Section A - Internal Quality Assurance Cell: Fill & Download for Free

It's an exciting field! Sometimes you don't want to know how the sausage is made. However, this is totally fascinating to know about.My adviser is very fond of saying that drug production is modern day alchemy. That is it's the process of taking cheap organic matter and converting it into a product that is worth way more than gold.Chemical engineering is largely about understanding how one can control and manipulate processes to obtain a desired product. As with all chemical processes, there are additive, reactive, and removal steps that are selected.Drugs aren't any different. I will warn you that I only know about the production process of biopharmaceuticals and I can't go into details about small molecule productions. Biological drugs are particularly tricky since they are going into patients and there are insanely high standards on creating a reproducible, consistent product that is virtually pure, stable, and scaleable.In the case of biologics, we can largely divide the process into three stages:Production (fermentation or cell culture)Purification (separations)Packaging (fill and finish)Depending on the drug process and demand, the rate limiting step easily differs. 15 years ago, cell culture was the limiting step. Now that the yield has increased 1,000x for antibodies, purification became the limiting factor. When enough purification columns were finally built, they overwhelmed the fill and finish stages. The takeaway message is that all of these steps are important but some are more important than others depending on the process.Also important to recognize is that there are hundreds of quality control checks throughout the process. All of this occurs in a Current Good Manufacturing Practices (cGMP) environment. Anyone who has worked in manufacturing can tell you that there are numerous Certificates of Analysis (CoA) and Standard Operating Procedures (SOPs) that must be followed for Quality Assurance and throughout the process, samples are collected and analyzed to make sure that the process is in check. These documents are then examined by the FDA as part of the approval process and later inspections. As this is going into people and affects lives, it's taken quite seriously. Variations away from cGMP may result in recalls.At this point, you can look at the figure below, give me an upvote, and call it a day.However, I'm only getting started. We're talking about curing lives here.ProductionCell culture is the goal of using recombinant technology to make cells convert one product into another. In most cases, this is either a feedstock like glucose or aminoacids like glutamine. By the point it gets to a manufacturing stage, the desired cell and desired product have been selected. Depending on the drug, different host organisms would be used but the most common are E. coli, Yeast, and CHO Cells.The goal of cell-culture or fermentation is to produce the most active drug / liter of culture-time consistently.The industry amusingly uses farming terms and those will be highlighted along the way.Unlike chemical synthesis where the ingredients tend to be consistent, cells may change or evolve during the course of the process. To prevent cell drift and to be ensure consistency, a single cell is grown in a small batch and then is saved into hundreds of culture vials and frozen away as a MASTER CELL BANK, with the assumption that they are all going to be the same. From this master lot, a working lot is then made using a similar process.When a batch is started, one of these vials (containing 2e6 cells) is thawed and seeded into the media. Once growing, the goal is to grow the cells to the highest density at the largest volume in the shortest amount of time. The best strategy is to keep cells growing at the log phase for as long as possible and hit the stationary phase in the largest reactor. Start too small and you fall into the lag phase; go too high and you have to to passage more frequently.The best way to do this is to constantly cultivate cells as they reach a critical density. In the manufacturing campaign I worked in, we passaged every 3 days using a 1:5 split from 200 mL -> 1 L -> 5 L -> 25 -> 100 L -> 500 L. The entire process took us 2 weeks before going into the 500 L. Larger companies like Merck and Pfizer have 10,000 L reactors. The timescales differ depending on the host organism.This is a "small" 3 liter biostat. Costs around $10,000 on ebay.A medium sized E. coli reactorA big one. (It goes underground)During the growth process, it is incredibly important that the cells are in an environment where they are willing to produce your drug. They are like any manufacturer so they need food, an appropriated temperature environment, and air.Several conditions are often measured and they includepHOxygen intake and levelsGlucose intake and levelsAmino acid intake and levelsCell DensityTemperaturePressureStir-rateLike humans, if your neighbors are sick, you might get sick too so if any of these process measures fall out of range in the defined SOPs, the entire culture might begin to die at once and your drug gets destroyed. People monitor this very very carefully. To counteract imbalances, fed-batch approaches are often used by adding in acids or bases, air/oxygen, and other feeds.Equally important is the source of the media. The media used is a carefully designed buffered solution that includes necessary salts and chemicals that maintains the appropriate osmotic pressure and pH. They also have to come from FDA approved chemicals which are free from animal-derived products that may infect humans.When the cells reach their maximum density and achieve a stationary phase, the cells are then it is time for HARVEST!The all important drugs gets stored in cells via different mechanisms. Typically, E. coli cells store the protein internally. Mammalian cells typically excrete their products. Thus, the harvesting protocol differs.As E. coli cells store their drugs, we're