WOMEN IN PHARMA
OSD SUPPLEMENT
REPUTATIONAL RISKS OF COVID-19
November/December 2020
CONSISTENCY IS KEY
Natoli Engineering explains the importance of understanding punch length and cup depth in regard to punch wear and more.
Let us help you get therapies to patients faster. www.gconpods.com | sales@gconbio.com | +353 (0) 56 449 1491
Contents Nov/Dec 2020 | Volume 20 Issue 6 REGULARS 5: EDITOR’S DESK
How the industry has come together during Covid-19.
6: A SMALL DOSE
A brief round-up of some of the latest developments in the industry.
10: OPINION
The risks pharmaceutical companies are taking in the attempt to develop a vaccine for Covid-19.
14: IN THE NEWS
A short selection of stories from the world of science.
16: COVER STORY
Natoli Engineering president, Dale Natoli, explains the importance of understanding punch length and cup depth in regard to punch wear and more.
42: TALKING POINTS
Stories to consider and what to look out for in EPM in the coming weeks.
FEATURES 8: PERSPECTIVE ON PHARMA
The use of single-use systems to scale up development in biomanufacturing.
18: WOMEN IN PHARMA
The final part in a mini-series of articles examining the life sciences industry and its perceptions of women.
20: LYOPHILISATION
Sustainability and the implementations of technology are some of the topics in this feature on lyophilisation.
31: OSD SUPPLEMENT
The latest advancements and thought pieces surrounding the oral solid dosage market.
35: AN INSIDE LOOK
The company helping to protect pharmaceutical products from counterfeiting.
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#cleangreen
From Waste to Wipe Contec introduces a range of cleanroom wipes manufactured from recycled materials
RECYCLED BOTTLES Post-consumer bottles are collected
FLAKE
Bottles are chopped into flake and cleaned
CHIP
Flake is melted, filtered, and formed into chip
RECYCLED FIBRE Chip is melted and made into yarn
Contec ReFIBE Wipes - Recycled 100% knitted polyester cleanroom wipes providing a sustainability story in a single-use world. Contec’s range of ReFIBE cleanroom wipes provides a sustainable solution for critical environments without jeopardising quality or performance. Each cleanroom wipe is constructed from 100% post-consumer recycled plastic bottles (35+ bottles per pack of wipes), saving waste from going into oceans or landfill. The bottles go through a rigorous cleaning process before being converted into polyester chip, which is then extruded and spun into yarn before being knitted into fabric. See more at www.contecinc.com/refibe
WIPE
Yarn is knitted into ReFIBE Wipes
5 HEAD OFFICE
A COLLECTIVE EFFORT
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FOR LIFE SCIENCES TO ANSWER THE CALL TO COVID-19 THIS YEAR THOUGH HAS BEEN A RATHER HEARTENING SIGHT.
EDITORIAL editor reece armstrong reece.armstrong@rapidnews.com publisher duncan wood
PRODUCTION head of studio and production sam hamlyn
ADVERTISING robert anderton tel: +44 (0)1244 952359 robert.anderton@rapidnews.com head of media sales, plastics & life sciences lisa montgomery lisa.montgomery@rapidnews.com
SUBSCRIPTIONS subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £249 outside qualifying criteria UK - FREE, ROW - £249 please subscribe online at www.epmmagazine.com Address changes should be emailed to subscriptions@rapidnews.com European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals. Volume 20 Issue 5 © Sept/Oct 2020
While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.
BPA Worldwide Membership ISSN No - 2052-4811
I
t’s fair to say that 2020 has been a tough year. When Covid-19 hit earlier this year, it was difficult to imagine that the virus would still be here come Christmas. Offices emptied as workers were sent home, items flew off shelves as people panic bought goods, and hospital wards filled up with patients who’d contracted a virus that was alien to healthcare workers. Clinicians came face-toface with something they didn’t know how to treat. Their usual approach of
medicines, therapies and surgical interventions were suddenly not the goldstandard approach they were used to. This simplifies the work of our doctors, nurses, surgeons and everyone else involved in healthcare, but in essence, it’s what they had to deal with when Covid-19 first hit. It’s easy to be cynical when writing about pharma and life sciences. It’s an amazing industry but one which comes with its own closet full of skeletons; historical scandals, dodgy dealings,
EDITOR’S DESK lobbying, insider trading, price hikes and patent blocking, to name just a few. For life sciences to answer the call to Covid-19 this year though has been a rather heartening sight. Straight away we saw the industry come together in a bid to develop new ventilators for Covid-19
patients. Diagnostic firms began developing and launching polymerise chain reaction (PCR) and antibody testing kits in a bid to better trace the virus. Healthcare groups from all over the globe started making, then donating masks to protect us from the virus. Some firms even managed to produce personal protective equipment (PPE) in an attempt to bolster the reduced supply in the NHS. In the pharma industry, the race was and is still on to find a promising vaccine for Covid-19. Though it’s easy to argue about firms chasing profits, I truly believe that the people working on these therapies are doing so for the betterment of the world. Recently we’ve seen major pharma firms sign up to vaccine sharing schemes, in which lower income countries will be granted access to millions of Covid-19 vaccines once they become available. This isn’t the answer to richer nations pre-purchasing stock of vaccines, but it is an example of the good that can come from collaborations between industry, charities and healthcare organisations. So, a note of hope for the end of the year? Possibly. We’re still in the midst of this virus though and caution must still be taken. The life sciences industry has taught us this year that it’s at its best when working together. So, take a lesson. Stay safe, keep others safe and let’s make it into the new year.
6
A small dose
Cambrex expands pharma services in Edinburgh
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mall molecule company Cambrex has completed an expansion of its solid form screening and crystallisation process development facility in Edinburgh, Scotland. Described as a major expansion, the project has seen the facility’s total footprint doubled, with existing laboratory space refurbished as well. “We have seen an increase in demand for services, and specifically for largerscale crystallisation projects, so this expansion increases our efficiency and ability to respond to these requests,” said Tom Loewald, chief executive officer of Cambrex. “The work we carry out at the Edinburgh site is one part of Cambrex’s integrated drug substance offering, and the investment increases
our flexibility to work on projects at all stages of drug development.” Cambrex’s Edinburgh site provides solid form development services for drug substance and drug product. Scientists at the site work on projects both as a standalone service to pharmaceutical customers, as well as with other Cambrex sites to offer an integrated process development service. Due to the expansion, the site now holds an additional 13 fume cupboards in the laboratory, allowing the team to increase capacity and provide clients with larger process crystallisation development. The expansion will also enable Cambrex to recruit 40 more scientists with the potential for further growth in the future.
This expansion increases our efficiency and ability to respond to these requests.
CellGenix completes second phase facility expansion
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aterials supplier CellGenix has completed the second phase of a facility expansion designed to increase capacity for cytokines. The company has implemented an automated filling and freeze-drying line, as well as increasing its bulkware production footprint, in order to increase its finished product capacity for cytokines. CellGenix hopes the expansion enables it to meet the fast-growing demand for critical raw and ancillary materials as more customers reach late-stage clinical development and
commercialisation of their cell and gene therapies. The newly expanded facility enables CellGenix to streamline its production processes. The automated filling process also provides increased accuracy and reduced risks, which further increases the safety of its preclinical and GMP cytokines.
CellGenix is now well prepared for the future growth of the cell and gene therapy market.
It follows the company’s first expansion phase in 2018, during which CellGenix added additional space and personnel in its quality control, R&D, logistics and warehouse departments. By finishing both expansion
Microbiome company awarded €2m to develop personalised probiotics delivery technology
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icrobiome therapeutics company MyBiotics has received €2 million from the European Union’s Horizon 2020 Program. The funding will support the development of a novel technology enabling efficient delivery of personalised probiotics to prevent gutrelated diseases and recover damaged gut microbiota.
