On-Going Development Demands in Manufacturing and Distribution
CMOs Face Capacity Challenges, Talent Shortages As Pandemic Increases Demand For Their Services
European Parliament Pushes For More Data On COVID-19 Vaccine Distribution
Preparing For The Return Of US FDA Inspections
European Inspectors Spot GMP Deficiencies In India During ‘Virtual Tours’
US FDA And NIST Form Partnership To Boost Advanced Manufacturing Techniques
US FDA Urges COVID-19 Transmission Risk Mitigation In Cell And Gene Therapy Manufacturing
Merck’s COVID Manufacturing Deal With US Government Goes Well Beyond J&J Vaccine
The need for more plant capacity, process scale-up and skilled workers are major challenges cited by a CMO in producing clinical trial materials for COVID-19 vaccines. Recent white paper says 70% of manufacturers expect to outsource activities due to pandemic.
Capacity constraints, scale-up challenges and the need to find talent are some of the obstacles contract manufacturing organizations (CMOs) face in producing materials for COVID-19 vaccines, according to a panel of experts LifeSciences Connect convened 1 December on the topic of effectively scaling up COVID-19 vaccines.
The Thermo Fisher and BioPlan panelists noted that the recent emergency authorization of a COVID-19 vaccine using messenger RNA technology for use in the UK has set high expectations that these obstacles can be overcome. These strains may soon be exacerbated, as a recent white paper says more manufacturers plan to outsource due to the pandemic.
The purpose of the discussion was to gather input from CMOs on some of the challenges they have in working with manufacturers in supplying materials for COVID-19 vaccines as well as how the CMO-manufacturer relationship can be improved.
Thermo Fisher is a contract manufacturer that develops analytics and processes for viral gene transfer systems used in clinical trials for cell and gene therapies. Humanigen announced a Thermo Fisher partnership to expand manufacturing for COVID-19 therapies lenzilumab on 23 September. (Also see "Deals Shaping The Medical Industry, September 2020" - In Vivo, 7 Oct, 2020.) Also in September, Inovio announced that it signed a letter of intent with Thermo Fisher for the CMO to manufacture its DNA COVID-19 vaccine candidates IN0-4800. The company will manufacture the drug and perform fill finish of the products at its commercial facilities in the US.
Asked to describe some major challenges in producing clinical materials for COVID-19 vaccines, participants responded that a major obstacle is finding enough capacity to produce clinical materials, finding the talent to make the materials and scaling up manufacturing processes.
Brandon Pence, VP and general manager of purification and analytics, said “the challenges are significant. … It feels like everything has changed because of COVID-19. … Capacity constraints seem to be on the CMO and the manufacturing side and the COVID-19 environment has intensified that. In an otherwise more traditional environment, the capacity constraints would not be as significant as what we are seeing right now.”
Panelists said the UK Medicines and Healthcare products Regulatory Agency's recent emergency use authorization of the Pfizer Inc./BioNTech SE vaccine, which uses mRNA technology, has set a high bar, and has paved the way in proving that COVID-19 vaccine therapies can be scaled up quickly. MHRA granted emergency authorization for the vaccine just nine days after receiving the final Phase III results from Pfizer. (Also see "UK Grants First Worldwide Authorization For Pfizer/BioNTech COVID-19 Vaccine" - Scrip, 2 Dec, 2020.)
Pence said that "front runner vaccines for COVID-19 are using mRNA technology, which is a new application in that we do not have vaccines using mRNA technology. Yet in 10 months, we have gone from proof of concept to completing clinical trials and an emergency use authorization. The role that technology plays is something that we have often talked about in years past but has taken a big spotlight in the COVID-19 technology development."
Christopher Murphy, VP and general manager for the viral vectors services group, concurred that the emergency use authorization of the mRNA vaccine has raised the bar.
"When you look at when these modalities were first being developed, they were to treat rare diseases and cancer. They weren't a billion plus doses needed in the next ninth months."
Yet he acknowledged that scaling up is not an insurmountable obstacle. What is needed to rapidly scale up production of COVID-19 vaccines is enough capacity to make product as well as a skilled workforce that can produce the vaccine.
"What you are seeing is an extraordinary race for talent and expertise. ... You need the capacity to support the larger scale manufacturing of the new molecules for vaccines and you also need the talent to be able to support that. This is our version of a moonshot but it is happening in an 18-month period in terms of rapid development and innovation to support these modalities to treat COVID."
The biopharmaceutical industry, concerned about worker shortages, is expanding its presence on college campuses to recruit future workers proficient in advanced manufacturing, cell and gene therapies and combination products, as executives say that not having enough skilled workers keep them up at night. (Also see "Workforce Of The Future Initiative Aims To Close Skills Gap In Biopharmaceutical Industry" - Pink Sheet, 22 Jun, 2020.)
Murphy added that the safety profile for mRNA-based treatments has been “very well established for decades.”
“The mRNA technology has been tested in very sick people for decades, what is helping accelerate these trials is that the safety profile has been high. ... The regulators are not cutting corners, they are reflecting on the rich history of these trials, and this will be important to the public to understand, this was not something that has just been invented in the last nine to 10 months.”
Another challenge is the pandemic's impact on business continuity plans, said Murphy. He explained that producing materials for these vaccines is labor intensive, yet the pandemic is making it impossible to have fully staffed plants.
