm/s) = 15/w

Here, w is the width of the probe that passes perpendicular to the direction of movement (cm).

For example, when using a 3cm x 3cm probe, the width of the probe passing perpendicular to the direction of the scan is 3 cm, hence the scanning velocity can be calculated as follows:

Scanning velocity (cm/s) = 15/3 = 5 cm/s

Scanning for leaks

Typically, HEPA filters have a space between the filter and its housing so the gasket is situated to the rear. To locate gasket leaks in the area between the filter frame and housing, the probe is inserted into that area and then the area is scanned.

The particles from a gasket leak will spread out and fill the space between the filter and the housing (see Figure 2). When scanning around the area looking for a gasket leak, the tester will encounter a high concentration of particles some distance from the actual leak leading them to think that a leak has been found. In this situation is recommended to remove the probe from the sample tube and scan with the much smaller tube area to locate the point of highest particle penetration reading, hence determine the gasket leak.

Figure 2: Spread of particles from a gasket leak

In the case of a substantial gasket leak, it is possible to apply a particle-free air jet to the leak area to clean out particles; even a few wafts of air from a plate can help.

Scanning the filter face

The entire face of each filter should be scanned for leaks by using slightly overlapping strokes of the probe and moving the probe at a rate not exceeding the maximum scanning speed calculated. The probe should be held approximately 30mm from the filter media.

Figure 3: A baffle used when scanning a filter with leakage coming from the gasket

Figure 3: A baffle used when scanning a filter with leakage coming from the gasket

If a leak is detected, it will be necessary to return to the face passing slowly over it and return slowly again to determine the exact position. Removing the probe and using only the tube helps to identify the location of the leak accurately. It may be necessary to pass slowly over the leak several times on each axis to identify the exact position.

When there is a gasket leak, particles may spill over onto the filter face and leaks can erroneously be reported as being on the filter face. It is, therefore, recommended to start the filter scanning at the gasket area.

False readings can be largely overcome by using a baffle plate held on the filter face as the adjacent filter face is scanned (see Figure 3).

Dealing with entrainment

Air entrainment is an issue when testing isolators in non-unidirectional cleanrooms if HEPA filters or unidirectional workstations are being performed at the same time. Here, spillage of test challenge can cause a significant particle concentration in the room.

Figure 4: Air entrainment. Contaminated air with particles of test aerosol onto the filter

These particles may be drawn to the space between the filter and frame, or spill over onto the filter face, hence it is difficult to decide whether there is a leak and, if there is, whether the leak comes from the casing, gasket or media filter (see Figure 4).

This problem may be minimised by use of an anti-entrainment wall. The wall is pushed against the ceiling and the filter side of the wall being checked for a leak. A practical solution is to use the hood of the balometer as a wall, covering the filter and then getting into the hood to test the HEPA filter (see Figure 5).

Figure 5 shows an example using the hood of a balometer as an anti-entrainment wall

Figure 5 shows an example using the hood of a balometer as an anti-entrainment wall

Fixing a leak

A final word of wisdom: if a leak in the HEPA filter is found, the best way to fix it is by following the recommended fill patching procedure. Various sections in the IEST RP-CC034.2 state: “Fill repair should not block or restrict more than an additional 3% of the filter face area, and no single repair should have a dimension exceeding 3.8 cm (1.5 in).” After the repair is complete and suitable cure time has been allowed for the patch to set, check for leaks near the repair area.



About the author

Jesus Casas is a mechanical engineer based in Caracas, Venezuela. His career spans more than five years of experience in the pharmaceutical sector. Casas specialises in the areas of validation, qualification and metrology.



Cut energy use in the lab

Energy consumption in laboratories, particularly from moving, heating or cooling air, makes it difficult to meet carbon targets. The S-Lab programme has designed an audit guide to assist in reducing energy use by addressing the design specification of ventilation systems and fume cupboards and instituting a monitoring strategy.

Laboratories are energy guzzlers and prime targets for efficiency measures to cut costs and carbon footprints. S-Lab, working with energy consultants on some ground-breaking audits, has found out where most lab energy is spent.

Laboratories consume large quantities of energy – often three to four times more than offices per square metre. In research-focused universities, for example, they can therefore account for up to 60% of non-residential energy consumption, making it impossible for the universities to meet carbon targets without taking major action.

To improve our understanding of where energy is used and to identify opportunities for improvement, S-Lab, together with consultants Energy & Carbon Reduction Solutions and KJ Tait, have undertaken detailed pilot audits at five university labs: Biosciences Building (Liverpool); Edinburgh Cancer Research Centre (ECRC); Department of Biology (York); Department of Chemistry (Cambridge); and Department of Chemistry (Manchester).

