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What is Providence Health Services?
Providence Health & Services is a not-for-profit Catholic network of hospitals, care centers, health plans, physicians, clinics, home health care and affiliated services guided by a Mission of caring that the Sisters of Providence began in the West over 160 years ago.
What is Providence Health Care?
Governance. Providence Health Care is a non-profit organization, providing services in partnership with the Vancouver Coastal Health and the Provincial Health Services Authority.
What is the Providence Medical Group?
Providence Medical Group is the area's largest non-profit network of primary care and specialty physicians with over 20 locations in South Alabama and Southern Mississippi.
What is Providence Medical Center?
Providence Medical Center, located in thriving Western Wyandotte County near the Legends and I-435, is a community hospital affiliated with Prime Healthcare. Providence is also associated with Saint John Hospital, located in Leavenworth, Kan.
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What is the ordering of modes (Ionian, Dorian, etc.) from least to most dissonant?
Intervals are dissonant/consonant so why wouldn't there be a way to measure the totality (or average?) of modes against the respective scale?
UPDATE: The ordering could start with the Ionian which must be the most consonant, least dissonant because the Ionian mode of a scale is the scale itself.
I have never heard of any such ordering of modes by dissonance.
You need a combination of tones or at least a succession of tone to produce dissonance.
I suppose you could make some comparison of dissonance by comparing scale degrees to the tonic. Noting that the Locrian mode has a diminished fifth for the 5th degree, or the Lydian has an augmented fourth for the 4th degree (and those are both important tonal degrees) does seem to point to some inherent level of dissonance for those modes. But I don't know how exactly you would then quantify and rank all seven modes.
I have see the modes compared and ranked in terms or color or 'darkness' by the successive addition of lowered degrees. That would make Lydian lightest and Locrian darkest.
Intervals can be thought of as either consonant or dissonant, but even those determinations aren't always set in stone. A perfect fourth is sometimes dissonant, but then other times it's consonant. Hindemith tried ranking the intervals from most consonant to least, but countless authors have disagreed with him.
I say this because any ordering of these modes, just like an ordering of intervals, is bound to be imperfect and subject to some disagreement.
Lydian and Mixolydian both have only one difference from Ionian. Lydian has ♯4 compared to Ionian, whereas Mixolydian has ♭7. I'm not sure how you'd determine which is more consonant than the other.
Dorian has two differences from Ionian: ♭3 and ♭7.
Aeolian has three differences: ♭3, ♭6, and ♭7.
Phrygian has four: ♭2, ♭3, ♭6, and ♭7.
And Locrian, if you consider it a mode, has five: ♭2, ♭3, ♭5, ♭6, ♭7.
To someone listening to the Ionian mode 400 years ago, it would have sounded dissonant. Even a hundred years ago, the tritone, used extensively in Blues, was considered dissonant. Dissonance requires minimum two notes played simultaneously - as does consonance. And the only real consonant interval is the octave.
The Ionian mode contained exactly the same notes as every other mode from that parent key, so the question is on a dodgy footing. The intervals for each are exactly the same! Some consonant (sort of), some dissonant (sort of). So listing an order - all equal!
The modes of the diatonic scale (Ionian, Dorian, Phrygian, Lydian, Mixolydian, Aeolian, Locrian) each contain exactly the same interval patterns - those of the diatonic scale. The only difference is the root note - so what must be meant by 'most dissonant' and 'least dissonant' here must in some way refer to the intervals that occur with respect to that root note.
Perhaps most importantly, in a musical context, we don't only hear intervals between the root and every other note, but every note and every other note. So we would have to somehow consider how to 'weight' the relative dissonances of intervals produced by notes other than the root in terms of importance. (if we were to weight them all the same, then each mode would come out as sounding no more or less dissonant than the other - because, as we said at the start, all modes of the diatonic scale have the same interval pattern).
Actually, if we just consider intervals from the root, the Ionian mode wouldn't be the most consonant mode of the diatonic scale - because a major seventh is a more dissonant interval than a minor seventh, the Mixolydian mode would be measured as more consonant.
So why might we nevertheless consider the Ionian mode more consonant than the Mixolydian? it comes back to that idea about considering the intervals from notes in the mode other than the root. If we look at the most consonant note in the Ionian mode other than the octave - i.e. the fifth - the intervals based on that are those of the mixolydian mode - i.e. very consonant! However, starting on the fifth of the Mixolydian mode generates the intervals of the Dorian mode, which would be less consonant. So the Mixolydian mode 'wins' in terms of consonance from its root, but 'loses' to the Ionian mode in terms of consonance from its fifth.
Put another way, we can see that the Ionian mode can produce especially consonant-sounding music when using triadic harmony, for example, because you have the (consonant-sounding) intervals of a major chord available from both the (also consonant) IV and V of the mode.
(Personally, I feel that part of the popularity of the major scale/Ionian mode is not just that it provides many opportunities for consonance, but also because the major seventh is an 'aching' dissonance that 'wants to' resolve to the root).
So, TLDR: It's hard to come up with an overall ordering of modes by consonance / dissonance. It's probably more worthwhile to note the different opportunities for consonance and dissonance that each mode allows in a musical piece.
Adam neely makes a great list of the modes ranked by a certain concept he calls "the Dorian Brightness Quotient" (but don't worry, he's making that name up). The idea is that each scale can be unambiguously defined by its brightness compared to the Dorian Mode, and therefore we can approach the idea of dissonance similarly. Now, Neely describes brightness as having a direct relationship with interval size, so brighter is not always more dissonant. However, it's definitely possible to say that in context, the farther apart the modes are, the more dissonant they'll be.
Not the answer you're looking for? Browse other questions tagged theory scales modes consonance-and-dissonance or ask your own question.
What does it mean for a mode to be "tonally effective"?


Color allows us to express emotion and our innermost through our interaction with people and the products we buy. It is the differentiating factor used by manufacturers to distinguish their products and attract consumers. Plastics Color Corp. (Calumet City, IL), a global provider of colorants, compounds, additive masterbatches and custom polymer technologies, has unveiled the latest in color development with its 2016 Color of the Year. The selection is indicative of today's leading consumer trends.
First place has been awarded to a bright, reddish hue named Giggles. This lively shade tops Plastic Color's list of hottest colors for 2016, which includes other provocative hues such as Deep Sea, Tomorrow Blue, Momentum, and Exhilaration.