One bright spot is that despite fears, there have been no shortages of the raw materials needed to produce these vaccines, said Eric Langer, president and managing partner of the marketing research for BioPlan Associates. He was responding to a question on current supply chain challenges in sourcing materials for COVID-19 vaccines.
Even so, it took Pfizer longer than expected to scale up the raw material supply for its COVID-19 vaccine. (Also see "Pfizer’s Expected 2020 COVID-19 Vaccine Production Fell By 50% After Scaleup Delays" - Pink Sheet, 3 Dec, 2020.)
Langer said that when the pandemic first hit, there were these fears of shortages. A BioPlan white paper released in May found that that 75% of biopharmaceutical manufacturers and 70% of suppliers feared a shortage of supplies. Yet, he said that these fears have not materialized.
The white paper is based on a survey of 21 US and EU bioprocessing executives and managers, 10 from suppliers of bioprocessing equipment and 11 with biopharmaceutical companies. It is called “COVID-19 Impact on Bioprocessing: Accelerating Trends: Long Term Impact of Novel Coronavirus On Biomanufacturing And Bioprocess Supply Chain.”
Kate Torchlin, VP and general manager of cell culture and cell therapy, said that partnering with CMOs early on can help manufacturers meet tight timelines for producing COVID-19 vaccines. She was responding to a question about how manufacturers and suppliers can collaborate better.
Torchlin said that manufacturers should also ensure “there are no esoteric logistics requirements.”
Langer weighed in that both manufacturers and CMOs should expect to contribute 60% to these partnerships. These collaborations will “require more stamina and forethought on the part of manufacturers and suppliers.”
Langer said the pandemic will prompt manufacturers and their partners to devise more creative partnerships to reflect an expected surge in outsourcing agreements, which is a finding from the May white paper.
According to the white paper, 70% of the manufacturers surveyed said they will be outsourcing operations due to COVID-19. The survey said the pandemic is “accelerating” more manufacturers to outsource their pandemic-related products, while others are outsourcing lower priority projects.
Langer said that “if [vaccine production] is not a core business, companies will determine whether this is something they should be doing. The lack of staff will create a pinch that people will not be able to get out of. So the only solution will be outsourcing to contract manufacturers.”
Transparency on the numbers of coronavirus vaccines being delivered to EU countries, and on the contents of vaccine contracts, is vital
to counter uncertainty and disinformation, say EU politicians.
Following the very public falling-out between the UK and the EU over the supply of the AstraZeneca PLC/Oxford University coronavirus vaccine, members of the European Parliament have urged member states to provide data on the number of doses they have ordered and had delivered so that a “facts-based” debate can be held on vaccine supplies across the continent.
MEPs also say that more transparency is needed on vaccine contracts between pharmaceutical companies and the European Commission, and that they want to hold a debate with political leaders and pharmaceutical company representatives on how production of currently available vaccines can be boosted in the EU.
“Only once we have a clear picture, can we build trust, address challenges linked to delays in supply and the speed at which vaccines are being administered, and fight back the growing wave of uncertainty and disinformation in Europe,” said MEP Pascal Canfin, who chairs the parliament’s environment and public health committee (ENVI).
During an 8 February webinar, Canfin said the EU member states had failed to provide sufficient information on how many vaccine doses had been ordered each month up to June 2021, and how many were actually being delivered to each country.
He displayed a chart drawn up by the ENVI which showed that only three countries – Denmark, France and Sweden – had provided full information on how many vaccines were expected to be delivered each month to June. Others, including Germany, Poland, Luxembourg and the Netherlands, only provided certain information.
There was no information at all from the likes of Italy, Spain, Portugal and Greece, Canfin said. “We don’t know how many doses are expected month by month.” The parliament will be pushing to make this information available, he said.
MEPs also criticized the lack of transparency over the vaccine supply contracts negotiated by the commission with pharmaceutical companies. The CureVac NV and AstraZeneca contracts have been made public, but with big chunks of text redacted.
Canfin said he recognized that there was some “legitimately confidential information” in the contracts, but “the price, number of doses, delivery timing, production times, liability and the intellectual property regime – we consider that these elements should be made public by both sides, the commission on one side and the company on the other.”
Transparency was important to create trust and “avoid fake news,” Canfin declared. “If we don’t have the data on the table, we can’t have a facts-based debate.”
Bas Eickhout of the Greens said that the lack of transparency also made it difficult to know whether the commission’s apparently slow pace in agreeing the contracts was due to its insistence that companies bear liability for any injury caused by the vaccines, as has been suggested. “We can’t really check that entirely” because of the redactions, the MEP said.
As to whether there were differences between the EU and UK contracts in terms of who bears liability, Eickhout said: “I think there will be, but we don’t know because we can’t compare the contracts.”
Ramping Up Production Referring to the slow rollout in the EU compared with countries like the UK, for example, Eickhout said that “intensifying production should be our key concern now, and that is where we have the biggest problem.” Noting that “we should have done it earlier” he conceded that it was “easy to say that now, I admit.”
Jytte Guteland of the social/democrat S&D grouping agreed that ramping up production of vaccines should be the priority. She said her group was asking for a debate with political leaders and heads of pharmaceutical firms involving the ENVI and the parliament's industry, trade and research committee (ITRE) “to put questions to companies on how to increase production". It was, Guteland said, "about pressuring the commission and also companies.”
