CPHI PHARMA 2021 REPORT: POST PANDEMIC LEGACY TRENDS - PLUS EXPERT VIEWS ON EXCIPIENTS, CONTINUOUS MANUFACTURING AND BLOCKCHAIN
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CPhI Pharma 2021 Report:
Post Pandemic Legacy
Trends
Plus expert views on excipients, continuous manufacturing and blockchain
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Contents
Introduction
This special CPhI Report is split into two halves featuring an expert roundtable,
global survey data analysis, and detailed expert contributions. In Part one
there is an in-depth write-up of the recent Post-Pandemic Roundtable, as well
as analysis of the CPhI executive survey data on ‘opportunities in the latter half
of 2021 and implications for pharma manufacturing’. Part two includes three
expert contributions on ‘the implications of QbD for excipients’, ‘Blockchain in
Pharma Trends’, and ‘Crystal Ball Predictions for Pharma in 2025’.
Part 1.
Post-Pandemic Trends Roundtable..............................................................................................................................................5
CPHI CONTENT TEAM
Perspectives on Pharma in 2021: Executive Survey............................................................................................................ 13
CPHI CONTENT TEAM
Part 2.
We are pleased to present a technical analysis from Brian Carlin and
collaborators reviewing the implications for excipients of IPEC Federation
guidelines on ‘Incorporation of Pharmaceutical Excipients into Product
Development using Quality-by-Design’ (published November 2020).
How to incorporate excipients into QbD studies for product
development and lifecycle management.............................................................................................................................. 19
BRIAN CARLIN, DFE PHARMA; CHRIS MORETON, FINNBRIT CONSULTING; DAVE SCHONEKER, BLACK DIAMOND
CONSULTING; KATHERINE ULMAN, KLU CONSULTING; JOSEPH ZELEZNIK, IMCD
The ‘eureka moment’ for pharma – Blockchain to be integral to every
therapy delivery in just 3-years ................................................................................................................................................. 32
RAJA SHARIF, CEO, FARMATRUST
Crystal Ball Predictions for Pharma in 2025........................................................................................................................... 37
EMIL W. CIURCZAK, PRESIDENT, DORAMAXX CONSULTING
Produced by Defacto
CPhI Pharma 2021 Report 3 Post Pandemic Legacy Trends
Part 1. Post-Pandemic Trends Roundtable
Authors
CPhI Content Team
Post Pandemic Trends Roundtable
Introduction
At the start of this year (January 2021) we spoke with a Our panel consists of:
range of experts from across the industry in a series of • Bikash Chatterjee, Chief Executive Officer for
special roundtable podcasts to explore what are likely Pharmatech Associates
potential opportunities in a post-vaccinated world in the • Parrish Galliher, Managing Director, BioProcess
latter half of 2021 and into 2022. In particular, we wanted Technology Group, a division of BDO USA
insights on what new discoveries and technologies might • Valdas Jurkauskas, PhD, VP Technical Operations at
offer the best potential, the approvals we might see in the Black Diamond Therapeutics
next few years, and what might be the long-term positive
Covid legacies – from speed of innovation and clinical The key question: will the world resume to the pre-
trials, to proprietary information exchange and the global pandemic strength?’ – with biologics, and oncology
supply chain. seeing the greatest growth – alongside continuous
manufacturing, digital health applications and AI as the
The experts we spoke to cover perspectives from the predominate new technologies adopted by industry?
innovators themselves, CROs, biotech consultants, and
analysts that specialise in the contract services.
Legacy trends accelerate by Covid
In fact, according to our experts many of the changes impossible. It’s often under-reported and appreciated, but
we discussed were already underway within the industry one of the key drivers behind the rapid development of
prior to the Covid outbreak. The pandemic has acted as a Covid vaccines has been the global exchange of ideas.
catalyst to accelerate adoption of these by two, three or Everything from the sequencing of the virus’ genome back
in some cases up to five years. One of the most notable of in the early part of the year to vital patient data from trials
these is how the industry has embraced digital technology and new therapeutic applications like RNA – all of which
to ease the logistics burden of clinical trials (which for was underpinned by a level of proprietary exchange that
a period ground to a halt) and how it has accelerated would have been unthinkable pre-Covid. Yet, with what
drug development timelines in ways previously thought has been accomplished in under a year, it does have many
CPhI Pharma 2021 Report 5 Post Pandemic Legacy Trends
in the industry thinking about the long-term benefits “One of the positives to come out of the back of 2020
of continued open access R&D. Is 2021 the start of a and moving forwards into 2021 is that intellectual
revolution in thinking amongst the industry and academia property is able to flow more globally, more quickly,
in how we approach the discovery, development and and with less boundaries. R&D data was shared in a way,
commercialisation of new therapies? as a result of pandemic, that we have not seen before
and I believe it’s something pharma will look to expand
upon in the future both in strategic collaborations and
informally in groups,” commented Chatterjee
What is in store for 2021?
Looking ahead it’s clear that a combination of strong year has proved we can move increasingly to remote
tailwinds bode extremely well for the industry in the latter and decentralised trials, but it does mean there is now
half of 2021 and into early next year. Pharma’s reputation additional importance placed on early-stage trial design,
amongst both the wider public and governments is planning, and contingencies. As an industry, it also means
perhaps at an all-time high. This, coupled with underused we can run more trials at once and even at potentially
VC capital that was put on hold in much of 2020, and a lower costs. But with every benefit comes slightly different
new wave of biotech innovations accelerated by lower challenges. So the experience of the CRO and, project
cost and more accessible technology is creating a super- managers in particular, has never been more important.
charged innovation environment. And that is before we Innovators need to look not just at the name and size of a
factor in the vital lessons that have been leant as a result of CRO partner, but at the experience, dedication and even
the pandemic including the success of decentralised trials, turnover of their actual trial teams.”