interested in harvesting the cells themselves. Using a giant centrifuge, the cells are pelleted down. To release the proteins, the cells are feed into a high pressure chamber to burst open the cells to homogenize the product. This lysate is then passed on to the purification team.Mammalian cells are different and in this case, we want the supernatent. We can clarify this supernatent by either centrifuging the cells and collecting the supernatent or using depth filters to trap the cells.PurificationPurification is the process of taking this mixture of proteins, sugars, lipids, and molecules, and isolating and cleaning the desired drug product.The goal is to collect the most product with highest purity per column consistently.At our disposal are a variety of separation techniques which mainly use Liquid Chromatography. Many of you should be familiar with your highschool chemistry lab which separated colors from a leaf using a piece of paper and solvent.This is pretty much the same thing except 1,000,000x harder. Also people die if you mess up.The essential idea of separations and purification is to use certain physical and chemical properties of your mixture to either retain or remove components. These properties include:SizeChargeHydrophobicityAffinity to certain compoundsWe did an initial step by removing cells and cell guts using centrifugation earlier. Most pharmaceutical drugs will use an Affinity Chromatography (AC) step to isolate the drug. In antibody purification, Protein A will bind to the Fc region of the antibody and retain the desired product.Size Exclusion Chromatography (SEC) or Gel Permeation Chromatography separates out proteins by size. Small molecules will be trapped in the pockets of porous particles while the larger molecules will run through the spaces.Ion Exchange Chromatography (IEX) uses charged beads trapped in agarose or cellulose which holds on to ions. As a protein of certain charge flows through, the protein binds to the column. Then, using changing salt or pH, the interactions between the column and the desired protein weakens. The typical resins in order of decreasing pI are Q (quaternary), DEAE(Diethylethanolamine), CM (carboxymethyl), and SP (sulphonyl).Hydrophobic Interaction Chromatography (HIC) takes advantage of the hydrophobicity of proteins. At high salt, these interactions are particularly strong and using a decreasing salt gradient, the less hydrophobic proteins fall off.Like before, here are some representative images of the various sizes involved with purification.This is one we use in the lab. A cheap AKTA goes for $16,000 online.Here is a medium sized one. The frame costs around $8,000Here is a big oneThe limiting factor in purification is the resin. An inexpensive affinity resin like Ni-NTA will cost around $1,000 / Liter. Protein A or Strep-Tactin costs >$10,000 / Liter. As a result, you are limited by the maximum capacity of the column and the yield of your protein after the individual cleaning steps.Unlike fermentation and cell culture which is driven by cost per run, purification is a fixed capital expense. That is, 1 run vs. 10 runs will essentially cost the same (sans operator costs) since the expensive components are the rig and the resin. Unlike the production stage, each run is a fixed amount of time; the typical purification scheme will take a week.For validation purposes, the FDA will mainly be concerned about the purity and consistency as they want manufacturers to show that they are aware of every component that will go into the patient. As the individual clinical trials go by, the expectation is that the purity and reproducibility continues to improve.To illustrate how stringent we approach this, below is an example of a "shoulder" which shows a slight contamination of a dimer. This would be considered a red flag in the eyes of the FDA.PackagingThe purified protein is the drug but what Pharmaceutical companies sell and the FDA approves is the drug product. For small molecules, this will include the pill and all of its excipients. For biologics, it's the vial. Decisions in this process determines the drug shelf-life and delivery. This is the process that I know relatively little about so I am likely missing entire processes in this section.The goal of fill and finish is to minimize defects in creating the drug product.Typically, this follows the process below of sterilizing vials, filling the vials, lyophilizing the drug, and finishing the capping and labeling process.Fill refers to the processes of adding the drug into the vial. An essential portion of the step is the formulation of the drug ie. what salts and buffers are used to stabilize the drug. This influences the shelf life and if there is any pain from injections. It may also influence whether or not there are any losses from binding to the glass vials.Matt Harbowy has a wonderful answer on how this process is done precisely What type of machine could I use to precisely manufacture pills so that they contain exactly 1 milligram of active substance in each pill?The mixed protein product is dispensed into the vials using a machine as shown.In certain cases, the liquid mixture is capped immediately and stored at 4C. However, for drugs that need to be shipped overseas or for longer uses, we can freeze-dry the mixture by lyophilization. The vials are placed under negative pressure and frozen to cause the water to sublime without going through a liquid-gas transition which may damage the drugs.Finish refers to processes of adding the caps, sealing the vial, labeling, and inspection.Here is one representative photo of "cappingGetting Approval from the FDAThe OP asked to avoid taking about approval but the manufacturing process is essential to the approval process. A large part why natural drug products aren't touched by drug companies and approved by the FDA is because the processes to reproducibly synthesize pure product is incredibly difficult.All of these processes are done in a clean room environment similar to Silicon