LYOPHILISATION

The advances in refrigeration technology that are helping to drive pharma to be more sustainable

Driving change

In recent years, the topic of sustainable practices in the pharmaceutical industry has become more prevalent, whether that be through discussions on how to affect change, or through strategies designed to reduce carbon emissions.

One of the best gauges for judging progress in an industry is through the introduction of new technologies. Here we speak to, Tsyplakov Vladyslav, development director at Mirai Intex about how the company’s air refrigeration technologies could help the pharmaceutical industry become more environmentally friendly.

Mirai Intex specialises in the development and manufacture of turbo compression equipment, which has led the company to develop “the safest, most reliable and most environmentally friendly air refrigeration machines,” Vladyslav says.

The technology used by Mirai Intex, Air Cycle, works by heating air during the compression stage and cooling down during the expansion process. By repeating this process Mirai Intex’s technology is able to reach and maintain ultralow temperatures to as low as -160°C.

Also known as the reverse Brayton cycle, air cycle technology was developed in the mid 1800s by John Gorrie and is used on aeroplanes for cabin climatisation and ventilation.

Mirai Intex’s expertise translates into the field of refrigeration across a number of industries, with its products being suitable for storage applications for biological materials, pharmaceuticals or vaccines and more.

The company’s Mirai Cold products come in two configurations - open and closed cycle.

Open cycle machines are suitable for storage and cryotherapy applications, coming with a unique humidity extraction device, which ensures great temperature uniformity and allows the customers to forget about defrost procedures.

Closed cycle units are equipped with an additional heat exchanger for the secondary working fluid (eg. silicone oil), and are more suitable for process cooling applications such as freeze-drying or solvent recovery.

The company’s cooling technology is made sustainable through the fact it uses air as a refrigerant to reach ultra low temperatures. Vapour compression technologies, Vladyslav says, typically use cascade stages to reach lower

We believe that through innovation this is the right way to drive change.

temperature levels, during which environmentally harmful refrigerants are used.

Vladyslav clarifies that vapour compression is a refrigeration technology in which the refrigerant undergoes a phase change (from gas to liquid) mostly F-gases or burnable refrigerants, whereas in air cycle technology, air doesn’t change its phase. “These refrigerants (R404A & R23) are really spread out in the industry, huge volumes are being used but the problem with them is they have a very high global warming potential (GWP),” Vladyslav mentions.

The emissions from one single gram of R23 in particular is equivalent to 15kg of CO2 being let out into the atmosphere, Vladyslav says, going on to explain how new revisions to the EU’s F-Gas regulation are aiming to ban the use of high GWP refrigerants.

With regulatory changes in tow, you’d think that industry would be more open to the idea of innovations that can help push pharma in a more sustainable direction. Vladyslav however says that the uptake of new technologies is slow.

“We see a lot of resistance in the market towards new technologies,” Vladyslav says, explaining how in pharma, there can often be a reluctance to change technologies that already work, despite it having problems.

“Of course, there has to be change if we’re driving innovation and we’re striving for a better future. We have to change the old technologies we use. So, we have to push for this.”

It’s a vital part of Mirai Intex’s company culture, according to Vladyslav, who believes advances in technology are the right way to go about causing change for the better.

“It’s not that we’re only passionate about the environment and sustainability, we’re also passionate about innovation and technology. We believe that through innovation this is the right way to drive change. It’s not about protesting, you need to propose the solution to change the world. So that is what we’re doing. We’re proposing the solution to the market that will help drive change for the better,” he says. Mirai Intex is a fairly young company, launching in 2015 - though Vladyslav does mention that its technology was in development for much longer. Coming into the pharma market is never easy, especially with a new approach to sustainability, an area where Vladyslav would like to see a lot more being done.

“To be honest I would like to see even more being done. Sometimes the choices that are made within pharmaceutical companies don’t always favour sustainability and they don’t always prioritise,” he says.

Whilst big pharma companies are starting to tackle sustainability, through yearly reporting, packaging initiatives and logistical changes, education around regulatory changes is key. For example, Vladyslav mentions that “many people in the pharma industry don’t know about the F gas regulation or what a refrigerant is, what they should and should not be using.”