and remote patient monitoring and data collection. The
irony is that many of the trials that suffered most during In fact, Chatterjee sees a wider benefit in terms of opening-
the pandemic – oncology trials for rare diseases – are likely up research for patients into many new areas, that haven’t
to be the biggest long-term beneficiaries of retaining new been seen as cost-effective trial options. He added:
approaches. These trials are well-known to have extremally “Getting the patient to the site, and keeping them at the
poor patient recruitment and retention, due to the wide site is very difficult with rare diseases and cell and gene
geographic spread needed to find patients. Thus, anything therapies, as people are so spread out. Decentralised trials
that aids their recruitment or even lowers the overall cost are potentially a huge change in how we undertake trials.
of recruitment will accelerate time to market for therapies. It means more rare disease research, and not just in the
high margin areas of oncology, can now take place. In the
For the CROs running the trials, undoubtedly one of the past, many prospering targets were discounted for fear
biggest logistical hurdles is monitoring patients; sick their development cost will be too high, so lots of these
patients travelling large distances to specialists centres innovations will come back into the consideration for
is clearly very challenging. A CRO insider - a senior VP development.”
from a top ten global CRO - added: commented: “this
What will be the hottest areas of biotech research this time next year?
Our experts pointed to the validation achieved by both “While they are now known for vaccines, the biggest
mRNA vaccines [Moderna and Pfizer] as a watershed moment potential applications for RNA platform technologies lie
– not just in the fight against Covid – but more broadly in in other areas, notably oncology and genetic disease.
bringing these new platform technologies forward and they The only potential question in terms of development of
see uses across many therapeutic indications. course, is can they be made in a cost-effective manner,
CPhI Pharma 2021 Report 6 Post Pandemic Legacy Trends
as obviously the vaccines rightly had tremendous Growth in the advanced therapy space is being
government backing and this helped keep the unit cost expeditated by lower cost trials, but also, by new genomics
down,” added Chatterjee. and diagnostics. Patients over the next five years are
predicted to be diagnosed far earlier and have specialised
In terms of RNA technologies, this year has given both diagnostic tools to identify the best therapies for the
Moderna and Pfizer a tremendous validation of their disease pathway’s unique biology.
platforms. Our experts expect that these technology
platforms will now be used in other indications and “Globally genomics is delivering a remarkable pace of
the only potential drag on growth is whether they can innovation – one only need look at the mere week it took
continue to be made in a cost-effective manner. One of the China’s scientists to sequence Covid – with AI also bringing
interesting aspects they highlighted about RNA platforms potentially step change improvements in early-stage
is that companies like Moderna always suggested that work. It means chemistry services and early discovery will
they would be able to commercialise products much more be less reliant on PhDs – work that is often conducted
quickly than previously thought. What COVID has done is on the other side of the world (in China and India) to
validate this approach on a massive scale. the sponsors – and even small companies can explore
advancing more potential targets simultaneously. In fact,
Parrish Galliher Managing Director, BioProcess Technology many commentators expect FDA approvals of more than
Group, a division of BDO USA, added: “The past year has 100 targets per year to become commonplace within the
been really quite remarkable and the approved mRNA next decade”, added Chatterjee.
vaccines have really opened the door to the potential
of other treatments using the same approach.” Another factor that will accelerate activity in the latter half
of this year is that a lot of investment decisions were put
Personalised medicine is another major growth area on hold in 2020 and there is a lot of ‘pent-up liquid capital’
especially as the industry adapts and learns how to scale- available. So the panel predict increased investment into
up – not out – therapies. In fact, there are more than 100 in personalised medicine particularly as these medicines
late-stage development and our experts foresee at least 10 become more cost effective as therapies move to scale-up
approvals per year from 2022 onwards. process rather than scale out.
How hot is the investment community and where are funds going?
One of the interesting things to emerge in the latter half of in the previous eight years combined (3576 in 2012-2019).
2020 is that preclinical and very early-stage companies are The implications of this are profound for the next few years,
running for IPOs earlier, and at much larger valuations than and not just for patients, as contract services, CROs and
we might have seen in the past. What’s more the post IPO many of the companies that attend at CPhI Worldwide take
valuations are in general rising at a staggering pace. centre stage.
Condition Mar-Jun 2020 compared Jul-Dec2020 compared
Dr. Valdas Jurkauskas, VP, Technical Operations at Black to March-June 2019 to July-December 20 19
Diamond Therapeutics, wrote a comprehensive historical CV disease -16% +39%
evaluation of the role pandemics play in stimulating Stroke -64% +34%
drug discovery innovation earlier last year in STATNews. COPD -38% +70%
To build on this idea, he looked in January 2021 at the Resp. infection +567% +484%
how many new products are entering trials, from which Lung cancer -5% +40%
sizes of companies, and for what indications. His findings Diabetes -19% +73%
showed that during the middle of 2020 there was a notable Alzheimer’s -35% +100%
acceleration of investigational new drug applications. The Data compiled by Valdas Jurkauskas, PhD, VP Technical Operations at Black
Diamond Therapeutics: At the start of COVID-19 pandemic, April through June
FDA received 3806 in April-June 2020, which is more than in 2020, we witnessed 5-64% reduction in clinical studies for six of the seven
CPhI Pharma 2021 Report 7 Post Pandemic Legacy Trendsleading causes of death. However, history repeated itself and an avalanche of experience, will we start to see problems and potentially
innovation shortly followed: there was a 34-100% increase in clinical studies in
July through September in 2020 when compared to the same period in 2019
even a rise in ‘rescue studies’. The latter is often the case
(source: data from Clinical.Trials.gov) when perhaps a very large CRO is partnered with a much
smaller customer. The conversations we are having suggest
“First, if we look at the numbers of studies, they are that many biotechs are looking for specialist expertise in
significantly higher than what we’ve seen before. Secondly, yes oncology and rare disease again. But also, in other areas
in 2020, accelerated development became a new norm like CNS and we have started trials for ALS, Huntington’s
for pharma. Now, if we put the two together, we see disease and Guillain Barre Syndrome amongst others in
large volumes of studies and the majority of them are the last year. In fact, there is expanding competition for
on accelerated regulatory pathways. So, we now see experienced CROs in these rare disease areas and what
large volumes of studies and the majority of them are on we now anticipate is that – unusually – mid and small size
accelerated regulatory pathways. How fast can the CDMOs sponsors are going to have to compete amongst each
and CROs expand? Another aspect of the situation is how other to partner with CROs. Rather than simply outsourcing
the studies progress. For example, preclinical companies services. It’s going to drive big changes in the next two to
start phase 1 studies, which are not large studies. They three years, as access to the best sites and expertise will
involve few subjects and the durations are not long. ensure who advances fastest”, commented a CRO insider.