Table 1 shows that main energy use is moving, heating or cooling air through laboratory spaces (especially in Chemistry), and that equipment use is high in Life Science. Audits also highlighted IT’s importance in many labs, such as Cambridge Chemistry, where server rooms mean that IT energy use accounts for 17% of total energy consumption.

Table 1: Energy consumption in labs
Indicative consumption split Chemistry Life Science
Space heating
Equipment and small power
*Excluding server room energy (17% at Cambridge)

A detailed analysis of equipment at two labs identified the main energy using types based on the formula:

number x rated power x hours of usage

For chemistry labs these were, in order of total use: heaters/stirrers (particularly in teaching labs); mass spectrometers; gas chromatographers; rotary evaporators; NMR; ovens; fridges; pumps (diaphragm and pumps); and water baths.

In life science they were: freezers (-20 and -80s); environmental growth chambers; water baths; incubators; ovens; ice makers; hybridisers; incubator-shakers; and thermal cyclers.

A rule of thumb is anything that is heating or cooling, is on 24/7, or has a 3-phase power supply is likely to be a significant energy consumer.

Energy saving actions identified by the audits were:

  • Optimising supply fan power consumption by delivering the actual pressure required, and not a theoretical design value
  • Switching off individual fan coil units when the rooms they serve do not require special ventilation for prolonged periods
  • Experimentally increasing cooling control range within fridge/freezer or cold room
  • Regularly checking filter conditions and replacing filters proactively (as clogged filters have a higher energy consumption)
  • Reviewing HVAC sensors to ensure they are optimally positioned
  • Turning off or powering down (selected) equipment when not in use, together with related devices e.g. AC/DC converters
  • Turning off lights when rooms/chambers are not in use
  • Examining equipment consolidation/ sharing opportunities
  • Switching off (overnight or permanently) those fume cupboards that are little used
  • Allowing reduced temperature out of hours – aligned to switching off
  • Encouraging closure of VAV fume cupboard sashes.
  • Applying whole life costing to purchases of actually or potentially “always on” equipment, such as computers and freezers.

All actions should be subject to a safety assessment before implementation.

An S-Lab audit guide based on the pilot audit experiences stresses the need to begin the exercise by establishing ownership (with senior management backing from both Estates and principal investigators being vital).

It recommends starting with a quick first stage with the aims of building relationships; understanding the lab building and its operation; creating a broad picture of energy consumption; identifying improvement opportunities; recording key lab features; and building momentum for change.

Professor Peter James of the University of Bradford, director of the S-Lab (Safe, Successful and Sustainable Laboratories) programme, said: “A key question is whether the design specifications of the ventilation system and fume cupboards are being achieved in practice – this is often not the case and unravelling the reasons why can be extremely revealing.”

A second stage can then prioritise immediate opportunities for improvement; scope medium-long term plans; and develop a monitoring strategy (e.g. new sub-meters, fume cupboard control data) to provide more target areas.



HVAC saves hospital $500,000 a year in energy costs

The rising cost energy to operate air conditioning systems is a problem for hospitals everywhere. But at Rio Grande Regional Hospital, a 320-bed hospital in McAllen, Texas, administrators are happy that, even in the face of a 33% utility rate increase, their electricity bill has declined over the past two years.

The rising cost energy to operate air conditioning systems is a problem for hospitals everywhere. But at Rio Grande Regional Hospital, a 320-bed hospital in McAllen, Texas, administrators are happy that, even in the face of a 33% utility rate increase, their electricity bill has declined over the past two years. The hospital attributes this drop to the incorporation of UVC lights from Steril-Aire into the air handling systems.

Oscar Molano, director of plant operations for the hospital, said: “We were looking for a way to save on air conditioning energy costs without compromising air quality or patient comfort.

Working with Rio Filter Supply Company, based in Harlingen, Texas, he learned that Steril-Aire UVC devices emit germicidal UVC energy that penetrates microbes and destroys their DNA and RNA, killing or deactivating them. UVC degrades mould and organic build-up deep inside HVAC systems to keep coils continuously clean – lowering HVAC energy costs by improving heat transfer and increasing net cooling capacity.

After reviewing the benefits, Molano received approval to retrofit all 26 air-handling units (AHUs) with Steril-Aire UVC Emitters on a phased basis. Before UVC, the four 465-ton chillers serving the hospital were running at 99% capacity. Eighteen months later, after most of the AHUs were equipped with UVC, the same chillers were running at only 62% capacity. During that period, electrical usage (in kilowatt hours) declined by 20.64%. This cancelled out a utility rate increase from US$.06 per kWh to $.08 per kWh. Thus, with the addition of UVC in 2005 and 2006, electrical energy costs from 2005 to 2006 remained at a constant average of $166,900 per month.