That’s why Mirai Intex is wanting to push its technology onto the market, so pharmaceutical companies know that sustainable options exist for things like freeze drying and lyophilisation, and that they’re nothing to be wary of.

Vladyslav hopes the industry listens. Within five years, he says, Mirai Intex would love to be supplying to most of the pharma companies that require ultralow temperatures between minus 70°-90°. The reason for this Vladyslav says, is “because we already know we are the best in this segment.”

Webinars create | engage | inspire

Our webinars offer an insightful and professional means of connecting you with your target audience through thought leadership and direct interaction.

• Showcase your expertise and industry knowledge • Raise brand awareness • Transform the way you engage with customers • Run a cost-effective and convenient alternative to conventional seminars • Gain more insights into your target audience • Attain clearly defined and qualified sales leads

TO FIND OUT MORE CONTACT

advertising manager robert anderton tel: +44 (0)1244 952 359 email: robert.anderton@rapidnews.com

EPM_Magazine EPM Magazine

C LING OFF

Considerations for lyophilisation closure selection and processing to protect moisture-sensitive drug products

Lyophilisation or freeze-drying is known as the removal of water from a frozen liquid product by a phenomenon called sublimation. The result is a solid, dried product inside the vial. This is an ideal process for moisture-sensitive drug products that may have a limited shelf-life due to external influences such as moisture ingress. If injectable drug formulations are unstable in aqueous solutions, due to the molecular interactions. they can degrade quickly in solution, which is why these drugs are often freeze dried. This will protect them from certain external influences and potential degradation.

Lyophilising moisture-sensitive injectables enables drug stability during their assigned shelf life until they are reconstituted into their liquid presentation prior to drug administration. An increasing number of injectables are marketed in a lyophilised form for various therapeutic indications, e.g., oncology and rare metabolic diseases.

Lyophilisation involves long production cycles in high capacity freeze dryers with a significant degree of automation to simultaneously process thousands of container closure system units. Process efficiency demands that the components meet requirements for integral drug containment, dimensional fit assuring container closure integrity, support machinability in fill-finish and maintenance of drug compatibility and stability. Glass has a very low moisture vapour transmission rate (MVTR), so when selecting a primary container for a moisture-sensitive drug product, glass vials are often used. However, when selecting a rubber stopper for the system, pharmaceutical manufacturers should be aware of design features and consider the rubber formulation to ensure optimised storage and moisture protection for the drug product. After filling the liquid drug into a vial, the stopper is halfway inserted into the vial to reach the intermediate lyophilisation position. Component design is optimised to ensure a stable lyophilisation position on the vial neck to allow moisture vapour removal through the remaining stopper-vial-gate into the freeze dryer chamber. Final stoppering to achieve full insertion into the vial occurs when the freeze dryer shelves move down after the process cycle.

Igloo stoppers offer a stable positioning in the freeze-drying phase because of their increased contact area with the glass vial. Due to their asymmetric balance point, however, the stopper may shift out of the vertical axis during stoppering, which requires optimisation on the filling line to avoid rejections during camera inspection of the seated stopper. Split designs are more flexible during stopper insertion. Their symmetric design keeps them horizontal during freeze-drying. However, prior to drug filling and stopper insertion, the two-leg design could potentially lead to closure twining, where stopper legs could intertwine during processing in the feeder bowl, which may cause issues

Author:

DR HEIKE KOFLE -

manager Technical Customer Support Europe at West Pharmaceutical Services

Compromised drug stability like the collapse of a freeze-dried product due to excessive moisture uptake during storage needs to be avoided.

including line stoppages and down time. Either design will work well for the freeze-drying process itself.

When considering the lyophilisation of moisture sensitive biopharmaceuticals, companies should consider that moisture transfer could occur via the stopper. High-quality elastomeric components used for aseptic filling are washed, dried, steam sterilised and dried again to help ensure cleanliness and reduced residual moisture content of the closures. There are two distinct points where moisture is driven into the stopper: initial pharmaceutical washing and the steam sterilisation process. Both are followed by a drying period that should be optimised for a moisture-sensitive drug product. Also, a protective bag packaging concept will keep stoppers dry after sterilisation and post-drying until introduction to the filling line.