MyBiotics has developed robust culturing, fermentation and delivery technologies for generating a highly stable and diverse bacterial community that can be efficiently delivered to the gut potentially restoring microbiome equilibrium. Currently available probiotic products may have limited clinical impact due to the low
survival rates of the delivered bacteria in the gastrointestinal tract. This significantly reduces the ability of probiotic bacteria to impact the microbial diversity of the gut, thus failing to create a healthier community of bacteria. The company will now develop multi-strain collections of human bacteria, enabling the generation of effective, personalised,
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phases, CellGenix hopes it has strengthened its position as a leading supplier for large scale manufacturing in the cell and gene therapy space. “The expansion of our facility is a result of the robust, sustainable, and profitable growth, generated by long standing and trustful customer relationships we achieved over many years. CellGenix is now well prepared for
proprietary, microbial nature-driven, enhanced technology combined with microbes with potential health benefit, holds the potential to greatly improve existing probiotic solutions,” stated David Daboush,
human-bacteria based probiotics. “MyBiotics’ technology enables the transformation of beneficial bacteria to clinically efficient products. Our
the future growth of the cell and gene therapy market. It supports our goal to further establish CellGenix as a key provider in the fight against disease, preferred supplier or raw and ancillary materials and trusted partner for large scale manufacturing of cell and gene therapies,” said Felicia Rosenthal, chief executive officer at CellGenix.
CEO of MyBiotics Pharma. “The Horizon 2020 Program grant is a significant validation and strong vote of confidence in MyBiotics and will support our development of more effective, next generation probiotics,” added Daboush.
VETTER MOVES INTO NEW HEADQUARTERS
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lobal contract development and manufacturing organisation (CDMO) Vetter has moved into its new headquarters in Ravensburg Germany. Vetter has invested around €50 million in the building which is designed for 1,000 employees and contains office space, the new ATRIUM company restaurant, a cafeteria and about 40 conference rooms. Vetter states the move to the new headquarters, known as Ravensburg Vetter Kammerbruehl, was made in response to the continuous growth of headcount and changing circumstances. “We are relying on sustainable and futureoriented activities with the focus on our customers and their patients,” managing
director Peter Soelkner said. The company’s former headquarters has been modified to be used as a training centre where it will offer employee qualification programmes and individual development opportunities on a continuous basis. Vetter is also developing its other sites, with a new a new combination building for manual visual inspection and secondary packaging starting operations at its Ravensburg Vetter Sued / Vetter Secondary Packaging site. “Part of our 360-degree approach includes investments in the expansion of our development capacities,” added Soelkner. “We have observed a steady increase in demand from
our customers as well as ever-more complex requirements for modern compounds.” The company is also planning a new cleanroom for the manufacturing of prefilled syringes at the Schuetzenstrasse site in 2021 and is wanting to further expand on its quality control. “We want to provide sufficient resources for the important step of final quality control and, at the same time, create greater flexibility,” managing director Thomas Otto said. “These actions will even better enable us to offer our customers either manual or automatic visual inspection depending on individual batch sizes and special characteristics of their products.”
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PERSPECTIVE ON PHARMA: From the factory
Scaling up
T
he rapid transition from drug development to full-scale production is crucial for biopharmaceutical manufacturers to realise a return on their R&D costs. Speed to market requires the efficient scaling up of a manufacturing process—whether it occurs in the same facility or moves to a new one. The adoption of singleuse systems (SUS), with their flexibility, portability, and ease of use, makes them the obvious cost-effective solution for scaling up. SUS accommodates increased demand, whether this occurs during development or only once full-scale production becomes necessary. Most importantly, incorporating SUS into R&D pilot processes makes it more efficient to scale up to commercial production.
The popularity of singleuse bioprocessing solutions continues to grow, with the market in the biopharma industry projected to be worth $26.89 billion by 2025, with a compound annual growth rate of 13.6%.1 Replacing traditional bioprocessing equipment with continually improving single-use technology and the expansion of single-use manufacturing Mark A. Sitcoske, founder & CEO of High Purity New England (HPNE) explains the benefits of using single-use systems to scale up from development to full-scale production in biomanufacturing facilities.
facilities by contract manufacturing organisations (CMOs) are key contributors to this growth. Demand is also being driven by its spread upstream and downstream into all areas of biopharmaceutical manufacturing, from research and development to fill-finish. While the shift to SUS has
revolutionised bioprocessing and manufacturing facilities, scaling up from discovery and development to fullscale manufacturing can be a challenge for biopharmaceutical manufacturers. Challenges include the need to design and implement a new process for commercial production
that may differ from laboratory conditions. Fortunately, innovations in single-use systems equipment and processes, along with vendor partners who can design, engineer, and build a fully customised solution, are helping companies that are looking for solutions.
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The following benefits of singleuse systems add up to reduced infrastructure costs and more efficient bioprocessing. FLEXIBILITY OF SINGLEUSE SYSTEMS ALLOWS SCALE-UP TO COMMERCIAL PRODUCTION The flexibility of SUS allows a company to adapt a process so as to produce a new drug in the future. This means that progressing from R&D to full-scale production, or to the manufacture of a different product, can happen in the same facility. As with traditional stainlesssteel equipment, aseptic conditions and containment during production are essential to protect workers and the final
product from contamination. However, while stainless steel technology follows industrywide regulatory standards, the use of SUS equipment, such as bioreactor bags and connectors, does not yet have set regulatory guidance documents to follow. Complicating matters, many single-use manufacturers resist the use of inter-company connectivity, preferring to promote their parts and making it difficult to move to another supplier once a process is in place. This makes it imperative to find a partner that is willing to customise a solution— incorporating equipment from multiple vendors if necessary— that can fit directly into any process and can bridge the gap until a completely bespoke solution is available. Relying
on a single vendor capable of providing engineering and design advice will ensure the compatibility of the components of single-use assemblies. Single-use systems offer scalability to production volumes of 50L, 250L, and 500L as standard sizes, which can be useful to meet the rising demand for cell and gene therapies, like monoclonal antibodies. The ideal single-use mixing system is designed to perform liquid/ liquid and powder/liquid mixing with a dispersion plate able to efficiently mix the most challenging buffer, media, and biopharmaceutical ingredients. STREAMLINING CLEANING VALIDATION The evolution of single-use systems in sterile manufacturing has made them a simpler and cost-effective alternative for cleaning and validation of bioreactors and downstream processing equipment. Prime examples are processes that require many steps, such as chromatography and purification. Unlike traditional bioprocessing, during which each tank needs to be cleaned before reuse, SUS bypasses this requirement, thus reducing downtime and increasing productivity. LOWER RISK OF CONTAMINATION Cross-contamination is a problem associated with reusable processing equipment,
including bioreactors, piping, valves, and mixers. The individual components of singleuse processing are closed operating systems, protecting products within them and leading to a greatly reduced potential of contamination. Because they are disposable, single-use systems also eliminate the kind of crosscontamination that is associated with reusable equipment that must be cleaned and sterilised before re-use. ALL LEADING TO REDUCED INFRASTRUCTURE COSTS These benefits—flexibility, no cleaning requirement, lower risk of contamination, and lower cost of disposable products— lead to substantial savings in infrastructure costs for manufacturers. Transitioning to single-use systems, or expanding the current use of them, requires partnering with an experienced team that has technical and unit operations expertise—with bioreactors, purification, and chromatography equipment— across all processes from R&D to fill-finish. These specialists provide the knowledge that will customise the scale-up of processes and equipment to maximise efficiency and speed, mitigate risk, and help avoid costly errors. REFERENCES 1 Low costs of dispersible products to drive single-use bioprocessing market
While the shift to SUS has revolutionised bioprocessing and manufacturing facilities, scaling up from discovery and development to fullscale manufacturing can be a challenge for biopharmaceutical manufacturers.
Opinion At the point of market entry, pricing decisions for Covid-19 vaccines are likely to face close scrutiny.