manufacturing and they go from dirty to cleaner environments. The cell culture environment that I worked in was a Class 10,000 (ISO 7) and by the time it reaches purification and fill and finish, it will drop to Class 1,000. Contamination checks for mold and endotoxins are frequently done.I heavily emphasized consistency. When a drug goes up for approval, the FDA will ask for a demonstration of 2 beginning to end runs at the full scale. For this to happen, construction on a full scale plant and process will start 2 years before regulatory filling which means a company will typically be paying for its plant in the middle of its pivotal phase III trial with no idea whether or not the drug is going to work and ultimately approved. This is a relatively small cost compared to the actual running of the trial but it's a cost that often gets forgotten when we talk about drug development.So that's that. Drug manufacturing is the process of making small and "cheap" chemicals into an expensive specialty chemical that will go into a human being. Through a variety of steps, mainly, production, purification, and packaging, our goal is to do this reproducibly without defects with the knowledge that errors costs lives.It's a constantly evolving field as people try to find ways how to make these drugs more inexpensively without sacrificing the quality that is required for these drugs to work.I'm getting my funding from the NIH. If any pharma company needs a shill to pay, you can find me by going to my Google+ page gplus.to/chrisvanlang

Government Medical College and Hospital, Nagpur (Marathi: शासकीय वैद्यकीय महाविद्यालय व रुग्णालय,नागपुर) was founded in 1947 in Nagpur, Maharashtra, India.[1] The college was affiliated with Nagpur University from 1947 to 1997, and subsequently Maharashtra University of Health Sciences (MUHS), Nashik.Its research activities are based on a community approach, oriented toward areas like maternal, neonatal, and child health care, infectious diseases, nutritional illnesses, and lifestyle disorders.•The college is located in south Nagpur, the winter capital of the state of Maharashtra. Government Medical College Nagpur is considered to be the best medical college of central India.The campus is stretched over an area of 196 acres.it The nearest square(Chowk)is called medical square(Chowk)——-medical square ( Chowk )•The college was the first center in India to have an Occupational Therapy and Physiotherapy School. It was also the first institution to have a Cobalt Unit and CT scanner in the state of Maharashtra. It also has Ultrasound 2-D Echo, an ICCU, Computerized Treadmill Testing, and AutoAnalyzers.* Best things about GMC, Nagpur:•Around 200 students are enrolled each year.•The hospital currently has 1400 beds.•The institute offers postgraduate studies in many disciplines of medical science.• Alumni of GMC, Nagpur1. Shrikant Jichkar, former member of the Indian National Congress2. Dr. Prakash Amte and his wife, Dr. Mandakini Amte, Magsaysay awardees3. Abhay and Rani Bang, Maharashtra Bhushan Award, social activists and researchers4. Ashish and Kavita Satav, 'Public Health Champion' award by WHO for 'Outstanding Contribution to Public Health in Country' in 2016′• GMC, Nagpur has many facilities like:1. DEPARTMENT OF ANATOMY•Body Embalming services2. DEPARTMENT OF PEDIATRICS•NICU•PICU•Sickle Cell Clinic3. Departmental Laboratory Facility Available4. Health Education for patient (documentaries, Lectures etc.)5. DEPARTMENT OF ENT•Pure tone Audiometry & Impedance Audiometry.•Temporal Bone Dissection Laboratory.•All routine ENT Surgeries.•Micro ear surgery.•Head & Neck surgery.•Phonosurgery & Micro-laryngeal Surgery.•Anti – drooling surgery.•Thyroid Surgery.•Endoscopy of upper aero-digestive tract.•Flexible Bronchoscopy.•Head & Neck Cancer Surgery.•Nasal Endoscopy & Functional Endoscopic Sinus Surgery.•Voice Therapy.5. DEPARTMENT OF OBGY•Antenatal clinic& Post natal clinic and•Gynecological and Family Welfare Clinic•6 days / week•Emergency Obstetric care – round the clock•Gynecological Operative Procedures•Critical Obstetrical Care.•U.S.G with T.V.S.•Diagnostic & Operative Endoscopies•Intensive Obstetric Care Unit•Gynecological malignancy management•Family Planning and Safe Abortion Services•Prevention of Parent to Child transmission Of HIV infection,•Preventive Oncology and Treatment Paps smear•Colposcopy•Cauterization•Management of post menopausal women•Infertility clinic•Sickle cell Patients care6. DEPARTMENT OF RADIOTHERAPY•Teletherapy ( Tele Cobalt-Theratron -780 E )•Brachytherapy- ( Microselectron Remot after load HDR Brachytherapy)•Chemotherapy for solid tumours•Oral morphine for cancer pain management•Palliative care•Cancer counseling•Population based cancer registry•Cancer awareness Programmes for the prevention and early detection of cancer7. DEPARTMENT OF TUBERCULOSIS•60 Bedded Ward for Inpatient services•OPD services•Asthma Clinic•MDR Ward for treatment of MDR TB cases under DOTS Plus•Laboratory facilities for establishing the diagnosis of tuberculosis including sputum smear examination, culture and drug resistance test for Mycobacterium tuberculosis.Specialised accredited Mycobacteriology Laboratory with advanced facilities like Line probe assay for culture DST.•A unit for chest radiology for in-patients and Chest OPD patients.•Plethysmogrphy•DLCO•Pulmonary Function Test•Cardiopulmonary Stress Test8. DEPARTMENT OF PATHOLOGY•Specialty clinics and services•Department of Pathology is para clinical department and runs two parallel OPD, One is clinical pathology OPD and another is Cytology OPD . In Clinical OPD Screening of Sickle Cell disease is done. Daily patients attendance is average 200-250. It performs 108110 average investigations annually.•Pathology department also provided emergency service after 5 p.m.(Central Clinical laboratory).•Department of Pathology also runs “A” type blood bank which gives 24 hours services and had Blood Component Separation Laboratory.