I’m seeing more instances where phase 2 studies yield
statistically significant results and address the unmet
medical needs. These studies become pivotal and market There is remarkable buoyancy in biotech,
application-enabling, obviating phase 3 studies – which particularly and unusually among much
would require hundreds and hundreds of patients. The
industry has been focused on developing drugs to address
younger companies, suggesting the
unmet needs, and thus, many programs enjoy accelerated market is currently more confident and
regulatory reviews and approvals. This means we quickly comfortable with risk
see a massive jump in scale because there’s this aspiration
to file an application in phase 2. Therefore, the increase of
services demand is very rapid from phase 1 to phase 2.”, But these additional pressures should be eased for some
added Jurkauskas. by higher levels of financial resources. For example, many
of the biotechs that underwent IPOs in the last year have
This too has consequential potential pinch-points for done so at record levels of investment, and this should
accelerated development timelines, namely, access to empower them with liquidity to bring in senior personel
suitable CRO and CDMO resources. For the CROs, especially earlier and hasten development timelines. In fact, Valdas
in the case of rare diseases, sponsors are going to be highlighted remarkable buoyancy in biotech, particularly
able to secure partners with enough experience, and/ and unusually among much younger companies,
or capacity at a senior level to ensure both its integrity of suggesting the market is currently more confident and
design and expeditious nature of delivery. comfortable with risk. In fact, of the 71 companies that filed
for an IPO in 2020, some 21 were at the pre-clinical stage,
“I don’t think sponsors will have too much trouble getting with a further 26 in phase 1 development. Yet this alone
CROs to take the work off them in the early stages. But is not the most startling filing, as already these preclinical
as resources become tight, especially for those smaller companies have seen staggering growth in terms of
pharma companies with less in-house regulatory trial market capitalisation.
Summary of investment in biotechs from 2020
[Data compiled by Valdas Jurkauskas, PhD, VP Technical – Primary indication of company involved in IPO cancer
Operations at Black Diamond Therapeutics]: (40), rare diseases (17), immune diseases (9) and
• Number of biotech IPOs in 2020: 71 infectious diseases (8).
CPhI Pharma 2021 Report 8 Post Pandemic Legacy Trends– Stage of development: Early-stage development The biggest bottlenecks, in Jurkauskas view, are moving
companies dominated the biotech IPOs, 66% of total, away from whether therapies can be funded and whether
in 2020 with 21 IPOs for preclinical stage and 26 IPOs we have the technologies and knowledge to advance them
for phase 1 clinical stage companies into the realms of whether enough service companies
• Timings of IPO: During the first three months of the meet the demand. “CROs are extremely busy and CMOs are
pandemic (March through May, 2020) there were only at capacity in some instances. I think the opportunity for
6 IPOs amounting to $0.779 billion, a lowly 5% of yearly CROs and CMOs to grow is incredible. Will they grow and
proceeds. However, there was a tsunami of IPOs in the reinvest in their capacities and capabilities? The challenge
subsequent three months (June through August): 30 is not only to enlarge equipment capacity to make more
IPOs amounting to $7.903 billion, a spectacular 54% of drugs, but also, to diversify equipment and a set of skills
total proceeds in 2020 to address the need for large molecules, antibody drug
• Cumulative valuations at time of IPO: $14.748 billion conjugates, Cell therapies and personalised medicines. The
• The preclinical development companies enjoyed question for both CROs and CDMOs is whether to remain
more than ten-fold difference between their market very focused on one area or expand and grow with the
capitalizations in mid-January of 2021 ($41.7 billion) and industry, because right now there is an avalanche of clinical
the total proceeds at the time of their IPOs in 2020 ($4.0 trials. My instinct is that the constraints will first come
billion) (source: data from biopharmadive.com) in terms of people – which will drive wages higher and
mobility - but then also facilities.”
“The total proceeds for all preclinical companies in 2020
was $4 billion at the time of IPOs. Yet as of mid-January The crisis in the biologics pipeline could be particularly
[2021], the combined market capitalisation for the same acute, but single-use technologies do potentially offer
companies had risen over ten-fold to $42 billion”, added some solutions, both in terms of helping CDMOs set up
Jurkauskas. He continued, “the implication of this is that for demand and for innovators thinking of going it alone
these companies have the resources to hire CMC and on manufacturing. The shift to single-use in particular,
clinical research professionals far earlier and therefore coupled with increased funding, has accelerated the re-
further speed-up development timelines. It also means that evaluation amongst innovators. Improved approaches in
the next few years look extremely promising for both CROs biologics manufacturing and titre mean that facilities can
and CDMOs that can expect to help conduct the trials and now be operated on a smaller footprints with smaller, less
make ingredients and clinical materials for these potential expensive equipment. In fact, Parrish Galliher predicts that
therapies.” in the next few years we will see titres of 100 g/L, which
should help alleviate some of the capacity demands, and
shows how quickly the bioprocessing methodologies are
“The market capitalization for those now maturing.