COVID-19: THE REAL PRIZE FOR BIG PHARMA MAY BE REPUTATIONAL BUT THE RISKS ARE HIGH Authors: Adrian Tombling and Dr Nicholas Jones - partners and patent attorneys at Withers & Rogers
The risks pharmaceutical companies are taking in the attempt to develop a vaccine for Covid-19
W
ith dozens of clinical trials progressing around the world, the pharmaceutical companies involved in the search for a vaccine to prevent the spread of Covid-19 will be eyeing their potential prize. However, the direct commercial rewards for being the first to develop an effective treatment could be underwhelming, so should the industry be looking for value elsewhere? Â There are at least 51 vaccines currently under development around the world, and more than 30 of them have reached significant clinical trials. The fact that so many companies are simultaneously investing in the development of different candidates for the same indication may be unprecedented, and is a direct response to the current health emergency. Despite the efforts being made, the commercial rewards for developing a vaccine and
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OPINION
securing regulatory approval are likely to be small. This is mainly due to pressure from governments, some of which have provided funding to research programmes, as well as the World Health Organisation (WHO), which is aiming to ensure equitable access for all. Earlier this year, the WHO launched its COVAX plan, which sets out a ‘fair allocation mechanism’ to distribute the vaccines on a country-by-country basis as soon as they become available. In the first phase, the number of doses given to each country will be proportional to its population, with the first 3% used to protect frontline workers. At a time of heightened global concern about the spread of Covid-19, the pharma industry has responded by waiving certain IP rights and collaborating with competitors to accelerate research programmes, where there is opportunity to do so. Illustrating the depth of the collaboration that is taking place, Sanofi and GSK are currently running clinical trials for a protein-based vaccine and anticipating results in early December. They have also established a supply collaboration with the EU’s COVAX facility and signed a contract to supply member states with up to 300 million doses of its vaccine. At the point of market entry, pricing decisions for Covid-19 vaccines are likely to face close scrutiny. Clearly, the ‘winner’ of the innovation race will be hoping to at least cover their costs. However, setting the right price will involve a complex set of considerations based on the shelf-life of the vaccine, the cost of manufacture, its efficacy and how it will be administered. For example, flu vaccines are typically unstable, biological formulations that need to be administered by injection within a defined time period, which means they have to be produced and distributed regionally. Distributing a vaccine for Covid-19 will probably require a similar approach. While definitive decisions on pricing can’t really be reached until an effective vaccine is found, Sue Middleton, president of the executive board of Vaccines Europe, has recently suggested that a price range of $6-18 per dose is ‘reasonable’ for Covid-19 vaccines.
To avoid a scenario where a pharma company that develops a vaccine for Covid-19 is forced to produce and distribute it at a loss, some protections are urgently needed. For example, the company should at least be able to cover its costs, perhaps based on an agreement that any excess profits are ploughed back into other coronavirus-related research programmes. In addition, pricing decisions taken during the pandemic should be time limited, so there is flexibility to increase prices in the future if necessary. Without these protections, the industry could be facing an uncertain future and some businesses that have invested heavily in coronavirus-related R&D could be rendered unviable. For pharma companies involved in the global race to find a vaccine, the stakes are high – from both a global health and commercial perspective. For those that succeed in bringing a vaccine to market, the rewards are likely to be more reputational initially, although this could bring commercial benefits in the longer term. For those that are forced to drop out of the race however, the commercial costs could be considerable. To remain viable and continue to thrive in the future, pharma companies need to be afforded some protections and their commercial interests must be considered fairly. Much has been done to date to accelerate the search for a vaccine and this must continue. However, it is also becoming apparent that businesses need to spread risk by maintaining a healthy innovation pipeline, which they can pick up once a vaccine is found. A well-managed intellectual property portfolio will be critical to bouncing back profitably when the time comes.
For pharma companies involved in the global race to find a vaccine, the stakes are high.
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14 COVID-19 TECHNOLOGIES MUST BE REGULATED TO AVOID BIGBROTHER SOCIETY
T
echnologies used to help stop the spread of Covid-19 must be regulated to avoid the normalisation of a big-brother-like society, researchers from Durham University Business School have argued. The research draws from the concept of ‘societies of control’, developed by the French philosopher Giles Deleuze, in order to analyse the technologies currently being used to tackle the covid-19 pandemic. The study acknowledges the technologies’ health benefits but states that they must be cross-examined. Dr Jeremy Aroles says, assistant professor, said: “Presented as ways to curb the immediate progression of the pandemic and improve safety, the acceptance and use of these technologies has become the new “normal” for many of us, therefore it is important that these systems of control are heavily vetted and cross-examined before being rolled out to the wider public.”
IN THE NEWS
Expert group launched to advance research into rare diseases
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group of European experts have banded together to advance research into new orphan drugs and therapies for rare diseases. The European Expert Group on Orphan Drug Incentives has been established ahead of the upcoming Pharmaceutical Strategy and ongoing Evaluation of the Orphan Medicinal Products (OMP) Regulation. The group will provide input to the ongoing OMP Regulation Evaluation and is currently working to develop proposals to be unveiled by 2021. The European Expert Group on Orphan Drug Incentives consists of patient alliance EURORDIS and EUCOPE, the
association for small to medium-sized companies in pharma and medtech, as well as experts from academia, patient groups, investors and others. Initially the group will focus on accelerating regulatory pathways, launching new development incentives and addressing therapeutic
areas where there are no treatment options. EURORDIS’ chief executive officer Yann le Cam said: “After two decades of the Orphan Medicinal Products Regulation, we have witnessed great progress as well as important challenges both on development and access to therapies. The new
European Expert Group on Orphan Drug Incentives allows for reflection on rare disease patients’ opportunities for treatments: how can we take stock of progress that has been made over the past two decades, and ensure we move forward at pace so that no one is left behind?’’
The majority of rare diseases are thought to be genetic.
Rare Disease Day takes place on 28 February.
Did you know?
Rare diseases are thought to affect up to 5.9% of the population.
In Europe a rare disease is defined when it affects fewer than 1 in 2,000 people.
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anufacturing tablets to a uniform hardness, weight, and thickness requires tablet press punches of consistent length. Using rotary tablet press punches of consistent length is critical, as their length directly relates to the uniformity of the hardness, weight, and thickness of the compressed tablets. If not correctly understood, tablet defects could be attributed to the wrong source. Thus, it is important to establish a punch inspection and maintenance program that will verify all punch lengths and cups are within dimensional tolerances. WORKING LENGTH The working length of a punch is measured as the distance from the head flat to the lowest measurable area of the punch cup (Figure 1). The figure also illustrates the cup depth and the overall length, which is the distance from the head flat to punch tip. The punch tip comprises the cup and the land, as shown in Figure 2. FIG 1: Cup depth, working length, overall length, and head flat of a tablet press punch.
COVER STORY
FIG 2
Understanding working length leads to consistent overall tablet hardness, weight, and thickness. If the working length varies within a set of tools, then tablet hardness, weight, and thickness also will vary. The working length of punches is engineered to a standard range of 0.002 inch (0.051 mm). Periodically inspect the punches to ensure working lengths do not exceed that tolerance (or the range your company specifies). It is important to inspect the upper punches independent of the lower punches. It is also important to measure correctly. Do not calculate the working length by subtracting the cup depth from the overall length, that method can produce results showing some tools are out of specification when in fact they are not. The working length of the punches should be measured for
deviation from punch to punch rather than from a calculated number and using a digital indicator mouthed on a steel post fixed to a granite base. It’s important to measure from the deepest accessible area of the cup with the tip of the indicator. Once the lowest area of the cup is identified, be sure to measure consistently from there when checking the entire set. Most reputable tooling manufacturers can provide a working-length matching report when they deliver a new set of punches. The matching report pairs each upper punch with a lower punch, from the longest to shortest, and numbers them accordingly. Matched punch sets create the best possible consistency in tablet hardness and thickness, and a matching report offers helpful guidance during press setup. The length of the lower punch is more critical than that of the upper punch. That’s because the length of the lower punch largely determines how uniformly product (granulation) fills and doses in the die. Deviations in the amount of product allowed into the die affect tablet hardness and weight.
Natoli Engineering president, Dale Natoli, explains the importance of understanding punch length and cup depth in regard to punch wear and more.
The length of the lower punch is more critical than that of the upper punch.