By autumn of 2006, as Rio Grande was wrapping up the conversion to UVC, it determined that the hospital was now too cold, even with chillers running at reduced capacity. It was able to shut down two chillers completely, along with the chilled water pumps, condenser water pumps and cooling towers.

The two remaining chillers now run at 80% capacity. From January – May 2007, energy costs were down by $240,885 compared with 2006 – a 29.5% saving.



UV light cuts spread of TB

Ultraviolet lights could reduce the spread of tuberculosis (TB) in hospital wards and waiting rooms by 70%, according to a new study, published in PLoS Medicine.

The study, which explored the transmission of TB from infected patients to guinea pigs, suggests that installing simple ultraviolet C (UVC) lights in hospitals could help reduce the transmission of TB, including drug-resistant strains.

Every year, more than 9 million people are infected with tuberculosis and nearly 2 million people die from the disease, according to the World Health Organisation. Infection rates are particularly high in places where vulnerable people are crowded together, such as hospitals, homeless shelters and prisons.

Spread by droplet infection, the bacteria can be killed by hanging a shielded UVC light from the ceiling with a fan to mix the air, say the researchers, from Imperial College London, the University of Leeds, Hospital Nacional Dos de Mayo, Lima, Perú and other international institutions.

UVC light kills tuberculosis bacteria, including drug-resistant strains, by damaging their DNA so they cannot infect people, grow or divide. It is already used at high intensity to disinfect empty ambulances and operating theatres.

Plans are already underway to install upper room UV lights in the chest clinic at St Mary’s Hospital, London, which will be the first hospital to have them in the UK. Introducing UVC lights could be a relatively low-cost measure, say the researchers. Currently, a typical UVC ceiling light costs around US$350 (€263)and replacement bulbs cost from US$25 (€19). The researchers are now working to develop more affordable US$100 (€75) units.

The impact of UV lights is greatest when combined with careful management of the air flow on the wards. “The lights must be set high enough to ensure patients and health workers are not overexposed, but if the lights only treat air at that level, there will be little benefit,” explained Dr Cath Noakes from the University of Leeds’ Faculty of Engineering. “To be most effective, ventilation systems need to create a constant flow of treated air down to patient level, and potentially infected air up towards the lights.” The research was funded by the Wellcome Trust, Sir Halley Stewart Trust and the Sir Samuel Scott of Yews Trust, Proyecto Vigia (USAID) and the charity Innovation for Health and Development (IFHAD).



Sartorius launches GMP platform BIOSTAT RM TX single-use bioreactor

New cell therapy expansion system features a gravity harvest concept that reduces contamination risks and maximises cell number recovery

Sartorius Stedim Biotech has announced the launch of the BIOSTAT RM TX single-use bioreactor. The unit, the company said, is a new mixed system developed specifically for closed, automated expansion of consistent quality cell products such as ex vivo cellular immunotherapies.

The equipment will be introduced to the market at Phacilitate Leaders World 2019. he event takes place on 22-25 January at the Hyatt Regency Miami

Designed as a new GMP platform, it combines Sartorius established single-use Flexsafe bag technology with the company’s expertise in biopharmaceutical automation.

The equipment will be introduced to the market at Phacilitate Leaders World 2019. The event takes place on 22-25 January at the Hyatt Regency Miami.

“Combining single-use technology with advanced automation for the expansion of cell products ensures control of process variability and enables safe, robust and affordable cell production,” explained Dr Franziska Faulstich, Global Product Manager Regenerative Medicine and RM Bioreactors at Sartorius.

“Working extensively with leaders in the cellular immunotherapy field, we have identified the right technologies and best practice workflows, which we have incorporated into our new BIOSTAT® RM TX bioreactor,” she added.

Key features

The BIOSTAT RM TX single-use bioreactor is designed for scale-out expansion of cells including patient-specific T cells. It is a closed system, consisting of an automated control unit and up to two rocking platforms to gently agitate single-use Flexsafe RM TX bags (up to 5L working volume).

The bag is the core of the system and built on SSB’s Flexsafe film, which is already well-established from clinical development to GMP manufacturing of vaccines and biologics by major global biopharma companies.

The film formulation is developed to minimise leachables and extractables, guaranteeing consistent batch-to-batch culture performance of even sensitive cell types, such as genetically modified T cells.

Reduced contamination risks

Sartorius said its proprietary Flexsafe RM TX bag is designed with a special port for hands-free gravity harvesting.