During the webinar, key MEPs stepped up to support the European Commission’s unified approach to negotiating COVID-19 vaccine procurement, laying the blame for the recent spat over supplies of the AstraZeneca/Oxford vaccine squarely at the company’s door.
Canfin said that the parliament had supported the commission’s approach from the beginning. “Imagine if we had 27 contracts, 27 different prices, 27 ordering processes. That would be a real mess to be honest, and public opinion wouldn’t understand anything.”
He noted that the commission had been criticized for prioritizing lower prices for vaccines over maximizing the number of doses ordered from companies. But, he said, “we have secured 2.3 billion doses, we have enough to vaccinate the EU population more than twice.”
Eickhout also noted that progress may have been slowed down because some member states were reluctant to buy the newer mRNA vaccines. There was “a lot of concern among member states and not all were ready to go for them, so here blaming the commission is a bit too easy.”
Canfin said the problem was not the number of doses ordered but that “companies do not produce enough at speed to deliver on time.” Looking at the argument between AstraZeneca and the commission, he said the company had failed to stockpile and deliver the doses promised. The commission president, Ursula von der Leyen, “was right to say this was not acceptable,” Canfin said, adding: “Why should we accept that and not say anything?”
FY2020 review highlights drop in inspections, preparations for growing backlog, and pandemic test of Janet Woodcock’s 21st Century proposition – developments that will likely reverberate in the years ahead.
As waves of fear gripped the world, travel restrictions due to the SARS-CoV-2 pandemic last year swiftly brought profound changes to the US Food and Drug Administration’s enforcement program that are continuing to unfold today and will reverberate in the years ahead.
Compared to the year before, FDA data shows that agency inspections of drug manufacturing facilities in fiscal year 2020 fell by 60%. As the pandemic continues in FY 2021, the inspection rate will remain depressed.
It remains unclear how the agency will reduce the backlog without resorting to so-called virtual inspections that involve video plant walk-throughs, an imperfect alternative that other regulatory authorities like the European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency have to varying degrees embraced. (Also see "How The European Medicines Agency Inspected Thermo Fisher’s Florida Plant Without Leaving Europe" - Pink Sheet, 20 Jul, 2020.) (Also see "UK MHRA Relies On Remote Drug GMP Inspections As COVID-19 Pandemic Grounds Inspectors" - Pink Sheet, 16 Jul, 2020.)
Meanwhile, the inspection hiatus will test the pharmaceutical industry’s progress toward the vision that acting FDA commissioner Janet Woodcock set forth in 2004 when, as director of the agency’s Center for Drug Evaluation and Research, she called for a 21st Century manufacturing sector that “reliably produces high-quality drug products without extensive regulatory oversight.”
Facilities that have strong quality cultures and robust quality management systems will look to showcase their ability to maintain a high level of quality without much oversight when FDA investigators are able to revisit them. Others may dread the agency's return.
FDA inspectional activity was close to FY 2019 levels in the first half of the fiscal year, then nose-dived as authorities reacted to the spread of the SARS-CoV-2 virus that causes COVID-19.
The agency evacuated China staff at the end of January. By March, the FDA had suspended virtually all foreign and domestic inspections, though in July it allowed domestic inspections to resume under certain conditions that turned out to be rare.
The agency continued to conduct inspections it deemed mission critical to the extent that it could, but it was not always possible to anticipate issues. In one case, an investigator on a mission-critical foreign inspection of the active pharmaceutical ingredient manufacturer for a drug that was in shortage was stranded for five weeks when the country went into lockdown, unable to get home or even reach the US embassy, noted Bruce Ross, director of the agency’s Office of Global Operations, in remarks last October at the American Public Health Association’s virtual annual meeting.
An agency database had logged just 614 drug quality assurance inspections for the US federal fiscal year that ended 30 September 2020 when it was updated in December, compared to 1,517 such inspections for FY 2019.
Over the previous decade, the agency had conducted 1,500 to 2,000 such drug good manufacturing practices inspections annually.
The FDA’s inspection classification database does not include every drug GMP inspection. It excludes some pre-approval inspections, for example. And it does not list a site inspection until the agency makes a final determination based on that inspection on how it will classify the site.
As the year wore on, the difficulty of inspecting manufacturers during the pandemic was turning a safe $7bn bet for Celgene stockholders into a more dicey proposition.
When Bristol Myers Squibb Company acquired Celgene Corporation, it agreed to pay Celgene shareholders an extra $9-per-share contingent value right if certain conditions were met, one of them being FDA approval of Celgene’s lisocabtagene maraleucel (liso-cel) chimeric antigen receptor T-cell therapy by 31 December. (Also see "It Was Inevitable: FDA Inspection Delay Postpones BMS’s Liso-Cel Approval" - Scrip, 16 Nov, 2020.)
Because that approval hinged on an inspection of a contract manufacturer’s facility, there was a flurry of interest among investors in the likelihood of a timely FDA site or remote video inspection.
But when the FDA finally completed a site inspection at the Lonza Group AG viral vector facility in Houston on 10 December, it was too late for the Celgene shareholders. The FDA finally approved Breyanzi (lisocabtagene maraleucel) for certain types of Large B-cell lymphoma on 5 February.
FY 2020 aligned with historical trends in site classification. During the fiscal year:
32% of the inspected sites were classified as “no action indicated,” or NAI, which means they are good as is;
60% were classified as voluntary action indicated, or VAI, which means the investigator or team of investigators that visited the site observed some issues, described their observations in a Form 483 report, and expect the site to fix the problems before the agency’s next inspection; and
8% were classified as official action indicated, or OAI, which means there may be a warning letter or, failing that, company officials may be called in for a meeting with the FDA about improvements the agency expects them to make.