preclinical companies from 2020 was just
Highlighting the dilemma facing many firms now,
$4 billion at the time of filing, yet as of
Galliher added: “What we have seen in the last 5-years
mid-January [2021], this had risen over is an overall reduction in available CDMO bio capacity,
ten-fold to $42 billion”, as a result of a big jump in pipeline that has come into
commercial production. Consequently, what we now
hear is a lot of activity around building your own capacity
In the medium-term, this will present some interesting versus outsourcing, with biotech exploring building first
conundrums for successful CDMOs who will need to decide early stage and then later stage manufacturing facilities.
whether, where and how to invest for future growth. Typically, Understandably, that has resulted in a re-examination of
in the past, CDMOs have often waited for a pharma customer the economics of plants and what types of facilities are
before investing in facilities – to reduce risk and unused best. Obviously single-use becomes very attractive as a
capacity – but we might now see attempts to ‘follow the less expensive initial option.”
molecule’, and get a head start over competitors on where
and for what future capacity is needed. Similarly, CDMOs are increasingly building more adaptable
CPhI Pharma 2021 Report 9 Post Pandemic Legacy Trendssingle-use facilities, and even fully flexible suites, with next few years.”
scales of 500-2000L common in development and reactors
run in parallel once commercial, or in a few cases, single- These consequences are especially noteworthy to the
use at the 4000L size. The investments of Fujifilm DioSynth, CPhI global pharma community as, with events not
Thermo-Fisher, AGC, Lonza, Avid and WuXi are well-known, returning unit the second half of 2021, our experts
but Eric Langer suggested in the recent CPhI Annual Report anticipate increased pressure to find partners over
2020 that among the top fears of the industry were now a the next 6-18 months, with potentially a surge of
shortage of single-use systems. partnering once events return. Unusually, our experts
foresee a situation, at least over the next 12-months,
Chatterjee highlighted that, if they have the funds whereby demand for early-stage contract projects
available, there is an opportunity to capitalise on demand, could quickly exceed supply and innovators will need
and therefore he predicts increased equity investment for to start conversations with outsourcing partners
CMO/CDMOs over the next few years: “Lonza’s decision much earlier (i.e. now) with a view to accelerating
during COVID to build these fully flexible (modular) this quickly in Q3 and Q4. Their advice is that even
factories – without existing customer orders – could have preclinical organisations now need to have a defined
big implications and deliver some available capacity to manufacturing strategy, with selection targeting and
innovators of biologics. It’s breaking the mould and we contract conversations starting much earlier to ensure
are already seeing a really hot M&A activity in contracts they don’t get caught out by a lack of demand when
services and I expect to see that continue strongly in the they need it.
Our experts boldest predictions for the next 5-years?
All of the experts foresee a particularly bright few years traction on, such as multiple sclerosis or ALS. Also the
ahead, where the industry can capitalise on the ‘good will’ application of AI, whether it’s on the early precursor
their pandemic efforts have delivered and the increased chemical synthesis processes, or done in the formulation
investment available. Yet the fundamentals in the development processes or in the treatment algorithms
industry are also improving at the same time, with new that are being used today are a huge catalyst right now
technologies lowering the costs of manufacturing and to be able to look at that what ifs very, very efficiently. For
increasing hit to lead speeds. example, there was a new company that said recently
they’ve disentangled MS to some level – rapid onset MS
– and they have found a mechanism of action that could
Perhaps the biggest prediction I can make potentially benefit from a vaccine.”
is that in the next four to five years we’re Automation is also taking off quickly and not just in
going to see drug therapies come out for AI-driven drug development. Manufacturing and smart
one of the multi-modal disease states, factories are now improving efficiencies and enabling even
real-time remote monitoring. Galliher suggested that it is
that have been incredibly difficult to gain the confluence of all these factors that will see the industry
traction on, such as multiple sclerosis achieving record levels of development. “Well with the
or ALS many new drugs coming in, there is a big push to increase
the efficiency of manufacturing through automation
and, for instance, applying AI to reactor operations. The
Chatterjee added: “Perhaps the biggest prediction I can advances in titre and single-use are working together to
make is that in the next four to five years we’re going to help reduce the scale needed, which reduces site size, and
see drug therapies come out for one of the multi-modal ultimately, lowers the capital cost of those facilities. So
disease states, that have been incredibly difficult to gain process efficiency, process productivity and yield through
CPhI Pharma 2021 Report 10 Post Pandemic Legacy Trendsthe application of genetics and automation and novel unit operations together could bring step changes in the cost and numbers of candidates advancing.” Both Chatterjee and Jurkauskas suggested that the convergence of all these trends should see a steady rise in approvals and we could even see FDA approval numbers of 100 per year, given a further five years of continued improvements. Another crucial element is that attrition rates should continue to fall, and molecule selection improve, as tools like next generation gene sequencing help understand whether a molecule is going to have efficacy in a particular disease state. Jurkauskas concluded the roundtable with a very optimistic view of the industry for the next few years. “I believe that FDA approvals will increase by around 50%, so in 2025 we’re in the 70-75 range, probably not at the 100 level yet. But that is the next significant barrier and after then who knows. It’s such an exciting time to be in the industry and I hope we can, globally, continue and build on this year’s collaborations. It’s also why I am looking forward to getting back out to meet partners again. When we partner well we all benefit and achieve more. That’s the biggest lesson from the last year”. I believe that FDA approvals will increase by around 50%, so in 2025 we’re in the 70- 75 range 1. https://www.statnews.com/2020/07/29/pandemics-wreak-de CPhI Pharma 2021 Report 11 Post Pandemic Legacy Trends
Part 1. Perspectives on Pharma in 2021: Executive Survey
Authors
CPhI Content Team
Perspectives on pharma in 2021:
executive survey
What are the 2021 and beyond implications for pharma manufacturing?
