CAR-T Milestones, Abbvie and Eli Lilly M&A Moves, and More

Behind the Headlines, Episode 20

ICH Q12 and Post-Approval Changes

The quickly evolving development of biopharmaceuticals is impacting innovation in the industry overall.

Advancements in Biopharma Spur Innovation

What Pharma Manufacturers Need to Know

Every Pharmaceutical Manufacturing Professional Should Know

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Since the beginnings of aseptic processing, personnel participating in the process were recognized as a major source of contamination. Most of the improvements can be linked to the desire to mitigate the negative consequences of the operator’s presence. Remotely operable filling machines, automated component delivery, aseptic gowning upgrades, unidirectional air, substantially increased physical separation, and more have helped improve the performance of the aseptic process. In most systems, including many of the more advanced designs of restricted access barriers (RABs) and isolators, the operator plays an essential role amidst the many supportive elements needed. The potential for contamination ingress and dispersion is exacerbated by the activities the operator is needed to perform. This situation persists because 

the perfect intervention is the one that is not required” (1,2).

The author initially used the terms ‘routine’ and ‘non-routine’ to distinguish between those activities that are required as part of the process and those that would be needed to rectify the occasional failure. The need to reduce the incidence rate of interventions was included, with the primary focus expected to be on the ‘non-routine’ activities, as their elimination should be the goal in every aseptic process. Unfortunately, multiple firms have tolerated extensive ‘non-routine” interventions to correct repetitive faults in their operations as ‘routine’ because they happened frequently. That was completely contrary to the intent and was addressed in a subsequent publication where the now prevalent terms of ‘inherent’ and ‘corrective’ were introduced (3). Inherent interventions are those operator manipulations necessary to initially prepare the equipment and maintain operation throughout its execution. In an ideal world, no other operator activity would be needed in the critical environment. Corrective interventions would address the actions needed to return the line to operation after a fault or stoppage. This terminology is now generally accepted, but the desired goal is still somewhat distant.

Recommendations for detailed descriptions of each intervention included in operating procedures accompanied with still images, video, and hands-on training were recommended to ensure uniformity of execution and adherence to best practices. These would be employed to support media fill execution and improved consistency in daily execution. Later publications endeavored to make further distinctions in corrective interventions (4,5). The simpler corrective interventions require removal of jammed or broken items, adjustments to equipment, and similar tasks which are typically short duration. A new term was added, ‘critical corrective’, to describe interventions that entail the replacement of sterilized product contact equipment that often require increased manipulation and longer time. While ‘critical corrective’ interventions are common at some firms, consideration should be given to their elimination by ceasing production when these are encountered rather than accept the added risk associated with their execution.

In parallel with these intervention focused publications, James Akers and the author have published on aseptic processing risk assessment that focused on interventional activity (6,7,8). The initial risk assessments published in 2005–2006 arbitrarily assigned greater risk to ‘corrective’ interventions relative to ‘inherent interventions.’ The authors also used a linear scale for potential contamination dispersion. After working with multiple clients applying the method in a variety of different settings, it was revised substantially in 2017. Rather than an arbitrary categorization, the authors shifted to a time-based risk factor for interventions within the critical zone. This resulted in a major shift as a ‘corrective intervention’ of three seconds duration should be considered less risky than an ‘inherent intervention’ requiring 45 seconds to complete. The simple removal of a downed vial would thus be considered less risky than the lengthy addition of stoppers to a feed hopper. The other major change was changing the ‘proximity’ factor from linear to an ‘inverse-square’ approach, thereby eliminating an arbitrary (and hence potentially misleading) metric in the method. The recommendations included within this publication were made with the 2017 revision to the A-A risk method in mind.

The publications summarized above only go so far. Redefinition of terms and refinement of risk evaluation methodology only point the general direction to take as they do not detail the specific actions needed. To establish those, it’s useful to consider the “perfect intervention” objective somewhat differently. It could be restated as—as it is not possible to perform an intervention without adding to the risk of contamination ingress, every effort should be made to eliminate interventions entirely in aseptic processing. If they cannot be completely eliminated, they need to be made simpler and/or less frequent.

Some basic principles for reduction in intervention and contamination risk can be used to guide the practitioner (see 

Table I: Strategies for reduction of intervention risk.

Strategies to tactics–inherent interventions

Inherent interventions may not appear to provide opportunities for reducing the contamination risk, because the necessary activities are explicitly required in operating procedures or manufacturing/filling records. This presupposes that those activities have already embraced the goal of minimizing operator interaction with sterile materials. In the author’s experience, the guiding principles are rarely considered sufficiently. The following real-life examples are unfortunately typical:

In reviewing the sterilization validation for an aseptic filling system there were more than 60 separate pieces of the filling manifold being individually wrapped and sterilized. The firm indicated that these would be aseptically assembled after sterilization to avoid difficulties with steam sterilization equilibration time. A custom-fabricated replacement was substituted and sterilized as a single item.

In the final stages of making a small-scale sterile suspension, a sample was taken immediately after transfer from the mixing vessel to the dilution vessel. Leaving a sample size amount in the mixing vessel eliminated the sampling intervention in the materials to be further processed.

