Daria G. Husni

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As CPHI North America, held at the Pennsylvania Convention Centre (May 7-9, 2024) approaches, experts predict that US-based contract development and manufacturing organizations (CDMOs), especially small to mid-sized, should invest throughout 2024 if they wish to maximize on the rise in contract services funding predicted for 2025. Other key trends for 2024 include exploring pilot-scale manufacturing of new technologies, improving supply chain resilience, and ‘friend shoring’.

CPHI expert, Brian Scanlan, operating partner–Life Science Edgewater Capital Partners, sees 2024 as a “holding pattern year”, where funding gradually returns to biotech, as reported in a CPHI press release. He stated that he is already seeing this begin to filter through toward the outsourcing community. But if US-based smaller and medium-sized contract research organizations (CROs) and CDMOs want to benefit from a likely 2025 resurgence, they cannot just wait for the market to return. “They need to be focusing now on operational efficiencies and commercial effectiveness,” Scanlan stated. “This means investing in manufacturing process improvements, like continuous and titer reductions, as well as other areas of the business that could bring overall efficiencies, from enhancing quality management to areas like AI [artificial intelligence] to enhance/accelerate process development and quality trend analysis” (1).

Scalan emphasized that these companies should take every opportunity to invest. “Any area that drives more efficiency in CDMO operations, even streamlining and enhancing effectiveness in new business development using AI enabled tools [is worth pursuing]. So, this will be a year of seeking productivity excellence and cost containment to prepare for a potentially bigger resurgence in outsourcing in 2025,” Scalan said. CPHI North America plans to cover at least one of these potential applications—making use of generative AI to analyze upcoming requirements for pharmaceutical drug manufacturers and distributors as the Drug Supply Chain Security Act comes into effect in November 2024.

“What you are seeing in the USA—and in some ways it’s not a new trend—is a much more considered approach to sourcing,” added Bikash Chatterjee, president and chief science officer at Pharmatech Associates, in the press release (1). “Companies are looking to ensure they have alternative supply and potentially also in different geographic locations from their primary options ... What’s driving this? Well, we have seen a whitepaper come out from HHS [Health and Human Services] earlier this month on preventing drug shortages, and in the next few years we could see companies even scored on their supply chain resilience. So, we might be entering a period when companies are willing to pay more for extra resilience in their networks.”

Chatterjee added that in the next six months many companies will be looking to prepare for 2025, focusing on highly detailed planning for supply chain resilience, as well as a greater short-term focus on ‘near’ or ‘friend shoring’ options (instead of domestic US sites). These countries are currently better prepared, he said, to pick up resources and build ingredients and starting materials networks. More and more North American manufacturers are diversifying their sourcing of ingredients, looking not just to India as an alternative to Chinese suppliers, but also exploring options worldwide, including within Europe and South America.

At CPHI North America, where an anticipated 4000 attendees and 300 companies are planning to attend, these shifting trends will be present. This year’s event is focused on “empowering the North American ecosystem with the new insight and next-generation manufacturing approaches” (1) that it will need to “retool” before the 2025 outsourcing surge. The event will see 58 sessions, with notable keynotes on “Sustainability: Accelerating the Path to Net Zero” and “the Importance of Excipient Grade in Pharmaceutical Drug Development.”

Sarah Griffin, event manager, Pharma Brand US at Informa Markets, emphasized that it is critical for companies to use this event to plan their activity in 2025. "CPHI North America is at the heart of pharma in the US,” she added (1). “It's not just about staying informed and connecting with existing contacts; it's about actively engaging in the collaborative ecosystem that sustains success in the pharmaceutical industry.Participating companies can access invaluable resources, forge vital strategic partnerships, and, most importantly, establish the networks and technologies needed to maximize revenue potential in 2025 and beyond.”

Informa Markets. CPHI North America Experts ‘Mid-Sized Domestic CDMOs Need to Invest in Operational Efficiencies to Drive “Real” Reshoring’. Press Release. informamarkets.com, Apr. 30, 2024.

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Key areas to invest include manufacturing process improvements, quality management, and AI.

CPHI Experts Report that Small to Mid-sized US CDMOs Must Invest Now to Benefit from 2025 Contract Funding Surge

The United Kingdom has launched The Circularity in Primary Pharmaceutical Packaging Accelerator (CiPPPA) initiative to develop and implement strategies for end-of-use recycling of medicinal devices and pharmaceutical packaging. CiPPPA is a collaborative non-profit initiative connecting stakeholders from across the pharmaceutical supply chain. It is managed by a steering committee composed by representatives from within the pharmaceutical and healthcare sector who are committed to creating a future where used packaging from meter dose inhalers (MDIs), blisters, and injectables can be easily recycled.