CONSIST THE K
STENCY’S E KEY
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CUP DEPTH The cup depth is the distance from the tip edge of the punch to the lowest theoretical point of the cup. The cup determines the configuration and appearance for the tablet faces. The area between the two tablet faces created by the die is called the tablet sidewall (Figure 4). Although the sidewall is generally not inspected or measured, it is critical to tablet appearance and manufacturing. Ideally, the sidewall width will be well proportioned with the overall tablet thickness. A tablet with an excessively thick sidewall creates the perception that the tablet will be uncomfortable to swallow and requires the tablet press to exert greater force to eject the tablet from the die. The width of the sidewall depends on the tablet hardness, weight, and thickness in relation of the cup depth. As the punch tip wears, cup depth decreases and sidewall thickness increases. Thus, when comparing two tablets—made from a shallow-cup punch and a deep-cup—the shallow-cup punch has a thicker sidewall. The wide sidewall of a shallowcup tablet also can cause difficulties during film coating because the tablet may erode at the sharp corner where the shallow-cup radius and the vertical sidewall meet. Most tablet press punches have a cup-depth tolerance of ±0.003 inch (0.076mm), which is published in the Tableting Specification Manual. This ±0.003-inch tolerance is widely accepted by the tablet compression industry and is used by tooling manufacturers worldwide. But while the published tolerance is adequate for most applications, it may be too liberal if manufacturing small-size tablets or too
17
FIG 3: The area between the two tablet faces is called the tablet sidewall.
conservative if manufacturing large-size tablets. To eliminate excessive cupdepth deviation, consider specifying the tolerance as a percentage of the desired cup depth. Cup depth inspection is simple and uses the same basic measuring instruments used to inspect the working length: a digital indicator mounted on a steel post fixed to a granite base. OVERALL LENGTH The overall length is a reference dimension that comprises two or more critical dimensions; the working length and the cup depth. As long as the working length and the cup depth are confirmed to be within the acceptable range, then the overall length will be consistent, and inspection is unnecessary. If your company’s standard operating procedures require inspection of the overall length, use the same basic equipment used to inspect the working length and cup depth. A WORD ABOUT PUNCH WEAR With normal use, punches show the most wear at their tips, which reduces the cup depth. Any wear of the head flat (not as common as punch-tip wear) will further reduce the overall
length, as well as reduce the working length. Head flat wear does not affect cup depth. Wear can also occur at the land (Figure 2), which is the narrow flat area located at the perimeter of the punch tip. The land is subject to abrasion during compression and is commonly the first area of the punch to wear. When the land wears, the tip edge becomes very thin, even razor sharp, sometimes causing a condition referred to as J-hooking (Figure 4). J-hooks normally occur on the upper punch tip and are a common cause of tablet capping and lamination. Polishing the punch using a soft cotton wheel and a polishing compound will remove the J-hook and restore the land. FIG 4: When the land of the punch tip wears, it becomes very thin and may form a J-hook.
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WOMEN IN PHARMA
An inclusive approach to diversity A scientist by training with a PhD in Organic Chemistry, Barbara Morgan is responsible for the CDMO business of Lubrizol Life Science Health (LLS Health). She is passionate about women in leadership and science and is the co-chair for Women in Lubrizol Leadership (WILL). In this series, Barbara discusses key themes around women in the pharma industry and offers advice for aspiring female leaders and their wider teams.
Author: Barbara Morgan, general manager, CDMO services, Lubrizol Life Science Health
D
iversity has taken its rightful place high up on the corporate agenda and many companies strive to achieve it through their recruitment drives and internal programmes. However, supporting diversity in the workplace is not just about ensuring representation. It is about valuing everyone in the business as a unique individual and giving them a voice. To reap the benefits of a diverse workforce, it is essential to have an inclusive environment, where individuals feel they can achieve their potential. There are two vital questions that leaders should consider when discussing diversity and inclusion: what is the true definition of diversity? And, what exactly does inclusion mean when it comes to diversity? Diversity differentiates groups and people from one another; it encompasses a range of factors including race, age, gender, ethnicity, religion, sexual orientation, education, national origin, and disability. A good approach to diversity involves respecting and celebrating what makes people different, in order to empower them. Less visible but equally as important is the diversity of experiences and the diversity of personalities: the internal aspects that make an individual different.
A diverse workforce can only feel empowered and achieve their potential if they operate in an inclusive environment where their needs are listened to, respected, and valued. Inclusion is the glue that holds a diverse workplace together and it takes organisational effort to ensure that this culture is present. Individuals with differing backgrounds must be culturally and socially accepted by their business and they must be equally treated. Being inclusive is about allowing yourself and others to adapt along the way. There are three main questions all employers must ask themselves when addressing inclusivity: • Are we listening to our employees? • Are we acknowledging and celebrating them? • Are we considering their viewpoint when we are making decisions? If employers are listening to and cherishing their employees’ thoughts, feelings, and ideas, then they should start noticing the benefits that a diverse workforce can bring. There are many steps that businesses can take towards being inclusive and ‘unconscious bias training’ is one of them. Unconscious bias is social stereotypes that are
automatic and unintentional but can often unknowingly influence behaviour. For example, some people may display positive bias towards those who they perceive to be highly intelligent or more action-oriented, while anyone outside of those categories is viewed more critically. Unconscious bias training can expose hidden biases and help adjust automatic patterns of thinking and the subsequent actions. Being aware of your unconscious bias is one of the key things you can do. We all have these biases - and it is important to remember that it is bias not prejudice - and by knowing yours you can minimise it. Transparency and trust are other vital steps towards inclusivity. Being aware of your differences, strengths and weaknesses and those of your colleagues is extremely important. I strongly believe that people should always be clear about these so you and your team can build upon each other’s strengths and complement each other in areas where those strengths differ. And to build upon these strengths, it has to be about more than the individual – the focus should be on what we can achieve together building upon the capabilities of the team.
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We all have our natural preferences for working with certain personalities over others, but this is where being mindful of inclusion and diversity is so vital. Oftentimes the best work can be achieved by working with those who think differently, as ideas and imagination go one step further. Of course, it can feel uncomfortable to put yourself in situations where you are speaking directly with people who have very different views. However, always remember that every individual brings a fresh perspective. Once we learn to respect our co-workers as diverse individuals and find
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ways to complement each other’s skills, the power of inclusion and diversity is clear. Speaking from personal experience as a woman in the pharmaceutical industry, Lubrizol is a great example of a company that is committed to developing a diverse team and fostering an inclusive culture. By setting diversity goals, embedding diverse practices into our processes, and enabling access to mentoring and leadership programs, it is helping to ensure that people from diverse backgrounds are given the best possible chance of success. In summary, there are a handful of points that every individual needs to structure into their approach to work, in order to support diversity and inclusion in the workplace. • • •
Be aware of your unconscious bias so you can minimise it. Invest in training and developing your team and make it clear that you expect everyone to seek out alternative points of view. Be transparent with yourself and your colleagues. Celebrate each other’s complementary strengths and build upon those.
Once we learn to respect our co-workers as diverse individuals and find ways to complement each other’s skills, the power of inclusion and diversity is clear.
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LYOPHILISATION
The advances in refrigeration technology that are helping to drive pharma to be more sustainable
I
Driving change
n 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.
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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.
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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.”
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LYOPHILISATION
C
LING OFF Considerations for lyophilisation closure selection and processing to protect moisture-sensitive drug products
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yophilisation 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 KOFLER - manager Technical Customer Support Europe at West Pharmaceutical Services
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LYOPHILISATION
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.
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The importance of temperature stability in clinical environments to prevent drug wastage
Waste Not, Want Not P
harmaceutical 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
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LYOPHILISATION
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?
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CONTAINMENT & CLEANROOMS
Connect 2 Cleanrooms shines a spotlight on the importance of cleanroom design for cell & gene therapy suites.
Shine a light C Author: FIONA KERRproject business development manager at Connect 2 Cleanrooms.