Not only were there far fewer inspections in April-September than in first half of the fiscal year, those that did occur were more likely to result in favorable findings. But because of the small numbers involved, the sharp improvement in inspection outcomes did not have much effect on the annual inspection trend.
An increased focus on pre-approval inspections for high-priority drug products is likely why the agency saw fewer problems at the 36 sites inspected during the second half of the fiscal year.
The FDA classified 50% of those sites as NAI, 47% as VAI and just 3% as OAI.
It may seem counterintuitive that the share of sites without any GMP problems jumped from a third to a half of the total during this period, considering the FDA began restricting itself to mission-critical inspections in March. Although the agency in July allowed domestic routine surveillance inspections to resume in localities where COVID-19 disease transmission had declined significantly, transmission subsequently increased in many parts of the country.
There may well have been an increased focus in the second half of the year on pre-approval inspections for important new drug products and perhaps even some follow-up inspections of OAI facilities that the agency was confident had been fully remediated.
It is hardly surprising, given the travel difficulties, that after years of turning its attention increasingly abroad, the FDA refocused on domestic inspections during the pandemic.
A chief goal of the July 2012 FDA Safety and Innovation Act was to shift the FDA’s inspection program to focus more on facilities in foreign countries.
This reaction to the globalization of the pharmaceutical industry worked. In the years leading up to the legislation, 70% to 80% of FDA inspections had been domestic. Afterward, the domestic share steadily declined, reaching a low of 43% in FY 2019, the FDA inspection classification database shows.
In FY 2020, that all changed. There was an uptick in domestic inspections during the first half of the fiscal year to 51%, then a dramatic surge after the US and other nations imposed travel restrictions in March in their efforts to slow the spread of COVID-19.
The FDA conducted very few inspections after that, and 89% of them were in the US.
But as the pandemic continues, the agency is working to resume foreign inspections. The FDA says that in October 2020, it started inspecting again in China, and that it plans to resume Indian inspections “shortly,” depending on trends in the coronavirus outbreak there, much as it has been doing in the US since July. (Also see "US FDA Resumes China, India Inspections In Bid To Keep Drug Approvals On Schedule" - Pink Sheet, 26 Jan, 2021.)
FDA officials have relied on alternative approaches to obtain information about facilities while it cannot inspect them during the pandemic.
The most significant alternative is expanded use of the authority Congress granted in 2012 to request records in lieu of or in advance of inspections under Section 704(a)(4) of the Food, Drug and Cosmetic Act.
By the end of the fiscal year, the agency had issued 438 records requests to pharmaceutical manufacturing facilities and another 140 to biologics facilities, or 578 in all, the FDA told the Pink Sheet.
The agency acted based on the record reviews as well. For example, of the 111 records requests made through August in support of drug application reviews, 77 led to approval recommendations and 15 to withhold recommendations, FDA assistant commissioner Elizabeth Miller told the Parenteral Drug Association/ FDA conference in September. (Also see "US FDA Assesses Over 500 Biopharma Plants Remotely Via Records Review; Refines Process" - Pink Sheet, 17 Sep, 2020.)
The FDA has been more reluctant to take enforcement actions based on records reviews, although on 22 January, it finally issued a warning letter based on one. That letter to Yuyao Yijia Daily Chemical Co. Ltd. in Ningbo, China, focused on testing irregularities around its alcohol-based hand sanitizer that surfaced in its response to a 31 March records request, not long after the agency suspended all inspections. The timing suggests that this could be the first of many such warning letters. (Also see "Chinese Firm Hit With Pandemic's First Remote-Records-Based FDA Drug GMP Warning Letter" - Pink Sheet, 27 Jan, 2021.)
However, the remote reviews do not take the place of inspections, and therefore are not noted in the agency’s inspection classification database, the FDA told the Pink Sheet. Rather, the agency explained, “these remote records assessments allow us to prioritize and prepare for on-site inspections.”
In other words, the nearly 600 records reviews conducted in FY 2020 simply paved the way for a backlog of inspections the agency intends to conduct once its investigators can travel again.
Similarly, the agency does not classify facilities based on analytical results, for example, from border testing of alcohol hand sanitizers for poisonous methanol. (Also see "US FDA's First-Ever Countrywide Import Alert For Drugs Bans Mexican Hand Sanitizers" - Pink Sheet, 29 Jan, 2021.) (Also see "Deadly COVID-19 Hand Sanitizer Production Surge Prompted US FDA's New Import Alert Category" - Pink Sheet, 17 Sep, 2020.)
The agency did not say whether it classifies facilities based on inspections by other regulatory authorities such as EU inspectorates, who share findings under a mutual recognition agreement.
Industry has clamored since at least the summer of 2020 for the FDA to follow the lead of other regulatory agencies in relying at least partly on video streaming technology to conduct remote inspections. FDA officials say the agency has been piloting such technologies and has been drafting guidance for their use, but there has been no indication yet that it has adopted them.
Industry has run into difficulties when its inspection priorities diverge from those of the FDA, particularly in getting the follow-up inspections required for the agency to reclassify OAI sites following GMP remediation – and in getting preapproval inspections in time to meet user fee goals dates for approval of drugs, particularly those that might have more profit potential than public health impact.