Currently, the health industry faces a great deal of challenges in regard to recycling primary pharmaceutical packaging (PPP), according to a press release from CiPPPA. Present regulations are strict to uphold the safety, efficacy, and regulatory compliance of each active medicinal product, but they have been unable to consider long-term environmental effects. PPP recycling is also not part of mainstream consumer recycling due to the problematic materials involved, resulting in broader environmental, financial, and regulatory obstacles.

To address these obstacles, CiPPPA has established three action task forces, focused on creating packaging solutions for blisters, inhalers, and injectables. Each task force is led by subject experts who make use of organizational schemes and industry collaboration to drive the initiative forward. The task forces are critical, CiPPPA states, in bolstering collaborative efforts and utilizing member organizations’ expertise and resources to tackle the difficult environmental challenges around pharmaceutical packaging. Leading pharmaceutical companies, global over-the-counter (OTC) brands, and healthcare systems such as the National Health Service are closely involved with the initiative, signaling an “united industry commitment to influencing societal and cross-industry change for the benefit of the environment and the community” (1).

“Having previously sold thousands of tons of blister pack materials into the UK, and knowing that none of it was getting recycled, I became frustrated at the lack of sustainable solutions for the packs' end-of-life,” said Duncan Flack, Global Sustainability Lead at Honeywell and Chairman of CiPPPA, in the press release (1). “By founding and establishing CiPPPA, we are able to deliver enhanced end-of-life for blister packs and related pharmaceutical packaging such as metered-dose inhalers and injectables. The willingness of leading pharmaceutical companies and global OTC brands to support the initiative has been tremendous, and as CiPPPA continues to grow, so too does our ability to influence societal and cross-industry change.”

“We’re proud to be a founding member of CiPPPA and join forces with partners across the sector to address the sustainable packaging of medicines and vaccines,” said Claire Lund, vice president of Sustainability, GSK (1). “We have ambitious company targets across climate and nature and through collaborative initiatives such as CiPPPA, we believe we can make a positive impact through the increased recycling of packaging, helping to protect the health of both people and the planet.”

CiPPPA. Circularity in Primary Pharmaceutical Packaging Accelerator (CiPPPA) Launched to Take Collaborative Action on Pharmaceutical Packaging. Press Release. Apr. 24, 2024.

The non-profit initiative puts collaboration at the forefront as it tackles the challenges surrounding recycling primary pharmaceutical packaging.

UK Launches Circularity in Primary Pharmaceutical Packaging Accelerator Initiative to Implement Pharmaceutical Packaging Strategies

The European Medicines Association (EMA) and the European Commission’s (EC) Directorate-General for Health and Food Safety (DG SANTE) have signed a working agreement with the Ministry of Food and Drug Safety (MFDS) of the Republic of Korea in order to share confidential information on medical and medicinal products. This partnership will build on the close cooperation fostered between the two regulatory authorities during the COVID-19 pandemic and is intended as a step toward mutual recognition and regulatory harmonization as they work to improve human and animal health. The agreement also builds on the previously established ad-hoc arrangement, which ensured the exchange of medicinal information used for diagnosing, preventing, and treating COVID-19 and related infectious diseases.

The arrangement, which came into effect on Apr. 25, 2024, will allow participants to exchange sensitive information on medicinal products as part of their regulatory and scientific processes. This will include confidential information about the safety, quality, and efficacy of human medicines which have been authorized or are under evaluation, as well as information on inspections, regulatory guidance, and legislation. These types of confidentiality agreements can allow for faster exchanges of information on quickly emerging global issues, such as medicine shortages, quality concerns, and safety questions.These type of confidentiality arrangements, EMA said in a press release, “are the cornerstone of global cooperation” (1). This arrangement between the EU and Korea is valid for an indefinite period and will not need a renewal.

In its International Agreements page, EMA states that it has formalized its working relations with a number of third-country regulators through bilateral confidentiality agreements, which allows the parties to exchange confidential information and provide a framework for regulatory cooperation. “The emphasis,” the agency states, “is on exchange of information concerning regulatory guidance, legislation and non-public information on products, as well as safety information including adverse reactions, good manufacturing practice (GMP) and good clinical practice (GCP) inspection findings” (2).