There has been much pharma industry debate about and cost advantages this is unlikely to change quickly,
what the longer-term implications of COVID-19 might despite global intentions.
be for pharma manufacturing – especially now that a
post pandemic world is coming into view as vaccine
production and administration is scaled up. The globalised
supply chain and the role of potential secondary and even
tertiary sources of manufacturing bearing much of the
focus. In our survey of more than 500 executives, perhaps
unsurprisingly, 56% believe that the next few years will see
more of the supply chain ‘repatriated to domestic sources’,
as governments and companies look to reduce complexity
and increase regional self-reliance. Coinciding with this
finding, 35% of our respondents believe that European-
and US-based CDMOs will therefore be big the biggest
beneficiaries of geo-sourcing strategies. Interestingly,
32% of respondents stated that they believed big pharma
will also look to deleverage some of its exposure in Asia
– and utilise in-country manufacturing or on a regional
basis. However, emphasising the markets increased
uncertainly and ambivalence on this issue, 49% of
1 More of the supply chain will be repatriated to domestic sources
respondents suggest that, despite short-term disruptions, 2 R&D will be slowed as chemistry services move away from China
3 API sourcing will remain internationalised, but final dosage manufacturing
‘pharma manufacturing will continue with a significantly will move towards domestic providers
international supply chain’. 4 There will be short-term disruption, but pharma manufacturing will
continue with a significantly international supply chain
5 European- and US-based CDMOs to be big beneficiaries
This reflects that at present the majority of ingredients and 6 Big pharma will deleverage its risk exposure in Asia
7 Biotechs and start-ups may come under VC pressure for localised
intermediaries are still produced in Asia – particularly development (national level) to reduce risk
India and China – and with sizable economies of scale 8 None of the above/too early to say for sure
CPhI Pharma 2021 Report 13 Post Pandemic Legacy TrendsIs it realistic to try and bring the manufacturing of starting increased supply chain security is an overall beneficial
materials home to Western markets (from low-cost hubs in development.
Asia, where 80% are sourced from)?
We asked our respondents ‘if it is realistic to localise
the manufacturing of starting materials into Western
markets’, in an effort to reduce the dependence on the
often more competitively priced suppliers from Asia.
Perhaps surprisingly or as consequence of changing
market sentiments 48% said yes, while 37% said no,
citing it is too disruptive to a complex industry such as
pharma. The remaining 15% also said no, but cited that
it ‘would not be a desirable move and have significant
complications’. There is no doubt that higher labour costs
would result in higher prices for raw materials should
they be increasingly manufactured in the West, but our
respondents seem fairly split regarding whether they
believe such a trade-off between increased prices and
What type of manufacturing is best suited to international sources?
Following the recent spate of national attempts (e.g. in chain security concern – such as for certain essential
India, the USA and the EU to name but a few) at reshoring medicines. Yet, the much-publicised Phlow Corporation
of pharma manufacturing, particularly in the latter half deal for essential medicines production in the United
of 2020, what has gone somewhat under the radar is the States (including APIs) does seem, thus far, an outlier not
detail of which elements of the manufacturing process the beginnings of a mass shift in approach .
are best suited to national or international sourcing. In our
survey, we asked respondents to select the product types Manufacturing of innovative final dosage forms was
that are best suited to being manufactured by international selected as the least suited for international sourcing,
sources. ‘Generic APIs’ were selected as the most with only 17% of respondents believing so. Such a low
suitable, with 48% of respondents believing so. However, percentage might reflect the growing desire of finished
surprisingly, ‘Innovative APIs’ were the second most dosage manufacturing to become increasingly re-shored
chosen by 30% of executives. It would be interestingly or at least dual sourced from two different geographic
to speak with respondents about the reasons behind the regions. Biologicals and, surprisingly, starting materials
latter view, but we can perhaps speculate that is indicative & ingredients both received 26% of the vote. The latter
of the international nature of CDMOs – which are often finding perhaps alludes to the growing awareness of
commissioned internationally for API development work. critical quality attribute (CCA) concerns arising from
adulterated or poor-quality starting materials. Alternatively,
The overall implication here is that large volume generic it may simply be a reflection of the desire to shorten supply
APIs, which still have sizable cost variances between chains so that pharma manufacturers are not dependent
markets, are unlikely to be reshored to more expensive on bulk ingredients coming from China, which is often is
domestic markets unless there is an underlaying supply the only source.
CPhI Pharma 2021 Report 14 Post Pandemic Legacy TrendsDo you think pharma production/manufacturing will increase or decrease in your country in
the next five years?
Encouragingly, the industry remains bullish in its outlook of the major industrials sectors, pharma will strongly
for the medium and longer term, with 65% of respondents outperform all others in the medium term.
believe that pharma production and manufacturing
will increase in their country. Executives cited increased
‘exports’ as the primary growth driver followed by a
‘growing domestic market’. A further 14% of respondents
deemed that the level of production and manufacturing
in their respective countries will remain the same, with
just 7% of respondents believing that manufacturing will
decrease.
Monetary policy implications
The downside implications of looser monetary policy
in most nations are yet to be fully felt by international
markets with a majority of advanced economies held up
by unprecedented levels of Government stimulus. Pharma
undoubtedly has been the major beneficiary of investment
throughout the pandemic and overall the global industry
should benefit from a lasting post COVID legacy. However,
as debt burdens increase undoubtedly there has to be
marginal and growth downsides for pharma manufactures
Blue = Increase, thanks to exports and a growing domestic market
as economies seek to reduce deficits in the medium term.
