Covid-19 has affected design and conduct of all kinds of clinical trials, specific areas of vaccines, and therapeutics directly related to SARS-CoV-2. It has also impacted in other major therapeutic areas such as oncology/cancer treatment.
At the ongoing PMWC 2021, there was a session on how Covid-19 has changed clinical trial dynamics and environment. The participants were Dr. Ms. Jia Xin Annie Yu, Anna Maria Kellen, Clinical Accelerator, Cancer Research Institute (CRI), and Dr. Ms. Kristina McGuire, Regeneron Pharmaceuticals Inc. Patrice Hugo, Q2 Solutions, was the Session Chair.
Patrice Hugo laid out five facts. The first is the global regulatory environment. We have decided to use four global hubs, USA, UK, Singapore, and China. China does not handle/test samples from patients with suspected or confirmed Covid-19 samples, nor will central labs perform SARS-CoV-2 testing. Next point is, how to cope with scientific innovations? There is a viral load by nucleic acid tests, which is the gold standard for detecting infection. Serological tests indicate past exposure and immunity status, and antigen tests are for limited use in trials. In the USA alone, 235 nucleic acid assays, 64 serological tests, and 12 antigen assays were submitted.
Next, there is the technology vs. the intended use. There are SARS-CoV-2 serology tests to support the clinical trials. Fouth, how do you adopt new technologies? There are SARS-CoV-2 PCR qualitative and quantitative tests, serological total Ig, IgM, IgG tests, next-generation flow cytometry, genomic analysis, bioanalytical PK, vaccine immunogecity. It also comes down to delivering on-time high quality lab tests.
In conclusion, consider good science first, and be mindful of global and local regular requirements. You need to engage with drug developers to discuss and get alignment. You also need to engage with IVD and reagent manufacturers.
Dr. Ms. Kristina McGuire said that there are challenges to clinical trials during the pandemic. Clinical trials were initially negatively impacted as the world shut down. The Covid-19 trials themselves had become an unprecedented urgency. Trials also overburdened the infrastructure. Now, it has become a marathon. Ongoing trials have resumed and Covid-19 trials are top priority. However, the business infrastructure has not been that elastic.
Regeneron has a rapid response for global good. Using VelociSuite technologies, discovery, and pre-clinical validation have been speeded up. Co-ordination and flexibilty are now required. There are critical Covid-19 trial elements, such as testing, trial protocol, clinical trial kits, supplies, sites/subjects, clinical logistics, contracts, and central lab. Be prepared for the unexpected at every turn.
Shortages impacted clinical trial kits, patient visits, hoarding tendencies, etc. There were initial shortages of toilet paper, PPEs and swabs/media. Just when things were looking better, cryovials and sample collection tubes were on backorder or unavailable. Covid-19 trial kits demand doubled the usual kit production. Clinical trial kits contain everything to collect samples to support trials. Point-of-care and lab testing challenges were also impacted by the speed and volume.
Labs, vendors, test providers and biotech/pharma companies had to come together to solve problems of the trials and the patients. They have been assisted by the central labs, specialty labs, suppliers, and logistics. We have all learned to be better together. Demand has been met by extraordinary measures. The industry has been continuously improving processes, supply, resources, etc.
Dr. Ms. Jia Xin Annie Yu, CRI, said they started with a methodology to understand the impact of Covid-19. The enrollment was negatively affected globally. Patient risk-benefit was the key consideration for ongoing and new trials. There were delayed or cancelled visits that impacted more than half of the respondents. A shift towards telemedicine was seen early in the pandemic.
There were over 200 IQVIA managed oncology trials surveyed in March 2020. Oncology clinical trials were also suspended initially. The total trials stopped had peaked in June 2020. Recovered trials are largely interventional oncology trials.
Dr. Anthony S. Fauci, Director, US National Institute of Allergy and Infectious Disease (NIAID), and National Institutes of Health (NIS), was facilitated this evening at the ongoing PMWC 2021, by Dr. Leroy Hood, SVP and Chief Science Officer, Providence St. Joseph Health, Chief Strategy Officer, Co-founder, and Professor, Institute for Systems Biology (ISB), and Co-Program Chair, PMWC 2021. Dr. Fauci was presented the luminary award.
Dr. Fauci was appointed Director of NIAID in 1984. He has served as a relentless crusader for some of humanity’s most virulent medical threats. He has advised six Presidents on HIV/AIDS. He oversees an extensive research portfolio of basic and applied research to prevent, diagnose, and treat established infectious diseases such as HIV/AIDS, respiratory infections, diarrheal diseases, tuberculosis and malaria as well as emerging diseases such as Ebola, Zika and now, Covid-19.