•Pathology department have various laboratories like Haematology, Cytology, Histopathology, Immunology and PCR laboratory. These laboratories are fully equipped, All these laboratories act as reference laboratories for Vidarbha region and adjacent areas. This laboratory also participates in the External Haematology Quality Assurance programme based on guidelines issued by International Haematology quality Assurance Scheme and W.H.O.•Cytology laboratory is accredited by Indian Academy of Cytology for both diagnostic services and teaching and training to cytotechnicians and cytotechnologists. It performs 11726 average investigations annually. This laboratory also participate in External Quality Assurance Programme of the Indian Academy of Cytologists ( National body)•Hematology laboratory perform various investigations and specialized in Coagulation studies and Sickle Cell Test. It performs 51889 average investigations annually. HPLC equipment is installed for screening of all abnormal hemoglobins in neonates and adults.•Histopathology section performs 20399 average investigations annually .9. DEPARTMENT OF PATHOLOGY SSH•Histopathology•Cytology.•Haematology Investigation- Haemogram, Bone Marrow examination, ESR•Urinesis, Stool Examination10. DEPARTMENT OF FORENSIC MEDICINE•Postmortem examinations•Exhumations•Recognized centre for conducting autopsy in custodial deaths•Medicolegal age estimation•Examination of alleged accused in sexual offences•Sample collection for DNA profiling11. DEPARTMENT OF ANAESTHESIOLOGY•Anaesthesiology Deptt. alongwith routine O.T. (i.e. 21 tables) is providing services to Radiology (CT, MRI, Interventional ) & Radiotherapy, Super Speciality, Recovery Room, Attending calls of CPCR. We are I/c of VIP/ VVIP visits12. DEPARTMENT OF NEUROLOGY SSH•Complex Neuro trauma Surgery•Neuro Onco Surgery•Vascular Neuro Surgery•Paediatric Neuro Onco Surgery•Spinal Trauma Surgery•Spinal Onco surgery•Corrective Surgery for Congenital Neural Tube Defects13. DEPARTMENT OF RADIOLOGY•M.R.I. Examinations•C.T. Scan examinations•Interventional Radiographic Procedures•Mammography examination•Color Doppler examinations•Ultrasonography examination•I.V.U. Procedures•Barium Studies.•Routine radiographic procedures.•USG guided FNAC.14. DEPARTMENT OF PLASTIC SURGERY•Most plastic surgical procedures carried out like congenital anomalies,maxillo-facial injuries, hand surgeries, head-neck malignancies and cosmetic surgeries like rhinoplasty,breast reduction and breast augmentations, etc.•PHYSIOTHERAPY SCHOOL•Cardiac Rehabilitation,•Pulmonary Rehabilitation•Obesity Clinic•Neuro-developmental clinic•E.M.G.•Prognostic & Therapeutics Lab•Gait lab•Fitness clinic15. DEPARTMENT OF OPTHALMOLOGY•CATARACT SURGERY BY RIGID AND FOLDABLE IOL’S•TECHNIQUES:•PHACOEMULSIFICATIONA.ROUTINEB.MICS (MICRO •INCISION CATARACT SURGERY) WITH ROLLABLE IOL’S•SICS(SMALL INCISION CATARACT SURGERY)•CONVENTIONAL E.C.C.E.•GLAUCOMA SURGERY•TRABACULECTOMY•COMBINED SURGERY•IRIDECTOMY•KERATOPLASTY•SQUINT SURGERY•PEDIATRIC SURGERY•OTHER MAJOR SURGERIES•DCR•PERFORATING INJURIES•AMNIOTIC MEMBRANE GRAFT•ENUCLEATION•EVISCERATION•OTHER MINOR SURGERIES•DCT•CHALAZION•PTERYGIUM WITH AMG/AUTOGRAFT•PROBING OF LACRIMAL PASSAGE•PARACENTESIS•INTRA VITREAL INJECTION•EXCISIONAL BIOPSY•LASER TREATMENT-Nd YAG LASER•POSTERIOR CAPSULOTOMY•PERIPHERAL IRIDOTOMY16. DEPARTMENT OF ORTHOPEDICS•Fracture clinic•Spine clinic•Arthroscopy & Sports Medicine•Arthroplasty & Rheumatology clinic•Paediatric orthopaedic clinic•Sickle cell clinic run in association with Department of PaediatricsThere is lot more about GMC but in Short it's the best government medical in central India

Simple - Alien Dreadnought.Alien Dreadnought is what Elon calls the machine that builds the machine. When you take apart a Tesla, all you get are what parts there are and how they fit together. It tells you very little about the machine that puts it together.When you see two plates fastened together with a bolt, do you know if that bolt was installed and tightened by a person, a machine or a combination of both?Tesla has invested tremendously in automating the process to make stuff. From basic stuff like car seats to installing wiring harnesses in cars. Most car makers laughed when Tesla had to rip out a large portion of the Model 3 lines when robots couldn’t effectively install wiring harnesses. This missed the obvious point - wiring harnesses are hard, but if you can beat that manufacturing problem with robots, then pretty much the entire process can be done with robots.Thus with Model Y, a redesigned wiring harness with 90% less wire than the Model S and designed from the start to be handled by robots were patented by Tesla. We will have to wait to see if it actually makes it into production in 2020, but if it does, it means Tesla will be another step ahead of the competition.Vertical integration - as part of the machine that makes the machine, Tesla also ensures its part supply. By making its own parts it has total control of the quality and design of them, it can make compromises or absorb higher costs that a parts contractor might not be willing to do. This doesn’t show when you look at a part, all you can do is estimate how much it cost. By controlling all of these aspects, Tesla can make changes quickly and with less red tape and expense than a standard car maker who has to deal with separate parts suppliers.If you find a part that shows unique welding or shape from forming, you don’t necessarily know how it was done. All you can see is the final result. For instance, Tesla has patented a new casting machine to make the frame to the Model Y, a crazy machine that could reduce a car frame from 70 separate parts that need to be formed and assembled to a single piece. Tesla Goes Patent Crazy With Huge Casting Machine For Model YThat said, it doesn’t really matter that you can’t tell this process from just looking at the pieces. Tesla has released all its patents for any company to read and use. Most choose not to do so. All Our Patent Are Belong To YouUPDATE: 01/15/2020Thanks