The collection is part of the 2016 Color Trends palette developed by Plastics Color. All of the colors fit the central theme of "TechYes," a concept developed to explain the synergy that exists between technology and color. Both technology and color exist in tandem and they allow the expression of ideas, emotions and thoughts, says Plastics Color.
The 2016 Color Trends collection and the accompanying theme TechYes will be used to help Plastics Color's customers choose the most appropriate and effective colors to integrate into their products and packaging. It's an important part of the company's comprehensive effort to help clients understand the power of color, and its relevance in consumer products.
Color is one of the most influential factors impacting product design and consumer buying trends. Selecting the right shade is so important for marketers. The color experts at Plastics Color regularly work with companies in consumer packaging and products, personal care packaging, healthcare applications and more to evaluate their color options and lead them towards the best selections for their needs.
We go beyond the usual services by blending the Art of Color with the Science of Plastics. Let color take you to the next level. E-mail us at Info@PlasticsColor.com.


Yesterday, when we had the kittens at the vet we were able to pick up Otter's ashes. I have never had a pet cremated before so I wasn't exactly sure what to expect when they returned the ashes.
I have to say that I am impressed with the way this very sensitive matter is handled, at least by our vet hospital.
The ashes were returned in a very nice decorative wooden box and also there is a nice little certificate that certifies that they are returning your pets ashes and it has her name and date and our names on it. They also include a little engraved nameplate that you can stick on the box.
We also received her memorial stone on Monday and John put it out in the yard yesterday with Zach and Ruthie.


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CompIC 2017 returned to Amsterdam and featured speakers from architect's UNStudio and Lemercier-Bona plus Witteveen+Bos, Atkins Global, Gurit Composite Components, Construction Composites and many more. The conference explored the current and future use of composites in construction and the benefits they provide to the construction industry.
CompIC 2015 saw the start of the Composites in Construction series of conferences in Amsterdam. Over 100 delegates from across the globe attended the event and saw people from across the supply chain interacting, looking at issues and progress being made, and working together to increase the use of composites in construction.


Dr. Ramzi Salti on KZSU 90.1 FM Stanford.
Here is the link to all my Podcasts from KZSU 90.1 FM so far. Each link takes you to my Playlist for that program and to an arrow at the bottom right of that page that enables you to listen to the podcast for free (or right click to download then "Save Link As" to save the MP3 file on your computer).


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Here's Why The Russian Invasion Of Ukraine Is Dubbed The "TikTok War"
Using Social Media To Find Information
Have you been following the Ukraine war on TikTok? Everyone, it is said, as Russian Invasion dubbed TikTok War. In February, New York Times columnist Thomas Friedman stated, "This is the first conflict that will be covered on TikTok by super-empowered citizens armed solely with smartphones."According to CNN's chief media journalist Brian Stelter on Sunday's "Reliable Sources," Ukrainian Instagram influencers are now warzone witnesses, and urban warfare experts are tweeting recommendations to Ukrainian forces. However, the barrage of words and images is generating a perplexing media environment rife with misinformation.
Many are referring to Russia's invasion of Ukraine as the TikTok war, because users of the network were actively commenting about the military escalation even as Russian officials denied it. Many people are also using social media to become "anti-war activists," according to Stelter.
When you consider Russia's state-owned media, the news environment is growing increasingly complex. Social media, according to David French, a senior editor at The Dispatch, is showing Americans how "extremely awful" this battle is, but such platforms don't provide an overall strategic view, such as Russian soldiers' positions or the true number of dead.
The immediacy of these social media posts, according to French, may have encouraged Western governments to "fall in line swiftly" on tougher sanctions. "The inspirational quality of Ukrainian resistance," French remarked, "is shame a lot of Western countries into action."
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A video of Russian paratroopers uploaded on TikTok and Twitter that turns out to have been filmed in 2015 was referenced by Stelter as a perfect example of misinformation being propagated on social media. Few individuals understand information warfare as well as most Ukrainians, according to Jane Lytvynenko, an investigative reporter and researcher specializing in deception.
"Every conflict has propaganda," Lytvynenko explained. "And the objective of Russian propaganda right now is to undercut Ukrainian narratives and to terrify Ukrainians," she explained. Lytvynenko warned against reports on social media of "Russian forces, Russian military moves, and disinformation," which Ukrainian news outlets are debunking in real time.
According to Stelter, a "fog of war" has descended over Ukraine, making it difficult to determine what is going on in areas even 20 miles outside of Kiev. According to French, we may not know the outcome of the conflict for days or weeks. "As a general rule, the more explicit and dramatic the information, the more mistrust you should apply," said French, who served in the Iraq War. "Right now, the more high-level, more ambiguous reports are going to be the more reliable news."
Whether this is the "first TikTok War," the assertion is tainted by wishful thinking. People have excellent cause to look for a new, significant distinction between the images of one conflict and those of all previous wars. If something is novel, it's possible that we've avoided the same old scenario in which many people die for no apparent cause. If something is novel, it has the potential to be unique. However, looking for that difference in a technological company's offerings is obviously sad and foolish. We will undoubtedly witness the first Twitch war, or the first Discord war, or the first conflict on some other platform that has yet to be invented in the next years.
Alternative Social Media And Politics In America
Many of these explicitly position themselves as alternatives to more well-known social media websites like Facebook, Twitter, and YouTube, particularly by criticizing the widespread free speech restrictions they claim exist at those sites but now it's time to talk about alternative social media and their relation to politics in America.
Benefits Of Social Media Use In Science - Become A Renowned Scientist With Our Tips
Social networks are among the most commonly used technologies in our day, which is no secret. Social media is now used by around 40% of people worldwide, and those numbers are only increasing and scientist can get benefits of social media use in science.
Social Media Platforms In Africa - New Opportunities In Digital Marketing
Social media usage has significantly increased over time. Social media platforms in Africa initially enjoyed greater popularity among younger generations than among older generations. But as technology has advanced, everything has changed; social media platforms are now the most popular means of communication.
Sell Jewelry On Social Media - The Road To Success As A Jeweler
Interested in learning how to sell jewelry on social media? It might be challenging to interact with customers online when you first start a small jewelry business, but more and more small businesses are now taking advantage of social media's wide reach.
Celebrities Do Weird Things On Social Media - Examples And Stories
It's simple to deceive ourselves into thinking we know everything there is to know about celebrities and the extremely famous due to the amount of scrutiny they are subjected to and the time spent in the spotlight. But the truth is that sometimes the celebrities can do weird things on social media like us.