As the innovative therapies market is maturing, the UK is fast turning into a global leader.
ell 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.Â
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ANALYSIS
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
A
s 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
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.
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
OSD SUPPLEMENT
Discussing the latest oral solid dosage challenges and trends with two leading players in the industry.
Quick Questions with John Ross, president at Metrics Contract Services & Maria Lundberg, vice president Product Development at Recipharm. Q: Can you outline the key challenges and growth opportunities that have happened in the OSD market recently? ROSS: The major challenge for the market lies in the misalignment of installed capacity compared with the contemporary needs to produce today’s OSD drug products. Many large-scale installations that were used for producing blockbuster drugs, for example, simply do not fit or fulfil the requirements for producing most new drug products. The rising demand for orphan drugs and personalised medicine requires smaller scale batch sizes. Companies will have to invest substantially to remediate or retrofit legacy equipment
and sites; alternatively, they can choose to work with more niche contract partners. The growth in highly potent active pharmaceutical ingredient (HPAPI) programmes is seeing an increased need for installed contained operations. Regulatory controls concerning HPAPIs have become more stringent, requiring companies to rely on engineering controls rather than simply standard work practices and personal protective equipment (PPE) to keep workers safe. Installing contained equipment, such as isolators, bag-in/bag-out filters and split butterfly valves, requires significant investment. As the number of poorly soluble and poorly bioavailable APIs in development continues to rise, so too do the challenges for formulation scientists trying to develop pharmaceutical dosage forms. It is these qualities that contribute to poor attrition rates of drugs in development, which translates into longer development times to formulate new products and delays in getting them to market. Companies need to invest in installing solutions that enhance
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solubility and bioavailability properties of new drugs; for example, multi-particulate drug delivery, spray drying, hot melt extrusion, and extrusion spheronization. Controlling impurities in APIs and drug products remains a critical issue for the industry. Greater evaluation and understanding of impurities — such as trace metals or nitrosamine — in APIs and drug products can be achieved by installing appropriate analytical instrumentation and expertise. LUNDBERG: While oral solid dose (OSD) products may seem unfashionable compared with the steep increase in new biopharmaceutical products, they remain extremely popular. There are many reasons why OSD forms remain the strongest in the market, most notably for their effectiveness, patient-friendly nature, and ability to extend product lifecycles by implementing extended, controlled, and rapid release formulations. However, there are, of course, many challenges to overcome when developing these different formulations.
OSD SUPPLEMENT
Importantly, advances in formulation technology are aiding patient compliance. One of the main hurdles in the market is ‘user-friendliness’. Oral formulations are user friendly in the sense that swallowing things is natural to humans. However, it is crucial to ensure that swallowing is not unpleasant for the patient, due to the size, taste, or odour of the product. The challenge for OSD products is to maintain their advantage as other dosage forms such as parenteral products advance, leading to increased cost competitiveness and user friendliness.
formulations result in once-a-day dosages, which are particularly helpful to those patients who forget to take their medication or find it difficult to manage dosage frequency. The growth in fixed-dose combinations and reformulations of injectable drugs to oral delivery is also testament to their benefit in enhancing patient compliance and/or patient experience. Mini-tablets have in recent times shown their enormous potential as a patient-friendly drug delivery system, particularly for paediatric populations. These single- or multiple-unit oral dosage forms offer versatility of route of administration across varied patient populations and highly precise dosing options.
Q: Do you think there have been any recent advances in technology that have impacted the quality of the OSD market? ROSS: Oral solid dosage forms still represent the largest (in terms of numbers) and remain the most popular dosage form in the pharmaceutical industry today. They also account for the greatest number of new drug approvals each year.
LUNDBERG: The industry has continued to see growing interest in precision medicine and products that are tailored for smaller groups of patients. One of the most notable advances in technology is 3D printing, which allows for a high degree of individual adaptation of the medicine. However, several issues regarding quality assurance and cost may limit the use of 3D printing in the future.
Several advances in technology are helping drug formulators to bring the benefits of OSD administration to molecules that previously had to be delivered by other means or could not be tolerated well in legacy formulations. There has been an increase in more complex molecules in an attempt to deliver targeted therapies. Developing such molecules with a modified release profile is enabling them to be made into OSD forms.
The most important advances may be less conspicuous. Adapting conventional manufacturing technology, making it more flexible and allowing smaller batches may be particularly useful. Pellet technology and mini-tablets are examples of conventional manufacturing technology that allows a high degree of flexibility as it is easy to combine different pellets and/or mini-tablets to achieve combinations of different drugs in different doses and different release rates.
Importantly, advances in formulation technology are aiding patient compliance. Long-acting
It is likely that in the future, more and more patients will demand
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control over their own medication. Packages and devices that communicate with the likes of smartphones or tablets make it possible to track dosing and increase compliance may also become increasingly common. Q: How has Covid-19 impacted OSD drug development? ROSS: The current coronavirus pandemic has impacted OSD drug development less than the injectable drugs space. It has, however, spurred on the numerous additional OSD therapeutics in consideration for symptomatic relief or accelerated recovery, such as antivirals. Government funding has been far more prevalent for sponsors however such contracts bring additional obligations and requirements. Although the pursuit of non-Covid therapies has remained largely unchanged, clinical trial processes have been adversely affected. For example, the availability of patients and patient monitoring due to social distancing policies have been challenging. In some cases, where funding sources have been affected, drug development programmes have been delayed or even stopped as a corporate cash preservation action. LUNDBERG: The Covid-19 pandemic has had a relatively limited impact on OSD development. Of course, throughout the pandemic there has been a lot of focus on vaccines and parenteral dosage forms. However, that does not change the basic fact that oral administration, in the cases where it is feasible, is the most convenient and economical administration route. While the resulting vaccine is unlikely to be an OSD the medication in circulation to treat secondary symptoms for example, antibiotics, will remain in this format.
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Four key considerations addressing the challenges for oral dosing with minitablet dispensing innovations.
Tough pill to swallow Author: BJØRN KNUD ANDERSEN - director, Front-End Innovation and Head Technology Accelerators and IPR, Phillips-Medisize, a Molex company
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hen it comes to orally dosing solid tablets and/or capsules, certain patient populations such as paediatrics, geriatrics and oncology may find it a tough pill to swallow – quite literally. These patients often need highly flexible oral dosing based on their age, weight, body surface area or other variables. Alternative liquid dosing such as syrups pose some disadvantages, including the need for refrigeration, poor taste (especially for children) and the possibility of microbial contamination.
Minitablets provide an easier to swallow alternative. However, the need to depend on the patient or caregiver’s ability to accurately handle and count the minitablets for the correct dose presents its own set of challenges. Most current systems rely on volumetric measuring principles using a syringe plunger to fill the cavity
with minitablets, which can be imprecise. How can the industry better meet the unique oral dosing needs of these special patient populations? Let’s explore some of the newer evolutions in device design, and where future innovation is headed. Here are four key considerations: 1. ELIMINATE GUESSWORK There should be zero room for error. Newer minitablet dispensing innovations eliminate guesswork and enable patients and caregivers to more
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OSD SUPPLEMENT
In the future, such minitablet dispensing devices have the potential to be part of the growing connected health ecosystem. accurately and reliably administer the exact number of minitablets needed per dose. One example is a dispenser that mounts directly on a standard Ø38 mm tablet bottle neck and can be used with minitablets ranging from ~2.0–2.5 mm diameter. It can be integrated/ co-packaged directly with the bottle or supplied separately to help meet the growing needs of patients who require consistent, customised oral dosing. With the dispenser positioned directly on the bottle, only counted and dispensed minitablets come into contact with the outside environment. The patient simply unscrews the child-resistant bottle cap, mounts the dispenser onto the bottle and repositions the cap. When it’s time to dispense medication, the user inverts the bottle to shake the minitablets into the dispenser metering chamber, which has a transparent lid. The user then turns the bottle back upright and shakes it gently. The correct number of minitablets automatically fall into the indentations on the dosage disc (one per indentation) and the rest shake off and drop back into the bottle. After visually confirming that there’s a minitablet in each hole and therefore the count is correct, the user rotates the transparent metering chamber lid and pours the minitablets onto a spoon, food or other option.