Following the subdivision of a sterile powder blend into sterile containers in a closed system, samples were aseptically taken from selected containers. Introduction of sample size containers fillable using the closed system eliminated exposing materials intended for filling.

After automatic loading of a lyophilizer through a “pizza-door”, the entire door would be opened to place thermocouples in containers on each shelf. The process would be reversed at the completion of the process to remove the thermocouples before unloading. Awareness that the process was not controlled or adjusted in any way due to the thermocouples in the containers resulted in their removal after completion of lyophilization process validation.

It is important to look at the aseptic process holistically to lessen process vulnerabilities. This may entail changes at the detailed level, including equipment configurations, sequence of activities, sampling requirements, and more. An activity or configuration that might be entirely satisfactory from a process perspective may include easily avoidable microbial contamination risks that can be reduced or eliminated.

. To the casual observer, the aseptic process begins when formulated sterile product and components are first exposed within the critical environment. The preparation of equipment for use within the aseptic environment is the true starting point. This can require direct contact with sterilized items very differently from what is necessary during the aseptic process itself. Adherence to core aseptic technique principles such as ‘first air’, ‘slow and deliberate’ movement, avoidance of direct contact, etc. can be difficult given the unique nature of the manipulations. Useful tactics for aseptic set-up include the following:

To the maximum extent possible, product contact equipment should be pre-assembled prior to sterilization. Alternatively, a one-piece custom fabrication could replace multiple individual pieces. Sterilization processes can be adapted as necessary.

A pre-sterilized single-use disposable system can replace complex piping configurations. This is increasingly commonplace. It introduces other factors for consideration such as material compatibility, system integrity, etc., but the elimination of numerous set-up interventions is clearly advantageous.

 of the filling parts after assembly eliminating remote sterilization and aseptic assembly.

Components for the set-up should be prepared and sterilized separately (and cleared from the line prior to the start of the fill) from those used for the process to avoid exposing components for extended time periods.

Process equipment, especially that intended for aseptic filling and sealing, should be selected for ease of set-up and preferably remote adjustment, initially and during use.

Sterilizing filters that are included in the set-up should be integrity tested prior to sterilization. The availability of confirming validation on filter integrity following sterilization avoids uncertainties that have resulted in requests for PUPSIT (Pre-Use Post-Sterilization Integrity Tests) as a routine requirement. 

Use of filling machines able to remotely adjust for fill weight, container height, rail spacing, and other parameters to allow for minimal interventions for product, fill, and container changeover.

Tactics for aseptic filling/processing inherent activities. 

The aseptic process is the focus of attention as interventional activities can be frequent during its execution. Inherent activities for aseptic filling processes are either material handling or monitoring related, such as:

Component introduction linked to the speed of filling/processing, and items sterilized in sealed containers are introduced as needed.

The use of larger component containers to reduce the frequency of interventions.

The repetitive actions associated with component addition make them well suited to the use of robotics.

Robots and automation are also effective in the transfer of containers to/from and, loading/unloading of lyophilizers.

Rather than an arbitrary time interval as the basis for weight checks, define the interval based upon filling system performance which can allow for a longer-periods without sampling.

The use of robotics for sampling throughout the aseptic process.

Remote monitoring and adjustment of fill weights eliminating interventions. An investment in newer, more sophisticated, and safer equipment is needed.

Elimination of thermocouples from product containers within lyophilizers.

Less frequent environmental monitoring based upon operational trends.

Elimination of sample points remote from operator activity due to their limited utility.

Elimination of mid-process monitoring of personnel as an avoidable and overly risky intervention.

The use of passive (settle plates) rather than active air samples to eliminate the more difficult interventions needed for loading and unloading of active air samplers.

The selection of viable monitoring systems that simplify the introduction and removal of test samples.

Greater emphasis on post-process surface and personnel monitoring to avoid interventional activity mid-process in the critical environment.

Strategies to tactics for corrective interventions. 

There should be no tolerance for corrective interventions in aseptic processing. Their continued presence reflects a willingness to accept the consequences of defects in a variety of areas: process design, equipment selection, component cost, and operating procedures. While not all corrective interventions are difficult to perform or time-consuming to execute, they each represent avoidable faults in the process. Measures to prevent their reoccurrence should be taken to eliminate the need for the interventional activity. The following real-life examples are representative of the problems they present, and potential for their elimination and remediation:

Shortly after successful factory acceptance testing (FAT) and site acceptance testing (SAT), and initial media fills without adverse incident and meeting all requirements, the firm experienced serious problems with vial stoppering with frequent broken containers requiring line clearances. Investigation in conjunction with the equipment supplier revealed that the firm used vials of the same configuration with less restrictive acceptable quality levels (AQLs) on vial dimensions concurrent with the start of production with the expectation that it would have no adverse impact. Reverting to the equipment manufacturer’s more restrictive AQLs for the vials quickly resolved the problem.

Media fills for lyophilized vials on a multi-use line resulted in multiple contaminated units. Solution fills with the same vial were consistently free of any positives. Review of the lyophilization media fill video revealed frequent operator interventions into the stopper bowl to remove clumps of stoppers. Corrections to the stopper preparation and sterilization processes eliminated both the clumping and the subsequent corrective operator intervention.