Instagram Lessons To Learn From Celebrities
These celebrities have shown that they are just as hot on social media as they are in real life, whether it be by creating the ideal photo dump or killing it on IG Reels. Here are some instagram lessons to learn from celebrities.
Social Media And Healthcare - How To Do Social Media Strategies For Doctors
The challenges of social media in the healthcare industry can be difficult to handle. If 2022 has shown us anything, it's that social media and healthcare can work well together.
Why Halalgoogling Doesn't Work With Islamic Search Engines
If you've heard of Islamic search engines and tried them, you've probably come to the same conclusion as us: they don't work.
How To Prevent And Defend Your Forum From Spam And Prevent It From Happening Again
Forum Spam is one of the most complex issues that forum masters/owners can face. A spam attack can ruin your rankings and scare users leading the forum to failure.
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What Is Social Media Marketing? Learn More About The Most In Demand Niche In 2022
What Are The Copyright Violations In A Social Media App
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Sidha Kura Janta Sanga – बाल व्यापार गर्ने बालवालिका केन्द्र प्रशासनको नियन्त्रणमा, घुस सहित यातायातका कर्मचारी पक्राउ | Ep. 163 – This program always give a interest to the viewer to watch it because it always try to show a different cases and helps many people who are in need. This is the 162 episodes of sidha kura janta sanga by Rabi Lamichhane. 26th December 2017. Let's share this video and comment about it.


We can't see the future, but one thing's for sure: Medicare is here to stay. Medicare provides health insurance to more than 50 million Americans. Forty-two million are people age 65 and older and the other 8 million are younger and have disabilities.
Part A (Hospital Insurance) helps cover inpatient hospital care, skilled nursing care, hospice care, and home health care. Most people get Medicare Part A premium-free since it is earned by working and paying Social Security taxes.
Part B (Medical Insurance) helps cover services from doctors and other outpatient health care providers, outpatient care, home health care, durable medical equipment, and some preventive services. Most people pay a monthly premium for Part B. In 2014, the premium for most people is $104.90, the same as it was in 2013. Some high-income individuals pay more than the standard premium. Your Medicare Part B premium also can be higher if you do not enroll when you are first eligible, also known as your initial enrollment period. There also is a Medicare Part B deductible of $147 in 2014.
Part C (Medicare Advantage) allows you to choose to receive all of your health care services through a provider organization. This plan includes all benefits and services covered under Part A and Part B, usually includes Medicare prescription drug coverage, and may include extra benefits and services at an extra cost. You must have Part A and Part B to enroll in Part C. Monthly premiums vary depending on your state, private insurer, and whether you select a health maintenance organization or a preferred provider organization.
Part D (Medicare prescription drug coverage) helps cover the cost of prescription drugs. Many people pay a premium for Part D. However, people with low income and resources may qualify for extra help from Social Security to pay the premium and deductible. To see if you qualify for extra help visit www.socialsecurity.gov/prescriptionhelp.
To learn more about applying for Medicare when you plan to delay retirement, read our publication Applying For Medicare Only—Before You Decide, available at www.socialsecurity.gov/pubs.


At New Leaf Windows and Doors we are proud of our ethical approach to the use of sustainable timber in our natural wood product ranges. The demand worldwide for cheap hardwood is the prime cause of destructive logging in the rainforests of many countries, and results in deforestation in many others. It is harmful to the planet, and furthermore it is completely unnecessary, as there are now many reputable sources of sustainable timber from many countries.
We work closely with manufacturers to ensure that wherever possible, New Leaf products are sourced from Forest Stewardship Council (FSC) certified suppliers. In addition, we aim to achieve full chain of custody for all the natural timber used in the doors and windows we supply and fit.


Registration for this program has moved to FamilyID. Please log in to FamilyID to register.
Childcare for select Special Events is provided by TNCS staff.
For evening programs, dinner is not included, but packed meals can be brought if you wish for your child to have dinner during the event.


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AI could take your job, but Baidu's newest AI can also help you find one
By Matthew Griffin Intelligence and the Senses 29th October 2018
Artificial Intelligence is being used more and more to vet candidates, now it could soon be used to help match them to jobs too.
Recently I wrote a report on the Future of Education 2020 to 2070, and there's been plenty of speculation about what type and just how many jobs will be automated away by Artificial Intelligence (AI), but now thanks to a Chinese company we might have an AI that actually finds you a job. Now careers and guidance counsellors can keep their copies of What Color Is Your Parachute? to themselves, because neural networks may soon be able to find the perfect jobs for you – that is, atleast, the perfect job that it thinks is right for you based on the information it has about you and its profile of you.
Fortune CEO's plan to abandon shareholder first model and be more future focused
In a recent paper, Baidu researchers revealed they've been working on a neural net that can match resumes with skills listed in job postings, finding the exact right match for positions.
The neural network, which is still a work in progress and that's bluntly called Person-Job Fit, identifies words and phrases in certain job listings, like "program management" and "project development," and matches them to skills listed on a candidate's resume, like "developing projects" and "managing projects."
If the algorithm identifies relevant experience on someone's job history, the candidate will be flagged as a potential match for the job opening and they'll either then be contacted, or, screened – a task that is also becoming much easier to do at scale as more and more companies use AI powered hiring tools like those I've discussed before from companies like HireVue which seems to be taking the market by storm at the moment.
Future EV's with 16,000km range and space elevators made possible with new Chinese Nano-Cable
Baidu's new job counsellor still has a little learning to do, though. According to researchers when it came time to sorting people by educational requirements, the algorithm was stumped because nearly every job required a "bachelor's degree or higher," get your degrees, folks, and nearly every candidate had a bachelor's degree or higher, which made it difficult for the algorithm to come up with a short list of candidates.
So, for now at least, I guess those guidance counsellors still have jobs, for now anyways, but the proposition of AI not just taking our jobs, but then helping us find new ones, that we might actually like better and be a better fit for, is an exciting one.