EMA has listed the countries it has standing confidentiality agreements with, which are: Australia, Brazil, Canada, Japan, Switzerland, the United States, and now the Republic of Korea. It also has this agreement with the European Directorate for the Quality of Medicines and HealthCare (EDQM) of the Council of Europe, and the World Health Organization (WHO). The agency states that it can also establish ad-hoc confidentially arrangements with international regulators to address specific public-health needs; such agreements have a limited scope and duration.

The agency also has signed several mutual recognition agreements on the conformity assessment of regulated products, which covers the mutual recognition of GMP compliance for human and veterinary medicines. These agreements aim to “facilitate market access while protecting consumer safety and encourage greater international harmonization of compliance standards” (2). EMA has signed mutual recognition agreements with Australia, Canada, Japan, New Zealand, Switzerland, and the United States. It has also signed this agreement with Israel, though the agency notes the agreement is on conformity assessment and acceptance of industrial products.

Confidentiality Arrangement between the EU and the Republic of Korea

ema.europa.eu/en/partners-networks/international-activities/international-agreements

The agreement, which will allow participants to share confidential information on medical and medicinal products, builds on the cooperation fostered between the two regulatory authorities during the COVID-19 pandemic.

Confidentially Agreement Signed Between European Union and Republic of Korea Regulatory Bodies

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N4 Pharma, a pre-clinical stage specialist pharmaceutical company, has formed a research collaboration agreement with SRI, a global R&D company, to increase intracellular delivery to specific target cells. The collaboration will combine N4’s Nuvec, a silica nanoparticle delivery system created to carry nucleotides to be developed as cancer therapies and vaccines, with SRI’s FOX Three Molecular Guidance System (MGS). The companies intend to co-market the combined technology and work to develop and follow new business opportunities collaboratively.

SRI’s MGS is a system that uses propriety technology to enable the delivery of macromolecular payloads first to target cells, and then to subcellular locations within those cells. It was designed to overcome cellular barriers that were stopping intracellular delivery of large-molecule biotherapeutics. SRI has successfully tested the MGS technology on more than a dozen macromolecular payloads, including functional enzymes, nucleic acids (such as small interfering RNA [siRNA], antisense oligonucleotides, and DNA), antibodies, nanoparticles, and liposomes. It has delivered these payloads to targeted, intracellular molecular-target locations that were previously considered unreachable.

Nuvec’s irregular surface structure allows the nanoparticle to trap and protect siRNA, RNA, and DNA in their delivery to the cell membrane. When it is inside the cell, it releases the genetic material into the cellular machinery, allowing for the chosen pathway response (protein transcription, protein silencing, or other immune response). When combined with MGS, there is potential to facilitate targeted and effective treatments in precision healthcare.

In an N4 press release, Kathlynn Brown, president of SRI’s Biosciences division, said, “We’re excited to work with N4 Pharma to advance nucleic acid therapies and expand the number of applications of their Nuvec nanoparticle technology using the FOX Three Platform. The key properties of Nuvec, including preventing enzymatic breakdown of nucleotides and large surface area allowing multiple copy number of cargo, together with the targeting provided by MGS, may significantly enhance the use of nucleotide therapies. This strategic partnership marks an exciting journey towards expanding treatment possibilities and transforming the landscape of biomedicine” (1).

We are delighted to be working with SRI and to have entered into this collaboration agreement. Combining our technologies successfully will lead to working with major pharma companies in the fields of oncology and vaccines with the exciting potential to develop novel products,” said Nigel Theobald, chief executive office of N4 Pharma. “SRI collaborates with a broad range of strategic partners from small and virtual biotechnology companies to top 10 pharmaceutical companies and other leading industry partners, which will give us unparalleled access to potential commercial partners on the back of any successful combined technology resulting from our research. This marks an exciting new chapter for N4 Pharma, and I look forward to providing further updates as the research work progresses, as well as on our other work streams such as oral applications of Nuvec and the development of ECP105 for an orphan indication with Nanogenics” (1).

N4 Pharma. N4 Pharma Announces Collaboration with SRI to Target and Treat Cells in the Human Body that Have Been Previously Unreachable. Press Release. Apr. 25, 2024.

The collaboration will combine N4’s nanoparticle delivery system with SRI’s molecular guidance system.

N4 Pharma and SRI to Collaborate on Intracellular Delivery to Specific Target Cells

Report on the Performance of Drugs and Biologics Firms in Conducting Postmarketing Requirements (PMRs) and Postmarketing Commitments (PMCs) for Fiscal Year (FY) 2022.