In combination with the innovative Flexsafe RM TX Harvest Device it reduces the contamination risks from manual handling, maintaining cell integrity and cell viability. “Unlike other cell therapy expansion systems, which use pumps for cell recovery, this unique gravity harvest concept reduces the risk of shear stress on these delicate cells to maximise cell number recovery,” the company explained.

A benefit of using the BIOSTAT RM TX bioreactor in combination with the Flexsafe RM TX bag for cell culture is the possibility for walk-away monitoring and culture control.

“Cell product developers visiting Booth 410 at Phacilitate World Leaders 2019 will discover how using this cleverly designed system can help improve their process performance and as a result the integrity and consistency of their promising cell therapies in development,” the company enthused.

BIOSTAT® RM TX and Flexsafe RM TX bags are for research and further manufacturing use only – not for use in therapeutic or diagnostic procedures.

Sartorius noted that both products “are not CE marked for in vitro diagnostic use nor are they medical devices. Drug manufacturers and clinicians are responsible for obtaining the appropriate IND | BLA | NDA approvals for clinical applications”.



Injectable drugs: Stability, sterility and shelf life boost with flexible packaging

Pharma companies are turning to flexible structures for packaging injectable medicines due to new technology provides improved stability, sterility and shelf life over the glass counterpart. Robin Van Landeghem explains

Before embarking on a discussion about flexible material types that are suitable for injectable or parenteral drugs, it’s important to understand the key attributes that are typically required and the growth trends driving this sector of the marketplace.

Recent research conducted by consultancy firm IQVIA shows strong growth in speciality medicines that target chronic, complex or rare diseases: cancer, autoimmune, HIV, etc. There is also an uptake in biological drugs versus chemicals. The research showed that although oral solid dosage forms still dominate the marketplace, injectable medicines are growing at a more rapid pace.

The study continued to point out that increases in healthcare costs are prompting a shift from hospital to home-based care. This, in turn, is driving packaging innovation that facilitates the ability of the patient to self-administer medications.

Because many of these therapies are delivered by injection, medical device dosage forms have evolved from vial/syringe combinations to prefilled syringes to flexible reservoirs in wearable devices. The drivers are lower cost, reduced exposure to nosocomial infections and patient preference for independence.

Flexible packaging selection criteria

To select the right materials for injectable drugs, several attributes need to be considered. The most important ones include shelf life, temperature, moisture loss/ingress, oxygen ingress, light (photostability and transparency), sterility/microbial barrier and extractables/leachables/sorption. Let’s look at these individually.

Shelf life: desired shelf life will play a significant role in what packaging structure is chosen for the application. How will the material protect the contents with the passage of time? The longer the desired shelf life, the higher the material expectations.

Temperature: how sensitive is the drug’s efficacy to temperature variations? It’s important to take into consideration environmental and home usage scenarios to understand how to engineer the packaging so that the product is not compromised. Further, since many temperature-sensitive drugs are transported via cold chain distribution, it is important that the films be resistant to “cold cracking.”

Moisture loss: if the packaging structure selected does not provide sufficient moisture barrier for the liquid drug it contains, then that aqueous solution will start to evaporate, thereby changing the concentration of active ingredient. On the other hand, if the package contains a powder that needs to be reconstituted before use, that also requires protection against moisture ingress.

Light: some active ingredients are sensitive to light. However, visual inspection requirements frequently specify the structure to be transparent, putting the two objectives at cross purposes. The ability to conduct a visual inspection is especially important for liquid injectables. The goal is to make sure there are no visible particulates that would compromise injection.

One workaround that can be considered is an aluminium foil outer package that protects against light but can be removed so that the contents are inspected in their primary transparent packaging immediately prior to use.

Sterility and microbial barrier: Typically, these liquid drug packages are sterilised after filling/sealing. The package needs to have a hermetic seal to prevent leakage and contamination. The structure also needs to be puncture resistant and not degrade during the selected sterilisation process.

Drug/material interaction: the relationship between drug and packaging material needs to be evaluated so that there is no unwanted interaction that would impact efficacy.

Packaging structures

If you look at key requirements such as stability, sterility and shelf life, selecting a packaging structure for pharma applications requires consideration and expertise. Although glass containers can provide many of the desired attributes, their heavy-weight and breakage susceptibility make the material less than ideal for use with these products.

On the plastics side of the material spectrum, drug developers tend to gravitate towards either multilayer films or injection moulded containers to deliver key performance objectives. Rigid containers can typically fulfil barrier requirements more readily due to increased wall thickness inherent in the process.

Flexible structures, on the other hand, enable a higher level of design flexibility and functionality. For example, drugs need to flow consistently through the delivery system without air being trapped. Small reservoir pouches for wearables and IV bags that are easy to empty are just two examples of how flexible materials are used to facilitate proper dosing.