Source: Baidu ACM
Artificial IntelligenceBaiduChinaFuture WorkforceHuman ResourcesRecruitment
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IBM's AI learns how to predict the outcomes of chemical reactions
WHY THIS MATTERS BRIEF Chemistry is the basis and foundation of everything on Earth and being able to predict the outcomes of new chemical reactions…
A new AI tool is mastering how to create complex drugs and molecules
WHY THIS MATTERS IN BRIEF Chemistry plays a vital role in our society and being able to create new drugs, and chemical cocktails and compounds,…
Watch your mouth, Google's DeepMind lip reads better than humans
WHY THIS MATTERS IN BRIEF Machines and computer systems that can lip read accurately will help enhance the lives of people living with hearing impairments,…
MIT's latest breakthrough? Getting AIs to explain their decisions
WHY THIS MATTERS IN BRIEF Artificial intelligence systems are increasingly running more and more of our world, and its digital fabric, but in many cases…
MIT tests the future of cybersecurity, pits AI's against AI's
WHY THIS MATTERS IN BRIEF In the future cybersecurity will be almost fully automated using AI, and many say we've already entered into a new…
World first as drones and robots plant, tend and harvest their own crops
WHY THIS MATTERS IN BRIEF It was only a matter of time before robots autonomously grew and harvested their own crops, and now it's happened….
Canadian gamers made an intriguing dynamic VR game with interactive AI characters
WHY THIS MATTERS IN BRIEF As AI improves it's going to open up a whole new realm of dynamic entertainment where the content creates itself…
Microsoft wants to democratise Artificial Intelligence
Microsoft wants to to give everyone access to artificial intelligence and a supercomputer Earlier this year, Google's DeepMind artificial brain conquered a world class champion at the…
Prototype zero emission jet engine generates thrust using nothing but air and electricity
WHY THIS MATTERS IN BRIEF Aircraft today burn huge amounts of fossil fuels that pollute the world, this latest breakthrough would make them zero emissions….
World first as scientists create nanobot swarms capable of performing surgeries in humans
WHY THIS MATTERS IN BRIEF By future standards today's most advanced surgical techniques will look neanderthal, nanobots and nanomachines that can perform in vivo surgery…
IBM injected a virus into a neural net to create an undetectable cyberweapon
WHY THIS MATTERS IN BRIEF Even today's cutting edge cybersecurity products have no defence against virus laden, weaponised neural networks. It's been a very…
China rolls out its Social Credit Score complete with Orwellian overtones
WHY THIS MATTERS IN BRIEF The technologies to create an Orwellian state surveillance and ratings system already exists, but without the will and resources to…
JPMorgan is automating the world of finance
WHY THIS MATTERS IN BRIEF The world of finance is being automated faster than almost any other industry and JPMorgan is leading the charge. …


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Home » GaBI Journal » Volume 10 / Year 2021 / Issue 1 » Review Article » Continuous manufacturing versus batch manufacturing: benefits, opportunities and challenges for manufacturers and regulators
Continuous manufacturing versus batch manufacturing: benefits, opportunities and challenges for manufacturers and regulators
Generics and Biosimilars Initiative Journal (GaBI Journal). 2021;10(1):44-56.
Visits: 5292 total, 15 today
Keywords: batch manufacturing, challenges, continuous manufacturing, harmonization, opportunity, regulatory
Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Teh Kee Siang, BSc (Pharm)(Hon); Associate Professor Chan Lai Wah, BSc (Pharm)(Hon), PhD
Continuous manufacturing (CM) is the integration of a series of unit operations, processing materials continually to produce the final pharmaceutical product. In recent years, CM of pharmaceuticals has transformed from buzzword to reality, with at least eight currently approved drugs produced by CM. Propelled by various driving forces, manufacturers and regulators have recognized the benefits of CM and are awaiting the completion of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q13, a harmonized guideline on CM that would be implemented by ICH members.
Although significant progress is evident, the uptake of CM is still sluggish in the pharmaceutical industry due to many existing challenges that have hindered manufacturers from adopting this technology. The top two barriers that manufacturers currently face are regulatory uncertainties and high initial cost. These issues are crucial in unleashing the untapped potential of CM, which has significant implications on patients' access to life-saving medicines, while mutually benefitting manufacturers and regulators.
Despite numerous studies, there have been few existing publications that review current regulatory guidelines, highlight the latest challenges extensively and propose recommendations that are applicable for all pharmaceuticals and biopharmaceuticals. Therefore, this critical review aims to present the recent progress and existing challenges to provide greater clarity for manufacturers on CM. This review also proposes vital recommendations and future perspectives. These include regulatory harmonization, managing financial risks, hybrid processes, capacity building, a culture of quality and Pharma 4.0. While regulators and the industry work towards creating a harmonized guideline on CM, manufacturers should focus on overcoming existing cost, technical and cultural challenges to facilitate the implementation of CM.
Submitted: 30 November 2020; Revised: 20 December 2020; Accepted: 21 December 2020; Published online first: 6 January 2021
Continuous manufacturing (CM) is the integration of a series of unit operations, processing materials continually to produce the final pharmaceutical product. This CM technology started in the eighteenth century during the first Industrial Revolution and has since been adopted by many industries [1]. However, it is only in recent years that CM of pharmaceuticals has transformed from buzzword to reality.
To date, there has been no standardized definition of CM, and the terms 'continuous manufacturing', 'continuous production' and 'continuous processing' are often intermingled [2]. Nonetheless, these terms are not interchangeable as they have different nuances. As the name suggests, 'continuous production' refers to a production schedule operating continually for 24 hours, seven days a week [2]. On the other hand, 'continuous processing' refers to a single unit operation where raw materials are continuously being loaded, processed, and unloaded without interruption [2].
There are many interpretations of CM and its related terminologies. However, end-to-end CM according to the US Food and Drug Administration (FDA), refers to an approach where the drug substance and drug product process steps are fully integrated into a single continuous system [3]. On the other hand, the hybrid approach is a combination of batch and continuous processing steps [3]. The pharmaceutical industry is increasingly adopting hybrid systems as it combines the advantages of batch and continuous processes [4–6].
Although significant progress is evident, the uptake of CM in the pharmaceutical industry remains sluggish due to various challenges [5–8]. Moreover, a lack of harmonized regulatory guidelines on CM has resulted in uncertain regulatory expectations by different regulatory authorities (RAs) [8]. To overcome the regulatory challenges and to reconcile CM-related concepts, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is developing a new quality guideline, ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products [9].
At present, multiple studies have elaborated on significant technical and regulatory challenges for the CM of specific dosage forms, while others have conducted economic analyses on CM [10–14]. For example, Lee et al. [10] reviewed the benefits of CM, emphasized prime quality considerations and proposed solutions to address them. Additionally, a recent review by Vanhoorne and Vervaet [11] presented an overview of the technical aspects of CM and discussed regulatory guidelines on CM, specifically for oral solid dosages (OSDs). Despite many studies, to date, there have been few publications that review existing regulatory guidelines, highlight the latest challenges or make recommendations that are applicable for all pharmaceutical and biopharmaceutical products.
