Human Normal Immunoglobulin (The Japan Blood Products Organization)

Developments in the pharmaceutical industry over the past several years have been marked by increased demand for new therapeutics delivered at a lower cost. Despite (or perhaps because of) that demand, the industry is still wrestling with the challenge of how to rapidly scale the manufacturing process. The concept of continuous manufacturing (CM) is not new to pharma — ruminations about shifting from a batch-based to a continuous process began more than 20 years ago — and yet, increasingly, CM comes up as a potential answer to many of the industry’s current challenges. CM has gained momentum in the pharma and life science spaces, in large part from advocacy by regulators like the FDA and EMA. It has also gained the attention of guidance bodies including The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and International Society for Pharmaceutical Engineering (ISPE). ICH Q13 (Continuous Manufacturing of Drug Substances and Drug Products Guidance for Industry) was endorsed in January of 2023 and then reproduced by the FDA in March of 2023 . At this writing, the ICH working group training materials which were planned for this past June to complete the ICH Q13 guidance, have not been published. This article reviews the benefits, risks and design challenges associated with continuous manufacturing. Reduced capital costs In CM, continuous flow and very high equipment occupancy allow manufacturing facilities to reduce each unit operation’s instantaneous throughput and holdup volume without compromising the target annual production typical of a batch operation. When combined with a reduction or elimination of intermediate holding tanks, manufacturers can reduce the capital cost associated with equipment procurement and facility footprint. Additionally, CM is compatible with real-time monitoring of critical process parameters (CPP), as opposed to traditional offline measurement after a batch step is complete. This allows for immediate adjustment of process inputs In new facilities employing predictive analytics, the process automation system can extrapolate deviations in an in-line measured value and prompt the automation system (or operator) to adjust inputs before the product goes out of spec. This is especially true for products or intermediates that are unstable, such as cells harvested from a perfusion bioreactor. Reduced waste/improved scalability A CM process can have significantly less waste than a fed-batch process, by minimizing the need for large-scale storage, reducing the volume of rejected batches, minimizing the volume of cleaning fluids sent to drain, maximizing equipment occupancy, and reducing cleanroom footprints. CM also reduces waste in the drug substance pipeline, by providing site leadership with improved flexibility. Instead of scaling-up an operation from clinical to commercial, single product manufacturers may be able to scale-out by using identical unit operations and CPP’s by adding capacity through parallel skids and higher equipment uptime. CM allows manufacturers to gain efficiency in design, commissioning, qualification and validation (CQV), and chemistry, manufacturing and controls (CMC) changes. And it does so while simultaneously reducing the risk creating an unexpected emergent property, which can be the result of order-of-magnitude scale-up. During operation, the same flexibility is possible for scaling production volumes with changing market demands or raw material availability. While all new capital expansions in early-phase design should consider implementing CM, new products or expansions for advanced manufacturers pursuing Pharma 4.0 are especially compatible with CM. In these cases, CM can offer considerable risk mitigation. It’s important to keep in mind that hurdles to technology implementation can be exacerbated with well-established products. These cases typically require integration with existing systems, and cross-training existing staff to interpret trends that lead to excursions in the manufacturing process. Technology implementation can also worsen in existing facilities where products or processes may be incompatible with commercially-available inline instruments — or where a niche technology is only supplied by non-partnered vendors, making implementation commercially disadvantageous. The most notable consideration for risk mitigation in CM implementation is robust engineering design. Instrumentation, automation, and system integration scope on capital projects is larger and should enter the project earlier. For example, fully automated skids and facility-wide enmeshed systems require detailed sequences of operations (SOO) defining each unit operation’s response to local, upstream, downstream, and adjacent (e.g., buffer) upset conditions. Without intermediate hold steps, the engineering team must decide if flow can be stopped for a limited period, or if an active, recirculated hold is necessary. Without break tanks, upstream pressure transfers and utility sources require precise pressure control to prevent blowing through sanitary diaphragm pumps downstream. Variability of equipment speeds and occupancy require detailed modelling of the production schedule, and reaction/separation characteristics to mate upstream to downstream flows. Utility systems that require periodic sanitization should