everyone for the Upvotes!With more comments from Elon regarding Full Self Driving being “feature complete” in 2020, the importance of Alien Dreadnought becomes more important. Software, AI and full self driving capabilities are definitely products that competitors can’t replicate simply by taking the car apart. Even looking at the software code, especially for the AI doesn’t tell you how Tesla got there.Tesla is pushing AI faster and farther, not just in the end product Self Driving AI, but in the training techniques and even the hardware used to run the software to train. This is all part of the Alien Dreadnought - build the machines that build the machines.Tesla Quietly Acquired a Machine Learning Startup That's 'Squeezing' A.I.As for the “parts supply” of this portion of the machine, it is driving data. And Tesla has worked hard to make sure it has a nearly endless supply of driving data. With every Tesla equipped with sensors and most equipped with the full self driving suite of sensors such as cameras, radar and ultrasonics, every Tesla on the road is feeding data back to Tesla, billions (with a B) of miles of it every year. To put that into perspective, Waymo just hit 20 million miles of data total, currently running about a million miles per month. Waymo’s autonomous cars have driven 20 million miles on public roadsAI’s train best on lots of unusual data. Having access to billions of miles means Tesla’s have probably seen lots of weird things on the road - flying cars, kangaroos, planes landing on the highway etc. And with Sentry cam, it can record things even while parked. Tesla's millions of cameras are capturing some crazy things - videos - Electrek This is useful for teaching the AI about human behavior, not just things that happen on roads, so perhaps in the future the AI can determine social interactions like “a fight is happening” and predict that people are going to run out into the road.By designing its own processing chip and designing teaching supercomputers like Dojo, Tesla continues to make the machines to make the machines. Something conventional automakers are completely unable to do.Elon Musk hints at Tesla's secret project 'Dojo' making the difference in race to full self-driving - ElectrekUpdate 02/24/2020And the Alien Dreadnought rolls on - Tesla Self Driving Computer, designed from a clean sheet of paper, puts Tesla years ahead of the competition. Designed in house using the best talent in the world and manufactured exclusively for Tesla by Samsung in Austin.Tesla Self-Driving Computer architect Jim Keller is confident about solving autonomous driving - ElectrekThe issue is not that other companies can’t design their own chips to match the technology, but they can’t get rid of their current contracts and manufacturers for years. Again, by bringing manufacturing in-house, Tesla continues to ensure the supply.“The real reason for holding off? Automakers worry that computers like Tesla’s will render obsolete the parts supply chains they have cultivated over decades, the engineer said. Such systems will drastically cut the number of electronic control units, or ECUs, in cars. For suppliers that depend on these components, and their employees, this is a matter of life and death.” Tesla teardown finds electronics 6 years ahead of Toyota and VWUPDATE 4/28/20Additional evidence that “Alien Dreadnought” is the correct path. VW has had to delay the release of the ID.3 due to “software issues.”. From a highly optimistic 2018 prediction that VW would be producing a vehicle to match Tesla for “half the price” by 2020 - VW Claims By 2020, Its Electric Cars Will Match Tesla At Half Price to the stark reality of having thousands of vehicles bricked and sitting in lots - VW ID.3: thousands of electric cars spotted being stockpiled in Germany - Electrek the reality of failing to invest in the machine to make the machine is evident. While the machine in this case is software, VW’s lack of investment in internal software development shows how unprepared the entire company is for the future of vehicle production.“Today, our share [self-developed software as a portion of all software in Volkswagen Group vehicles] is less than 10 percent. That is clearly too small. In the Volkswagen Group, we want to achieve a share in software development of more than 60 percent by 2025.”Volkswagen Software Comments — 10 Months Ago vs. TodayShortages of robots (Tesla bought the company VW was using), shortages of programmers (Tesla produces most of its software in house and already has a massive team of programmers), a lack of integrated design (VW is trying to integrate dozens of different hardware/software suppliers) all prevent VW from producing a viable vehicle at this time. The machine that makes the machine isn’t working.Now in discussions with Daimler-Benz to try to pool software resources, they are very late to the game and late to the realization that software is as important as hardware. Daimler flirtet mit BMW und VW Simply building the physical isn’t enough, what runs the car is as important, if not more important than the physical parts to producing a top rate EV.UPDATE 05/19/20VW is learning that the future of cars IS to treat them like smartphones. Their software issues now extend to a conventional model - The iconic VW Golf (Gen 8). Failure of the emergency call system is halting their delivery of even conventional vehicles because of software difficulties. Despite having 46 years of experience producing the Golf, VW seems very inexperienced with software. It will have a difficult time building the expertise to handle these problems, let alone getting ahead due to the huge demand worldwide for such expertise as EVERY carmaker realizes that software is the future of the car.https://www.motor1.com/news/423689/vw-golf-software-issues-arise/New Volkswagen Golf Mk. 8 Deliveries Stopped Over eCall Software IssueUPDATE 06/30/20Building the factories to house the machines that makes the machine.As proven by the build speed of