Orange = Increase, thanks to a growing domestic market
That said, our survey suggests that the industry remains Grey = Remain the same as the industry is stable
bullish that it will remain well funded and its production Yellow = Decrease due to cheaper sources of manufacturing abroad
base will continue to grow. The collective view is that, Cyan = Decrease due to more advanced manufacturing capabilities abroad
CPhI Pharma 2021 Report 15 Post Pandemic Legacy TrendsOverall, has COVID-19 increased the business outlook for the pharma industry in 2021? The majority of our respondents – a substantial 61% more than 6 billion doses will now be produced in 2021 . – believe that COVID-19 has improved the business outlook of the pharma overall for 2021 and beyond. This Yet despite these favourable headwinds heading into 2021, undoubtedly reflects the expanding global demand 20% believe that the business outlook will remain the from the existing COVID treatments, coupled the same, with 19% believing pharma’s outlook has decreased impending vaccine production now needed to meet perhaps reflecting the wider economic uncertainty, and the tens of billions of dose demand. Already in 2021, disparities between how well different economies have in just the first few weeks/months of approvals, we are managed to maintain growth and, in the longer term, more seeing innovators struggle to scale production to meet importantly, how employment levels may affect structural demand. Further vaccine approvals are also expected in deficits in Western economies. Q1 and Q2 of this year increasing capacity constraints and overall pharmaceutical production volumes. This however has already resulted in another huge opportunity for CDMOs and biological manufactures with Serium Institute of India, Wacker, Emergent BioSolutions, Avid Bioservices, Lonza, Delpharm, Catalent, Recipharm and HALIX just a small smattering of the companies that have received sizable outsourcing contracts. In fact, PharmSource estimates that globally What type of pharma machinery will pharma manufacturers invest in the most in 2021? Filling and packaging systems were voted as the machinery type that pharma manufacturers will invest in the most in 2021, taking 24% of the vote. The underlying reason cited for this was the expansion and modernisation of finished dose manufacturing. For example, dug production is gradually moving closer to the point of consumption and drug product CMOs/CDMOs are investing to become one-stop shops in a move to aid innovator desires to simplify and streamline outsourcing. This is of course, not to mention the huge logistical challenge of filling billions of Covid vaccines. As in previous years (pre-Covid), large- scale bioreactors and fermenters were the second most popular choice, with 13% of votes. Manufacturers will look to expand their capabilities and capacity for biologicals and capitalise on the impending wave of biologics approvals over the next few years. Other popular machinery types included small molecule reactors (12%), purification systems (9%) and single-use bioreactors (8%). CPhI Pharma 2021 Report 16 Post Pandemic Legacy Trends
What is the most important factor when buying machinery? Significantly, unlike the cost-based decisions often seen in other areas, 53% of our respondents stated that ‘quality of machinery and lifespan’ are the most important factors when buying machinery, whilst 24% believe it to be reliability. 11% and 8% of respondents believe flexibility in use and cost to be the most important factors, respectively. CPhI Pharma 2021 Report 17 Post Pandemic Legacy Trends
Part 2. How to incorporate excipients into QbD studies for product development and life- cycle management
Authors
Brian Carlin, DFE Pharma; Chris Moreton, FinnBrit Consulting; Dave Schoneker, Black Diamond
Consulting; Katherine Ulman, KLU Consulting; Joseph Zeleznik, IMCD
How to incorporate excipients into QbD
studies for product development and
lifecycle management
Introduction
The International Pharmaceutical Excipients Council of medicines by helping to preserve the efficacy, safety, and
Federation (IPEC Federation) [1] is a global organisation stability of active pharmaceutical ingredients (APIs), and
that promotes quality and safety in pharmaceutical helping to ensure that they deliver their promised benefits
excipients. Excipients play a critical role in the manufacture to patients.
A unified voice to promote the best use of excipients in medicines
In November the IPEC Federation will publish a new guide: formulation practices, due to the introduction of QbD,
Incorporation of Pharmaceutical Excipients into Product impact excipient manufacturers and suppliers,
Development using Quality-by-Design (QbD guide) [2]. The • provide understanding for excipient manufacturers
guide will be applicable globally. and suppliers as to what excipient users will likely
require when applying QbD principles during product
The Guide defines a pharmaceutical manufacturer as a development, and
“user”, and a “supplier” as either an excipient manufacturer • provide understanding to excipient users and regulatory
or a distributor. agencies regarding what may or may not be possible
when considering the impact of excipient variability
The objectives of the QbD guide are to in the application of QbD principles throughout the
• introduce Quality-by-Design (QbD) and pharmaceutical product lifecycle.
formulation development concepts to excipient
manufacturers and suppliers, This Guide includes recommendations related to the
• provide an explanation of how changes in pharmaceutical impact of excipient variability on drug product quality
CPhI Pharma 2021 Report 19 Post Pandemic Legacy Trendsduring development, and to justify management of approach described by the International Conference on
excipient variability in the control strategy (CS). It contains Harmonization (ICH) Q8 [3] as well as other applicable ICH
useful explanations and suggestions for both the makers Guidelines such as ICH Q9, Q10, Q11, and Q12 [4-7].
and users of pharmaceutical excipients.
The guide will be available, initially exclusively to IPEC
The Guide is applicable to excipient use throughout members for a three-month period, on the IPEC Federation
pharmaceutical product development and lifecycle and national/regional members’ websites. Thereafter, the
management using the Quality by Design (QbD) guide will be made available to the general public.
Why the need for a QbD Guide on excipients?
The ICH guidelines are high level and focus on the The pejorative illogicality of the excipient “impurity”
active pharmaceutical ingredient (API) and finished drug is illustrated by non-crystallizing sorbitol syrup which
product. Applying API logic to excipients can lead to contains oligomers. Substitution with a purer crystallizing
counterproductive adaptations inconsistent with QbD grade renders the finished product unusable if the patient
principles. cannot open the bottle due to cap locking. So-called
excipient “impurities” are often essential to functionality
Silverstein [8] contrasted the control of API quality versus or performance, hence the preferred term concomitant
that of excipients. components.