It is possible that as the FDA works through its concerns about remote video inspections, the agency will find a way to begin using them to start working through its backlog of inspections this year.
Over the previous decade, the NAI rate fell from nearly half to about one third as the agency refined its inspection site selection model to focus more on the riskiest sites. Meanwhile, the VAI rate advanced from 50% to 60%, while the OAI rate increased slightly.
OAI rates bumped up in fiscal years 2017 and 2019 as the FDA worked through its inventory of never-before-inspected sites, many of which were Chinese cosmetics firms that made some over-the-counter drug products without following many US drug good manufacturing practice requirements.
It is unclear whether China’s OAI rate would have declined in FY 2020 as the FDA cleared its never-inspected backlog; there were no OAI results among the 11 inspections conducted there in the first quarter, nor with the single second-quarter inspection, completed 10 January at Haimen Pharma Co. Ltd. in Haimen City across the Yangtze River from Shanghai.
The rate in India jumped in fiscal years 2013 and 2014 and remained elevated in subsequent years as FDA investigators became more sophisticated in identifying data integrity issues.
The OAI rate for domestic inspections increased after the September 2012 multistate outbreak of fungal meningitis, traced to the New England Compounding Center in Framingham, MA, led to a surge of sterility assurance inspections of compounding pharmacies and has continued to increase as the agency began also to focus on the manufacture of homeopathic medicine.
The one region where OAI rates consistently remained low through the past decade in Europe. Because of the recent US/EU mutual recognition agreement, FDA inspections there are likely to continue declining in number as well.
Domestic inspections have been declining throughout the decade as the FDA shifted its focus abroad. Foreign inspections meanwhile increased, but to a lesser extent, a reflection of the increased time and expense required to conduct them.
A senior inspector at the European Directorate for the Quality of Medicines & HealthCare explained how some “out-of-the-box thinking” was leading to a new approach for inspecting companies.
The European Directorate for the Quality of Medicines & HealthCare (EDQM) is planning to make “real-time remote inspections” a permanent feature of its good manufacturing practice (GMP) inspection program following early positive results from an ongoing pilot.
The pilot was initiated after COVID-19-related travel restrictions led to the postponement of onsite inspections. It has so far resulted in EDQM inspectors conducting a “virtual tour” of two pharmaceutical manufacturers in India from their desk in Europe.
“Deficiencies were identified during both these remote inspections” based on visuals that were live streamed from the manufacturing sites, said EDQM inspector Cristina Baccarelli.
“You could almost think you were there,” Baccarelli said. The EDQM inspector was speaking about the directorate’s experience with the two virtual inspections – which took place in the last quarter of 2020 – during a webinar on 27 January. The webinar was run by Medicines for Europe, as part of the drug industry group’s annual Regulatory Affairs and Pharmacovigilance conference.
Key to both of the inspections was the use of a head-mounted camera that was worn by a trained operator from the company at the site being inspected and which streamed real-time videos to inspectors in the EU, Baccarelli explained. The camera is worn on a helmet and the operator walks around the manufacturing facility as instructed by inspectors.
“We ask the operator to stop and look around… We give directions and the operator just follows the directions slowly” and “it really gives the impression that we are there,” Baccarelli said. The EDQM inspectors took photos of the site while the video was being streamed in real-time and were also able to identify some deficiencies. At one of the sites, for example, they identified maintenance issues in the wash area. (See pictures below).
The inspectors were able to give precise instructions on operating the camera, as both of the sites included in the pilot had been previously inspected by the EDQM. “We had the layouts,” explained Baccarelli. “Sometimes there were some short interruptions… especially in small rooms with many walls. But on the whole, it worked well. We just have to be patient sometimes and wait for an image to come back.”
Examples of images taken by EDQM inspectors during a virtual inspection. Source: EDQM
The inspectors were also able to get real time-access to non-electronic documents from the inspected company via a secure online tool. To ensure coordination, one staff member of the company being inspected acted as a “facilitator” and interacted with other colleagues and clarified the demands/queries of inspectors, Baccarelli said.
Baccarelli acknowledged that the remote inspection approach was not yet perfect. During a regular onsite inspection inspectors are free to walk into any part of the manufacturing facility but during a virtual tour the manufacturer “might just say there is no connection” in a certain room that inspectors want to look at, she explained.
It is for this reason that the EDQM wants to set up criteria on when remote inspections may not be suitable. This includes sites that have never been inspected or where there is a high risk of falsification.
For now, the EDQM’s remote inspections pilot is focused on drug manufacturers in India “because it's easier – there is less of a time difference [between the EU] and there is no need for an interpreter,” said Baccarelli. Each inspection conducted at the two sites last year lasted for five to six days, with the inspection work being conducted for around six hours per day.
The EDQM is planning to conduct more remote inspections in India. “The next one is in less than two weeks. And we will do more until summer,” said Baccarelli. The directorate wants to also carry out such inspections in China.
While the pilot is still on, the “first impressions are promising” and indicate that virtual inspections could potentially become a “regular process for sites that have showed a good level of compliance during previous inspections,” she said.
A virtual inspection could be used, for example, to verify compliance with corrective and preventive actions (CAPAs) identified in previous inspections. It may also be used for the urgent evaluation of a specific issue that might pose a risk to public health. In this case, she explained, a remote inspection would not replace an onsite inspection, but would allow an immediate assessment of the specific situation.