be fully redundant or have scheduled downtime synchronized with an adjacent skid clean-in-place (CIP) system. While there are many persuasive reasons to adopt CM in pharma manufacturing, it can require considerable documentation upfront to ensure optimal operation. Take, for example, the case of a pharmaceutical company involved in the manufacture of intravenous immunoglobulin (IVIG) drug substance. IVIG is an essential plasma-derived therapeutic for the treatment of life-threatening immunodeficiencies and autoimmune diseases. This company employs a process with proprietary, novel technology for semi-continuous downstream processing of source and recovered blood plasma into IVIG. The semi-continuous nature and complex automation involved in its manufacture required the company to create SOOs for pre-use, shutdown, operations, sanitization, and hold states which defined control parameters, alarms, aborts, and sampling requirements while depicting toggled and active flow paths. This was applied to all core process skids as well as supporting utility and buffer systems. In general, it's essential to consider both upstream and downstream requirements when adopting CM. Pharma companies making use of CM often require upstream continuous bioprocessing with high density cell banks, combining a production bioreactor with a cell retention device such as an alternating tangential filter in perfusion mode, with continuous media supply and cell harvesting. In many cases, the perfusion step is a continuous clarification step, which then moves to a viral inactivation phase where it may be briefly held before downstream processing. Downstream considerations often include multicolumn capture chromatography. This approach can enable continuous operation because one column can always be in the loading cycle. The parallel columns have a column count in direct proportion to the loading time, with one column loading while the others are in wash, elute or equilibration. CM processes often draw utilities and buffers around the clock. This can be a strain on a company’s redundancy efforts and limits their ability to bring systems down for periodic sanitization. There are, however, design considerations that can accommodate these challenges. Buffers and CIP systems Systems should be designed with inline dilution of buffer concentrates. (One company recently chose a unique redundancy philosophy, where tanks were grouped in interchangeable triads.) For CM operations, it’s advisable to design systems with distribution networks that use inlet and outlet rings local to the skids, and mix-proof valve arrays for CIP distribution. Water for injection (WFI) systems WFI systems usually have nightly or weekly scheduled downtime for heat sanitization. Continuous manufacturers often distribute WFI at ambient temperature to simplify dosing to the unit operations, continuously ozonating the tank and periodically ozonating the distribution loop. In these circumstances they can take down the distribution loop for shorter durations compared to heat sanitization and jog the operations schedule to avoid downtime of the core process. On a recent project, a client operating 24/7 mitigated WFI sanitization downtime risk by designing two fully redundant alternating hot and ambient distribution loops, with a single continuously ozonated ambient storage tank. Continuous manufacturing should be more common in life sciences than it is, and new facilities should be designed with CM in mind. For companies that have not taken on this type of effort before, there are some important considerations that will improve success with continuous manufacturing. From a capital expenditure perspective, CM has inherently higher equipment occupancy than conventional manufacturing. Therefore, it also offers the potential to reduce process equipment expenses. From a scalability perspective, CM offers appreciable scale-out expansion capability (especially in ATMP and single-use biomanufacturing). By increasing equipment uptime, CM gives a company the flexibility to scale-out from clinical to commercial batch sizes with the same equipment size by increasing equipment uptime. CM also reduces waste, by minimizing the need for large-scale storage, reducing the volume of rejected batches, minimizing the volume of cleaning fluids sent to drain, and reducing cleanroom footprints. Fully automated skids and facility-wide enmeshed systems demand detailed SOOs. These sequences must define each unit operation’s response to local, upstream, downstream and adjacent (e.g., buffer) upset conditions. To facilitate the 24/7 operation demanded by CM, consider ambient WFI with a continuously ozonated tank and redundant distribution loops to simplify dosing to the unit ops. Additionally, consider inline dilution of buffer concentrates at the point of use, with redundant concentrate tanks. This will allow continuous, on-demand supply of at-strength buffer without having to maintain large buffer hold tanks and predict consumptions. Finally, consider employing multicolumn capture chromatography. This can enable continuous operation by always having one column in the loading cycle. By taking a measured approach to continuous manufacturing, pharma companies can make dramatic improvements to their operational efficiency — and respond to the call for new therapeutics to be delivered quickly and at a lower cost.