“API quality is improved by reducing the presence of all APIs are synthesized for pharmacological effect whereas
materials other than the desired chemical…... Extraneous most excipients have multiple applications beyond their
substances may be harmful to the patient in that they may pharmaceutical uses. For example, HPMC is a binder in
lead to side effects, or they are inert, thus reducing API wall board and cellulose is used in paper and viscose
purity and thereby compromising efficacy. production. Pharmaceutical applications may be a very
small portion of an excipient usage.
Excipient quality is described quite differently. While one
would again refer to compliance with the compendial Traditional pharmaceutics focused on the functionality
monograph (if there is one) or the manufacturer’s of the excipients, which drives the choice and level
specification, a higher assay is not always better. While of incorporation of the excipients in formulation. The
this may seem counterintuitive, excipients are often formula tended to be frozen early in development, once
complex mixtures that include constituents arising from clinical and stability data accumulated. Scale-up often
raw materials, catalyst, solvent, initiator residue, or side confounds small-scale data and the end result is poor
reactions. The International Pharmaceutical Excipients manufacturability, where the finished product is not robust
Council (IPEC) refers to these other unavoidable substances with respect to the inevitable variability in raw material.
in the excipient as concomitant components. The
performance of many excipients in the drug formulation Moreton [9] defined a robust formulation as being ‘able to
may rely on the presence of such substances in the accommodate the typical variability seen in API, Excipients
excipient. Concomitant components in the excipient and Processes without compromising the manufacture,
may aid in solvating drug components, improving stability, performance or any other attribute of the product
excipient functionality, etc. Excipient quality, therefore, critical to the patient’s care or well-being.”
is characterized as compliance to the monograph or
specification and having a consistent concomitant In QbD, the emphasis shifts to the impact of excipient
composition.” variability, which is a potential major (not exclusive) source
of finished product performance problems. Excipient
CPhI Pharma 2021 Report 20 Post Pandemic Legacy Trendsattributes can vary from batch-to-batch and from supplier- variability only within the limits of their process capability
to supplier. Not all attributes will be on the specification so and for which the processing equipment was designed and
some variabilities may not be apparent. constructed. [10]
Excipients are inherently variable as they are not controlled There are many degrees of freedom, associated with
at an individual parameter level. There are many degrees the excipients, and the products into which they
of freedom associated with polydispersity of particle size, are formulated. The application of simple rules, such
molecular weight and/or chemical composition, all of as compliance and fixed formulae, can give rise to
which may be process/supplier dependent. Particle size unanticipated emergent behaviours, which is the definition
is usually controlled as an average or distribution, and of complexity [11]. Emergent behaviours are another name
dilute solution viscosities are often used as surrogates for for Special Cause Variation [12].
molecular weight distributions. The composition profile
of a complex mixture may not be well defined and the Factoring excipient variability into Design of Experiments
impact of the many components on performance is poorly (DoE), Control Strategy (CS) and Lifecycle Management
understood. Excipient manufacturers can control excipient (LM) will increase finished product robustness.
Structure of the QbD Guide
The guide is divided between incorporation of excipients and drug product development and goes on to discuss
into the formulation (traditional pharmaceutics) and Quality by Design and how it relates to excipient attributes,
incorporation of excipients into QbD activities such as DoE including variability (both common cause variation (CCV)
and CS. Without good pharmaceutics it is unlikely that the and special cause variation (SCV)) and CMAs, which are
QbD objective of product robustness will be achieved. extra to the pharmacopeial monograph or manufacturer’s
specification)
In the previous era of large multinational pharmaceutical
companies, product development was vertically integrated Following on from this there is more detailed discussion
between discovery and manufacturing. Large development of how excipients may interact with product criticalities,
groups were centers of excellence, and pharmaceutics including percolation effects. Product, process and
was the bridge between discovery and manufacturing. excipient drift are discussed and the potential for interplay
The modern era is much more fragmented with the rise between them. Risk management is an important aspect
of generic and contract development/manufacturing of modern pharmaceutical industry practice. The QbD
companies. There has also been a proliferation of discovery Guide stresses the importance of risk assessment in the
start-ups many of which have the business model of development of robust pharmaceutical formulations. In
hoping for acquisition on proof of concept, often with little addition, there is discussion of continuous monitoring,
or no pharmaceutics expertise. For this reason, a primer continuous verification, and the use of multivariate analysis.
on drug and finished product development was deemed
necessary. These concepts and the general principles of There are two Annexes to the QbD Guide. Annex A is an
QbD will be familiar to pharmaceutical scientists. However, overview of the pharmaceutical development process.
the incorporation of excipient variability into DoE and Annex B describes Kano Analysis which is an R&D/Design
lifecycle management requires new concepts, and new technique, adapted in the guide to determine which
ways of thinking about how excipient variability impacts attributes of the excipient, API or product, and process
product performance and manufacturability. parameters are important in an application.
The QbD Guide starts with an introductory section which
is intended for those excipient makers and users unfamiliar
with pharmaceutics. It provides an introduction to drug
CPhI Pharma 2021 Report 21 Post Pandemic Legacy TrendsDetailed Overview of the IPEC Quality-by-Design Guide
Once the prototype formulation and manufacturing Unknown does not mean unknowable. What may be
process have been developed, emphasis shifts to assessing unknown to users may be known to excipient makers and
impact of excipient variability on finished product quality. thus discoverable in discussion with the maker. Justification
Excipient suppliers and users should identify and, if of reliance solely on pharmacopeial specification should
necessary, control relevant excipient material attributes, include the results of such discussions.
some or all of which may not be included in pharmacopeial
or excipient manufacturer’s specifications. Reliance on Excipient complexity, and products into which excipients
compliance with pharmacopeial or supplier specifications are formulated, should not be underestimated. A definition
alone may not be sufficient for QbD as compliance of complexity, which is very relevant to excipients in QbD
does not warrant fitness for purpose in a particular is:
pharmaceutical product.