Baccarelli said preparing for a virtual inspection was more complex because inspectors must review a larger number of documents beforehand compared with onsite inspections. Also, prior agreement is needed on the use of various technological solutions needed to support the inspections.
The EDQM inspector discussed the following tools that were used during the EDQM pilot:
A secure document sharing tool – The EDQM granted the inspected company access to a “pre-defined folder structure” (eg, relating to the topic or date of the inspection) in the tool to upload documents in real-time during the inspection.
Cell phones/tablets – As drug manufacturing sites usually stock various solvents, which may be highly flammable, Baccarelli said it was important to ensure that the cell phones and tablets used were “intrinsically safe” and do not pose a risk of explosion.
A head-mounted camera – While these cameras “really give the impression that we are there,” their battery lasts for just two to three hours, which should be taken into account when planning a virtual site visit, said Baccarelli. For the pilot, these cameras were purchased by the companies being inspected.
Document viewer – This comes in handy for providing the inspectors with real-time access to non-electronic documents, such as batch manufacturing records, logbooks etc. However, while the document viewer worked satisfactorily for typed text, the images of handwritten notes was not as clear and, in some cases, it was preferable to scan and share these, the EDQM inspector said. The companies being inspected chose to rent document viewers for the virtual inspection.
Web conference applications – Baccarelli recommends installing two web conference apps on all phones, tablets and computer systems “as part of a back-up strategy” and also to “allow the inspectors to work in parallel where needed.”
Internet connection and mobile Wifi hotspots – These should be tested before the inspection.
To encourage global coordination on remote inspections, Baccarelli said the EDQM has been sharing its experience with international regulators, including the European Medicines Agency’s inspectors working group.
The EDQM carries out around 40 onsite GMP inspections every year as part of its certificate of suitability (CEP) procedure. The CEPs certify that the quality of an active substance can be suitably controlled by the relevant monograph of the European Pharmacopoeia. In 2010, the EDQM introduced paper-based GMP assessments (ie, assessment of the paper dossier submitted by the company) to complement its onsite inspections.
Baccarelli explained that the pilot on real-time remote inspections was initiated after the EDQM was forced to do some “out of the box thinking” in light of COVID-19-related travel restrictions, which resulted in all onsite inspections being postponed.
The use of remote inspections, if established as a “third pillar” within the EDQM for the supervision of the ongoing GMP compliance, could help the directorate to dedicate its onsite inspections only to sites which are more critical, she said.
The US FDA and NIST have agreed to help industry modernize and update pharmaceutical manufacturing methods and to improve supply chain resilience.
A five-year agreement signed 15 January may show whether two government agencies are better than one when it comes to getting the pharmaceutical industry to adopt new manufacturing technologies.
Under the memorandum of understanding, the US Food and Drug Administration and the National Institute of Standards and Technology will strive to accelerate the uptake of new technologies in pharmaceutical manufacturing like artificial intelligence and machine learning to better prepare for future supply chain disruptions.
Such uptake is needed to boost outdated manufacturing methods and to improve the resilience of the global pharmaceutical supply chain, which the coronavirus pandemic has disrupted.
The action was announced by then FDA Commissioner Stephen Hahn in a 15 January blog post. He said that “the COVID-19 pandemic has shown us that the existing manufacturing structures, with a small number of facilities fed by long and complex supply chains, can be disrupted. This has also been demonstrated in the aftermath of hurricanes in recent years. This can elevate risk and create shortages in the US. The reality is that it isn’t enough to just respond to the current pandemic.”
Previously, Hahn had said in an August 2020 blog post that “typical manufacturing processes that use long shipping lines or outsourced supply chains render US manufacturing vulnerable to delays, disruptions and quality control issues. These existing supply chain vulnerabilities have been exacerbated during the COVID-19 pandemic.”
The MOU says modernization of traditional manufacturing would involve “new capabilities, smart technologies, cutting edge science and digital technologies.” It asserted that these technologies “are not widely deployed in the manufacture of pharmaceuticals, biopharmaceuticals, vaccines and medical devices.”
Transitioning to these new technologies will require “modernized regulatory structures, new standards and measurement tools and enhanced methods for data analysis and cybersecurity in order to encourage domestic production.”
It would also leverage the complementary skills of the FDA’s regulatory expertise and NIST’s precision measurement technologies and engineering knowledge.
Under the MOU, the parties also agreed to collaborate on interdisciplinary research in measurement sciences to “implement best practices in manufacturing process and quality control, including advanced and innovative assays and measurements, modularization of unit operations, understanding appropriate uses of centralized and decentralized manufacturing trains, application of synthetic intelligence and adaptive process control strategies.”
The agencies agreed to meet for quarterly progress updates – and to avoid exchanging confidential or proprietary information.
Hahn said that the MOU will build on existing initiatives that promote advanced manufacturing, including the Center for Drug Evaluation and Research’s (CDER) Emerging Technology Program and the Center for Biologics Evaluation and Research’s Advanced Technology Program.
The ETT was launched in 2013 to promote the use of new technologies in pharmaceutical manufacturing while the CBER’s Advanced Technology Team was created in 2019 to encourage early discussion with innovators and offer early input into manufacturing and is an interactive mechanism to help those developing advanced manufacturing and testing techniques such as continuous manufacturing or gene therapies and other CBER-regulated products. (Also see "FDA Clarifies Scope Of Its Emerging Technology Program" - Pink Sheet, 2 Oct, 2017.); (Also see "US FDA CBER Chief Calls For Industry-Academia Collaboration In Developing Treatments For Ultra-Rare Diseases" - Pink Sheet, 2 Jul, 2019.)