Dr. Fauci said it is a great honour to receive this award from Dr. Hood. He also recalled in 1968, where, there was a Journal Club. Dr. Fauci was invited to join the club by Dr. Hood.
Covid-19 challenge and benefits
Dr. Fauci added that one of the clear things was how we showed the investment in vaccine technologies and pathogens, to go from the availability of a sequence, to a vaccine going to the arms of patients in 11 months. So many people do research. People were talking about vaccine all along. People thought it was a gap
Dr. Fauci spoke about the need for unity throughout this pandemic. He said: “This requires unity because we are all in this together. When wearing a mask becomes a political statement that is antithetical to combating a pandemic. We have a reasonable chance of crushing Covid-19 like we did with polio, measles and smallpox, but it will require global collaboration. It can’t be a thing that only rich countries get vaccinated.”
For the future, if we are able to remember the lessons, we would do well. We will have the capabilities to respond better. Go back a few years. SARS-Covi had happened in 2002. The time has come to develop a universal coronavirus vaccine. We have a very efficacious vaccine, which helps people by about 94-95 percent to get better. The efficacy level has remained constant. When this is over, we need to have a commission, and look at what we can do about the future problems.
Dr. Hood next asked about the RNA approach. Dr. Fauci said there are three platforms for Covid-19. One is RNA. If you need to change it, that’s very simple, as you need to pull it out. The idea that you can do with mRNA is better. Some vaccines are problematic, such as HIV, cancer, malaria. Messenger RNA (mRNA) is a single-stranded RNA molecule that is complementary to one of the DNA strands of a gene.
Pathogen sites can be a target. We were doing work on RSV. Respiratory syncytial virus (RSV) causes infections of the lungs and respiratory tract. It is so common that most children have been infected with the virus by the age of 2. Respiratory syncytial (sin-SISH-ul) virus can also infect adults. We were looking at the stabilized primer of the HIV. It was unstable. It took 2-1/2 years for the right mutations to stabilize.
Dr. Hood said that with cancer, people have long sought vaccines. What is the possibility with cancer tumors to make RNA vaccines for them? Dr. Fauci replied that these are exciting possibilities. The mRNA was really good for the efficacy. People were thinking more new stuff will be coming along.
Dr. Hood next asked: if you just have one shot of the vaccine, how good is that protection going to be? Dr. Fauci said that Moderna and Pfizer RNA showed that the optimum response gave 50 percent protection. If you have a gap between two shots, you get a 10-fold increase in protection. There is a prime, and a boost. There is a single-shot vaccine that is being tested in USA, Africa, etc. Once that is available, it will help.
Immunity does not last forever!
However, Dr. Fauci does not know how long will the vaccine prevent against Covid-19. The immunity does not last forever! When you are vaccinated, you get an open response. It will be probably for a longer duration. We need to get a substantial proportion of the world vaccinated. We will then develop a degree of herd immunity. There will be few susceptible hosts in the community. However, we are not going to crush it, unless you have a multi-year global vaccination campaign going.
With Moderna, the antibodies were said to be six times less effective. Dr. Fauci said there are two lineages of the vaccine — one in the UK, and one in South Africa. It does have a factor of transmissibility. The cushion of efficacy for the vaccines against the South Africa strain is high enough. Moderna is starting to make variants, along with the booster. They are testing for safety and immunity. We only talk about antibodies. These vaccines do induce immunogens for CD4 or CD8.
An immunogen is any antigen capable of inducing humoral and/or cell-mediated immune response, rather than immunological tolerance. This ability is called immunogenicity.
A normal CD4/CD8 ratio is greater than 1.0, with CD4 lymphocytes ranging from 500 to 1200/mm3, and CD8 lymphocytes ranging from 150 to 1000/mm3. If your ratio is higher than 1, it means your immune system is strong, and you may not have HIV. You may get HIV/AIDS if your CD4 count is less than 200/mm.
A CD4/CD8 ratio is considered normal when the value is between 1.0 and 4.0. In a healthy individual, that translates to roughly 30 to 60 percent CD4 T-cells in relationship to 10-30 percent CD8 T-cells. He added that there are new single-cell technologies. There are lot of labs who are developing those.
Antivirals and their effectiveness
Next, what about the antivirals? How effective are they? Dr. Fauci said there is no data available so far. In HIV, you drop the virus, and you get better. We are not yet sure with Covid-19. The treatment is hospitalized patients with oxygen. There are variable results with other studies. There are IL6 receptors, etc., that seem to have an impact.
Anti-IL-6 receptor antibodies are used in the treatment of Coronavirus-associated pulmonary pathology. During the global SARS-CoV-2 pandemic (2019-2020), antagonistic antibodies against the IL6 receptors were tested in clinical trials to assess their use in treating or preventing severe pneumonia in critically ill Covid-19 patients. We need to have drugs that can be given early on. You need to develop better antibody response.