The stoppers will then be used in the lyophilisation process to aseptically contain the freeze-dried drug product. The fully stoppered vials are released from the freeze drier, crimped with seals and stored. West Pharmaceutical Services conducted a study which revealed that MVTR was more important to long-term storage of freezedried product than initial closure dryness.1 Results confirmed that moisture content in stoppers prior to filling the drug is dependent on its rubber formulation and applied drying conditions. It is recommended to optimise drying cycle parameters for removal of moisture driven into the stopper during the autoclave cycle of the drug product.

Measuring the moisture content of lyophilised lactose as a model for a freeze-dried product over three years showed that moisture migrates from the environment through the stopper and accumulates in the freezedried product over storage time. Moisture uptake by the dried product correlates with the MVTR of the rubber formulation, not solely with the moisture uptake of the stopper after washing or steam sterilisation.

Moisture can reach a lyophilised drug product in a variety of ways. The simplest source of moisture ingress is a lack of seal integrity between the stopper and the vial interface. If there is not a tight seal, moisture can travel easily into the vial and permeate into the freeze-dried drug product. Secondly, residual moisture inside insufficiently dried closures may affect the drug product as the captured excess water vapour could be released from the rubber stopper into the vial headspace and permeate into the lyophilised drug product over time. Finally, water vapour can constantly migrate from the environment through the rubber stopper during long-term storage. Every rubber formulation has a MVTR, a characteristic rate for water vapour to migrate through the material over time. The amount of moisture that could negatively affect the drug product varies based on the size of the freeze-dried drug product and its contents.

With these considerations for selection and preparation of packaging components for a container closure system, stability of lyophilised drug products can be maintained despite their moisture sensitivity. Compromised drug stability like the collapse of a freeze-dried product due to excessive moisture uptake during storage needs to be avoided. Making the right choice of packaging appropriate for the drug product can help reduce the risk of costly recalls or rejection of the drug product at its point of use.

REFERENCES:

1: Technical Report TR 2007116 Lyophilization Stoppers and EndProduct Moisture Evaluation West Pharmaceutical Services, Inc.

ACKNOWLEDGEMENT

This article is based on a study conducted by Amy Miller and Jennifer Riter of West Pharmaceutical Services, Inc., without whose significant efforts this article could not have been written.

The importance of temperature stability in clinical environments to prevent drug wastage

Waste Not, Want Not

Pharmaceutical waste is a universally accepted problem within the NHS and, while there are many contributing factors to the problem, the safe storage of temperature sensitive products remains one of the most important – but one which is sometimes overlooked.

The safe storage of medicines in hospitals and pharmacies is paramount to reducing waste and costs for the NHS. The rising price of medicines is a major focus for a healthcare sector that is struggling with financial challenges. The most recent figures from NHS Digital report that NHS spending on medicines rose from around £12bn to £18.2bn in the seven years up to 2017/18. So why is storage so important? The active chemicals in any medication can change in molecular form when exposed to different temperatures, potentially resulting in decomposition of the medication. This can make medications less effective and may even result in new or dangerous effects. As a result, temperature sensitive medication which has ‘spoiled’ due to incorrect storage must be disposed of.

Vaccines may lose their effectiveness if they become too hot or too cold at any time. They naturally biodegrade over time and being stored outside the recommended temperature range may speed up loss of potency. This impact cannot be reversed and a vaccine may then fail to create the desired immune response and give protection. Vaccines cost the NHS around £200 million a year, so wastage from inappropriate storage must be avoided at all costs. In addition to vaccines, biologic drugs - such as insulin - and drugs to treat conditions such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and various forms of cancer are often sensitive to temperature extremes and, if compromised, may put patients at risk. Biologics represent an innovative and rapidly expanding category of drugs – by 2022, it is estimated that sales from biologics will account for roughly 30% (or $326 billion) of prescription drug sales globally. However, maintaining the safety and efficacy of these cutting-edge therapies can present unique challenges. Patients who use medicines whose potency has been reduced or even destroyed by incorrect storage may experience clinical setbacks, recurring symptoms and other adverse events.