Hahn also announced the formation of a new entity called the Center of Excellence for Advanced Manufacturing, which will be operated by CDER and CBER. The center will explore science and risk-based assessment, establish best assessment and inspection practices, support standard, policy and guidance development, and provide training to staff related to novel manufacturing technologies.
Hahn resigned as commissioner and Janet Woodcock assumed the role of acting commissioner on 20 January when Joe Biden became president. Woodcock had been director of the agency’s Center for Drug Evaluation and Research until late last year when she began advising Hahn as well as Operation Warp Speed’s efforts to develop COVID-19 therapeutics.
The pharmaceutical industry has been slow to embrace advanced manufacturing technologies. Eric Schaller, the senior managing director of Accenture, a global professional services company, told an International Society for Pharmaceutical Engineering meeting in early 2018 that while pharmaceutical executives say that investing in digital technologies is a priority, this had not actually occurred in practice. (Also see "Pharma Sector Explores How To Embrace The Fourth Industrial Revolution" - Pink Sheet, 7 Mar, 2018.)
The risk of inadvertently growing SARS-CoV-2 virus in cell and gene therapies and possibly infecting patients and workers should be assessed and mitigated, the agency advises.
Companies developing cell and gene therapies should pay close attention to starting materials and certain manufacturing processes, such as cell expansion and viral reduction steps, and screen allogeneic and autologous donors to prevent the virus from being transmitted to plant workers and patients, the US Food and Drug Administration said in recent guidance.
The guidance covers manufacturing considerations for licensed and investigational cell and gene therapy products regulated by the FDA’s Center for Biologics Evaluation and Research during the public health emergency and is intended to supplement June 2020 guidance. It provides more detail on assessing donor risk than the earlier guidance, which focused on minimizing the risk of virus transmission in facilities and employees. (Also see "Protecting Rx Manufacturing From COVID: US FDA Offers Directions For Firms" - Pink Sheet, 21 Jun, 2020.)
The recommendations in the guidance specifically consider the source material such as cells and tissue recovered from donors and how the product will be manufactured, such as cell expansion in culture, viral reduction steps and the formulation.
To minimize the potential for contamination of products, the guidance said that companies should focus on the “unintended expansion of SARS-CoV-2, and transmission of SARS-CoV-2 to facility personnel during manufacturing, manufacturers should consider starting materials, manufacturing processes used to control viral spread (e.g., cell expansion in culture, viral reduction steps, producer cell lines, controls for open systems), and contamination risk during manufacturing.”
FDA said that the virus “has been shown to be capable of infecting and replicating in cells commonly used for vector production (e.g., HEK293 and Vero cells).”
The guidance also echoes the June document by reiterating that manufacturers should ensure that employees practice good sanitation and health habits to prevent or mitigate potential COVID-19 transmission.
It said that “to ensure compliance with cGMP requirements, CGT product manufacturers must ensure that employees practice good sanitation and health habits, in accordance with 21 CFR 211.28(b), 21 CFR 600.10 (c) and are expected to prevent or mitigate potential adverse effects on the safety and quality of drugs from an infected or potentially infected employee engaged in drug manufacturing.”
The FDA said that firms should also conduct donor risk assessments, and screen both autologous and allogeneic donors for virus to ensure products don’t contaminate patients.
The agency said routine screening measures are already in place for evaluating COVID-19 infections in allogeneic donors, and that manufacturers must determine and document the eligibility of a cell or tissue donor under 21 CFR 1271.50.
Yet these screening measures are not in place, but should be, for autologous donors “due to the potential for expansion of SARS-CoV-2 during the manufacturing process.”
Autologous cells are those that come from the patient while allogeneic refers to cells that come from other donors.
The FDA said in the 28 days prior to the collection of cells, manufacturers should evaluate whether allogeneic and autologous donors either cared for, lived with, or had close contact with individuals diagnosed with COVID-19, or had been diagnosed with or suspected of having a COVID-19 infection, or had a positive test results from a diagnostic test but never developed symptoms.
The FDA does not advise testing or screening asymptomatic donors, as well as those who have been vaccinated with the “non-replicating, inactivated, or RNA-based COVID-19 vaccines.”
The guidance will remain in effect for the duration of the public health emergency.
To comment, go to www.regulations.gov and refer to docket FDA-2020-D-1137.
‘Wartime’ contract with BARDA will fund up to $268.8m in production site upgrades so Merck can also produce other COVID-19 vaccines and therapeutics as needed.
Under a deal brokered by President Biden’s administration, Merck & Co., Inc. will manufacture Johnson & Johnson’s newly authorized COVID-19 vaccine as well as other vaccines and therapeutics against the virus. The investment comes at a time Merck, a longtime leader in the vaccine space, was already intending to make capital investments in its vaccine manufacturing network.
The US Biomedical Advanced Research and Development Authority (BARDA) invoked the Defense Production Act to provide up to $268.8m, including an initial investment of $105m, so that Merck & Co. can convert, upgrade and equip two of the company’s facilities to manufacture the J&J vaccine and any other COVID-19 vaccines or treatments from Merck and any other drug makers contracting with the US government.