During media fills performed as part of the validation of a substantially modified filling line, the firm was unable to successfully perform stopper bowl replacement without contamination. In reviewing their operational history, the firm realized that that intervention had only been required once in the previous eight years of operation. It was decided that eliminating the intervention entirely and re-starting with a fresh set-up in the event a mid-process replacement was necessary, was more appropriate.

The examples included two distinct types of corrective interventions. The easiest corrective interventions to perform are those that entail removal of an object or adjustment of an already installed piece of equipment. These are generally easy to perform and are ordinarily of comparatively brief duration. The more challenging are more complex entailing replacement of a sterilized equipment item that is a part of the initial set-up (e.g., a filling needle, stopper bowl, etc.) should be considered critical correctives and are generally more complicated and of longer duration

Tactics for aseptic filling/processing corrective activities.

 Ideally an aseptic process can be completed without requiring a corrective intervention. This should be the goal for all processes; regrettably, it is only rarely achievable. Firms should collect data on their corrective intervention experience and use the data constructively to identify means for reducing their frequency. Some ofthe more frequently encountered corrective interventions include:

Stopper misfeeds or clumping can be a consequence of hidden variations in their preparation and sterilization processes.

The use of more restrictive AQLs for component dimension/configuration can reduce the rate of misfeeds, jams, breakage, etc.

The use of neck-hold vial handling avoids misalignment of the closure with container seal surfaces as well as elimination of container mis-feeds at conveyor transitions. This can also serve to reduce spillage.

Equipment set-up that is more automated/reproducible can result in better performance during the fill.

Remote adjustment of conveyor rails, fill needle height, and other equipment provides for less invasive adjustment and more precision in set-up and vial change-over.

Equipment designs that accommodate self-clearance for mis-fed components can eliminate their manual removal.

Relocation of controls, and adjustment locations outside the critical zone.

Tactics for aseptic filling/processing critical corrective activities. 

The invasive nature of critical corrective activities coupled with the time required for their execution should make these a rare occurrence in any operation. The contamination risk from these activities is substantially greater than that associated with inherent or ordinary corrective interventions. Tolerance for their routine execution in any process or line should be extremely limited. The more common critical correctives include product filter change, filling needle replacement; fill-pump replacement; and stopper bowl changes. The execution of these may entail significant human manipulation within the critical zone and, while certainly possible, may present extraordinary contamination risks. As such, they should be closely scrutinized to ensure they should be maintained as a continued practice. The contamination potential from these due to the product contact nature, proximity and execution time is greatest, and their elimination is highly recommended.

The attention focused by regulators on aseptic processing activities brought attention to all of the interventional activities performed on a filling line. Firms were asked to include interventions in process simulations to support their ability to execute them with contamination ingress. In their eagerness to be compliant, some firms identified activities that fall outside the realm of aseptic processing. There are several categories of these:

Operator activity outside the critical zone that does not involve aseptic handling of exposed sterile materials or equipment. These have no impact on the aseptic process and need not be included in a firm’s media fill program.

An activity that compromises the integrity or performance of the system or air supply to the critical zone should be understood as unacceptable during an aseptic process. It should result in immediate cessation of operation, and rejection of all exposed sterile items. There is no defendable rationale for continuing aseptic operations when interventions that interfere with the system’s primary protection (e.g., barriers, gloves, partitions, etc.) occur.

Any intervention that cannot be performed with proper aseptic technique while maintaining the critical environment within the required limits should not be tolerated.

The aseptic operator is universally recognized as the primary source of microbial contamination in the critical environment (9). There is also definitive evidence that increased activity levels result in increases in viable and non-viable particles (10,11). This supports the original premise that there are no truly safe interventions with respect to aseptic processing regardless of the underlying aseptic technology (1,2). Nevertheless, as system perfection is still an elusive goal in manned aseptic processing and system automation is not universal, there will be instances where operators will be required to manipulate sterile items in either preparation for or during the aseptic process. It behooves the firm to review every expected interventional activity regardless of type in detail to identify the preferred process for its execution. Adherence to good aseptic technique is required and review by an experienced microbiologist is recommended. Once the intervention is defined, it should be well documented and used as the basis for operator training. Documentation should incorporate written instructions, drawings, still and video images detailing the practice in detail such that all operators can execute it in a near identical manner. Confirmation of acceptability should be confirmed by incorporation within the media fill program at a frequency that meets or exceeds its use in routine production.

There are two guiding principles to adhere to for the improvement of intervention practices in aseptic processing:

A useful principle to follow to is to make every intervention as simple as possible to execute such that all operators can successfully execute it at all times. This holds true regardless of whether the operators are highly proficient or new to the job. Extraordinary skill should never be necessary to execute any intervention. The objective should be to make any intervention so safe to perform that the operator can perform it on their worst day.

Just because an intervention can be done doesn’t mean that it should. Interventions always increase the risk of contamination ingress. Whether they are corrective or inherent, firms should be committed to their eventual elimination. The pursuit of the “perfect intervention” should be continuous in all aseptic operations.

Agalloco, J. Management of Aseptic Interventions. 

Agalloco, J.; Akers, J. The Truth about Interventions in Aseptic Processing. 