Further, does aging alone increase risk? Dr. Fauci said that yes, it can be a problem. Age alone is an individual factor. Obesity is a prominent factor for high-risk diseases. People in the minority group are also open to getting infected due to the nature of the jobs that they do. You can stay generic. With obesity, it is a mechanical issue. There is a problem with the free flow of the diaphragm. The difference between races is miniscule. It is dependant on the social determinants of health, that create co-morbidities.
The British probably do many more sequence surveillance than the USA does. We need to do that, as well. The CDC has put together a consortium called SPHERES. The consortium includes 37 state and local public health laboratories, several large regional and national clinical diagnostic corporations, and academic and non-profit leaders, in pathogen genomics, bioinformatics, and public health from across the country. This consortium collects genomics-related data. We have to do comprehensive sequencing to know much more about the African strain.
It is a real phenomena, for those with symptoms of disease. After they clear the virus, they are RT-PCR compliant. There are variable degrees of symptoms that are common, such as fatigue, muscle ache, brain fog, etc. People get upset when you say that.
Dr. Fauci further added that we need to develop large cohorts. We also need to find the symptoms. We need to find any inflammatory markers, etc. We need to look at these, and other things clinically. We are going to ask the Congress for resources, for cohorts for the other diseases. The single-cell analysis will be transformational in the future.
Next, can we get things under control? He added that we have to get as many people vaccinated, as quickly as possible. We are certainly going to get variants. A multi-varient vaccine can help us crush this disease. The world has to pull together. We need to have co-operation, collaboration, and solidarity. The virus will continue to evolve with countries who are not able to clear it rapidly. The virus will mutate. There will be highly suppressed population.
Dr. Fauci said that back in February 2020, he had to contradict policies of the previous administration. N=1 is not a scientific process, it is an observation. To have a serious historic outbreak occur, when there is political divide in the country, is not a good thing. One, we needed to own the problem, back in 2020. We needed to double down, and it is a serious situation. On working with the previous administration, Dr. Fauci said, “I took no pleasure in having to contradict an administration, but I had to do that early on, because we saw discussions around anecdotes instead of science.”
He added: “The first thing we have to do is we have to get as many people vaccinated as quickly as possible to shut off these ridiculous numbers. “The virus is continuously to evolve and if you give the virus an extra few days in a host it will mutate to survive – the immune system is going to push the virus to mutate.”
Every country in the world has been hurt badly, since then. The federal government should not fix local problems, and the local governments should not be left on their own. The virus does not care about the border between the different states. People should also not avoid mask wearing, and doing congregations and gatherings.
He added that the WHO was delighted that the USA had returned to its fold. Today, USA is really very concerned about the virus. Public health messages are now going out. Let’s not be so divisive that we now let a viral enemy win this war. It is an enormous challenge for the country. We are now facing a grand challenge.
If someone close were to fall ill, we will need to get the vaccine that attacks the virus early. We can get him or her dexamethasone, probably. It was tested in hospitalized patients with Covid-19 in the United Kingdom’s national clinical trial RECOVERY, and was found to have benefits for critically ill patients. Sometimes, putting patients on the ventilator could be the worst thing that you do.
Finally, there are some gaps in the education for infectious disease. There should be greater interest among the students, interns and residents. We are not spending enough time on the infectious diseases.
On a personal note, may I take this opportunity to thank Dr. Lee Hood for inviting me to this great conference. It was an absolute pleasure listening to and covering Dr. Anthony Fauci.
The next session at PMWC 2021 was on building a health data platform that supports Covid-19 health care. Understanding disease trajectories and clinical outcomes require an accelerating, holistic data collection and analysis platform that will deliver new insights into the classification of patients into distinct categories and an understanding of the immune response to disease.
Dr. Joel Dudley, Tempus, was the Session Chair. He talked about data sharing, testing, etc. This session reviewed the enormous business opportunities that the ecosystem will provide for each one of the partners.
Prof. Christopher E. Mason, Weill Cornell Medicine, said that they had quickly profiled the patients. The scale and the speed were unprecedented. There have been new partnerships for data sharing and data platforms. We need to build data to create a pool. There is clinical metadata that was missing. We built that in around six weeks. There is data privacy, as well. There should be more universal consent from all the other hospitals. That will help us with research. There is a delicate balance for data sharing currently.
James R. Heath, Institute for Systems Biology, elaborated that they did deep scientific studies with the electronic health records (EHR). A challenge was that you were typically into the data sharing issue. You were limited to the demographics to the hospital you are connected to. Most of the EHRs are designed for re-imbursement, not for disease. The EHRs were woefully incomplete. The pandemic has also taught us how little we really understand immunology.