Gigafactory 3 (Shanghai) going from a muddy field to a producing manufacturing line in less than one year and with the ground breaking and rapid build out of Gigafactory 4 (Berlin), Tesla shows how important Alien Dreadnought is. Knowing what processes and parts that need to be manufactured and scaling the buildings from the beginning allow Tesla to create a factory space rapidly and repeatedly. If Gigafactory 5 (Texas) becomes an operational reality in 2021, then Tesla will have built 3 operating mega factories in less than 3 years.Breaking! Tesla Gigafactory 3 Groundbreaking In China In A Few Hours — UPDATEDTesla’s Chinese factory just delivered its first carsTesla breaks ground on foundation at Gigafactory Berlin, brings in heavy machinery - ElectrekInteresting details during construction, especially regarding the Model Y. For American built Model Y’s, the back frame is two cast parts, not the one part envisioned in the patent.However, for Giga Shanghai and Fremont, new supersized casting machines were ordered.Tesla Giga Shanghai Could Be Constructing The Next Level Casting Machine for MIC Model YSo a single piece rear frame casting could come online this year for Model Y. I would assume that Giga Berlin will also be equipped with the “Gigapress” for European Model Y production.UPDATE 07/08/2020More signs that vertical integration, cross pollination and diverse investment can prove to be innovative. A bonus efficiency when you control all aspects of the Alien Dreadnought.So it appears that Tesla is looking for a visual image engineer to work at the new Fremont Battery Factory. Current theories run that Tesla is going to apply visual AI to the quality assurance process. This is an indicator that Tesla’s investment in AI, particularity visual AI will provide additional benefits other than driving.Quality control is one of Tesla’s biggest current problems. It involves inspecting pieces and work, identifying if they are correct or incorrect and then (sometimes) fixing the problem. This has traditionally been a human job since the variety of problems (paint problems, panel gaps, incorrectly installed wires, misted headlights, etc.) was too much to simply program in with a huge variety of visual cues. With an AI visually learning what a problem looks like and its thousands of variations, it could quickly be able to inspect, flag and note how to correct any imperfections during the manufacturing process, thus saving time and effort at a later date. Since it will be run by robots and AI, this means it will always be vigilant and always provide a complete inspection.“Vision Systems Engineer, Cell EngineeringSAVETeslaFremont, CAApply on LinkedInApply on Careers For Veterans At Tesla - Veteran HiringApply on Jobilize LLCApply on JobsApply on BIGHiredApply on LocalJobs.com25 days agoFull-timeThe RoleTelsa’s cell manufacturing engineering group is looking for a highly-motivated equipment development engineer to accelerate our next-generation battery cell manufacturing program. This role will be involved in the design, development, commissioning and ramping of high-throughput equipment, while working in a cross-functional team to test, validate, and roll-out process and product design changes. The battery cell is a critical component in Tesla vehicles and storage systems. This role will have the opportunity to make meaningful contributions to our products. The work environment is demanding, fast-paced and incredibly exciting. The ideal candidate should be ready to push their limits, as they join in a highly motivated and capable team to make unbelievable things into reality.Responsibilities • Drive design, commissioning ramp of a complex manufacturing tool that is the first of its kind at Tesla • Work collaboratively as the equipment expert to ensure production lines run in a safe, efficient manner producing high-quality parts. • Become owner/subject matter expert to drive equipment-related process improvement including detailed troubleshooting and root cause analysis. • Troubleshoot and recover processes by PLC, HMI, or tool management software, and implement changes/improvements • Build training material, maintenance routines, and related documentation for equipment life cycle management • Lead safety and ergonomic improvements to production equipment which meets or exceeds regulations or best practices. • Identify equipment critical spare parts and ensure sufficient coverage to prevent extended downtime situations • Participate in supplier/ internal equipment buyoffs • Debug and optimize automated processes to maximize cycle time and uptime. • Develop and manage FMEA risk assessments to prioritize equipment improvement projects and ensure sufficient repair strategies. • Provide hands-on support to the maintenance team to troubleshoot and resolve extended downtime situations. Requirements • Either a BS with 6+ years’ relevant experience or an MS with 3+ years relevant experience in interdisciplinary/integrated engineering, manufacturing engineering, or equivalent • Evidence of exceptional ability. • Strong engineering foundations. Aptitude to learn • Demonstrated experience ramping equipment into manufacturing - automation equipment, web handling, design of electromechanical systems, PLCs, motion controls, and data capture • Demonstrated experienced solving complex electromechanical and software systems with limited documentation to debug issues, build process know-how, and kick off improvement projects • Structured thinking and problem-solving abilities. Proven through a number of root cause analysis following a data-driven approach, statistical software (JMP) a plus • 2D ACAD experience in creating/validating layouts, tooling drawings, Pneumatic and electrical schematics • Experience with robot programming, backup, and restoration a plus • Experience in automotive or high volume manufacturing is highly desired”UPDATE 07/29/20Alien Dreadnought - Building edition. Tesla has gained sufficient experience to make even the manufacturing of factory buildings faster and more efficient. Pre-fab concrete panels to accelerate the building of Gigafactory Berlin.Giga Berlin will come together at an impossible-seeming speed. The prefabricated construction method in Germany is extremely impressive.