Agalloco, J.; Akers, J. Revisiting Interventions in Aseptic Processing. 

Agalloco, J. Uncommon Sense in Execution of Process Simulations. 

Agalloco. J. Complications in Process Simulation Execution. 

Biologics and Sterile Drug Manufacturing 

Agalloco, J.; Akers, J. Risk Analysis for Aseptic Processing: The Akers-Agalloco Method. 

Agalloco, J.; Akers, J. The Simplified Akers-Agalloco Method for Aseptic Processing Risk Analysis. 

Agalloco, J.; Akers, J. A Revised Aseptic Risk Assessment and Mitigation Methodology. 

Avallone, H. Current Regulatory Issues Regarding Parenteral Inspections. 

Journal of Parenteral Science & Technology,

, 2nd Edition, John Wiley & Sons, Chichester, 1999

Ljundvist, B. and Rheinmuller, B. Modern Cleanroom Clothing Systems: People as a Contamination Source. 

PDA Journal of Pharmaceutical Science & Technology

Articles

Aseptic processing has evolved to minimize contamination risks, primarily from human operators. Despite advancements like automated systems and improved gowning, operators remain crucial, often necessitating interventions that increase contamination risk. The distinction between 'inherent' and 'corrective' interventions is now standard, with efforts focused on reducing the latter. Risk assessments have shifted to time-based evaluations, emphasizing the need to simplify or eliminate interventions. Strategies include pre-sterilization assembly, robotics, and remote monitoring. Ultimately, interventions should be minimized, with a focus on making them as simple and infrequent as possible.

Addressing human interventions to reduce their impact on contamination requires addressing broader considerations than limiting operator activities. Equipment, automation, procedural and component changes can be utilized to make the aseptic activities safer. This article offers suggestions for reducing the adverse impact of intervention throughout the aseptic process.

Interfering with Interventions in Aseptic Processing

Jason Waite, international trade expert, discusses cross-functional trad compliance as a critical piece to addressing Trump administration tariffs and trade policies and shifting supply chains.

How Pharma Can Build Resilient Supply Chains Amid Trade and Tariff Shifts



In Part 4 of our multi-part interview series, Jason Waite, an international trade expert at Alston & Bird, underscores the urgent need for pharmaceutical companies to build cross-functional trade compliance teams in response to rising global trade tensions—particularly potential Section 232 tariffs. Waite advises that compliance, especially around product origin, classification, and valuation, must be embedded early in R&D, manufacturing, and go-to-market strategies to avoid downstream disruptions. He emphasizes that proactive communication between departments—R&D, finance, logistics, tax, and trade—is a hallmark of companies that successfully navigate trade policy changes.

Waite also addresses uncertainty surrounding country-specific exemptions, noting that while 232 tariffs have historically applied universally, some countries—such as India—may be positioned for favorable treatment due to their role in supplying generics and acting as a potential bridge away from Chinese API dependence. He acknowledges that final tariff frameworks could evolve over time and recommends that companies immediately begin diversifying supply chains, particularly away from China, in anticipation of shifting United States trade priorities focused on domestic production and supply chain security.


What Pharma Manufacturers Need to Know About US Trade Policy Changes

Tariffs & Trade Policy: What to Watch for, Cost Impacts, and Supply Chain Strategies

Trade Policy Shifts: Compliance and Cost Strategies for Pharma

For over 25 years, Jason Waite has advised clients on all regulatory aspects of international trade and investment, including customs and trade agreements, export controls and sanctions, and related policy matters. Jason conducts internal investigations and compliance self-assessments, develops internal trade compliance and training programs, represents clients in audits and origin verifications, and guides clients through voluntary disclosures of actual and potential import and export violations. Jason has significant experience representing clients that are the subject of government investigations involving alleged violations of the export, import, and economic sanctions regulations. In transactional and strategic planning matters, Jason conducts international trade compliance due diligence, negotiates trade compliance responsibilities among parties to transactions, and develops supply chain optimization and global customs planning strategies. He regularly advocates before agencies in Washington for favorable advance rulings, advisory opinions, and commodity jurisdiction and classification determinations, and handles complex export licensing matters.

He is a frequent speaker at seminars and conferences on international trade topics and has been recognized in 

*Editor’s Note: This transcript is a direct, unedited rendering of the original audio/video content. It may contain errors, informal language, or omissions as spoken in the original recording.

I'm not sure anybody has successfully navigated it yet, 'cause the waves are still coming over the side of the boat here on us. But I do think that a trade compliance management team that is cross-functional, where there are, effective communication channels between people in the R&D teams, the manufacturing teams, tax, finance, sales, logistics, these cross-functional teams usually overseen and coordinated by trade compliance professionals, this is a hallmark of successful trade management organizations that we've seen. 

Of course, as I've said before, paying attention to these key issues like origin, classification and value, and doing it from the outset, like building it into the development process, building it into the go-to market process, making sure that somebody from the trade compliance function or wherever it's housed, you know, the function that's going to be responsible for managing compliance and duty burdens, building that into early stages of particular projects so that the impact of duty can be assessed from the outset of a particular development project and of a manufacturing plan or a go to market strategy.

These are all best practices that we've seen be effective, and I think that they'll continue to be.