`The health data opportunity is huge. You need to take major learnings and do a deep dive with the clinical data. We are also uncovering places where you can’t do that. As we go forward, we need to know about the patients under care. We need to make the data in the records more deeply informative.
Carlos D. Bustamante, Stanford University, said that we need to see where the pandemic was earlier. We need to see who handled it well, initially. It clearly goes beyond the EHR. There is less about data, but more about relationships. Data on its own is just a bunch of stuff! Treatments tend to be developed later. We need to start sequencing everything, and everyone, including the minority population.
Solving Covid-19 will help solve many other issues. Even Stanford was quite unprepared. There was lot of work to be done. A lot of people were told to work on the EHRs of people. We did not do what the UK could do. We also need to look at other middle-income countries, and see what they are doing. The first thing out of Covid-19 genomics was the antibodies. There was a lot of variation. We need to go back and look at the triggers. We need to make a healthcare system that is affordable and better for all.
Ms. Anne Wyllie, Yale School of Public Health, added that a lot of research was driven towards Covid-19 response. We looked at a whole array of the incoming data. It can teach us more about the future. We also needed to get the swabs for research, and clinical diagnostics. Saliva was performing pretty well from the samples that we got. We have now built a platform for saliva testing. We also tried to make testing more affordable. Data sharing is very important.
We now need to share the experience, and make science more open. We need to make the testing process for saliva even more affordable. Saliva samples are also hard for some labs to get. We made sure that we had the different number of combinations of free agents. We need to reduce prices, and keep competition between the different suppliers. We have seen a growing collaboration of Clear Labs. We now have a network of labs that can also go out. We need to learn from all of the different experiences, going forward.
Precision Medicine World Conference (PMWC) 2021 began in Silicon Valley, USA today. Keith Yamamoto, UCSF and Session Chair, welcomed the audience. The panel discussed how Covid-19 led to disruption of biomedical research and healthcare.
Healthcare practice, data sharing, telemedicine, clinical trial design, and enrollment adapted in real time, and opportunities emerged to establish value-based strategies that could transform 21st century healthcare through collaboration around a big-data ecosystem.
Dr. Jeffrey R. Balser, Vanderbilt University Medical Center (VUMC), said there is a need to collect patient information. REDCap (Research Electronic Data Capture) facilitates co-operative research.
REDCap is a web-based software solution and tool set that allows biomedical researchers to create secure online forms for data capture, management and analysis with minimal effort and training. The Shared Data Instrument Library (SDIL) is a relatively new component of REDCap that allows sharing of commonly used data collection instruments for immediate study use by research teams. There is also a cancer patients database. These kinds of tools are critical.
We are trying to prioritise the vaccine, which is right now in limited quantity. We can develop automated ways to pull out patients. That capability is not yet there at scale in the USA. There is also lot of mechanical stuff around telehealth. At Pfizer, people pay by the month. We are not there yet. We need pre-authorization for everyone to do telehealth business. We need to schedule people for vaccination. We need an infrastructure around telehealth that scales for the country.
Dr. Yvonne Maldonado, Stanford University School of Medicine, added that this has been a challenging time. Besides being an academic researcher, part of her role is to work on clinical response. They were able to build a proprietary FTA PPE for Covid-19. They rapidly developed clinical trials for the outpatients. We took care not to risk the exposure to the other patients. We studied, patients, trends, and risk factors. We are tracking several thousands of people around the Bay Area. We studied the population impact of this disease. We also built more community engagement.
One other aspect that needs to be conquered is: how do we find people? They have access to different modalities. We need to approach them at the community level. There are mobile phones that can be tapped into, if required. Where is also the national framework for healthcare? We need to deal with that. We have the opportunity now.
Dr. Peter Walter, UCSF, said that their labs were initially shut down. We used technology for a different purpose. The nanobody was developed. It is a simple version of the antibody. We accomplished our tasks within five months. The research needs to be continued, and carried on to the next steps. We have some information, so far. We need more clinical testing to be done. We also need to take the ball from one player to another. The distribution of nanobodies would become easier, over time. There is need for a more creative approach for the future.
Dr. Ralph Snyderman, Duke University, noted that poor people have less access to telehealth. We need to extend those. There is a tremendous need for interconnectedness. There has been a failure, and there is need for an infrastructure for the continuity for care. Developing solutions were a series of one-off. We need to bridge the last mile. They had immunized 14,000 people, but that is a small number. We also need to have implementation science. Also, to participate at a minimum, you need a smartphone. If people can come to the health center, we can look after them. Who can give every participant a smart device? We need to have the capability to get distance technology to the people. Basic science alone will not be sufficient.
Jean-Christophe Eloy, CEO and President, Yole Développement, presented on Innovation in Advanced Packaging is Coming from AI Processors, at the ongoing ISS 2021.