As portrayed in Figure 1, the implementation of CM is attributed to many factors. Therefore, this review aims to identify the benefits and opportunities of CM, assess the current extent of implementation, review existing regulatory guidelines and comprehensively highlight the existing challenges. The review also includes recommendations to facilitate the implementation of CM. The general concepts discussed in this review apply to all pharmaceutical dosage forms and biopharmaceutical products.
Overview of continuous manufacturing
CM is a combined process consisting of a sequence of more than one unit operation, developed to process materials continually to produce the final product [3]. As shown in Figure 2, CM is the integration of individual continuous unit operations with process analytical technology (PAT) which monitors and controls the critical process parameters (CPPs), critical material attributes (CMAs) and critical quality attributes (CQAs) [10]. Furthermore, CM streamlines manufacturing processes by eliminating work-up unit operations [10]. As such, CM equipment is typically smaller and is located within a single facility [10]. Batch manufacturing (BM), on the other hand, involves discrete unit processes with off-line quality testing and storage before each step [10]. Moreover, BM involves shipping of intermediates from one facility to another.
QbD and PAT
CM can improve pharmaceutical manufacturing with an enhanced development approach of Quality by Design (QbD) and the use of PAT [3, 10, 11]. As depicted in Figure 3, a comprehensive QbD approach allows for continuous improvement through product and process understanding to ensure better product quality [11, 15–17].
PAT is necessary for highly automated processes and continuous processing, as it fulfils quality requirements, such as residence time distribution (RTD) [18–21]. RTD refers to the distribution of time that materials remain in a unit operation; thus, it is critical for material characterization [21]. PAT uses multiple data sources for real-time product quality monitoring and control to achieve an integrated QbD quality system [10, 22]. CQAs such as the percentage of active pharmaceutical ingredient (API), particle-size distribution, granule size, and many others can be monitored with PAT [23]. As PAT and QbD tools can also be used in BM, manufacturers would be able to gain a better understanding of these processes, thereby facilitating a smoother transition to CM [22].
Benefits of CM
As listed in Table 1, there are various benefits of CM, which have been recognized for more than a decade [24].
In contrast to BM, CM provides greater scale flexibility in terms of its ability to scale-up production without any hindrance [10, 34, 35]. As depicted in Figure 2, CM eliminates the need for off-line testing and storage, thereby reducing the number of manufacturing steps [24, 29, 36]. Therefore, CM is more efficient than BM, as it reduces the processing time from raw materials to finished drug products, potentially by several months.
Also, CM has a greater response capacity to supply chain disruptions and drug shortages [10, 30]. This benefit of CM is accentuated in pandemics such as COVID-19, where ramped-up production of vaccines is required [29, 37]. As a result, there could be vast implications on global health and recovery of economies. On the other hand, it is difficult to adjust the production schedule of BM to meet changing demands [31], as building a new BM line in response to crises takes several months [10].
Benefits and opportunities for generics manufacturers
Realistically, generic manufacturers operate on low-profit margins and need to constantly take measures to keep drug prices low [38]. With increased processing speed and control from CM, it will lower the cost of production and grant tremendous cost advantages, especially with high-volume production [39]. Furthermore, as CMAs and CPPs are kept constant, there would be lower batch-to-batch variability [10]. Hence, CM allows generic manufacturers to match the narrow process variability of branded drugs [38]. Therefore, adopting CM is an opportunity for generics manufacturers to be prepared for new drug products from originator manufacturers [38]. At present, generics companies such as Dr Reddy's Laboratories, Mylan Pharmaceuticals and Aurobindo are developing CM lines in India [4], while Lupin Pharmaceuticals is developing a continuous purification process for a biosimilar monoclonal antibody drug [40]. Therefore, CM is beneficial for both brand-name and generics manufacturers.
Driving forces of CM
The principal driving force for the implementation of CM is its potential to cut production costs, as manufacturers seek to maximize profits [14, 41]. Pharmaceutical companies are facing a threat to their earnings due to competition from generics and biosimilars manufacturers, increasing research and development costs, a forecasted low growth rate in developed economies, and greater demand for the affordability of drugs for patients [42]. As such, manufacturers are exploring the use of CM as it has proven to reduce operating expenses and capital expenditure [18].
Secondly, there is an increasing demand for speed to market for breakthrough therapies [14, 24, 31, 43]. CM can accelerate product development, delivering life-saving medicines to patients more quickly [31] without compromising product quality [11, 14, 24].
Thirdly, the pharmaceutical industry is transiting from large volume blockbuster drugs towards the production of personalized medicines [24]. This requires a shift from the current BM system towards CM, which is flexible in volume output and product variety [24, 31]. This feature is beneficial for the production of personalized medicines.
Lastly, environmental conservation will be a point of contention in the coming years, mounting greater external pressure on manufacturers. As CM supports greener processes and is proven to have reduced environmental footprint [11, 25, 28, 44, 45], the Pharmaceutical Roundtable recommends CM as the top priority in green engineering research [46]. These external trends, coupled with its compelling benefits, serve as fundamental driving forces for the adoption of CM.
Initiatives by international organizations to advance CM
Furthermore, there are various initiatives taken by international organizations to advance CM. In particular, the International Society for Pharmaceutical Engineering (ISPE) organized the 2020 ISPE Continuous Manufacturing Virtual Workshop, whilst the Massachusetts Institute of Technology (MIT) and the Continuous Manufacturing and Crystallisation Consortium (CMAC) organized the International Symposium on Continuous Manufacturing of Pharmaceuticals (ISCMP), which brought together various stakeholders and culminated in white papers on CM [47]. As listed in Table 2, there is an increasing number of global consortia collaborating to develop and share knowledge on advanced manufacturing technology [48]. Undeniably, these initiatives would accelerate the transition from BM to CM.
Extent of implementation of CM
From the first approval of drug products manufactured by CM in 2015, there have been a total of at least eight drug products approved. However, all of the currently approved drugs are OSDs. Hence, further development of CM for API, biopharmaceuticals and other pharmaceutical dosage forms is imperative.
The approved drugs in Table 3 utilize separately produced APIs [52]. At present, while there is a development of end-to-end CM that integrates continuous API production with drug product processes, there are none that comply with the current good manufacturing practice (cGMP) standards as of yet [25, 56]. This owes to the fact that there are more technical challenges in continuous processes for drug substances compared to drug products [25, 52, 57, 58]. Continuous API manufacturing is more complicated due to longer residence time [25, 52], higher quantity and diversity of unit operations [25, 57, 58], and intractably greater complexity of distinguished key molecules [57]. !However, many organizations are developing continuous flow processes for APIs [44, 52, 58-64]. For example, the Novartis-MIT collaboration has demonstrated that there are opportunities for integration of API and drug product processes with their end-to-end CM of aliskiren hemifumarate tablets [25]. Hence, cGMP-compliant end-to-end CM would most likely be realized in the future.