Absent a country specific deal, 232 tariffs are expected to apply equally to all countries. That's how they've applied in the past for steel and aluminum and automotive, right? That's how these 232 cases have proceeded. They apply equally to all countries, so it seems, at first glance, unlikely that there will be different impacts for different geographies or different countries.

However, as I said before, there does seem to be a recognition by the administration that this market is more complicated, that building out domestic production and supply chains is a challenge. There are certain economic realities that that faces. So, as I said, I think it's possible that you might see some differentiation.

We just have to see how that comes about. And it's even possible that you might not see that when it's announced, but that it could be over time, it could evolve. The president can change. The president could announce a program on August 1st and it could be changed later. So India reportedly has not received a tariff letter, a general letter on the reciprocal tariffs.

They are reportedly one of the countries that's close to reaching an agreement with the United States or some type of a deal. And of course, everybody knows India is a major supplier of generic medicines to the US market. And I think it's also recognized that it does offer a bridge to transition supply chains away from China, right?

So some have asked and advocated for this administration to recognize this and try to carve out, you know, maybe accommodations there. There are good policy arguments like the ones I just hinted at to provide some leeway to India. And it's no secret that an objective of these tariffs is to reduce reliance on China for APIs and medicines.

There's also an overarching objective to spur more US domestic production. But maybe it needs to take a couple steps and maybe diversifying away from China is step one and rebuilding US production is step two. And so it's possible there could be some accommodation made for India.

I think everybody's kind of figured this out by now, but certainly we suggest that companies be diversifying their supply chains outside of China. Beyond that, I think we just have to wait and see whether any countries enjoy any kind of better treatment than others when it comes to these tariffs as they get announced sometime soon.

Videos

Cross-functional trade compliance planning is critical as pharma braces for broad 232 tariffs and shifting United States-China-India supply dynamics.

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The European Medicines Agency (EMA) announced on July 25, 2025 that its Committee for Medicinal Products for Human Use (CHMP) has approved a change in the existing gas propellant used in budesonide/glycopyrronium/formoterol fumarate (BGF, Trixeo Aerosphere and Riltrava Aerosphere) (1,2). The propellant may be replaced with a low global warming potential (GWP) gas alternative that has a 1000-fold reduction in GWP, 99.9% lower than currently used. BGF will be the first inhaled drug in the European Union to use the new low GWP propellant, according to EMA.

The new formulation is the first pMDI to use the low global warming potential (GWP) gas alternative.

New propellant has a 1000-fold reduction in GWP.

High GWP propellants, such as hydrofluorocarbon gases, are being phased out to comply with the EU regulation regarding 

fluorinated greenhouse gases (EU Regulation 2024/573)

BGF is used as a fixed-dose triple-combination maintenance therapy for adults with moderate-to-severe chronic obstructive pulmonary disease (COPD). The usual dose is two inhalations twice daily using a pressurized metered-dose inhaler (pMDI). The propellant used in pMDIs is a liquified compressed gas that generates an aerosol cloud to deliver the API to the patient through inhalation. These propellants that are typically high GWP, such as hydrofluorocarbon gases, are being phased out to comply with the EU regulation regarding 

New formulation is therapeutically equivalent to existing formulation

AstraZeneca AB, the drug’s marketing authorization holder, focused on a lower GWP propellant for the reformulation, which uses the same API and dose characterized in guideline requirements (4). CHMP’s positive opinion was based on results from the next-generation propellant clinical development program, according to AstraZeneca (2). The new formulation of BGF was found to be therapeutically equivalent to the current product, according to EMA (1). The company plans to transition more of its pMDI portfolio to the new propellant by 2030.

“Respiratory medicines delivered by pressurized metered-dose inhalers are essential for millions of people living with respiratory diseases in Europe, including specific vulnerable populations such as children and the elderly,” Frederik Trinkmann, professor and senior pulmonologist at the Thoracic Clinic at Heidelberg University Hospital, Germany, said in the press release (2). “The transition of Trixeo to the propellant with near-zero Global Warming Potential ensures clinicians’ treatment decisions can focus on clinical needs while also supporting environmental goals.” 

“The CHMP positive opinion of Trixeo Aerosphere with the next-generation propellant allows us to address the needs of both patients and the planet and is a significant milestone in our commitment to delivering innovations for sustainable healthcare in the EU,” Ruud Dobber, executive vice president, BioPharmaceuticals Business Unit, AstraZeneca, said in the release. “Starting with Trixeo, the transition to the near-zero Global Warming Potential propellant across our pressurized metered-dose inhaled respiratory medicines is an important step towards achieving our Ambition Zero Carbon strategy.”

Susanna Palkonen, director of the European Federation of Allergy and Airways Diseases Patients' Associations, added, “COPD is a devastating disease and the third-leading cause of mortality in the world. People living with COPD need access to a treatment which is right for them as well as a healthy environment and clean air. We welcome the positive opinion from the CHMP for the inhaled respiratory medicine containing the next-generation propellant with a significantly reduced carbon footprint.”