There is a classification of processor chips, such as vision processors, AI accelerators, and GPUs. There are programmable logic processors, such as configurable SoCs and FPGAs. Server market is the most growing logic market. Datacenter is also around. There are edge datacenters that do AI training, and apps are pushing the demand.
The road to augmented intelligence is here. Led by PCs, and later, smartphones, it has moved on to robotics, holographic interaction, etc. AI inference and training have different requirements. High computing is required for these. More and more models are trained with the growing number of data. Computing requirements rely on the app. You need different devices for learning and inference.
Impact of AI
The impact of AI is huge. AI in imaging is also possible. There are AI acceleration chips. The revenues for logic for datacenters is also increasing, from $18 billion in 2019 to $33 billion in 2025e.
High-end performance packaging is growing. It is defined as the front-end packaging technology. Hybrid bonding is the new wave of integration. 3D SoCs are also emerging. There are advantages of die partitioning. It consists of splitting a dye’s functions and redistributing them.
3D SoC is likely to be adopted in telecom and infrastructure servers, and mobile and consumer, for game stations and laptop PCs. Large OSATs are separated from the rest. The top 8 OSATs have continued with heavy investment in capex and R&D. In the packaging supply chain, there is need to go head-to-head or along with the big guys.
The overall advanced packaging revenue forecast for mobile and consumer is high, at CAGR of 5.5 percent. Megatrends are pushing devices, such as AI, Big Data, 5G, IoT, smart, etc. Packaging is adapting to these trends.
Yole Développement and System Plus Consulting provided an understanding of today’s 2.5D/3D packaging market and its evolution. Intel, TSMC, and Samsung have tapped into the advanced packaging market’s growth with finite element (FE) and BE capabilities. They have achieved faster time-to-market than outsourced semiconductor assembly and test (OSATs) players for the high-end performance packaging. This strategy poses a formidable threat to OSATs.
Favier Shoo, Technology and Market Analyst, Package Assembly and Substrate, Yole Développement, said that the semiconductor industry today has only three players left with leading-edge manufacturing capabilities, namely, Intel, Samsung, and TSMC, at 7nm. How many will remain at 5nm/3nm remains to be seen.
There is leading-edge node, with steep investment cost, in the combined roadmap of 3D interconnect density and technology nodes. Front-end scaling remains a work-in-progress in the background. The market drivers of 3D/2.5D packaging market include HPC PU in servers, from TSMC and Intel in 3D SoC. The types of technologies that will evolve by 2025 include hybrid bonding, embedded Si bridge, TSV, micro-bumps, 2.5D interposers, UHD FO, etc.
Mapping the players based on technology, UHD FO has ASE Group, Samsung, TSMC, Amkor, etc. In the 2.5D interposers, there are ASE Group, Amkor, BPIL, GlobalFoundries, Intel, Micron, Samsung, TSMC, etc. For 3D stacked memories such as TSV and micro-bumps, there are Micron, Samsung, SK Hynix, etc. The embedded Si bridge has Intel and TSMC as the leaders. In hybrid bonding or bump-less, there are XPERI, TSMC, Samsung, Intel, UMC, etc.
If we look at the IP landscape in hybrid bonding for 3D SoCs, 60+ patent assignees have filed more than 1,400 patents, and regrouped in more than 400 families, related to hybrid bonding and / or 3D IC technology.
Stéphane Elisabeth, Technology and Cost Analyst, System Plus Consulting, spoke about 2.5D packaging. With identical 2019 form factor and packaging technology, Nvidia increased the performances of its data center GPU over the year.
As preliminary result, size of the interposer showed that x2 pass reticle is needed to achieve large size. The interposer and the GPU have been designed to support six HBM stacks. This could may append in the future version of the Nvidia Ampere A100. If we look at the CoWOS vs. UHD FO solution, using passive interposer or UHB FO can be a question that industrial is asking themselves. The cost relatives are the determinant factor in this choice. The cost estimation is based on several hypothesis, and not on the actual devices.
When we look at the Intel Foveros solution, there is the first application of 2.5D packaging using the interposer in a consumer device. Moreover, the interposer is for the first time active with support of all major interface blocks. The TSVs are designed for efficient power delivery. Each signal TSV is single, and power TSVs are by group up to 12 TSVs per C4 bumps.
Additionally, to power supply function, the interposer features audio codec, USB 2.0, USB 3.2, UFS 3.x, PCIe Gen 3.0, etc. There is the touch hub to support continuous activity (always-on) I3C, SDIO, CSE, SPI/I2C.
Next comes 3D packaging. For state-of-the-art memory die stacking, differences can be noticed in the change of generation that enable higher stacking potential in the high bandwidth memory or HBM2, compared to the HBM1. Change could also come from manufacturing processes from Samsung and SK Hynix.