Materials selected for injectables have to provide excellent stability to support pharmaceutical efficacy. The most commonly used are polyolefins, which include polyethylene (PE), polypropylene (PP) and cyclic olefins, such as Cyclic olefin copolymer (COC) and Cyclo-olefin polymers (COP). Polyolefins have been widely evaluated and used for pharma applications for many years. Resin producers have developed dedicated resin grades with high purity to meet requirements.
The end result is that drug manufacturers have a significant amount of experience and documentation with using polyolefins as the pharmaceutical contact layer.

Specific attributes

Here are some specific attributes for the more commonly used polyolefins for drug applications:


  • Stable, well-known material
  • Good resistance to radiation sterilisation
  • Healthcare grades (USP & EP compliant) available from several suppliers


  • High-temperature resistance (suitable for steam sterilisation)
  • Property versatility (random copolymers, homopolymers)
  • Healthcare grades (USP & EP compliant) available from several suppliers

Cyclic olefin (co)polymer (COC/COP)

  • A highly inert, high-purity material
  • Meet requirements of USP & EP, and ISO 10993 biocompatibility
  • The preferred material for vials and prefilled syringes as a replacement to glass (non-breaking, low protein adsorption)
  • High transparency
  • High chemical resistance

Demanding applications

Cyclic olefins are now being used for more demanding applications when both PE and PP are not inert enough. The disadvantage of any olefin polymer on its own is that it typically does not provide sufficient oxygen and moisture barrier; environmental moisture, as well as evaporation.

This is where polychlorotrifluoroethylene (PCTFE), commonly known by the brand name Aclar, comes into play: a layer of Aclar can be added to the polyolefin layer to provide significant moisture barrier properties while maintaining transparency. The only other material that can provide even more barrier at the same thickness is aluminium foil, but the desired transparency is lost.

Additional attributes of the PCTFE Aclar include:

  • Flexible thermoplastic film
  • Ultra-high moisture barrier
  • Chemically very stable and inert
  • Low leachables/extractables
  • Sterilisation resistant

Table 1

Where moisture barrier is concerned, you would need 100 units of PVC to achieve the same effect to one unit of thickness of PCTFE (Aclar). View table 1 to see how the numbers compare. The goal with flexible structures is getting the best barrier at the lowest possible thickness.

Film lamination vs. co-extrusion coating

Adhesive lamination is a more traditional technique used to bond films together. Individual film layers are combined with adhesives to create the final structure.

Adhesive lamination offers significant material choice flexibility. However, the downside is that you have to form the individual films, then use adhesives to bond them, which adds another step to the process. In addition, adhesives are usually dispersions of small molecules that eventually cross-link into larger polymer networks, but with the potential of residual small molecules that can migrate out.

In the co-extrusion process, the multilayer film is created in one step. In this process, there are no adhesives involved, but “tie resins”: large molecules, created by grafting functional bonding groups onto a polyolefin backbone, and they will form a chemical bond between the layers.

Co-extrusion is the preferred process for injectable products due to low leaching attributes.
Here is a typical structure using either process:

  • Polyolefin contact layer
  • Tie resin
  • Barrier layer
  • Tie resin
  • Polyolefin outer layer

Polyolefin cohesive multilayer film

Cleanroom film manufacturing

Both laminated and coextruded films for injectable applications are produced in a cleanroom, which limits the number of particles in the air. The objective is to minimise the chance that the film will be contaminated. For pharmaceutical film manufacturing, a Class 8 cleanroom is typically required.

A film roll is typically double-bagged before it leaves the cleanroom for transport. This enables the converter or pharmaceutical manufacturer to remove the outer bag before bringing it into their cleanroom, where the second bag is removed prior to converting into pouches or other structures.

The sterilisation technique used for these products will depend on the specific drug type and the type of packaging that houses it. Most widely used is radiation (gamma or e-beam) followed by ethylene oxide (usually for packaging materials before drugs are filled), and steam, which is used to sterilise plastic structures with higher temperature resistance; radiation sterilisation usually occurs at ambient temperatures.

It’s also important to consider the radiation technique in conjunction with the impact on the plastic’s properties. For example, some plastics can be prone to yellowing or to becoming brittle when subjected to a specific sterilisation process.

Closure systems selected for these drug delivery packages need to provide enough protection so that shelf life is not compromised and that there is no leakage in transport.

There are a variety of closure types that are used ranging from elastomers that allow needle access to connectors that enable the drug to be dosed. Film manufacturers tend to work closely together with pharmaceutical companies to develop a custom-built structure that can meet performance requirements as well as easily accommodate the preferred closure device or system.