Similar to the CM of APIs, there is currently no fully continuous bioprocessing facility [13]. As today's continuous downstream unit operations are still in their nascent stage of development, hybrid systems are expected to be implemented before end-to-end systems [30]. Nonetheless, the development of continuous bioprocessing is also gaining momentum [58]. Therefore, drugs in various pharmaceutical dosage forms would likely be approved in the coming years as development of CM progresses.
Existing regulatory guidelines on CM
Currently, there are three main regulatory guidelines on CM from ICH, FDA and ASTM International. As stated in Table 4, ICH Q13 and FDA guidance are still a work-in-progress. Other RAs and international organizations such as the World Health Organization (WHO), the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and the Association of Southeast Asian Nations (ASEAN) do not have established guidelines on CM. As a result of this regulatory uncertainty, manufacturers would unlikely take the risk to implement CM as adopting new technology may lead to delays in regulatory approval, and consequently delays in delivering drug products to patients.
Nonetheless, the regulatory expectations for both BM and CM are essentially the same [3, 7]. Regardless of the mode of production, manufacturers are expected to have technically sound and risk-based processes to produce quality products [7]. For existing products manufactured by BM, filing for a post-approval change for the implementation of CM is a requirement by most RAs [3].
Notably, a key difference among the guidelines is that FDA draft guidance does not apply to biopharmaceuticals and APIs. Many stakeholders have expressed concern about these differences and expect FDA guidance to be aligned with ICH Q13 to ensure global harmonization [67]. Harmonization can be achieved through ICH Guidelines, since ICH is well-represented by regulatory and industry members [68].
While ICH guidelines are not mandated by law, ICH members are expected to implement ICH guidelines in Step 5 of ICH Procedure, as illustrated in Figure 4 [69]. Therefore, with the implementation of the harmonized ICH guidelines by RAs around the world, manufacturers will have greater clarity on the regulatory expectations of the various countries.
Challenges and opportunities in implementing CM
Although there is some progress, there is still considerable traction in the uptake of CM in the pharmaceutical industry. As listed in Table 5, there are various shortcomings of CM which may hinder manufacturers from adopting this technology.
Regulatory challenges
In multiple studies, the authors concur that the top barrier for implementation of CM is the regulatory challenges stemming from a lack of a globally harmonized regulatory guideline on CM [11, 23, 29, 70, 71]. Harmonization is crucial; otherwise, manufacturers must obtain approval from different RAs to market their products in various countries [72]. Historically, RAs tended to suppress post-approval changes to drug products, inadvertently ingraining a fixed mindset of batch processes in manufacturers' production philosophy [76]. Furthermore, fear of regulatory delays has hindered the adoption of CM by manufacturers [72].
Nonetheless, regulatory support for CM has grown in recent years. FDA, EMA and PMDA have established specialized teams to promote the adoption of CM. Established in 2014, FDA Emerging Technology Programme (ETP) aims to help manufacturers overcome implementation challenges [77, 78]. Furthermore, regulatory guidelines on key prerequisites of CM has been published to aid in the implementation. Guidelines include the definition of a 'batch' [3], process validation [3, 79], continuous process verification [80, 81], and PAT [19]. Also, with the implementation of ICH Q12 guideline in 2019 [82], unnecessary post-approval applications are reduced to promote manufacturing innovations [83]. Therefore, while regulatory uncertainty is currently the top barrier, it is plausible that ICH Q13 will address this challenge once the guideline is implemented.
High initial cost of investment
The development of continuous processes is costly, owing to the use of PAT and automation software [38]. The high initial cost is another crucial barrier for manufacturers in adopting CM [41], due to the difficulty in justifying the case for new equipment as existing batch equipment is still functional with established regulatory approval [49, 73]. Hence, investing in CM is not a priority for most manufacturers [49]. In particular, this is a significant barrier for generics manufacturers operating on low-profit margins [4, 84]. Unpredictable demand for generic drugs would further deter a generics manufacturer from investing in CM [85].
Despite the high initial capital investment required for CM equipment, manufacturers can expect to reap economic benefits, especially with high-volume production. In multiple studies, CM has proven to reduce the cost of production [6, 18, 25–28]. An analysis conducted by the Novartis-MIT Center for Continuous Manufacturing showed a significant reduction in labour cost, in-process inventory and energy consumption, resulting in more substantial cost savings [18].
Nonetheless, economic analyses for the CM of biopharmaceuticals show conflicting results. Studies conducted by Pollock et al. [86] and Klutz et al. [43] on continuous antibody production affirm that the hybrid approach is more economically favourable than end-to-end CM [43, 86]. However, Hammerschmidt et al. [87] contend that fully continuous processes allow for the most significant cost savings. The differences in findings are possibly due to the complexity of a myriad of factors in biopharmaceutical production [88]. Nevertheless, most economic analyses maintain that BM is the least economically favourable approach compared to CM [13, 43, 86, 87, 89]. Research has shown that the cost savings could outweigh the high initial cost of implementation [90]. Therefore, CM is an opportunity for manufacturers to generate long-term profits [91].
Quality, safety and technical considerations
Material traceability is a key quality concern as characterization of raw materials and intermediate properties are more complex in CM. It is difficult to define the start and end of each batch of product in CM processes [10, 70, 72, 92, 93]. This is exceptionally challenging in low-volume and low-dose drug products due to the high amount of excipients used [70]. To overcome this obstacle, RTD monitored by PAT is a potential solution to ensure material traceability by determining the time taken for the material to pass through each unit operation [70, 93–95].
Additionally, advanced process control strategies are critical for CM to assure process performance and product quality [80, 96]. According to ICH Q8(R2) and Q10 [80, 96], control strategies include material and product attributes, operating conditions, product specifications, and process control. ICH Q8(R2), Q9 and Q10 quality trio provide guidance on developing control strategies that incorporate QbD [80] and risk management [97]. As part of the control strategy, real-time process management segregates any non-conforming material, thereby ensuring the high quality of the drug product [73]. Also, start-up and shutdown can be minimized to reduce material loss and cost incurred [92].