Hybrid bonding has just started to enter the memory market with YMTC. For a long time, the technology was already used and enhanced in CIS market. The gain is not only on bit transfer rate. Specification of the memory is improved with the X-stacking of the logic. Hybrid bonding is a real game changer in this case.
As for the emerging technologies in 2.5D/3D packaging, the future will see the Co-EMIB or the co-embedded multi-die interconnect bridge solution. Co-EMIB solution is coupled with 2.5D and 3D stacking technology. If we look at the SoIC or system-on-integrated chips solution, TSMC goes beyond Intel’s solution with hybrid bonding.
Favier Shoo next presented the market forecast. The focus is on high-end segment. The high-end segment is defined as the market where an application is less sensitive to the cost, but requires smaller footprint in addition to high performance and reliability. It includes HPC, networking, and gaming. The mid-/low-end segment is defined by a good balance between cost sensitivity and performance. It includes sensing and lighting.
The high-end performance packaging market is expected to reach $4.7 billion by 2025 from $884 million in 2019, with a CAGR of 32 percent. By 2025, mobile and consumer segment will grow 40.8 percent, and telecom and infrastructure will grow by 58.4 percent. Automotive and mobility will grow 0.8 percent, and defense and aerospace will grow by 0.1 percent.
3D/2.5D packaging now essential
In conclusion, 3D/2.5D packaging has now become an essential part of the semiconductor industry, extending Moore’s Law at system-level. The 3D/2.5D integration is accelerating 3D interconnect density (3D ID) into new highs. Such is the value of 3D/2.5D packaging.
A strong adoption of end-system units in cloud computing, networking, HPC, and consumer devices, personal computing and gaming, has been observed. The trend is expected to continue. Future digital trends in end-systems require a far more intelligent and multifaceted devices. This leads to an intensive trend towards of finer pitch and 3D/2.5D integration at package level.
There is a dramatic shift in the fundamentals of semiconductor packaging. Leading companies, such as TSMC, YMTC, Xperi, XMC, Sony, Samsung Electronics and IBM) are starting to place priority on 3D IC and/or hybrid bonding IP strategy. The high-end packaging market size is valued at $0.8 billion in 2019, and projected to reach $4.7 billion by 2025, growing at a CAGR of 33 percent from 2019 to 2025.
David Jourdan, Global Sales and Support Co-ordinator, Yole Développement, was the moderator.
Yole Développement, France, and Chip Integration Technology Center (CITC), The Netherlands, organized a conference on RF packaging. Ms. Francesca Chiappini, Program Manager RF Chip Packaging, introduced CITC and the conference.
She said that in RF chip packaging, there are trends such as shift to mmwave frequencies (30-300GHz) for many apps calls for innovative high-performance and cost-effective packaging solutions. Introduction to the antenna-in-package (AiP) will help. The CITC and TUD approach has been the development of broadband measuring technique. They are also exploiting additive manufacturing (AM) methods and techniques for the realization of parts. 3D printed structural electronics has several advantages.
Ms. Emilie Jolivet introduced Yole Développement. The market apps roadmap is driven by mega trends. The main battle is between the substrate and WLP-based SIP. New capabilities are needed for multi-die solution. Packaging innovations are needed at various levels.
Designing advanced mmwave phased arrays
Jussi Säily, Senior Scientist, VTT Technical Research Center of Finland, presented on design of advanced mmwave phased arrays. So, why go mmwaves way? Directive antenna have small physical size. Rapid developments in silicon integration technologies, such as CMOS and SiGe are reaching over 200GHz. New PCB technologies and materials can be used up to 200GHz.
Phased array antenna basics include beam steering required for 5G and beyond radio systems and agile radar systems. Integrated phased array antenna have many qualities for mmwave. Multiple radiators are arranged in linear or grid patterns with close to half wavelength spacing. Array element types include microstrip patch, slot, etc. Phased antenna array has analog, digital and hybrid beam forming, respectively. The last one is popular for 5G mmwave.
Integration challenges of phased arrays are very large arrays needed with elements count over 1024. Low-loss PCB materials are needed with high layer count. Full-wave 3D EM analysis is usually not possible. Conformal array analysis is still very difficult. Calibration of phased arrays is difficult in production. MMIC packaging and connection to PCB are among the integration challenges.
Phased antenna arrays will be installed in 5G satellite connections, in satellite and ground station ends. Cost-driven development is toward larger core chips in CMOS/SiGe technologies. Large phased array antenna with over 1024 elements are needed for increased link distance and data rates. There are low-cost antenna integration platforms on PCB. Novel AiP solutions are needed for integrating steerable antenna arrays into mobile devices. The mmwave 5G systems require beam steering built into antenna.