— Elon Musk (@elonmusk) July 27, 2020Tesla Giga Berlin is coming together quickly thanks to prefabricated constructionWill Giga Berlin break the Giga China construction record? With Giga Texas already clearing land, will Texas be built even faster? With talks of a second China Gigafactory and another Gigafactory somewhere in Asia, the machine that makes the factories to hold the machines seems to be running faster and faster.UPDATE 09/23/20 - BATTERY DAYSo much vertical integration, Alien Dreadnought, and evidence that Tesla is not just an EV company. From investing in a new process to extract lithium from clay using water and salt and being able to return the dirt back into the ground, to producing larger, more capable batteries faster, cheaper and in less space than the 2170, utilizing new chemistry and integrating the battery pack as a primary structure, being able to recycle the batteries at the end of their life with minimal processing, Elon and Baglino showed how integrated manufacturing and vertical integration of the supply chain are the core of Tesla.Everything You Need To Know About Tesla's New 4680 Battery CellWhile it will take some time to ramp up production of the new 4680 cell, the pilot plant just down the street in Fremont is designed for 10 GWh of production, 1/3 that of Gigafactory Nevada in a building 12 times smaller. With limited production already beginning, design and testing of vehicles to use the new battery cell is well underway (Model S Plaid).Bigger batteries that are more efficient, cheaper to make, faster to make, more environmentally friendly and providing additional benefits to charging, structure, weight and longevity. All the result of Alien Dreadnought.UPDATE 10/28/20 - FULL SELF DRIVING BETALimited FSD beta releasing on Tuesday next week, as promised. This will, at first, be limited to a small number of people who are expert & careful drivers.— Elon Musk (@elonmusk) October 12, 2020With the recent release of FSD Beta, limited, it again highlights Tesla’s use of Alien Dreadnought. Since every recent Tesla with HW 3.0 chip is capable of FSD, Tesla has already built a test fleet of hundreds of thousands of vehicles. By slowing releasing beta to “expert & careful drivers” Tesla has recruited dozens if not hundreds of Tesla owners to test drive FSD, for free. Already on YouTube are hundreds of hours of video of FSD beta in action showing how it acts in all kinds of places, times, weather and situations. There are self reported testers in at least 9 states.Tesla Starts to Rollout Full Self-Driving FSD Beta for Different States' EAP MembersWhile the first days showed definite errors or quirks - always taking the leftmost turn lane even if there were two turn lanes, slowing, but not enough for speed bumps, mistaking an angle parked car as a moving car after a turn, taking longer to turn into traffic allowing a crossing car to come close, etc. patches are apparently fast and furious. With massive uploads of driving data - Tesla is collecting insane amount of data from its Full Self-Driving test fleet - Electrek Tesla is well positioned to acquire the data for cheap or free, have vast quantities of it, and apparently process it, use it to reteach the AI and update FSD within a day, if not hours. The machine to teach the machine is running fast and furious.Many of the “driver interventions” occur because FSD doesn’t drive in a fashion that makes the driver comfortable - staying in the center of a lane when there are parked cars rather than riding the dividing line, staying in the left lane when other cars are trying to pass, hitting speed bumps a bit fast, hitting the brakes at the last second, waiting too long to merge so the lagging car closes the gap quite close, etc. This information will be useful to Tesla in terms of creating a tolerable human interface, as many passengers, while quite safe with this driver, would find the experience unnerving.UPDATE 02/10/2021 -Elon Interview, Asking the right question.In an interview with Sandy Munro, Elon described why the first Model 3 wheel wells were a mess. As he mentions, they had many engineers working on the project and each one probably got the right answer for the part they were working on. One piece needed to be corrosion resistant, so the engineer picked the best corrosion resistant material, One part had a complex shape so that engineer picked a material that could be formed easily. One part was a heavy duty part that saw a lot of stress so that engineer picked a strong material. Individually each engineer came to the correct answer for her/his question. But the result was a mess - many parts, different materials, new problems in how to attach them together, new problems on how to seal the gaps due to difficulties in fitting them together well, etc. These questions had answers and they were implemented. It was a disaster. As Sandy noted, he hated how the early Model 3 wheel wells were constructed - too many parts, too many materials, too much labor. So Tesla had asked the wrong questions, and even though they had correct answers to those questions, it didn’t really provide the right solution. So Tesla engineers took a step back and asked the right questions - what does this part do, what does it need to made of and using Elon’s favorite design strategy - no part is the best part - how to eliminate the part. The result? Model Y rear structure megacasting - a single piece that replaces 70, is corrosion resistant, strong, and using the gigacasting machines, able to form complex shapes. As an added bonus, the removal of so many parts meant that 300 less robots were need to work on that section. Ask the right questions, get the right answer. Being vertically integrated allowed Tesla to move forward and scrap