Although CM is generally safer than BM in that there are fewer transition steps [15], still it presents critical safety considerations. Manufacturers need to prevent overfilling of material, over-pressurization of the system, and other potential hazards not found in BM [72]. In recent years, some publications have addressed these technical issues on CM [10, 73]. Moreover, many equipment manufacturers are collaborating with the pharmaceutical industry to overcome the technical challenges of CM. Therefore, technical challenges are not necessarily substantial barriers for manufacturers. As opined by Janet Woodcock, Director of FDA CDER, making the business case is a greater barrier than technical issues for biopharmaceuticals [29].
Equipment and technological challenges
There is currently a shortage of available CM equipment [14, 72]. Smaller manufacturers lacking such capabilities have to outsource their production to a limited number of contract manufacturing organizations (CMOs) with CM equipment [11, 49]. In this regard, manufacturers should also consider the risk of material cross-contamination and data security when engaging CMOs [98].
Apart from the lack of CM equipment, research on CM technology was initiated mainly by academic institutions and equipment manufacturers, without active involvement from the pharmaceutical industry [11]. Consequently, this led to late-stage adjustments to the equipment by pharmaceutical manufacturers, further delaying the adoption of CM [11]. The slow implementation by pharmaceutical manufacturers has decelerated the rate of innovation by equipment vendors [72, 99].
In addition, as asserted by several studies [33, 73], batch unit operations involve discrete equipment that can be easily rearranged to enable multiple manufacturing routes. However, discrete batch unit operations come at the expense of lower plant and equipment productivity [33]. While CM is currently less flexible in this aspect, 'plug-and-play' continuous equipment comprising distinct reconfigurable unit processes are being developed [23, 100].
Therefore, this challenge will presumably become a stumbling block of the past, as interest in CM is escalating amongst pharmaceutical manufacturers, spurring greater involvement in the innovation process. Biopharmaceutical manufacturers are also collaborating with equipment vendors to innovate new CM technologies for biopharmaceuticals [99].
Knowledge and skills gap
Highly skilled personnel are required to develop and implement CM technology in cGMP facilities [41]. As CM is still in its infancy in the pharmaceutical industry, there is a lack of personnel with the relevant skills and knowledge [41, 49, 57, 70, 72]. This is a hurdle for both manufacturers and regulators as continuous systems require statistically trained personnel to understand the data generated [72]. Although training has been conducted, addressing the knowledge gap would require greater multidisciplinary collaboration [41] and commitment from all relevant stakeholders [72].
Inevitably, the adoption of CM will also cause some manual jobs to become obsolete due primarily to automation [74]. However, since there is a need for highly skilled personnel, CM presents an opportunity to create new jobs in R & D and testing [74]. Additionally, reduction in labour intensity will also produce less human errors [4]. Therefore, there would be an increase in new job openings requiring highly competent workers.
Business, operational and cultural challenges
Optimally, CM should be implemented in the early phases of drug development [92] to eliminate regulatory requirements needed to prove equivalence to current batch processes [77]. Correspondingly for biopharmaceuticals, it is more effective to implement CM at the clinical stages rather than modifying existing batch processes [77]. This is because biopharmaceuticals are inherently more complex and highly process-dependent [77]. However, the steep learning curve for the CM of a new drug product may encumber a tight launch timeline [77]. Therefore, aligning the manufacturing innovation with a clinical trial timeline is an uphill task and may require structural changes within the organization [72].
Furthermore, regulatory uncertainty has led to a conservative culture in the industry, delaying the adoption of new technologies [57]. Hence, mindset and cultural changes are needed within the pharmaceutical industry to shift its production philosophy of BM [72, 73]. Additionally, new technologies need to have significant proven benefits before they are implemented widely in the pharmaceutical industry [72, 92]. Hence, it is paramount for international organizations to publish success stories of CM to build confidence amongst manufacturers [57].
Challenges for pharmaceutical and biopharmaceutical products
As presented in Table 3, all of the approved drugs manufactured by CM are OSDs. Tablets represent the majority of pharmaceutical dosage forms [73, 92], and there are existing technologies for the CM of OSD. Also, FDA draft guidance is tailored towards small-molecule OSD [3]. These factors enable manufacturers to implement CM for OSDs with greater ease. Nonetheless, a one-size-fits-all approach would not be feasible for all dosage forms. Off-the-shelf equipment made for small-molecule drug production is not applicable for biopharmaceuticals [13, 101, 102]. In light of the complexity of biopharmaceutical manufacturing processes and products, CM of biopharmaceuticals is more technically challenging than OSDs. Furthermore, in the manufacture of biological vaccines, there is a need to develop continuous processes for viral inactivation, ultrafiltration and diafiltration [103]. Therefore, more research and investments into biopharmaceutical CM are required to actualize it [90].
Nevertheless, there is promising progress in the development of CM for newer dosage forms. At present, PAT tools are available for formulations such as suspensions [104, 105], liquids [104, 106] and emulsions [104, 107]. Also, as reported by Worsham et al. [12], there are economical and quality benefits for the CM of liposomal drug products. Therefore, CM for various pharmaceutical dosage forms and biopharmaceuticals is gaining momentum and is expected to become more prevalent in the future.
Recommendations and future perspectives
Despite the challenges faced by manufacturers and regulators, progress towards the transition to CM is evident. In this section, key recommendations are proposed to facilitate the implementation of CM.
Regulatory harmonization
As emphasized throughout this review, regulatory harmonization is imperative to address the current regulatory uncertainty in the industry. Without harmonization, implementation will remain sluggish as regulators endeavour to understand new CM technologies [58]. This issue would be addressed in the upcoming ICH Q13, expected to be completed in 2022. With the ICH Q13, there would be harmonised expectations for dossier approval and lifecycle management [108]. Consistent regulatory assessment and oversight would likely speed up the adoption of CM [49, 65]. The benefits of harmonized regulations include process improvements, development of new manufacturing methods to produce new molecules, and ultimately improvement in the access of medicines to patients [65]. Currently, many of the major regulators are working on ICH Q13 as members of ICH. While ICH guidelines are not mandatory, it is still worthwhile for regulators that are not part of ICH to use the published guidelines as a reference to create their specific guidelines on CM. Assuredly, with global regulatory harmonization, implementation of CM would substantially increase, as manufacturers will have greater clarity on the regulatory requirements.