A look to the future

As we move into the next decade with an increasingly ageing population, more attention will be given to improving drug delivery methods, patient comfort and ease of use. The trend is coupled with the introduction of new connected devices that transmit data to physicians about patient compliance, dosage and more. These challenges will continue to push the boundaries of plastic packaging structures for this market segment.



A bold move to handle HPAPIs

Amadeo Ferreira, R&D Manager at Minakem, explains the design of its new manufacturing plant in Belgium featuring a containment strategy that protects both the product and the staff

The global demand for highly potent active pharmaceutical ingredients (HPAPIs) is deemed to have reached US$17 billion in 2018 and market research analysts forecast the sector will rocket to $26 billion by 2023; no wonder many contract development and manufacturing organisations (CDMOs) have been investing heavily in ramping up their facilities to accommodate the necessary equipment to boost production.

A facility upgrade, not to mention a construction project starting from scratch, requires careful consideration. HPAPIs are hazardous compounds, mostly used in oncology treatments, with an occupational exposure limit (OEL) of 10 µg/m3 or less.

Minakem, the pharmaceutical CDMO of the Belgium-based chemical specialist Minafin, made headlines in June last year as the company entered the final qualification run to open a new closed controlled environment at its manufacturing site in Louvain-La-Neuve, 30km southeast of Brussels. The project, a high containment production facility, began operation two months later.

“The Louvain-La-Neuve site has been handling HPAPIs for over four decades,” Amadeo Ferreira, R&D Manager at Minakem, points out. “Its activities in this area began with vinca alcaloïds (vinblastine, vincristine, vinorelbine and vindesine), a set of anti-mitotic and anti-microtubule alkaloid agents used for anti-cancer drugs, with an operational exposure limit (OEL) as low as 0.1µg/m3,” he says.

During this period, the company entered into several partnerships and engaged with the scientific community to further develop laboratory processes for the safe production of HPAPIs. “Minakem has continued producing commercial HPAPI with OEL of 0.1µg/m3 at this facility and is working on new process developments for future and promising drugs,” he enthuses.

Design of the laboratory

In 2018, Minakem invested nearly €2 million in the Louvain-La-Neuve site to expand R&D capacity of the 150sqm plant. The move also aimed to address new challenges in ensuring that containment levels of HPAPIs are met without compromising its ability to respond to increasing demand from customers to accelerate delivery.

“Minakem designed a state-of-the-art laboratory, paying close attention to how best to remain flexible,” Ferreira says. “As an organic chemist, it is important for Minakem to support its customers in multi-step synthesis with all the complexities involved in processes, new technologies and analysis while offering a containment level below 0. 1µg/m3,” he adds.

Risk management was the key priority during the lab design phase. According to Ferreira, to assess containment in a lab environment, Minakem evaluated two approaches.

Minakem’s manufacturing site in Louvain-La-Neuve, 30km southeast of Brussels

“A conservative approach would entail fitting lab suites with glove boxes where every chemical step would be conducted inside the air-tight chamber,” Ferreira says, adding that glove boxes are very well suited for high-risk environments.

Ferreira continues: “While it is paramount to avoid exposure, glove boxes are costly and offer less flexibility, and integrating other equipment in glove boxes is difficult. There are compatibility issues when using sealing joints with solvents and corrosion can occur when handling acids in stainless-steel glove boxes. Another drawback is that the gloves can impede operator dexterity.”

An alternative approach, Ferreira points out, would require using a standard laboratory design equipped with fume hoods. This configuration eliminates the need for glove boxes, but it requires operators to use personal protective equipment (PPE). “Based on its long track record and in-depth experience in handling very highly potent drugs, Minakem concluded that, depending on the outcome of its own assessment of the risk of exposure, the optimal solution would be a combination of both approaches,” Ferreira recalls. In this scenario, for example, the staff would use glove boxes when handling solutions or wet powders.”

Minakem set a market benchmark, Ferreira says, and carried out a risk assessment (RA) on individual tasks to lay out the principles behind the design of the laboratory. The RA identified that dry powder handling was the main potential exposure constraint, with solutions and wet powder handling being less subjected to the risk of exposure, even if the potency was still present.

“Based on this initial assessment, two main areas were defined for risk consideration: focus on the handling of dry powder and developing a process without direct exposure to the dry compound,” he explains.

Containment strategy

Minakem conducted a multiyear feasibility study to identify and describe the health hazards for each drug substance, and then calculate a health-based exposure limit. The investigation took into account an RA of cross-contamination including the batch size, the physical quality of compounds, the design of the room, equipment surface areas and cleaning process parameters, to name but a few.