2. MINIMISE CONTAMINATION RISK The risk of contamination is heightened these days and minitablet dispensing innovations can reduce this possibility. The type of dispenser design described earlier helps to avoid situations where the medication could incur unnecessary environmental or surface exposure. It prevents any potential contamination that could occur if patients poured the minitablets into their hand or onto a countertop, counted out the ones needed, and returned the excess back into the bottle. With this design, the user can adjust the dispenser to the desired minitablet count between one and 20. This “set and forget” approach requires the patient to pre-set the dispenser dosing disc only once. However, the setting can easily be changed if the medication dosage needs to be adjusted at any point during treatment. 3. INCORPORATE PATIENTFRIENDLY FEATURES Added design flexibility makes oral dosing dispensers particularly attractive to global pharmaceutical companies who continuously seek new ways to help ensure that patients are adhering to their medication regimens. While pharmaceutical and medical device manufacturers are making positive strides to address unique dosing needs, the industry will benefit from even more innovations that take into account human factors engineering (HFE) early in the design. The features of minitablet dispensing devices must be further validated to test child resistance and senior friendliness, as well as the need to accommodate other tablet dimensions and bottle formats.
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4. INTEGRATE CONNECTIVITY In the future, such minitablet dispensing devices have the potential to be part of the growing connected health ecosystem. Integrating a low-cost connectivity electronics module into the dispenser could make it possible to detect tablet metering, dispensing activity and other patient behaviours – thereby helping to monitor and support medication adherence from afar. This is especially important as remote patient monitoring and telehealth become more popular. CONCLUSION For special patient populations with customised oral dosing needs where minitablets are the best option, innovative dispensers offer a promising solution. Patients and caregivers can experience improved accuracy in counting tiny pills without requiring a new or different bottle. At the same time, the container minimises the risk of contamination. The ability to add connectivity in the future will help encourage medication adherence.
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AN INSIDE LOOK
at AlpVision The company helping to protect pharmaceutical products from counterfeiting.
I
t goes without saying that safety in the pharmaceutical industry is absolutely paramount. Every step of the journey, from drug discovery to formulation, through to packaging and logistics, is done with a common thread in mind: patient safety. As the industry has progressed, so too have the various ways in which medicines are protected throughout the supply chain. One significant area of concern is the rise of counterfeit medicines, which are estimated to cost the pharmaceutical industry €16.5bn every year, also affecting employment levels and not to mention potentially harmful effects on patients.
One company which has entered the market to help protect products from counterfeiting is AlpVision, which has developed a range of digital solutions that are able to detect the authenticity of drugs via a smartphone. The company was founded 19 years ago by Dr. Martin Kutter, Alpvision’s president, and Dr. Fred Jordan, the CEO. “This company is really a dream come true actually, we did not expect it to be so successful,” Jordan says. Like many fledgling companies, AlpVision started off in a garage. That was in 2001, where Dr. Kutter
and Dr. Jordan were trying to establish how technology they’d invented during a PhD could be put into different industries. “We tried to put this technology into many fields in 2001 when we were just trying to make money actually in one way or another. We tried it, essentially randomly in different fields, and one of the fields was product packaging so we use this technology to hide invisible information on printed packaging. This idea worked commercially. All of our other ideas were big failures,” Jordan laughs. The technology AlpVision developed is called Cryptoglyph which consists of a digital, invisible marking that is applied to printed products such as labels and blister packs. The technology works through a series of invisible micro-holes which are embedded into the varnish atop the product’s packaging. These micro-holes create the digital Cryptoglyph which can tell a vendor company whether or not the product they’ve ordered is authentic or not. All a company has to do is use AlpVision’s dedicated app which can scan a pharmaceutical package to provide the authentication. An important point that Dr. Jordan makes is how Cryptoglyph is able to be adapted into current manufacturing lines, meaning that pharmaceutical customers can use
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AN INSIDE
L
K
AN INSIDE LOOK
This company is really a dream come true actually, we did not expect it to be so successful. their standard printing process without having to install or revamp new and existing lines. “So it’s a very easy process. Right now I guess in the world there are over 200 printers which are officially qualified by us to print the Cryptoglyph technology. I’ve never met in 19 years of existence one single printer that was not able to print directly, with their machines, their technology, their varnish, the Cryptoglyph solution,” Dr. Jordan clarifies. The Cryptoglyph technology was invented in 2001 and brought to profitability two years later. By 2007, AlpVision was protecting 1 billion products every year through its technology, something which has only increased as the company has grown, and developed more protective technologies. For instance in 2010, AlpVision invented what it calls Fingerprint technology, a system designed to authenticate vial flip-off tops, bottle closures and other solid and plastic moulded or tooling parts. The interesting thing about ‘Fingerprint’ is that it is designed around plastic parts which already includes an anticounterfeiting feature – that is the microstructures of the plastic. What this means is that pharmaceutical products which use moulded plastic parts can be authenticated due to having the same microstructure in the plastic when viewed through a microscope.
With no changes required to manufacturers' moulding practices, AlpVision Fingerprint captures a digital image of a matte-finished surface, storing that image in a database which can then be used as a reference point for product authentication. “This means that if you take one single reference from it, with a smartphone, you can check the authenticity of millions of other plastic parts,” Dr. Jordan says. Whilst AlpVision works across a number of industries, Dr. Jordan tells me how pharma is the industry which provides the most revenue for the company, something which makes sense considering the sector’s safety requirements and regulations. As a technology company, AlpVision has had to get used to working within pharma’s strict regulatory requirements, particularly the Good Automated Manufacturing Practice (GAMP) guidelines, which means that any software a company produces for pharma has to be appropriate for its intended use. As an industry overall, pharma can be particularly
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slow-moving when it comes to the adoption of new technologies, but Dr. Jordan doesn’t think this is due to regulation. “A pharma company is not built like other companies. In pharma companies you have a lot of people who are dedicated to quality and checking regulations, so it’s a very complex, hierarchical organisation. So a decision like changing all the packages is going to touch many people throughout the company,” Dr. Jordan says. With pharma being such a complex industry to work in, AlpVision has had to get used to how to operate within its parameters, and flexibility has been the key to this, Dr. Jordan explains. “The IT organisation of the pharmaceutical sector is always complex and AlpVision learned how to adapt to each one, so that it can integrate seamlessly in existing architecture. From a software architecture perspective, flexibility is key.” *Cryptoglyph and Fingerprint are technologies under copyright by AlpVision.
Can Pfizer offer API supply and CDMO services?
Yes, we do. Collaborate with Pfizer CentreOne. And access our manufacturing network for your API and finished dosage form needs.
Welcome to Pfizer CentreOne. We’re a global CDMO embedded within Pfizer and a leading supplier of specialty APIs. Backed by Pfizer resources, we deliver technical expertise, global regulatory support and long-term supply. For more than 40 years, we’ve been guiding complex compounds securely and eciently from development through commercial manufacture.
APIs & Intermediates. As a leading provider of specialty APIs, you can count on us to deliver you a high-quality molecule over the long-term.
Small Molecule APIs. We specialize in small molecule API synthesis. We can perform almost any kind of chemistry you need.
Listening. Solving. Guiding.
Oral Solids.
Working together with our customers, we combine our knowledge with open dialogue to solve challenges.
We have integrated cGMP pilot facilities dedicated to formulation / process optimization, clinical drug manufacturing, and scale-up technology transfers. We also oer commercial manufacturing for global / large-volume solid forms production.
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Sterile Injectables. Access Pfizer’s global sites and experts, ready to support your sterile injectable’s toughest go-to-market challenges.
Development Services. We offer full process development and optimization, including formulation, manufacturing, analytical testing, validation and method development.
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SPONSORED CONTENT
Contec ReFIBETM: a recycled polyester cleanroom wipe providing a sustainability story in a single-use world.