EMA. First Reformulation of an Inhaled Medicine with Environmentally Friendly Gas Propellant. Press Release. July 25, 2025. 

https://www.ema.europa.eu/en/news/first-reformulation-inhaled-medicine-environmentally-friendly-gas-propellant

AstraZeneca. Trixeo Aerosphere Receives Positive EU CHMP Opinion as First Inhaled Medicine Using Next-Generation Propellant with Near-Zero Global Warming Potential. Press Release. July 25, 2025. 

https://www.astrazeneca.com/media-centre/press-releases/2025/trixeo-aerosphere-receives-positive-eu-chmp-opinion-first-inhaled-medicine-using-next-generation-propellant-with-near-zero-global-warming-potential.html

EU. EUR-Lex. Regulation (EU) 2024/573 of the European Parliament and of the Council of 7 February 2024 on Fluorinated Greenhouse Gases, Amending Directive (EU) 2019/1937 and Repealing Regulation (EU) No 517/2014. Eur-lex.europa.eu. Feb. 20, 2024 (accessed July 25, 2025). 

https://eur-lex.europa.eu/eli/reg/2024/573/oj/eng

EMA. Guideline on the Requirements for Demonstrating Therapeutic Equivalence Between Orally Inhaled Products (OIP) for Asthma and Chronic Obstructive Pulmonary Disease (COPD) (EMA, July 14, 2025). 

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-demonstrating-therapeutic-equivalence-between-orally-inhaled-products-oip-asthma-chronic-obstructive-pulmonary-disease-copd-revision-2_en.pdf

The European Medicines Agency has approved a new low global warming potential (GWP) propellant for the inhaled drug budesonide/glycopyrronium/formoterol fumarate (BGF), marking a significant environmental advancement. This reformulation, which maintains therapeutic equivalence to the existing product, aligns with EU regulations on fluorinated greenhouse gases. AstraZeneca plans to transition more of its pressurized metered-dose inhaler (pMDI) portfolio to this eco-friendly propellant by 2030. This initiative supports sustainable healthcare while addressing the needs of patients with chronic obstructive pulmonary disease (COPD).

The agency has given a positive recommendation for a change in the gas propellant in Trixeo Aerosphere and Riltrava Aerosphere that will have a 1000-fold reduction in global warming potential compared to the current propellant.

EMA Approves Lower GWP Alternative for Inhalation Medicine

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Despite extensive regulatory engagement throughout the development process, a growing number of companies are encountering chemistry, manufacturing, and controls (CMC) and analytical deficiencies that result in complete response letters (CRLs) from FDA (1-3). These setbacks, often surfacing late in the review cycle, underscore a critical disconnect between sponsor expectations and evolving FDA standards, including as they relate to assay reproducibility, validation, and tech transfer readiness.

Earlier this week, FDA doled out a CRL to Replimune, a clinical-stage biotech company focused on oncolytic immunotherapies. The unexpected response to the company’s Biologics License Application (BLA) for RP1 (vusolimogene oderparepvec) in combination with nivolumab for the treatment of advanced melanoma took the company—and biotech investors—by surprise. After all, the drug was on the accelerated approval pathway and had received breakthrough therapy designation and priority review. In reaction, Replimune CEO Sushil Patel, PhD, said, “We are surprised by this FDA decision and disappointed for advanced melanoma patients who have limited treatment options as highlighted by the granting of breakthrough status at the time we provided the IGNYTE primary data [1]. The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews. Additionally, we had also aligned on the design of the confirmatory study. We strongly believe that RP1 in combination with nivolumab can bring substantial benefit to advanced melanoma patients.”


Another unexpected late-stage denial from FDA came to Capricor Therapeutics just 11 days earlierregarding its BLA for deramiocel, the company’s experimental treatment for cardiomyopathy associated with Duchenne muscular dystrophy (DMD). “While this was an unexpected decision by the FDA, we remain committed to the DMD community to get Deramiocel through the approval process,” said Capricor CEO Linda Marbán, PhD (2). Marbán also noted that the company followed FDA “guidance throughout the process,” adding that “prior to the CRL, the review had advanced without major issues, including a successful pre-licensure inspection and completion of the mid-cycle review.”


“I wonder if part of the problem is that many biotechs do not have sufficient experience in-house, and rely on contract organizations,” said 

 Editorial Advisory Board member Chris Moreton, PhD, VP, Pharmaceutical Sciences, FinnBrit Consulting, from his perspective as a consultant for various industry companies over the years. “However, the contract staff may not be sufficiently familiar with the details of the project they are working on. Thus things fall between the cracks, so to speak.”

These CRLs come amid several big changes at FDA, including an unprecedented posting on July 10 

 issued between 2020 and 2024 for drug and biologic applications that were not approved during their initial review cycle. In March, FDA’s then-acting commissioner of Food and Drugs, Peter Marks, the director of FDA’s Center for Biologics Evaluation and Research, 

, pointing to an “unprecedented assault on scientific truth” that “adversely impacted public health” and the current administration’s concerns over vaccine safety in his resignation. In June, Secretary of Health and Human Services Robert F. Kennedy (RFK) Jr. 

announced the dismissal of all 17 members of the Advisory Committee on Immunization Practices

 (ACIP), a Centers for Disease Control and Prevention (CDC)-affiliated body responsible for guiding vaccine policy in the US. Then, earlier this week, RFK Jr. authorized the (newly appointed) ACIP recommendation to remove thimerosal, a mercury-based preservative, from all influenza vaccines distributed in the US, 

, including from those who say the anti-vaccine community’s long-held, oft-repeated contention that there is a link between thimerosal and occurrences of autism and other neurodevelopmental disorders in children is false. Plus, on Monday, FDA appointed George Francis Tidmarsh, MD, PhD, as the new director of the agency’s Center for Drug Evaluation and Research, which is tasked with ensuring the safety and efficacy of drugs in the US. The impacts of these changes on CRLs, the FDA's approval process, and the pharma industry overall are poised to be big but remain to be fully seen.