Author: MIKE BUTT -

managing director at Lec Medical

Vaccines cost the NHS around £200 million a year, so wastage from inappropriate storage must be avoided at all costs.

Following manufacture, vaccines and biologics need to be shipped and stored at lower than ambient temperatures to assure their quality and efficacy. They are often referred to as “cold chain products” or “fridge lines” and they come with strict temperature requirements. Failure to store medicines according to manufacturers’ recommendations can invalidate the expiry date and cause manufacturers to disclaim responsibility for any apparent failure of the medicine as the safety and effectiveness of such medicines can be significantly compromised or unknown. This can cause avoidable waste, often at considerable expense.

In any clinical setting where temperature sensitive medicines are stored, there must be named individuals responsible and accountable for the receipt and storage of vaccines/heat sensitive medicines, and the monitoring and recording of fridge and ambient room temperatures.

Crucially, refrigerators used for the storage of medicines must be designed specifically for that purpose. Standard domestic refrigerators cannot be used for storing cold chain products for a number of reasons, including an uneven temperature distribution (as a result of minimal air circulation) and a normal operating range of between 0°C and 10°C. Medicalgrade refrigerators offer a lot more than a standard fridge. Firstly, they maintain a more consistent temperature, which is vitally important for storing sensitive things, like vaccines and samples, that can be damaged by fluctuations. Medical grade refrigerators also feature visible and audible alarms to alert staff to any issues or faults. These alarms might go off if the door isn’t closed all the way, or if the temperature goes up or down unexpectedly, allowing medical staff to act quickly to avoid damage and dangerous changes to the medication contained within. In addition, the fridges can be locked and glass doors allow quick and easy stock checks.

The medical refrigerator used must also be of an appropriate size for the quantity of stock to be stored i.e. filled to no more than 75% capacity to allow adequate air circulation. It must also be reserved exclusively for the storage of vaccines and other pharmaceutical products and not used to store food, blood, milk, drink or anything else representing a contamination risk.

Care must also be taken to ensure the refrigeration unit is sited in a wellventilated room maintained between 10°C and 25°C, away from external windows and all heat sources e.g. radiators or direct sunlight, and at least 5-10 cm from walls and other units. To ensure its ongoing effectiveness, any pharmacy refrigeration unit must be serviced according to its manufacturer’s instructions and have its integral thermometer independently calibrated to ensure readings are true. Finally, the medical refrigerator must be cleaned regularly and the internal stock should be stored according to first expiry.

Industry predictions said that the cold chain industry would increase by 65% by the end of 2020, as temperature-sensitive pharmaceutical products continue to elevate. This prediction was made before the arrival of Covid-19, for which we anticipate – and hope for – a vaccine. Once a vaccine arrives, the effectiveness of refrigerated storage will become vitally important to avoid waste and get a life-saving medicine to the public. The vaccination required to protect us all will require a feat of mass manufacturing and will put pressure on cold chain logistic capabilities. While the world is waiting for a vaccine, ask yourself: when you get it, where will you store it?

Connect 2 Cleanrooms shines a spotlight on the importance of cleanroom design for cell & gene therapy suites.

Shine a light

Author: FIONA KERR-

project business development manager at Connect 2 Cleanrooms.

As the innovative therapies market is maturing, the UK is fast turning into a global leader.

Cell and gene therapies are providing patients in the NHS and private healthcare settings with life changing medicines across the UK and beyond. As the innovative therapies market is maturing, the UK is fast turning into a global leader. The Cell and Gene Therapy Catapult, which has the core purpose of building a world-leading cell and gene therapy sector in the UK, reported a 100% increase in phase III clinical trials in the past two years alone. With a 60% increase in manufacturing space within the same period, many Advanced Therapy Medicinal Product (ATMP) manufacturers are in growth with expansions planned or in progress.

Innovate UK is strengthening gene therapy in the UK by capital investment grants to advance the UK’s ability to produce viral vectors for use as an ATMP or in the development of cell-based ATMPs and to encourage partnerships between public and private organisations, to maximise further investment.