“the repeated application of simple rules in systems with
QbD seeks to minimize the risk that variability will many degrees of freedom that gives rise to emergent
adversely affect finished product quality. The impact of behavior not encoded in the rules themselves.” [11]
excipient variability will depend on the excipient role in the
formulation and the finished product CQAs. Formulation Pharmaceutical product development, control, and
and process development scientists should anticipate regulation have traditionally relied on simple rules, such
lot-to-lot and supplier-to-supplier variability in excipient as fixed formulae, fixed processes, and (over-)reliance
properties and address the following potential areas of on pharmacopeial compliance. The many degrees of
concern, which are novel concepts in terms of traditional freedom (variability) associated with excipients are
formulation development. complemented by additional degrees of freedom from
• unknowns and uncertainty the processes and the finished products themselves. The
• complexity resulting unpredictable emergent behaviors means that
• common vs special cause variation the excipients (and API), even if fully compliant, represent
• finished product criticalities a reservoir of potential special cause variation. Finished
• excipient, process, and product drift product quality may unexpectedly and disproportionately
• ensuring representative sampling of excipient variability become susceptible to the impact of a previously
[13] acceptable excipient variability within historical norms.
QbD places great emphasis on the management of risk. Common Cause Variation (CCV) vs Special Cause
Once a risk is quantified then a decision can be made on Variation (SCV)
tolerance versus mitigation of that risk using the criteria CCV is the intrinsic noise or variation due to phenomena
of severity, detectability and probability. However, there constantly active within the system. CCV is predictable
may be unknown factors associated with both the raw probabilistically from a historical experience base and is
materials and the finished product. Unknowns may be characterized by irregular variation around a mean with
unknown to the user, the excipient manufacturer, or both. no significance in individual high or low values. CCV data
Risk management requires that the impact of unknowns shows zero trend (no time or batch dependency).
(uncertainty) be minimized by involving all stakeholders,
including excipient suppliers. Excipient unknowns include: The term “special cause” was established by Deming [12]
• composition and its impact on functionality and and such variation is characterized by:
performance • new, unanticipated, emergent behaviors
• attributes not included in pharmacopeial specifications • inherently unpredictable
• variability • outside historical experience
• potential for interaction with latent criticalities in the • potentially, inherent change in the system.
finished product
SCV is attributable to a specific disturbance. Removing
CPhI Pharma 2021 Report 22 Post Pandemic Legacy Trendsall special causes leaves the intrinsic system noise, CCV. be what Deming meant by “inherent change in the system”
Deming’s reference to inherent system change is consistent when describing special cause variation. Criticalities in
with finished product criticalities. The type of variation is pharmaceutical products are most commonly associated
important to Corrective and Preventive Action (CAPA). with percolation effects or conflicting technological
objectives.
Due to the complexity of excipients, and the products
into which they are formulated, excipients represent a Percolation Effects
reservoir of special cause variation in the finished product, Percolation thresholds are common in pharmaceutical
which must be addressed by the designer. As SCV is, by systems, especially in powder mixes and tableting physics.
definition, unpredictable, it is not experimentally accessible An example is increasing the water content in a water-in-
during development, and must be factored into the CS. oil emulsion. The oil is the continuous phase in which the
Paradoxically, the more rigid or fixed the system is, the water is dispersed, but at a critical water concentration, the
more susceptible it is to the impact of excipient variability. system may invert to give an oil-in-water emulsion, where
Flexibility built into the system to cope with SCV then the water is now the continuous phase. Powder mixes may
becomes a criterion of design quality. There is little benefit exhibit similar behavior with particles of one component
in having products that work perfectly so long as nothing (A) dispersed in another (B). As A increases beyond a critical
changes. Products are subject to cumulative changes concentration, or percolation threshold, the mix becomes
throughout their lifecycle. Serial univariate changes (even a dispersion of B in A. If the properties of A & B are different
under change control) often lead to eventual failure as there may be a marked discontinuity in the properties
quality is a combination of multivariate attributes. The of the mix. In his review of the application of percolation
failure need not correlate with a so-called “critical excipient.” theory to powder technology Leuenberger [15] warns that:
It could also correlate with an attribute of a so-called “non-
critical” excipient, within its norms of variability. “formulations which contain a component with a critical
concentration, i.e. close to the percolation threshold, may
Finished Product Criticalities lead to non-robust conditions during scale-up and during
A criticality, or critical transition, is defined as “being in subsequent large-scale production activities.”
a state, or at a point, where some quality, property, or
phenomenon undergoes a definite change” [14]. An An example is a disintegrant in a hydrophobic tablet matrix,
example of criticality is critical micelle concentration, at a level just sufficient to provide a contiguous network for
where the properties of dilute solutions below critical water wicking. Even a slight variation in content uniformity
concentration are not predictive of the micellar system could render parts of the tablet batch non-disintegrating.
above, and vice versa. Another example is polymer solution
gelation, which occurs above a critical concentration. The Leuenberger also gave an example of a percolation
dilute solution viscosities commonly used to characterize threshold in tablet hardness vs relative density. Below the
polymer excipients are not predictive of higher application- criticality the granules disintegrate, above it they do not.
specific concentrations. Force transmission, and the resultant densities, within a
compact are not homogeneous, and may be dependent
Criticalities may exist within pharmaceutical products, on factors such as the tablet geometry.
unknown to the designer, and are therefore also known
as latent conditions. Criticalities, as points of transition Extreme cases may be described mathematically by a
from one state to another, were not included in the ICH binary 0-1 step function where the system goes from one
definition of criticality but can be critical if encountered state to another with little or no warning, hence the term
during production. Excipients may disproportionately “explosive percolation: From impossible to inevitable,
impact CQAs and manufacturability if their variability without ever visiting the improbable” [16].
interacts with product criticality. A previously unknown,
unremarkable excipient variability may unexpectedly start Conflicting Technological Objectives
to govern the transition from one state to another. This may Conflicting technological objectives are another source
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