what wasn’t working for a whole new direction without dealing with suppliers, contracts or unions.UPDATE 04/13/21 - To the Moon and Beyond - Vertical Integration of Sustainable energyAs Gigafactory Texas takes shape, the first Gigapress is starting preliminary operations using large tanks of Liquid Natural Gas for its furnace to melt Tesla’s proprietary aluminum alloy. It is assumed that this will eventually be piped in through a large natural gas pipeline when the factory is in full operation.Musk’s warming up to gas evident once more at Texas GigafactoryFour tanker trucks belonging to a Houston-based liquefied natural gas company could be seen parked outside the Texas gigafactory construction sitehttps://www.detroitnews.com/story/business/autos/2021/03/30/musks-warming-up-gas-evident-once-more-texas-gigafactory/7060681002/Liquid Natural Gas is methane. Elon has shown a path to make even this process sustainable.Capture Carbon.XPRIZE Carbon RemovalTruly Meaningful Impact The world's leading scientists estimate that we may need to remove as much as 6 gigatons of CO2 per year by 2030, and 10 gigatons per year by 2050 to avoid the worst effects of climate change. For humanity to reach the Paris Agreements goal of limiting the Earth’s temperature rise to no more than 1.5˚(C) of pre-industrial levels, or even 2˚(C), we need bold, radical tech innovation and scale up that goes beyond limiting CO2 emissions, but actually removes CO2 already in the air and oceans. If humanity continues on a business-as-usual path, the global average temperature could increase 6˚(C) by the year 2100. This four-year global competition invites innovators and teams from anywhere on the planet to create and demonstrate solutions that can pull carbon dioxide directly from the atmosphere or oceans ultimately scaling massively to gigaton levels, locking away CO2 permanently in an environmentally benign way. Solutions will be scientifically evaluated across multiple criteria such as; amount of CO2 removed, life cycle analysis of the removal process, energy efficiency, land footprint and sequestration capabilities. Any carbon negative solution is eligible: nature-based, direct air capture, oceans, mineralization, or anything else that sequesters CO2 permanently.https://www.xprize.org/prizes/elonmusk2. Convert carbon to methane, using hydrogen made from water and energy from solar.Correct, pure electric. Wish orbital rockets could be so too, but there’s no escaping Newton’s Third Law. SpaceX is already developing high efficiency CO2 capture with H2O to form liquid CH4 (methane) & O2. Critical for propellant production at Mars Base Alpha.— Elon Musk (@elonmusk) June 10, 2018Sabatier reaction - WikipediaMethanation process of carbon dioxide with hydrogen The Sabatier reaction or Sabatier process produces methane and water from a reaction of hydrogen with carbon dioxide at elevated temperatures (optimally 300–400 °C) and pressures (perhaps 30 bar [1] ) in the presence of a nickel catalyst . It was discovered by the French chemists Paul Sabatier and Jean-Baptiste Senderens in 1897. Optionally, ruthenium on alumina (aluminium oxide) makes a more efficient catalyst. It is described by the following exothermic reaction . [2] CO 2 + 4 H 2 → pressure 400 ∘ C CH 4 + 2 H 2 O {\displaystyle {\ce {CO2{}+4H2->[{} \atop 400\ ^{\circ }{\ce {C}}][{\ce {pressure}}]CH4{}+2H2O}}} ∆ H = −165.0 kJ/mol There is disagreement on whether the CO 2 methanation occurs by first associatively adsorbing an adatom hydrogen and forming oxygen intermediates before hydrogenation or dissociating and forming a carbonyl before being hydrogenated. [3] CO + 3 H 2 ⟶ CH 4 + H 2 O {\displaystyle {\ce {{CO}+ 3H2 -> {CH4}+ H2O}}} ∆ H = −206 kJ/mol CO methanation is believed to occur through a dissociative mechanism where the carbon oxygen bond is broken before hydrogenation with an associative mechanism only being observed at high H 2 concentrations. Methanation reaction over different carried metal catalysts including Ni, [4] Ru [5] and Rh [6] has been widely investigated for the production of CH 4 from syngas and other power to gas initiatives. [3] Nickel is the most widely used catalyst due to its high selectivity and low cost. [2] Applications [ edit ] Creation of synthetic natural gas [ edit ] Methanation is an important step in the creation of synthetic or substitute natural gas (SNG). [7] Coal or wood undergo gasification which creates a producer gas that must undergo methaneation in order to produce a usable gas that just needs to undergo a final purification step. The first commercial synthetic gas plant opened in 1984 and is the Great Plains Synfuel plant in Beulah, North Dakota. [2] It is still operational and produces 1500 MW worth of SNG using coal as the carbon source. In the years since its opening, other commercial facilities have been opened using other carbon sources such as wood chips. [2] In France, the AFUL Chantrerie, located in Nantes, started in November 2017 the demonstrator MINERVE. This methanation unit of 14 Nm3 / day was carried out by Top Industrie, with the support of Leaf. This installation is used to feed a CNG station and to inject methane into the natural gas boiler. [8] It has been seen in a renewable-energy-dominated energy system to use the excess electricity generated by wind, solar photovoltaic, hydro, marine current, etc. to make hydrogen via water electrolysis and the subsequent application of the Sabatier reaction to make methane [9] [10] In contrast to a direct usage of hydrogen for transport or energy storage applications, [11] the methane can be injected into the existing gas network, which in many countries has one to two years of storage caphttps://en.wikipedia.org/wiki/Sabatier_reaction3. Use methane to heat the furnace for melting aluminum alloys.So vertical integration of energy sources - solar to methane to heat, will allow Tesla to continue to pursue its goal of sustainable energy, even while using conventional technologies such as a natural gas furnace.