“REDUCE, REUSE, RECYCLE” is not just a concept; it is critical to the future of our planet. Much of the waste we generate is single-use plastic and since 1950, when plastic started to be used once and thrown away, over 6.3 billion tonnes of plastic waste has been generated.1 Of this, only 20 percent gets recycled or incinerated, with the rest ending up in landfill or oceans.1 Plastic Oceans International estimate that at least eight million tonnes of plastic ends up in oceans each year.2 Three hundred million tonnes of plastic are still being produced each year and more than 500 billion plastic water bottles are being used. In the US, 57.3 billion plastic water bottles were sold in 2014 – an increase from 3.8 billion in 1996.2 In the UK, an estimated 7.7 billion plastic beverage bottles are used each year and 700,000 plastic bottles are littered every day.3 These plastic bottles have an estimated life span of 450 years.4 Companies are becoming more aware of their environmental impact, especially multi-nationals, and are trying to incorporate sustainable business practices. Pharmaceutical companies are increasingly making public statements of sustainability and in Corporate Knights’ annual list of the world’s 100 most sustainable corporations, seven biopharmaceutical companies made the list in 2020: Sanofi, AstraZeneca, Takeda, Novo
GOING GREEN IN THE CLEANROOM Authors: KAREN ROSSINGTON and AMY RUSS - Contec, Inc. Nordisk, UCB, Merck and GSK.5 Sustainability in a cleanroom Being sustainable in critical and cleanroom manufacturing environments presents a challenge; not only because there are high energy costs involved in running cleanrooms, but the concept of reduce, reuse and recycle is difficult to put into practice. Cleanrooms use consumable products that cannot be recycled because of the ingredients they contain or because they have been contaminated with hazardous materials. For example, protected trigger spray bottles can neither be manufactured from recycled materials nor be recycled. One option cleanroom users could consider to reduce the amount of single-use contamination control materials used is to launder and resterilise them. This is not a new concept; gowns and garments
are regularly laundered and reused. However, there are risks associated with this option for wipes and mops used in highgrade areas. Relaundering cleanroom consumables Best practice for both wipes and mops in a cleanroom environment is to use single-use disposable products. This reduces the risk of cross contamination and ensures that contamination is physically removed from the cleanroom environment at the end of
a session. However, many facilities are considering laundering and reusing mops to reduce costs and provide a more sustainable alternative to single-use disposable products. Since disposable mops are made from new materials and follow a validated process, their performance and results are consistent and predictable. This remains constant even over a long period of time, as a new mop with the same parameters is used each time. Studies show that the effect of relaundering a mop can lead to the performance and quality changing over time due to inevitable degradation.6 The laundry process can cause irreversible damage to the delicate structures of the wipe or mop. When evaluating a reusable mop, it is necessary to project the performance and quality over time to estimate the life cycle and therefore related costs. As the actual quality, contamination profile and performance of reusable mops will change over time, such deviation could result in unintended and potentially unacceptable risk to the customer’s environment and the
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removing any doubt of quality being compromised for sustainability.
product they produce. From waste to cleanroom wipe There is now another way to be sustainable in a cleanroom; knitted cleanroom wipes, which are manufactured from polyester (polyethylene terephthalate - PET). Plastic beverage bottles are also made from PET and products made from rPET (recycled polyester from post-consumer plastic bottles) are becoming more prevalent in high end clothing brands, such as Patagonia, Fatface, Nike, O’Neil and Under Amour. So why not cleanroom wipes? Contec is excited to introduce the ReFIBE™ brand of wipes – the first of its kind. Made from recycled plastic water bottles, these wipes are made from 100 percent knitted standard weight polyester with heat sealed edges. These are ideal for cleanroom environments, with the additional benefit that they stop 35 plastic bottles
per pack going to landfill or polluting our oceans; therefore, a case of wipes saves up to 840 bottles from contributing to environmental pollution. Incorporating sustainability into the upstream wipe manufacturing process means ReFIBE reliably provides a sustainable single-use option for critical environment manufacturers without jeopardising quality or performance. The wipes are exceptionally clean, low in releasable particles and fibres and are compatible with a wide range of cleanroom solutions and disinfectants. These wipes can be used in place of traditional polyester wipes; and like Contec’s standard polyester wipes, they have been laundered and packaged in an ISO 4 cleanroom. ReFIBE wipes are subject to the same quality and process control protocols as virgin polyester products,
There are multiple steps taken to make ReFIBE wipes. 1. Recycled plastic bottles are collected. 2. They are then chopped into flake and cleaned. 3. The bottle flake is melted, filtered and formed into chips. 4. The chips are melted and made into yarn. 5. The yarn is then knitted, cut and laundered to manufacture ReFIBE wipes. Sustainable options for cleanroom manufacturers are not without challenges and not all “green” initiatives pass the risk assessment for cleanroom use, certainly in higher grade cleanrooms. A facility will need to perform thorough research and risk assessments to evaluate all possible outcomes before embarking on green initiatives such as relaundering. However, all companies must strive to do more to reduce their environmental impact and the use of cleanroom wipes manufactured from postconsumer plastic is a small step towards this. Every step, big or small, can help.
For more information visit www.contecinc.com/refibe/ or to request a sample please email infoeu@contecinc.com
REFERENCES 1 Production, use, and fate of all plastics ever made. Science Advances 19 Jul 2017 Vol. 3, no. 7 Roland Gyer, Jenna Jambek and Kara Law 2 Plastic Oceans International A Plastic Ocean – Education & Discussion Guide 3 www.parliment.co.uk. 2 Plastic Bottle Waste in the UK 4 The stark truth about how long your plastic footprint will last on the planet. The Telegraph 10 January 2018 5 2020 Global 100 ranking Corporate Knights 2020 Report 6 Contec White Paper 2017 Clinical Advantages of Disposable Microfiber Mops David J. Flynn, Peter K. Kang, Ph.D, Mark Wiencek, Ph.D.
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TESTING & INSPECTION
MAKE OR BREAK The factors that make or break a successful compliant method transfer.
M Author: WILLIAM E. WEISER - senior director, Global Quality Systems, Pharma Services at Thermo Fisher Scientific
ethod transfer is a vital process in pharmaceutical manufacturing, as scientists transfer methods between instruments that may be in different laboratories, sites or even organisations. However, successful liquid chromatography (LC) analytical method transfer can be a complex undertaking, particularly when transitioning from legacy to modern instrumentation. Deviations in instrument parameters can lead to difficulties in validating the method on the receiving instrument. Consequently, scientists in pharmaceutical manufacturing laboratories need to fine-tune multiple variables to obtain reproducibility and compliance, which often requires significant time and resource. Inefficient method transfers can represent a significant drain on productivity, given that pharmaceutical manufacturers may perform hundreds of method transfers every year. From a regulatory perspective, this process is being increasingly monitored and is a crucial consideration for manufacturers to stay compliant. THE RIGOUR: START STRONG WITH DETAILED DOCUMENTATION There are a variety of scenarios in which method transfer is required in pharmaceutical manufacturing. An analytical development laboratory that has created a method may need to transfer it to a receiving QA/QC laboratory, in some cases, on a different site; alternatively, a pharmaceutical analytical services contract laboratory might receive methods developed by customers. In every circumstance, at the
core of a robust method transfer is ensuring a seamless transition between the transferring and receiving laboratory. This is also important from a regulatory perspective; producing the method lineage from validation through release testing is a regulatory requirement across the world. To maintain the appropriate documentation, it is valuable to understand the requirements of pre-approval inspections and general inspections, particularly as failure to pass these audits can delay drug development timelines in the first instance and even result in warnings for the laboratory, such as the FDA Form 483, blackmarking the facility. Of equal importance, clear and thorough documentation with background information makes it much easier for the receiving laboratory to plan and execute a method transfer. If the transferring laboratory provides an abundance of detail, including highly defined system suitability criteria, the process can be completed much more easily. Where possible, strong communication between the laboratories is likely to result in a simpler, faster transfer, saving time and resource for the receiving laboratory, as well as reducing the likelihood that the transferring laboratory will need to provide support later in the process. THE BASICS: HAVE A DEEP UNDERSTANDING OF CHROMATOGRAPHIC PRINCIPLES Adjusting instrument parameters can be a highly complex process for scientists. However, trying to match settings is less about negotiating vendor-specific features and more about
understanding the underlying mechanism affecting analytical separation. For instance, disparities such as non-matching retention times may be caused by a range of factors, from different gradient delay volumes to column thermostatting principles. With a deep understanding of the basic working principles of chromatography, scientists can take a more informed approach towards troubleshooting and adjusting parameters. This also reflects regulators’ growing focus on the performance characteristics underpinning analytical methods. Regulatory agencies in the USA and EU now require analytical quality by design (AQED), to create wellunderstood, fit for purpose and robust methods. Key performance characteristics include: • Accuracy: The closeness of test results to the true value.