CMS released an unpublished rule Wednesday that includes increasing CY 2024 home health payments by 0.8%. Centers for Medicare & Medicaid Services (CMS) released a rule Wednesday that increases the 2024 home health payments by 0.8%, or $140 million. “The $140 million increase in estimated payments for CY 2024 reflects the effects of the CY 2024 home health payment update percentage of 3% ($525 million increase), an estimated 2.6% decrease that reflects the effects of the permanent behavioral assumption adjustment ($455 million) and an estimated 0.4% increase that reflects the effects of an updated FDL ($70 million increase),” the unpublished rule said. CMS expects increasing the rate will bring home health payments in line with statutory payment authority. In July, the Biden administration proposed cutting reimbursements to home health providers by 2.2% next year, or an estimated $375 million less than 2023 payment levels. It also proposed cutting home health rates by 5.1% or $460 million. Instead, CMS is finalizing a -2.89% adjustment, just half of the proposed home health cut earlier in the year, acknowledging that 5.1% could’ve been “too burdensome” a cut for many providers. The proposed rule will be published in the Federal Register Nov. 13, effective Jan. 1, 2024. Several home health advocacy groups criticized the final rule's implications on systems around the country. "The Partnership for Quality Home Healthcare is extremely disappointed that the Centers for Medicare & Medicaid Services (CMS) finalized a -2.89% cut to home health in its CY2024 Home Health Prospective Payment System (HH PPS) Final Rule," said the Partnership in a statement to Fierce Healthcare. "On top of last year’s nearly -4% cut, CMS’s decision to only partially mitigate their proposed cut to home health will cause further harm to patient access and create financial instability that will make it harder to provide care in the home." "Both patients and providers have described how difficult it already is to access and deliver home health services because of years of continuous Medicare cuts, a significant staffing shortage, and rising inflation," said CEO Joanne Cunningham. "I do not understand what the disconnect is. With labor and inflation costs continuing to rise dramatically and home health providers dealing with a national healthcare workforce crisis, any cut to home health will cause further harm. To put these numbers into context, the rule finalizes a base rate year-over-year increase of less than $1 per day to care for Medicare’s sickest patients. And while CMS is slightly delaying implementation of the permanent cut for next year, those dollars will be cut from home health in future years.” The Partnership stated that it shared both quantitative and anecdotal data with CMS showing that patients are struggling with access, and that these changes would result in more access problems. Cunningham called on lawmakers to block cuts to home health. “We continue to strenuously disagree with CMS’ rate setting actions, including the budget neutrality methodology that CMS employed to arrive at the rate adjustments,” NAHC President William A. Dombi told Home Health Care News. “We recognize that CMS has reduced the proposed 2024 rate cut. However, overall spending on Medicare home health is down, 500,000 fewer patients are receiving care annually since 2018, patient referrals are being rejected more than 50% of the time because providers cannot afford to provide the care needed within the payment rates, and providers have closed their doors or restricted service territory to reduce care costs.” Shortly after CMS released its 5.1% proposal in July, the NAHC petitioned the U.S. District Court for the District of Columbia to strike down and vacate the home health prospective payment system final rule, and to withhold apply the 2024 proposal, saying Congress would prohibit the pay cuts for causing "substantial financial harm" to home health agencies under the Bipartisan Budget Act of 2018. Other changes include increasing the CY 2024 home health market basket percentage by 3.3% before adjusting the rate by 0.3% to 3.0%, a finalized labor related share of 74.9% and non-labor-related share of 25.1% and codify a $270.09 payment toward home health purchases for disposable negative pressure wound therapy (dNPWT) devices. “The actions CMS is taking in this final rule will help improve patient care and also protect the Medicare program’s sustainability for future generations,” CMS said in a release. Wednesday’s rule drop included modifications to the Home Health (HH) Quality Reporting Program (QRP) as well, removing the Application of Percent of Long-Term Care Hospital (LTCH) Patients with an Admission and Discharge Functional Assessment beginning in CY 2025. It also removed two Outcome and Assessment Information Set (OASIS) items no longer necessary for collection. Additionally, home health agencies must meet a 90% threshold of all required OASIS items. Changes under the HH QRP is estimated to reduce cost by more than $5M by reducing unnecessary data collection. The Home Healthy Value-Based Purchasing (HHVBP) Model will codify the measure removal factors finalized in the CY 2022 final rule, replace the claims-based Acute Care Hospitalization During the First 60 Days of Home Health Use measures with the Potentially Preventable Hospitalization measure, effective Jan. 1, 2025, according to the release. “The overall economic impact of the expanded HHVBP Model for CYs 2024 through 2027 is an estimated $3.376 billion in total savings to FFS Medicare from a reduction in unnecessary hospitalizations and SNF usage as a result of greater quality improvements in the HH industry,” the rule said. Permanent coverage and payment of items related to IVIG (Medicare Intravenous Immune Globulin) for patients at home with a primary immune deficiency disease was finalized, now that the Medicare Demonstration program will cease payment using the average sales price (ASP) methodology at the end of the year. This should account for an increase in $8.7 million in total costs to traditional Medicare plans. Under the new rules, Medicare Part B will have an expanded definition for identifying lymphedema treatment that is covered. CMS also finalized plans that codify documentation requirements for Durable Medical Equipment, Prosthetics, Orthotics, & Supplies (DMEPOS) refills. “For the conforming change to sections in CAA of 2023 provision, the overall economic impact for CY 2023 and CY 2024 is an estimated $100 million in total cost to FFS Medicare,” the rule said. “For the lymphedema provision, the overall economic impact for CYs 2023 to 2028 is an estimated $150 million in total cost to FFS Medicare.”