Challenges of solder joint reliability
Hanwen Zhang, Global Product Manager of Advanced Packaging Solder Materials, Heraeus, spoke about the challenges of solder joint reliability in RF SiP modules. There are RF SiP modules available. They enable heterogenous integration for functional performance and faster time-to-market.
There are challenges in RF SiP solder joints reliability. These can be solder creep, solder bump voids, non-wet issue, solder beads, bridging, etc. Reducing solder defects requires stencil design guidelines. There is the area ratio rule, bigger than 0.5 rule. There is the 6-7 balls rule for round aperture, and 5-balls rule for square aperture.
There is water soluble vs. no clean chemistry solder paste. Over 80 percent of RF SiP packages are using water soluble chemistry solder pastes. Solder powder quality is also important in minimizing voids. Wafer bumps void propagations after multiple reflows can be minimized with specialized wafer. Reliability improvement can be with all-in-one printing. The benefits are lower processing steps, eliminating the flux cost and reduced paste wastage.
5G RF modules market growth is bringing opportunities and challenges. SiP technologies flexibility enables the heterogenous integration for functional performance.
Braham Ferreira, Prof., Power Electronics, Electrical Engineering, Mathematics & Computer Science, University of Twente, presented on fabrication plant for power electronic system-in-package (SiP), at the recently-held event on power and RF packaging. It was organized by Yole Développement, France, and Chip Integration Technology Center (CITC), The Netherlands.
Ferreira discussed a fabrication process for GaN heterogeneous integrated power modules. There is strong market growth for GaN. New-generation WBG (GaN and SiC) devices are potentially 100‐1,000 times faster and 100‐1,000 lower loss than today’s technology. GaN applications are used in power, RF and lighting. Market predictions for lateral GaN devices are very strong, heading rapidly to $1 billion.
He said that 5G needs GaN. From 4G to 5G, the power‐frequency product of cellular base stations increases 10x. At 400V, GaN offers the same high frequency performance as Si at 50V. At the same impedance, increasing voltage by 50, means, 400V yields 16x more power. Technology for packaging high voltage circuits is needed.
There is scope of HIPM. We target line connected power supplies. The power GaN industry focuses on packaging the active components in modules that we include transistors. The HIPM fabrication will include the passive components.
Power supply fabrication has somewhat stagnated. Passive components dominate size, weight and loss. Discrete components are soldered to PCB, and small profit margins are on passive components. The large parasitics due to multiple packaging layers makes it difficult to exploit the superior high frequency potential of GaN. Using parallel connection of small devices and capacitors 500V/ns has been reported.
Power supply miniaturisation is happening with GaN. The resistance per unit area of transistor chips is much higher compared to Si, as a result the efficiency is much higher. Lower resistance leads to higher efficiency. Lower switching losses makes it possible to reduce the size of passive components. Thru‐hole components can be replaced by SMT components.
More components, and higher power density is needed. University research
demonstrated advantages of hybrid conversion techniques. However, high component count means low reliability.
There is hidden secret in Moore’s Law. The scaling of early computer was impossible because of reliability limitations. High-quality circuit interconnection technology made high-component complex computing circuits possible. HIPM (host-initiated power management) makes 10x better reliability by fabricating all circuit inter-connections in one plant.
Let us look at the fabrication process for GaN heterogeneous integrated power modules. There is fab for diversity of converters in 20W-2kW power range. 3D converter is constructed from sandwiched organic substrates. System of copper and steel lead‐frames is required to create the optimal distribution of thermomechanical stresses, and to create cooling surface area for heat management.
In conclusion, the time is ripe, in view of the exponential growth of the power conversion and RF amplifier market, and the large forecasted production numbers, to invest in a dedicated power‐system‐in‐package fabrication platform. GaN power devices offer 10x potential improvement of “frequency x power” and power density.
However, this can only can be achieved if the suitable heterogenous integration fabrication technology can be developed. This can compete with the existing manufacturing technology a 10x better reliability is needed, which can be achieved by process quality control of interconnects under on roof, and optimize the (thermo‐) mechanical stresses of all interconnects.
Yole Développement and Teledyne organized a meeting on glass and silicon bioMEMS components. They looked at how these are the heart of tomorrow’s medical devices.
Opening the discussion, Sébastien Clerc, Technology & Market Analyst, Microfluidics, Sensing & Actuating, Yole Développement, said that there is prevalence and cost of chronic diseases. There are diseases such as sleep apnea, diabetes, infertility, Parkinson’s disease, epilepsy, cardiovascular events, etc. However, possible solutions do exist.