 The agency reported that applicants successfully completed or released most of the PMRs/PMCs for the year reported on. Few PMRs/PMCs are delayed, with the majority moving along according to schedule.

As stated by the FDA, a PMR is “a study or clinical trial that an applicant is required by state or regulation to conduct postapproval” (1). A PMC is “a study or clinical trial that an applicant agrees in writing to conduct postapproval, but that is not required by statue or regulation.” PMRs and PMCs can be instituted as a condition of an approval or post approval of a drug. There are various reasons that the agencycan require application holders to conduct postmarketing studies and clinical trials, such as: to assess a known serious risk, assess signals of that risk, or identify a serious risk related to the use of a drug product; to study new drugs for pediatric patients, if these drugs are not properly labeled for children; to verify and describe the effect or clinical benefit of drugs that have been approved with accelerated approval provisions; or for a drug which human efficacy trials are not ethical or feasible, and therefore was approved on animal efficacy data.

The FDA requires applicants of approved drugs and licensed biological products to submit annual reports on the status of each clinical safety, clinical pharmacology, clinical efficacy, nonclinical toxicology study, or clinical trial that the applicants have committed to conducting or were required by the agency to conduct. They are required to report to the FDA on the requirements and commitments made for new drug applications (NDAs) and abbreviated new drug applications (aNDAs).

This report combines data from both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) and provides information on PMRs/PMCs as of September 30, 2022. As of the date of reporting, there were 386 unique applicants with open PMRs/PMCs under 798 unique NDAs and biologics license applicants (BLAs). There were 277 unique NDA applicants (and 591 associated applications) and 109 unique BLA applicants (and 207 associated applications) with open PMRs/PMCs. Applicants must submit an annual status report (ASR) on the progress of each open PMR/PMC within 60 days of the US approval of the original application or an alternate reporting date that was granted by FDA. There were 746 NDAs and BLAs with an ASR due in 2022 (547 NDAs and 199 BLAs). Of the 547 NDA ASRs due, 83% were received on time, 10% were received late, and 7% were expected but not received. Of the 199 BLA ASRs due, 82% were received on time, 14% were received late, and 4% were expected but not received.

Report on the Performance of Drugs and Biologics Firms in Conducting Postmarketing Requirements and Commitments Fiscal Year 2022

https://www.federalregister.gov/documents/2024/04/23/2024-08649/report-on-the-performance-of-drug-and-biologics-firms-in-conducting-postmarketing-requirements-and

The majority of PMCs/PMRs are proceeding according to schedule.

FDA Reports on Status of Postmarketing Requirements and Postmarketing Commitments

® attended a panel discussion on contamination control strategies (CCS) for cell and gene therapies. The panel featured James N. Polarine, a senior technical service manager, STERIS Corporation; Matt Hofacre, senior director of technical services for the equipment and services group, STERIS corporation; Marsha Steed, founder and president, Steed MicroBio; David Talmage, vice president of education, Parenteral Drug Association (PDA); and Vanessa Vasadi Figueroa, chief microbiologist, VVF Science. The panel gave an overview of a CCS, going into detail on what regulatory bodies are requiring from manufacturers, as well as the best practices in regard to contamination control in clean rooms. The panelists went over challenges associated with cell and gene clean rooms, the most common ways that contamination occurs, and how manufacturers can implement a contamination control strategy, even without the resources for a fully isolated clean room.

As reviewed by Steed, a CCS is a “planned set of controls for microorganisms, endotoxins/pyrogen, and particles derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to active substance, excipient, and dug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control” (1). With new requirements put forward in Annex 1 and advanced therapy medicinal products (ATMP) guidance, a CCS is now mandatory for cell and gene therapy facilities.

Figueroa pointed out that these guidelines aren’t new to manufacturing. This is already a part of the industry, she said, and now it’s being formalized. Instead of the responsibility being on finish product release, the responsibility has shifted upward into to the process, she said. Every part of the process is critical for contamination control, and it is everyone’s responsibility now to understand the process and minimize contamination. The largest source of contamination, Figueroa emphasized, is people, followed by raw materials and process materials. She said that it’s important for manufacturers to check raw materials and process materials in house and to demand higher quality products from vendors. Having some version of a control process is a good business strategy, she said, whether it is being required or not.