As a result, rooms were equipped to provide environments of the highest standards to ensure equipment efficiency. The machinery was selected by its expected level of containment. Ferreira explains: “The dry powder area is equipped with glove boxes, pass boxes for chemicals, wastes and samples, and safety cabinets. Ovens are installed inside the glove boxes.”

According to this design, once the product is dry inside the glove box, it is then split into small quantities in vials with septum allowing the future introduction of solvents for processing needs without direct exposure. Ferreira continues: “In the chemical area, fume hoods compliant with EN 14475 and confinement test using SF6 at 0.02 ppm level have been chosen to be used for process development.”

The laboratory is now set up with several different areas: the entrance to an overpressured (+10Pa) room, a gowning/de-gowning area (-10Pa), a process laboratory (-20 Pa), and a powder area (-30Pa). Each room is interlocked and treated with HEPA filters, both the inlet and exhaust.

“The HVAC system was qualified by a certified third party. Substantial data, such as the air velocity in the room, the pressure in the HEPA system, the cascade pressure between rooms, and other parameters are monitored in real-time and alarms are present to signal any dysfunction,” he says.

GMP and keeping staff safe

According to Ferreira, Minakem’s reputation in HPAPI manufacturing is partly due to ensuring the required safety for its operators, the environment and patients. “Minakem has established a long track record in producing GMP compounds. Today, the lab produces HPAPI batches from a few milligrams to 100g that adhere to ICH.Q7 section 19 for use in clinical trials,” he notes.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a project that brings together the regulatory framework of Europe, Japan and the US with experts from the pharmaceutical industry in those regions to discuss scientific and technical aspects of pharmaceutical product registration.

“Minakem is seeing a growing number of clients looking for HPAPI services, where labs conduct more thorough audits and risk assessments when evaluating potential outsourcing partners,” he points out. To ensure smooth operations, Minakem systematically carries out rigorous risk assessments on the safe handling of hazardous drugs for each new project. Internal audits will then be conducted for equipment performance characterisation in Minakem’s actual lab against the supplier’s acceptable level of containment.

Risk analysis for handling HPAPIs

Ferreira says the company works on the assumption that a piece of equipment tested on the supplier’s premises may not necessarily perform to the same standards in different working environments, accounting for factors such as the design of the room, surrounding equipment or the security measures in place.

Three preparative, high-performance liquid chromatography (HPLC) units are operative

“The audit also includes tests using a surrogate molecule with a defined level of toxicity to generate data on the efficacy of Minakem’s monitoring equipment in avoiding exposure and contamination,” Ferreira explains. The assessment, he points out, follows the ISPE Good Practice Guide “Assessing the particulate containment performance of pharmaceutical equipment”.

Minakem sees its operational procedures as pillars in the effectiveness of containment. This recent investment, Ferreira explains, provided an opportunity to demonstrate the efficacy of internal standard operating procedures (SOPs) that have been developed through many years of experience in highly potent drug development and manufacturing.

For Ferreira, continuous training is essential to ensure sustainable growth. “With the laboratory available, the HVAC system qualified and SOPs, the site will continue to improve its operations using air and work in progress controls, or WIP, to develop a sustainable safety culture,” he says.. Every new project, Ferreira says, will go through a failure mode and effects analysis (FMEA) to identify Minakem’s strengths and weaknesses while, if needed, applying additional precautions. “This new facility offers a sustainable platform for new drug development in a safe environment,” he enthuses.

Aside from this new laboratory, Minakem also has GMP production at the Louvain-La-Neuve site with capacity from 100g to 100kg/batch for compounds with OELs as low as 0.1µg/m3. The company has recently invested in three preparative, high-performance liquid chromatography (HPLC) with columns from 50 to 300mm. “These capacities, together with a large toolbox of chemistries, will allow Minakem to further support clients in complex multistep processes under high containment, from early stages of clinical development to commercial launch and full lifecycle,” Ferreira says.

As the global offering in CDMO services increases, with many companies investing in highly potent capacity, Minakem’s recent investments targets further diversification in the industry, particularly in the oncology space.

Ferreira concludes: “Pharmaceutical companies are developing increasingly more complex and potent API to more efficiently target tumour cells, such as antibody drugs conjugates (ADC). With this new facility and equipment, Minakem will be able to provide the drug toxin and linker for ADC, further reinforcing its position in the market.”

By Murielle Gonzalez:


Sustainable knowledge transfer per EU GMP Annex 1

In pharmaceutical production, ongoing employee training is essential for product safety. In the revised “Annex 1 – Manufacture of Sterile Medicinal Products” of the GMP Guide, the EU Commission has established solid standards. But how can pharmaceutical manufacturers best implement these requirements?