There are many examples of bioMEMS-enabled systems. MEMS, and other sensors and actuators are used in many medical devices, either implantable, wearable, or external. There is need for more compact and comfortable systems. There can be mainstream vital sign monitoring, new monitoring systems, pacemakers, etc.
Micro-technologies are everywhere in healthcare apps. There are microfluidics, imaging devices, bioMEMS and biosensors. Microfluidics market is estimated to grow to $5.3 billion by 2025, from $2.7 billion in 2019. Imaging devices will grow from $4.3 billion in 2019 to $6.6 billion in 2025. BioMEMS and biosensors will grow from $4.9 billion in 2019 to $9.6 billion in 2025. BioMEMS market dynamics include use of microfluidics, silicon microphones, optical MEMS, etc.
Next-gen DNA sequencing is leveraging glass and silicon technologies. In 5-10 years, there will be DNA sequencing for less than $100. Silicon and glass for microfluidics are estimated to be huge. The supply chain for bioMEMS and microfluidic fabs is growing. In glass, there is Caliper, Schott, Philips, Invenios, etc. In silicon, there is XFab, Sensera, TSMC, Teledyne Dalsa, STMicroelectronics, etc. In polymer, there is ChipShop, Carville, Axxicon, Hochuan, Weidmann, etc.
MEMS platforms are accelerating the time-to-market. MEMS foundries are key partners to reduce the TTM and reach medical-grade devices.
Glass and silicon bioMEMS
Collin Twanow, Director of Technology, Teledyne MEMS, spoke about glass and silicon bioMEMS. He said that there is diverse need for medical monitoring, diagnosis, and treatment. There is the evolving demographics. There is the acceptance of technology advancements by doctors, regulatory bodies, and patients. There is continuing advancement and introduction of MEMS and microfabrication in this field.
Teledyne MEMS foundry services is no. 1 independent pure-play MEMS foundry. It has the largest portfolio of microfabrication technologies available in the world (non-captive). There are hundreds of unique prototypes built, and technologies for all sensor types and markets.
Teledyne has 150 mm and 200 mm wafer diameter production lines. Teledyne offers all the advanced processes and fabrication equipment. These include DRIE, metal disposition by sputter and evaporation, glass/quartz wet etching, RIE plasma etching, Si anisotropic wet etching – KOH, and TMAH, test and automatic optical inspection (AOI), back-end process, bonding, etc.
Teledyne bioMEMS fabrication includes platinum gold and other metals, CMOS post processing, patterned polyimide, silicon glass and other substrates. The apps served include diagnostics, cell treatment, drug development, antibody ID, disease testing, genetic analysis, etc.
MEMS and microfabrication for biotech includes silicon and glass microfluidics, CMOS post processing, thin-film bioassay substrates, CMUT arrays for medical imaging, other bioMEMS devices, and other medical device considerations.
In MicraFluidics, the silicon microfluidic process platform, there are features such as high-aspect ratio microchannels in silicon wafer, input/output ports in glass, consistent inorganic surfaces, suitable for functionalized coatings, and customer specified chip size.
The process includes pattern customized through-wafer ports in glass wafer, pattern microfluidic channels in silicon substrate with precise high-aspect ratio anisotropic etching, and glass and silicon wafer bonding providing a strong and reliable bond interface.
In CMOS post processing, there is integrated MEMS and CMOS electronics, extensive and flexible CMOS post-processing capabilities are available for next generation, integrated biochips, expertise to handle advanced CMOS wafers from multiple CMOS foundries for post processing using fully-compatible lithography tools, expertise to work with different polymers for microchannels and microfluidic wells definition, capability to deposit thin metal and dielectric layers for integrated electrical detection, and polymer wafer bonding, with microfluidic features, and CMP. Bioassay apps include consumable test chips, DNA capture and analysis, and genetic testing.
Capacitive micromachined ultrasonic transducer (CMUT) MEMS platform is the emerging transducer / receiver technology for medical imaging and treatment. The CMUT technology offers many potential advantages over traditional linear array piezoelectric transducer technology, including, advantages of wafer fabrication scale, 2D arrays offer higher resolution waveform shaping, greater sensitivity, superior acoustic impedance matching, potential to co-integrate with electronics, and SOI Layer that provides consistency of single crystal silicon for top electrode.
Teledyne’s phase-gate system ensures thoroughness in path to manufacturing. It provides a rapid, reliable path to high yield production. Design for manufacturing involves designing into an established process capability, and ensuring the expected process variation does not lead to product variation. Benefits include first-run prototype success, faster to manufacturing, stable yield and performance, and lower costs.
Teledyne MEMS is the world’s largest pure-play MEMS foundry. It has extensive experience in microfluidics and bioMEMS, with biocompatible materials. The foundry is structured for prototype development and large-volume commercial manufacturing for the medical industry.