Despite initial reporting that suggested the Biden administration-brokered agreement was related solely to Merck & Co.’s production of J&J’s vaccine, the US Department of Health and Human Services (HHS) revealed on 2 March that the retrofitting of certain unnamed Merck facilities is being done under an agreement with BARDA to provide large-scale manufacturing of a variety of vaccines and therapeutics for use in public health emergencies, including the current pandemic.
Merck & Co. said that under its agreements with J&J’s Janssen Pharmaceuticals Inc. it will use its facilities to produce drug substance, formulate and fill vials of J&J’s vaccine. Merck said BARDA’s funding will allow it to accelerate ongoing efforts to scale up manufacturing to enable timely delivery of COVID-19 vaccines and therapeutics.
Merck & Co. discontinued its own COVID-19 vaccine development this year but continues to test potential treatments for the disease. (Also see "The Tortoise, The Hare, And COVID Vaccines: The Hare Wins" - Pink Sheet, 25 Jan, 2021.)
Outside of the pandemic, however, Merck has previously said it would invest $20bn between 2020 and 2024 in capital improvements, including investments in its global vaccine manufacturing network. The company’s vaccine business generated $7.87bn in sales last year, or about 18% of its 2020 pharmaceutical sales of $43bn, and it is gearing up to expand its portfolio with a second vaccine to prevent pneumococcal disease. (Also see "Merck Sprints Toward Late 2020 Filing For Pneumococcal Vaccine V114" - Scrip, 9 Sep, 2020.)
The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices endorsed the use of J&J’s one-shot COVID-19 vaccine on 28 February, one day after the US Food and Drug Administration issued emergency use authorization for the vaccine. (Also see "ACIP Shies Away From COVID-19 Vaccine Comparative Efficacy And Safety Evaluations" - Pink Sheet, 28 Feb, 2021.)
The Biden administration said on 2 March that it also invoked the Defense Production Act to expedite materials used in vaccine production, including equipment, machinery and supplies, and the president has directed the Department of Defense to provide daily logistical support to J&J. The big pharma has agreed to begin 24/7 manufacturing to maximize its COVID-19 vaccine production output.
These efforts are being made to help J&J accelerate delivery of its vaccine from 100 million doses by the end of June to at or near 100 million doses by the end of May, but in the long term will double J&J’s US capacity to produce drug substance and increase its fill-and-finish capacity.
J&J said it is “pleased to collaborate with Merck as part of our global network to manufacture our COVID-19 vaccine” and noted that Merck & Co. “is the ninth manufacturer to join our global network and this significant collaboration will further enable us to deliver our COVID-19 vaccine worldwide.”
Merck’s commitment under its agreements with BARDA and J&J is to have its facilities ready to manufacture the J&J vaccine by the end of June, President Biden’s press secretary Jen Psaki said during a 2 March press briefing.
Psaki said the Biden administration became aware of J&J’s vaccine production falling behind expectations soon after the president took office in January and stepped in to help facilitate increased production.
While industry has not been eager to embrace the Defense Production Act, firms have been happy collaborators with the government on production enhancements.
In afternoon remarks, Biden himself evoked the historical origins of the Defense Production Act, calling vaccine production a “wartime effort.”
The press secretary also noted that US states will now receive 14.5 million and 15.2 million doses each week of mRNA vaccines previously authorized by the FDA from Pfizer Inc./BioNTech SE and Moderna, Inc. versus 8.6 million doses per week at the start of Biden’s presidency. States will receive 2.8 million doses of the J&J vaccine for a total of 18 million doses weekly.
Psaki said that the US “will have more than enough doses to vaccinate the American people, but there are a couple of factors that our team looks at, including the fact that we don't know which vaccine will be most effective on children [and] we don't know the impact of variants still under consideration and being looked at by our health and medical experts. We are, of course, securing all of these doses so we can plan for a range of scenarios.”
Facing questions about whether there was any concern that people receiving the J&J vaccine would be getting less effective protection against the coronavirus, Psaki commented that “we now have three vaccines that are safe, that are effective in preventing serious illness, effective in preventing death, and anyone in the country who has access to any of these vaccines should take them.”
She also cited public health expert opinions that “every American should take whatever vaccine they have access to in their pharmacy, at their health provider, at their community center, at the mass vaccination site, whatever it may be.”
The agreement for Merck & Co. to manufacture J&J’s third-to-market vaccine is one of a growing number of competitors working together to make sure enough doses of COVID-19 vaccines are produced. Sanofi said on 22 February that it also had agreed to formulate J&J’s vaccine and fill vials at a site in France at a rate of 12 million doses per month.
That agreement followed a deal Sanofi announced in January with BioNTech to finish off doses of its Pfizer-partnered vaccine for Europe, producing up to 125 million doses in total. (Also see "Sanofi Steps Up To Lend A Hand Producing Pfizer/BioNTech's COVID-19 Vaccine In Europe" - Scrip, 26 Jan, 2021.) That announcement was followed rapidly by an agreement for Novartis AG to also provide fill-and-finish services for the Pfizer/BioNTech vaccine. (Also see "Novartis Steps Up To Plate To Produce Pfizer/BioNTech COVID-19 Vaccine" - Scrip, 29 Jan, 2021.)
Merck KGaA revealed in early February that it revised an existing agreement with BioNTech for the
production of lipids used in the delivery of mRNA-based medicines so that more lipids will be available for COVID-19 vaccine production later in 2021.