Management of financial risks
Industry-wide pre-competitive initiatives such as efforts by global consortia could be organized to de-risk investments [24]. Also, CM technology that is applicable for multiple products will reduce the investment risk [33]. It is also essential to conduct a comprehensive analysis on the functions, costs and benefits of new technology [33]. Currently, most economic analyses are performed on finished drug products, but not on APIs [57]. Hence, there is still a need to develop a business case for the CM of APIs [109, 110].
Sustained financial investments from the government will also alleviate the high initial cost [72]. Historically, tax and regulatory incentives have led to industry-wide advancements [49]. Tax incentives, namely in Ireland, Singapore, and Puerto Rico allowed pharmaceutical manufacturing hubs to thrive [49]. As CM would ultimately benefit patients with improved access to medicines [65], governments should provide tax incentives for CM [49]. Today, government support for CM technology is steadily increasing [58, 111].
In addition, regulators should consider granting regulatory incentives to manufacturers for implementing CM, to expedite the approval process and grant a patent exclusivity period for drugs manufactured via CM [49]. With these incentives, manufacturers would be motivated to adopt CM as they would have the opportunity to break even faster and make greater profits.
Hybrid processes
Implementing the full end-to-end continuum of CM might be a quantum leap for manufacturers given the myriad of challenges. To overcome this hurdle, manufacturers can employ hybrid approaches to implement CM in a stepwise and progressive manner [33]. By combining the advantages of batch and continuous processes [112], manufacturers can leverage on hybrid processes to generate revenue to offset the high initial cost [39], increase output [36], and gain experience with continuous unit processes. Hybrid approaches are also economically favourable in the production of antibodies [43, 86]. Through this approach, manufacturers can assess the benefits of continuous processes and progressively transition towards end-to-end CM, thereby reaping all the benefits of CM for both small-molecule drugs and biopharmaceuticals [13, 41].
Capacity building, collaboration and publication
Training programmes must be conducted to address the lack of skilled workers in CM technology [67, 75, 113]. Currently, there are training programmes organized by various organizations, including ISPE, C-SOPS and the United States Pharmacopoeia (USP). The pharmaceutical industry can also learn from other industries that have implemented CM and adapt the processes for their products [57, 73, 75]. Implementation of CM also requires cross-departmental collaboration and institutional partnerships [24]. Manufacturers should engage in constant communication with regulators and industry experts [7, 84]. Global conferences, such as ISCMP [47] and national initiatives such as the 'Pharma Innovation Programme Singapore' [63] are cornerstones for fostering collaboration to drive innovation forward.
In addition, the publication of success stories and challenges of CM would build confidence in the industry and establish best practice standards [57]. Training programmes and publications are equally indispensable to ensure that the industry is well-equipped with the knowledge and skills needed to implement CM [49, 70].
Culture of quality
For decades, the pharmaceutical industry has been utilizing BM, steadily instilling a narrow mindset and conservative culture within manufacturing organizations [37, 57]. In a published interview, Jayjock [114] asserts that shifting organization mindsets is the most challenging issue of adopting CM. In recent years, however, manufacturers are growing in receptivity towards CM, and are adopting pharmaceutical quality systems (PQS) which are crucial for CM [96]. Nonetheless, PQS has its limitations as quality outcomes are contingent on people making quality choices [115]. Hence, manufacturers need to embrace a culture of quality to produce quality products via CM [116]. Organizations can also adopt Kaizen or Lean Six Sigma principles to develop cross-functional continuous improvement of quality [115, 117].
Industry 4.0 and Pharma 4.0
At present, there is an astounding amount of data collected in the pharmaceutical industry that is underutilized [117], with data integrity still being a pressing issue [20]. These issues would likely be exacerbated in CM due to an increase in data collection from systems such as PAT [117].
Nonetheless, the pharmaceutical industry is progressing towards Industry 4.0 to overcome the challenges highlighted above. Pharma 4.0, modelled after Industry 4.0, is driven by technological advancements, such as big data, Artificial Intelligence (AI) and cloud-computing [20]. These technologies process, store and convert data into useful knowledge [22]. For instance, cloud computing [21] and deep neural networks (DNN) [118] can support the implementation of PAT in CM systems. With the support of guidelines [119] and pharmacopoeias [120] on computerized systems, uptake of these technologies has been rapid. Organizations are also working with regulators to integrate AI into CM to enable real-time release [121].
With time, Industry 4.0 would cause a paradigm shift in pharmaceutical manufacturing. As technology advances, machine learning and predictive analytics may even enable preventative maintenance without shutting down continuous processes [122]. Though CM aligns with Pharma 4.0 objectives [90], manufacturers should conduct more research in integrating new technologies into CM, as data security processes must be robust to prevent cyber threats [122]. Also, manufacturers are advised to start with minimal cGMP impact processes [117].
The pharmaceutical industry and regulators have recognized the benefits and opportunities of CM. Propelled by various driving forces, several manufacturers have successfully adopted this technology. Since the CM of pharmaceuticals is an emerging field, there are still significant challenges that need to be overcome. However, with the implementation of ICH Q13, regulators would have specific guidelines on CM, thereby eliminating the top barrier to implementation. Thereafter, the implementation of CM would substantially increase with regulatory harmonization. Nonetheless, due to the complexity of pharmaceutical processes and products, there is no one-size-fits-all solution. Therefore, it must be emphasized that while regulators work towards creating a harmonized guideline on CM, manufacturers should work on overcoming existing cost, technical, and cultural challenges.
Perhaps these challenges could be seen as opportunities for growth. Other industries have paved the way forward towards an optimistic future. Now it is time for the pharmaceutical industry to rise to the challenge, seize the opportunities and revolutionise pharmaceutical manufacturing with CM. Ultimately, the world would benefit from greater response capacities to drug shortages and pandemics, while contributing to environmental conservation. Closer to heart, individual patients' lives would be improved with greater access to life-saving medicines.
Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc
Teh Kee Siang, BSc (Pharm)(Hon)
Associate Professor Chan Lai Wah, BSc (Pharm)(Hon), PhD
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
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Author for correspondence: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc, Senior Consultant (Audit and Licensing) and Director (Quality Assurance), Health Products Regulation Group, Health Sciences Authority Singapore, 11 Biopolis Way, #11-01 Helios, Singapore 138667


Introduction Although localized weakness and wasting following herpes zoster are well recognized, cases with severe involvement of the spinal cord and brain are uncommon. Death from herpes zoster is even rarer, and Boudin and his colleagues 1 found only seven records of autopsied cases in the literature and added one of their own. Because of the paucity of these cases, we report another autopsied case of zoster encephalomyelitis.