At first glance, internal knowledge transfer appears to have many advantages, like being cost-effective. Experts within a company would be theoretically available to train others, and existing procedures have been established. However, due to the complex nature of processes within cleanrooms, and the new requirements of the EU GMP Guide Annex 1, the question becomes: Is internal knowledge transfer sufficient?

The successful implementation of the revised EU GMP Guide, Annex 1 (published in December 2017) requires that pharmaceutical production employees obtain training that is specific to their individual work area. Consider an excerpt from Section 4.3 of the guide, which states:

‘All personnel (including those performing cleaning and maintenance) employed in such areas should receive regular training, qualification (including sampling of the operators bioburden, using methods such as contact plates, at key locations e.g. hands arms and chest) and assessment in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene, cleanroom practices, contamination control, aseptic techniques and potential safety implications to the patient of a loss of product sterility and in the basic elements of microbiology.’

Visualisation helps operators to raise awareness and change their behaviour

According to the EU GMP guideline, sound training is about learning the proper methods, which are process-specifically adapted to the users. External training providers are therefore important partners for pharmaceutical companies and make a valuable contribution to the safety and quality of the product.

Pharmaceutical companies with high security levels do not leave the selection of training providers to chance. They hire certified instructors whose teaching methods align with ISO 29990 standards. Currently, there are only a handful of suppliers worldwide with this unique certification. ISO 29990 is a quality management system standard for education providers that makes a critical difference in training, effectively guaranteeing its lasting success. Donald L. Kirkpatrick, an American economist and professor at the University of Wisconsin, aptly stated, “If the trainees do not apply what they learned, the program has been a failure even if learning has taken place.”

In-house training performed by an external instructor – like one of comprei’s ISO 29990 certified and internationally active cleanroom experts – can effectively guarantee a successful training course. Critical goals of this training include imparting understanding, awareness, and anchoring behavioural changes. Feedback from numerous well-known pharmaceutical companies has confirmed that comprei’s ISO 29990 certified education program provides an improved learning environment and participant motivation, along with a strong customer orientation. These factors have made comprei a highly desirable partner for leading pharmaceutical companies worldwide.

Only trained personnel who have passed the gowning assessment and have participated in a successful aseptic process simulation test, during which they performed their normal duties, should be authorised to enter any grade A/B area.’ – EU GMP Guide, Annex 1

Acclaimed and Well-Grounded Training

Regulations and internal SOPs provide a solid foundation for employee performance. In sensitive cleanroom environments, these robust guidelines are essential to maintaining the output of high-quality products. The EU GMP Guide, Annex 1 states:

‘The personnel working in a grade A/B cleanroom should be trained for aseptic gowning and aseptic practices. Compliance with aseptic gowning procedures should be assessed and confirmed and this should be periodically reassessed at least annually and should involve both visual and microbiological assessment … only trained personnel who have passed the gowning assessment and have participated in a successful aseptic process simulation (APS) test, during which they performed their normal duties, should be authorized to enter any grade A/B area, in which aseptic operations will be conducted, or are being conducted, whilst unsupervised.’


The comprei “cleanroom cuboid” – our mobile training cleanroom

… training should include reference to hygiene, cleanroom practices, contamination control, aseptic techniques …’ – EU GMP Guide, Annex 1

Employee knowledge of detailed operating procedures is essential. In addition, understanding the importance of a procedure – the underlying principles – transforms a well-trained and certified employee into a motivated and mindfully aware member of the company that contributes to its success. This is comprei’s goal – a ISO 29990 certified education provider recognised as an expert in cleanroom technology. Before any training begins, a personalised process analysis is performed to precisely determine customer-specific needs. This provides a detailed template of requirements and forms a solid basis for creating a custom curriculum tailored to customer needs.

Due to proprietary considerations, a hands-on training program in the actual production environment may not always be feasible. In such cases, the relevant processes can be simulated at the comprei cleanroom training facility in Villach, Austria, or in the mobile ‘cleanroom cuboid’, which was specifically designed for this purpose. This mobile training cleanroom brings the practise cleanroom directly to the customer – or to any other desired location. Different scenarios from typical activities can be simulated, their effects visualised, and any needed behavioural changes anchored by the hands-on experience.

Internal trainers vs. external trainers

In order to correctly choose to between using internal trainers or complementing with external trainers, the following must be clarified:

  • What results should the training achieve?
  • What kind of behaviour would be required of my employees to achieve these results?
  • What must they learn to be capable of this behaviour?
  • How can the training best reach them, achieving a welcome reaction?