The significance of human risk was brought up again by Talmage. People are critical in this process, he said, and the environment is crucial to preventing contamination. While the medicine of cell and gene therapy is innovative and groundbreaking, in a lot of cases the environment it’s being done in is a typical lab environment, and the behaviors of people translate into that environment. What Talmage often sees, he said, is a lack of gowning. Wearing multiple pairs of sterile gloves, and sterile sleeves, is very important, as well as considering the material flow. 

Hofacre brought an engineering perspective to the discussion, mentioning the equipment that regulatory bodies want to see when they inspect facilities. The ideal, he said, are closed, automated systems with as little contact and contamination as possible. But in the industry right now most processing is done by people in open clean rooms, with material management being a high source of contamination. Not all manufacturers are ready to switch to a totally isolated environment, so Hofacre said that putting in place good practices is a big step in lowering contamination. Having a dedicated, single pass, with one way in and one way out, helps prevent recirculation contamination risk.

When making a CCS, it’s also important to consider how individual people behave, said Talmage. You need to consider how a person sits, how they rest their arms, and how long they’re going to be in that environmental. Looking at the ergonomics, not just from a biocontrol standpoint, but from an operator fatigue standpoint. Developers should consider the operator: they should take variables such as arm length and height into consideration, for example, before designing something that an operator would need to reach into. Polarine brought up the importance of decontamination (decon). He said that he often sees people bring items in without passing through decon, and without wiping the item down before use. Carts are a big offender in this; even if companies have carts set aside, they still need to be properly wiped down with disinfectant and sporicide before use.

Steed talked about her own experience with bio safety cabinets (BSCs), saying that they were innovative when they were first used in the lab, but that now many years later there are multiple, better options in the form of isolators. A traditional ATMP incubator has a risk of contamination and cross contamination, with the risk of mold developing in the incubators due to human error. With modern isolators, human interactions can be kept to a minimum, greatly reducing risk. One of the advantages of isolators is that they’re empty chambers, so they’re easy to set up, Steed said, and they are a much more sterile environment if used properly. There are many options for isolators, with some examples being closed robotic isolators, and isolators with glove ports for manipulations. Closed robotic isolators reduce human intervention but can be expensive to set up. Many companies instead opt for isolators with glove ports, or a modular option that has some steps inside the incubator (such as thawing the starting material) and some steps outside (such as culture mixing and transferring oxygen). One thing to keep in mind with these isolators, Steed said, is that the smaller a manipulation is, the harder it is to do through the glove ports. Operators should consider this limitation in dexterity when doing manipulations.

Figueroa said that biologics should learn from the mistakes that have been made in traditional pharma and get into isolators as soon as possible. If that isn’t feasible, she recommended starting out with a BSC or implementing alternative tools. Manufacturers should map out a sequence of operation steps, and anything that isn’t necessary for the process should be removed from the area. People need to be trained, she said, and an aseptic culture has to be established. Operators need to maintain a certain level of discipline while at work, and companies need to take the topic out of training once or twice a year and into everyday conversation. Talmage added that Technical Report #90 (TR90) from PDA has a program for the culture of aseptic behavior.

Hofacre agreed that while isolators are the preferred option, most facilities aren’t at the point yet where they can use them. He outlined an alternative option for open cleanroom suites, called integrated vaporized hydrogen peroxide (VHP) systems, which can create a bio decontamination container without isolators. Instead of bringing in mobile equipment or setting up equipment each time, companies can build a centralized generator that is piped to each individual cleanroom. He gave an example of a contract development and manufacturing organization that did cell and gene therapy and had 17 suites, who was able to decontaminate each individual suite with a VHP system while the other suites were still in operation. 

As Figueroa said, the most important part of the process comes down to mindset. She encouraged companies starting a CCS to document where they are in their process today. They should document all controls, outline current elements, and then see where they can improve. That way companies can understand if their current controls are enough, or if more are needed. Steed encouraged manufacturers to work with the regulators to get current requirements down. Regulatory bodies are willing to help companies get a strategy down, she said. No matter where a company is at in their process, having better contamination control is a goal that benefits everyone.

Polarine, J; Hofacre, M; Steed, M; Talmage, D; Figueroa, V. Panel Discussion: Contamination Control Strategies for Cell and Gene Therapy Facilities. Presentation at the INTERPHEX Conference, New York City, New York, Apr. 16–18, 2024.

A panel of experts went over new regulatory requirements for contamination control and gave guidance on implementing a contamination control strategy in cell and gene therapy facilities at INTERPHEX 2024.