FACILITY DESIGN AND VALIDATION

For new facilities or expansions, it is vital to get all details of the design correct. For cell and/or gene therapy cleanrooms, the design must integrate process needs with meeting regulatory requirements, to provide an appropriate solution for product, process and people. The integration of utilities, specialist systems and equipment will be critical to the design process. To achieve GMP compliance, MHRA licensing and to meet any other regulatory requirements, the proposed facility will need an initial User Requirement Specification (URS) to fully define the requirements of the facility. A project team should be set up for the creation of the URS, with key stakeholders, including quality, production and facilities management. This team can review the process requirements, including the flow of people and products through the facility, to assess the optimum layout for regulatory compliance, efficient operation, any segregation requirements and the minimisation of cross contamination.

To meet the requirements of the URS, a detailed and documented design qualification (DQ) programme, including documentation, drawings, technical schedules and specifications, will underwrite the proposed design of the facility. Leading design principles and understanding of the relevant regulatory requirements will keep cleanroom entry, exit and the flow of personnel and materials separated. Sufficient space will be allowed in the layout for incorporating transfer hatches, material airlocks and multiple garment changes. Functional & mechanical system design of cell and gene therapy manufacturing suites will need to be qualified to systematically demonstrate and document that facilities, systems and equipment, perform as intended through installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) processes.

TECHNICAL SOLUTION

With many organisations in growth, being creative with space within and external to the facility will maximise available and potential future footprint and retain sufficient space for any future expansion, enabling organisations to scale up from ATMP early phase clinical trials to commercial manufacturing.

In cleanroom design, this can be achieved through implementing more modern methods of air handling. Using a decentralised air handling approach can achieve the same performance as an air handling unit. Benefits range from reduced constructional cost and complexity, to an increase in usable footprint, as a central plant room is not required.

How pharma manufacturers can avoid data mistakes and put the right technology in place at a critical time for global health.

UK EXCEL MIX UP DELIVERS REMINDER OF THE IMPORTANCE OF DATA AND SYSTEMS

As pharmaceutical manufacturers across the world anxiously await the outcome of vaccine trials, a costly mistake by the UK’s public health officials to lose nearly 16,000 Covid-19 tests has served as a warning about the importance of effective data systems.

Far from just an embarrassing mixup, the 16,000 Covid-19 test results lost by Public Health England recently is a stark warning for pharma manufacturers. The error, caused by the use of outdated XLS file formats which could only handle around 65,000 rows of data rather than the one-million rows Excel is actually capable of, has had a huge impact on public trust in the UK’s testing system at a time when cases are on the rise.

For those skilled in working with vast amounts of data, particularly in the pharmaceutical manufacturing sector, this is hardly a surprising revelation.

Spreadsheets are complex, inconsistent, prone to errors and out-of-date - not to mention time-consuming. With no visibility over processes, they are unable to show where there is capacity. Having a single source of data to base decisions on, by comparison, means no time lag and the assurance of a standardised dataset, leading to one single version of the truth.

The use of an advanced planning and scheduling (APS) system, for example, will be critical for pharma manufacturers to create a single real-time plan to reduce lead times and optimise resources. The granularity of data far exceeds that of spreadsheets and users are able to use this to model scenarios based on resources, constraints and process time, in order to make more effective decisions.

As the world seeks to ramp up vaccine manufacturing capacity consideration must be given to how modern planning and scheduling systems can ensure this is done in the most efficient manner to rapidly manufacture a vaccine en-masse. I’d argue that having the right technology and systems in place to ensure the best manufacturing process will be as important as having the means of production on standby. This will be key to ramping up vaccine production quickly. After all, without a firm, reliable basis of evidence, how can managers make informed decisions that ultimately drive performance? This will save all important time and reduce the likelihood of planning mistakes and delays - set-backs we can ill-afford.

Far from simply an embarrassing mistake, the UK government’s Excel blunder may have put lives at risk at a critical time for public health and pharma manufacturers must heed this warning. Spreadsheets will not be the platform that provides the planning and scheduling of the Covid-19 vaccine or future pandemics. Having the right technology in place is critical to optimise resources, reduce lead times and create a single plan to get the world back to some form of normality.

Author: ROD SCHREGARDUS

– pharmaceutical manufacturing expert at The Access Group

Having the right technology and systems in place to ensure the best manufacturing process will be as important as having the means of production on standby.