Guidance is not approval: The limits of early FDA feedback

It’s easy to interpret early-stage FDA feedback—received during pre-IND, pre-NDA, or mid-cycle Type C meetings—as a reliable indicator that their analytical approach or manufacturing plan is on firm regulatory footing (1-3). However, such guidance is non-binding and frequently based on limited preliminary data. As the FDA reviews a full submission and assesses integrated data from clinical and manufacturing domains, it may revise its interpretation of adequacy.

This risk is heightened when clinical results are modest, or when dealing with novel modalities such as viral vectors or gene therapies, which lack established regulatory precedents. The FDA has emphasized that complex products demand rigorous manufacturing control strategies and robust CMC data to ensure consistency, safety, and efficacy, especially as these therapies move toward late-stage development and licensure (4,5).



 Editorial Advisory member Board Henrick Johanning, senior VP, Quality & Strategy, Epista Life Science, echoed these thoughts, saying "Late-stage FDA rejections, even after seemingly smooth submissions and inspections, underscore that 'guidance' is not approval. Too often, analytical methods or tech transfer plans that passed early scrutiny collapse under the weight of commercial-scale expectations. The lesson is clear: CMC rigor and lifecycle planning must be treated—as I see it—as front-line regulatory strategy, not a post hoc technical detail."

Assay variability and method drift during scale-up

A recurring source of CRLs involves discrepancies in analytical assay performance, including in potency, purity, or impurity characterization methods (6-8). Problems arise when sponsors fail to adequately control for inter-laboratory variability, or when methods validated under early-stage conditions fail to perform consistently at commercial scale.

In some cases, sponsors transition assays between development phases or contract manufacturing organizations without fully bridging the methods. This may lead to discrepancies that obscure whether product differences are attributable to assay variability or actual quality deviations. For instance, the FDA’s CRLs for certain advanced therapies have cited lack of assay comparability and insufficient method validation at commercial scale (9-11).

Specific weaknesses flagged in recent CRLs include (12):

Unclear linkage between assay outputs and clinical effectiveness

Lack of justification for assay sensitivity (LOD/LOQ)

Use of different assay formats across phases without bridging or revalidation studies

Tech transfer weaknesses exposed under regulatory review

Even when clinical data appear positive, tech transfer gaps can derail a marketing application. The FDA increasingly inspects the coherence between the submitted CMC package and the actual state of commercial readiness (13). It’s very likely why 74% of CRLs issued from 2020 to 2024 cited quality or manufacturing (CMC) deficiencies (14).

Tech transfer missteps include differences in process parameters, raw materials, equipment, or control strategies between clinical and commercial sites, none of which are uncommon when outsourcing is involved (15). Without detailed comparability protocols and analytical bridging data, the FDA may question whether the clinical product is equivalent to the commercial one. This uncertainty is particularly damaging for biologics, where minor process changes can influence product structure or function.

FDA's Office of Pharmaceutical Quality has emphasized that a well-characterized, well-documented, and consistent manufacturing process is essential to ensure that efficacy and safety observed in clinical trials will translate to marketed product batches (16).

Incomplete process transfer or insufficiently documented process changes have led to significant delays for several companies (17,18). For example, changes in process parameters—such as fill-finish specifications or facility equipment—without aligned documentation or sufficient bridging led to regulatory requests for additional data, sometimes only discovered in late review cycles, resulting in extended reviews or CRLs.

Interpreting FDA language: When "inadequate evidence" means CMC

In CRLs, the FDA may not always explicitly identify manufacturing shortcomings. Instead, sponsors often receive general statements citing inadequate evidence of effectiveness or trials being not adequately interpretable (1,2), similar to the feedback that Replimune received. However, such language can be a proxy for deeper concerns about assay reproducibility, batch consistency, or process control.

While the agency officially cited trial heterogeneity in Replimune’s CRL for RP1, it’s possible that analytical variation across patient subgroups may have compromised the agency’s confidence in the submitted data. Without robust assay performance or clear comparability across lots, even well-conceived trials can appear inconclusive.

This underscores the need to interpret CMC-related risk not just through the lens of assay design, but also in terms of how variability is managed, explained, and documented throughout the product lifecycle (Table).

Table: Key Risk Points in Analytical & Tech Transfer That Invite CRLs

Given the increasing complexity of modern therapies and FDA’s shifting standards, companies are well advised to embed CMC excellence into every phase of development:

Simulate commercial-scale conditions early in validation and comparability planning. Waiting until NDA to finalize CMC strategy is a high-risk gamble.