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• Detectability: The ability to ensure low level impurities and degradation products are detected and quantified. • Linearity: The ability to elicit test results that are directly proportional to the concentration of analyte in samples. • Limit of Detection/ Quantitation: The ability to reliably detect and/or quantify impurities at the required regulatory limits. • Robustness: The capacity to remain unaffected by small but deliberate variations in procedural parameters. A deeper understanding of chromatography will also enable scientists to prepare for further regulatory developments, helping to futureproof the laboratory as well as supporting method transfer today. THE TECHNOLOGY: CHOOSE HIGH-PERFORMING INSTRUMENTS The instruments involved are another influential factor in a successful method transfer. For
instance, legacy LC instruments might not offer the flexibility to adjust parameters effectively. Given the importance of reliability and repeatability, using outdated technology that cannot maintain consistency between consecutive runs risks pushing the method towards the edge of failure. High-quality, reliable instrumentation minimises technology-related artifacts. Using instruments that provide parameter flexibility to modify and match experimental conditions can streamline method transfer. With customisable features, scientists can match instrument settings more easily. For example, gradient delay volumes can be affected by the design and mixing behaviour of pumping systems. A tuneable system can physically match the gradient delay volume of the original system, improving consistency and transferability across instruments. Additionally, system dispersion effects will be impacted by the proximity of the column to the detector as well as the size (ID) and length of connective tubing. A custom injection program can be utilised to overcome
these artifacts, matching the behaviour of the origin and new system. In addition to delivering greater flexibility, modern analytical instruments are integrated with real-time feedback capabilities that immediately communicate any failures or errors to either abort runs or troubleshoot. Systems can deliver warning notifications when results do not match method acceptance criteria. These tools also maintain comprehensive records that are useful when transferring methods and support full audit trails. Modern detectors, that provide an improved signalto-noise ratio, will also support a wide range of quantitation with better sensitivity. Comprehensive detector capabilities ensure that the protocol works for a diverse range of samples in the receiving laboratory. Altogether, with high performing instruments, reproducibility is better optimised, enabling scientists to spend less time troubleshooting and more time focusing on more value-added activities. THE OUTLOOK: DEVELOP A ROBUST PLAN AND STAY UPDATED Taking a robust approach to the method transfer process can enable pharmaceutical manufacturers to minimise unexpected issues. That means performing method transfers in conditions that are as realistic
41 as possible, instead of using artificial or synthetic samples as a ‘best case scenario’, which can pose significant challenges when the actual method is run with real samples. Equally, schedules should factor in workflow hiccups and unexpected problems, allowing sufficient time for troubleshooting when needed. Looking ahead, it is important for scientists to remain updated on the latest principles of method transfer. Examining the guidelines provided by regulatory agencies will enable organisations to learn from best practices, while reading warning letters relating to unacceptable documentation and negative audits provides details on poor practices. CONCLUSION In summary, to complete a successful and compliant method transfer, laboratories benefit from a rigorous approach to documentation, a detailed understanding of chromatography and highperforming technology that has been designed with ease-ofuse, reliability and robustness in mind. By pursuing best practice in method transfers today, laboratories can improve their performance and prepare for success as regulations evolve further. Ultimately, more streamlined method transfers can reduce the risk of delays to pharmaceutical manufacturing, ensuring that organisations can provide therapeutics for patients as planned.
In every circumstance, at the core of a robust method transfer is ensuring a seamless transition between the transferring and receiving laboratory.
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Talking points
OUTSIDE EPM
PHARMA LEADERS SIGN UP TO UK ONCOLOGY COLLABORATION
Sanofi & GSK sign up to Covid-19 distribution scheme
P
harmaceutical companies Sanofi and GSK will make 200 million doses of their Covid-19 vaccine available to a global procurement scheme. The companies have signed a Statement of Intent with Gavi to supply the vaccine to the Covax Facility – a global risksharing mechanism designed to equitably distribute eventual Covid-19 vaccines. Sanofi and GSK will make 200 million doses of their Covid-19 vaccine available to the Covax Facility, if it is approved by regulatory authorities. The Covax Facility was set up between the World Health Organisation (WHO), the Coalition for Epidemic Preparedness Innovations (CEPI) and Gavi, in an effort to “ensure fair allocation of vaccine supply”. The collaboration hopes to be able fund 2 billion doses of Covid-19 vaccines by 2021. Sanofi and GSK have initiated a Phase 1/2 study of their adjuvanted Covid-19 vaccine which includes a total of 440 volunteers. The companies expect the first results in December and are aiming to initiate a Phase 3 study before the end of the year.
A
collaboration between some of the biggest names in UK cancer research and four global pharmaceutical companies is hoping to bring forward innovations that could improve patient care. Led by Bruntwood SciTech with funding from Innovate UK and Cancer Research UK, the Oncology Development Programme at Alderley Park is aiming to develop an entrepreneurial culture amongst cancer researchers in the UK. Its ultimate goal is to bring forward commercial ideas to market more quickly, working with funding or collaborators that can increase their likelihood of success. Pharmaceutical companies AstraZeneca, Johnson & Johnson Innovation, GlaxoSmithKline and Roche will work alongside The Christie NHS Foundation Trust, Medicines Discovery Catapult and the Manchester Cancer Research Centre to support researchers and start-ups aiming to develop early-stage innovations. The delivery partner for the programme, Medicines
Discovery Catapult, will work with participating researchers and start-ups on their projects to help improve their likelihood of attracting future investment. Participants that progress through the programme will receive up to £60,000 of grant funding to support the development of their business plans, including provision for salary replacement. They will also receive support to develop an optional ‘virtual R&D’ business model, provided by the Medicines Discovery Catapult, without the need to establish a research laboratory. Tony Hickson, Cancer Research UK’s chief business officer, said: “We’re delighted to see this programme come to fruition as part of our Entrepreneurial Programmes Initiative. At the end of the day, we want to bring new, potentially lifesaving treatments to patients. Our initiative aims to drive entrepreneurship among cancer researchers and encourage innovation at the interface of academia and industry that can help bring ideas from bench to bedside.”
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ed-Tech Innovation News editor Ian Bolland speaks to Dr Tim Ringrose from digital health company Cognitant about its immersive technology platform that is designed to improve consultations between clinicians and their patients. Make sure to read the full article on www.med-technews.com
BE SURE TO READ
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PM speaks to Dr Sarah Halford, head of Medical Sciences, Cancer Research UK Centre for Drug Development about its efforts to expedite a clinical trial for an antiviral which could help fight Covid-19.
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Our biosafety testing laboratory provides testing support for the biosafety and characterization of raw materials, cell bank and virus seeds for vaccines, cell and gene therapies, monoclonal antibodies and other recombinant protein based biological medicines, including a vaccine testing solution for coronavirus.
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We provide established expertise and resources for all aspects of biopharmaceuticals characterization – from physico-chemical properties, to primary, secondary, and tertiary structures, as well as aggregation. Our characterization services include antibody testing and batch release testing for large number of doses. Our GLP/GCP compliant laboratories offer the expertise to both develop assays from scratch (including LC-MS/MS, immunoassays and cell-based assays). We support large-scale routine sample analyses, from regulatory pre-clinical (toxicology) to early and late clinical studies (Phase I to IV).
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