Implement assay lifecycle management tools to track drift, inter-lab variability, and trending across sites and tech transfer milestones.

Develop comparability protocols upfront, not reactively. The FDA expects a clear rationale and data package whenever process or site changes occur.

Maintain rigorous documentation of regulatory communication

 Misinterpretation of conditional feedback is a common—and preventable—pitfall.

Conduct pre-submission gap assessments or internal mock reviews. Third-party audits or cross-functional CRL simulations can flag weak spots before FDA does.

CMC is no longer a background concern; it is now a front-line risk factor for product approval. As FDA expectations tighten and more applications undergo heightened scrutiny, especially for complex or expedited pathways, manufacturing and analytical strategy must be treated as a core part of clinical success. Sponsors that invest early in robust assay validation, comparability, and tech transfer readiness are better positioned to avoid both the financial and reputational costs of a CRL.

Replimune Receives Complete Response Letter from FDA for RP1 Biologics License Application for the Treatment of Advanced Melanoma. Press Release

Capricor Therapeutics Provides Regulatory Update on Deramiocel BLA for Duchenne Muscular Dystrophy

Capricor Plans for Deramiocel Resubmission After FDA Rejection

Integrated Quality Assessment: Drug Product

Lurie, P. Comparison of Content of FDA Letters Not Approving Applications for New Drugs and Associated Public Announcements from Sponsors: Cross Sectional Study. 

Beware of BIMO: Complete Response Letter, Warning Letter and Shareholder Lawsuit Follow FDA Data Integrity Findings

Complete Response Letters Due to Failed PAIs – More to Come

ARM-USP Workshop “Comparability in Cell & Gene Therapies” Final Report

Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products

Comparability: What We Can Learn from the Review of Advanced Therapy Medicinal Products

FDA’s Pre-Approval Inspection (PAI) Program and How to Prepare for A Successful Outcome

Manufacturing Cell and Gene Therapies: Challenges in Clinical Translation.

Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices Guidance for Industry andFood and Drug Administration Staff

Top 5 Reasons Tech Transfer Keeps Breaking… And What We Can Do About it

A growing number of companies are receiving complete response letters (CRLs) from the FDA due to chemistry, manufacturing, and controls (CMC) and analytical deficiencies. These issues often arise late in the review cycle, highlighting a disconnect between sponsor expectations and FDA standards. Recent cases involving Replimune and Capricor Therapeutics illustrate the impact of inadequate assay validation, tech transfer gaps, and misinterpretation of FDA guidance. To mitigate CRL risk, companies should prioritize CMC excellence, simulate commercial-scale conditions early, and maintain rigorous documentation throughout the development process.

Many companies face FDA complete response letters due to ongoing chemistry, manufacturing, and controls, or CMC, and analytical issues despite early regulatory guidance. Review key risk points in analytical and tech transfer to better ensure commercial readiness.

CMC and Analytical Gaps in CRLs: Why They Persist Despite FDA Guidance and How You Can Position Yourself for Success

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

® has covered thus far in 2025 that involve outsourcing in some way include artificial intelligence (AI), quality support expertise, process development optimization, and the future of antibody-drug conjugates (1–4).

The crucial nature of the relationship between sponsor companies and contract development and manufacturing organizations (CDMOs) came into full focus at the Drug, Chemical & Associated Technologies Association (DCAT) Week in March 2025, where India-based Shilpa Medicare announced that it was launching a full-service, “hybrid” CDMO that aims to adopt a dual approach: offering comprehensive discovery, clinical, and commercial outsourcing services, but also including commercially ready, “off-the-shelf” novel formulations for business-to-business (b2b) licensing (5).

The changing demands of customers, along with continuous advancements in modalities and technologies, are all trends in outsourcing that deserve a deeper look.

According to Sridevi Khambhampaty, CEO of Shilpa Biologicals, a fully owned subsidiary of Shilpa Medicare, the bio/pharmaceutical industry is constantly evolving both in terms of the technology that is driving innovation in the field, and in novel treatment modalities (6). Because of this, Khambhampaty said, the outsourcing market is continuing to grow, placing even more emphasis on the sponsor–CDMO dynamic.

“With this plethora of technologies and modalities, it's quite challenging for any company to have all of these under their roof,” Khambhampaty said (6). “So, the small biotechs which want to pursue several new ideas in the novel therapeutic modalities would like to use the CDMO services, because they obviously don't want to invest in all the capex [capital expenditure] required for taking their ideas to market.”

Outsourcing in the bio/pharmaceutical industry is evolving, driven by technological advancements and changing customer demands. The relationship between sponsor companies and CDMOs is shifting from transactional to strategic partnerships, emphasizing integrated, long-term collaborations. The rise of novel modalities, AI, and personalized medicines is reshaping the landscape, necessitating flexible and modular services. Geopolitical factors are influencing onshoring trends, while strategic alliances focus on accelerating time to market. CDMOs are adapting by offering comprehensive services, leveraging expertise, and ensuring supply chain efficiency to meet the growing demand for innovative drug development.

While a one-stop shop still has its advantages, sponsor companies and CDMOs are starting to see each other not as transactional relationships, but true partners with a common goal of getting drugs to patients faster.

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