Aligning mRNA Progress with Regulatory Streamlining

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Dosage Forms: Roundtable on Oral Solid Dosage Trends

Drug Solutions Podcast: 

Pharmaceutical packaging must advance to adapt to new, complex modalities

Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

Drug Digest: 

The Importance of Appropriate Supplier Oversight

Ask the Expert

Jennifer Markarian is a contributing editor for 

Concept health and beauty. Close-up of Medical Ampoule Production Line at Modern Modern Pharmaceutical Factory. Glass Ampoules are being Filled. Medication Manufacturing Process. | Image Credit: ©volodyar - stock.adobe.com

Pharmaceutical manufacturers continue to look to automation for efficient fill/finish of parenteral drugs, and new robotic automation technologies offer the opportunity to further improve flexibility and efficiency. New robotic technologies also aim to eliminate the need to open an isolator to perform interventions to better comply with the European Union’s Annex 1 requirements for closed systems (1).

At INTERPHEX 2024, equipment supplier, Steriline, demonstrated a new robotic filling machine that uses a magnetically levitated system to transport containers (e.g., vials, syringes, cartridges) instead of conventional mechanical transport. The most significant benefit of this planar motor technology is lower particle generation due to the “zero friction” motion as containers are transported from one station to another, the company explains. Robots are used for loading and unloading, which allows a closed system that is designed for flexibility. The robotic arms can handle multiple container formats, which means it needs fewer change parts.

“The filling machine has the flexibility needed for small batches and can be optimized for the requirements of each process,” adds James Rorke, vice-president of North American Operations, Steriline. “Using asynchronous processing, the timing of each step can be adjusted as needed.”

Steriline uses sensors to detect inaccuracies in filling and stoppering, and the equipment is designed with a method to reprocess noncompliant pieces. In the automation system, the containers can move backwards, for example, to fix a stopper that is flagged during the 100% checkweighing and inspection step, Rorke explains. The design is part of what the company calls its zero-loss philosophy, which continues to move toward more efficient production.

All pharma equipment for aseptic manufacturing must be designed in compliance with good manufacturing practice (GMP) requirements and, in Europe, the new, recently approved Annex 1 guideline, asserts Paolo Simonazzi, sales director for Americas at IMA Life, which is one of three pharma divisions of the IMA Group. One of the most important challenges for the management of contamination risk is the first air protection principle, he confirms. Designers use computational fluid dynamics to simulate airflow, and the robotic automation is set up so a minimal amount of steam-sterilized parts, such as the filling needle but not any part of the robot, passes over the top of the open vial or other critical surfaces.

The company’s new Injecta fill/finish system is entirely robotized, allowing flexibility for switching between formats and minimal change over time. Compared to traditional automation, robotic automation has less movement and is therefore cleaner, IMA explains. The fully robotic equipment was installed late in 2023 in a new Bayer facility for parenteral medicines in Germany (2). A key requirement was that the machine automation would generate data for paperless production and integrate into Bayer’s management system.

New technologies in development allow an operator outside of an isolator to use a robotic arm to perform interventions inside the isolator without breaking the barrier. One of the drivers for the new technology is better compliance with Annex 1, explains Irina Rau, regional sales manager for Stäubli Robotics. Another advantage is avoiding opening the isolator, which would mean losing a batch of product. A challenge is to design the robot’s movements to ensure the ease of use for all operators. Flexibility, sensitivity, and making sure the process stays safe for the equipment and operators are all important. Stäubli has worked with telemanipulation technologies from multiple suppliers, including Force Dimension and SRI, and showcased a use case with AST during INTERPHEX 2024.

A telemanipulation system for sterile manufacturing environments from SRI, a nonprofit R&D institute, is a new extension of SRI’s technology that has been used for decades in robotic-assisted surgeries, as well as other remote applications, such as bomb disposal. SRI’s XRGo software is integrated with commercial third-party robots for remotely controlled repair and maintenance functions inside a sterile area, such as an isolator. This technology is particularly useful for infrequent activities that are not easily automated, such as changing a filter, fixing a machine jam, or cleaning up a broken glass vial, specifies Bill Rusitzky, general manager for XRGo at SRI. Today, these activities are performed either through gloves mounted to the isolator or by sending a gowned operator into the sterile environment, both of which present challenges. As an alternative, robot telemanipulation allows a robotic arm that is fitted with an end effector to be controlled from outside the isolator, operating as a remote extension of the operator’s arm and hand. The operator sees the action of the end of the robotic arm through 3D stereo streaming video to a virtual reality (VR) headset, and the handheld controller provides haptic feedback. A VR interface provides an augmented-reality environment and can add additional views or repair manuals. The video recording and other data can be used to document interventions digitally.

Although automation has historically been used for high-volume and large-scale processes, new technologies are driving automation down to smaller volumes. Comecer demonstrated its new semi-automatic system for cell and gene therapy filling, ValueCell FILL, at INTERPHEX 2024. The automated system fills 150–175 bags/h from a large mixing bag to smaller bags, which are thermal welded in preparation for freezing. A controller for the mixer allows flexibility in the parameters and in the fill size of the bags. Automation replaces gowned operators performing manual pipetting, which helps alleviate the problem of workforce shortages.

Catalyx, which specializes in automating pharmaceutical manufacturing, inspection, and packaging processes, sees increasing uses of robotic and artificial intelligence-assisted automation. For example, kitting for clinical manufacturing is a high-mix, low-volume packaging process that benefits from robotic automation, because the robot can be programmed to package whatever is needed (e.g., vials, syringes, pens, and leaflet inserts), with very low error rate, says the company, which delivered a system for this application late in 2023. The system uses Catalyx SmartFactory Machine Vision guidance for picking and placing.

“Telemanipulation adds value because the operator can perform the activity remotely,” says Rusitzky. “The operator doesn’t need to be within feet of the equipment; they can be down the hall or the next building. The stereoscopic camera view adjusts automatically so that the operator always feels directly behind the robotic hand. The precise video provides an intuitive, natural understanding of the scene, and the user interface allows people to use it with very limited training.”

Rusitzky explains that the software restricts where the robotic arm can move, so that it doesn’t damage equipment in the isolator. The robot is also programmed to move at the correct speed to avoid disturbing the air inside the sterile environment. SRI has worked with third-party robotic companies, such as Stäubli and Denso, and the system is available for testing use cases.

As with any process change, use of robotic telemanipulation will need regulatory approval before being used in a commercial, GMP process. FDA regulators are aware of the technology, adds Rusitzky, and see that it can be useful.

“Across the pharmaceutical industry, we hear that adoption of this type of technology is a question of ‘when’ not ‘if’,” Rusitzky claims.

“We expect that robot telemanipulation will play a vital role in ensuring precision, efficiency, and safety in pharmaceutical manufacturing,” Jean-Maxime Guay, senior manager, Manufacturing Intelligence at Pfizer, said in a statement. “By allowing people to manage issues without requiring proximity to the process, this technology would help aligning with the new EU [European Union] GMP Annex 1 revision through contamination risk mitigation, in addition to decreasing operational costs.”

SRI is collaborating with INVITE Research, a nonprofit joint research venture formed by Bayer Pharmaceutical and other companies to allow precompetitive collaboration to introduce technologies that can be broadly adopted across the pharmaceutical industry.

Charly Coulon, head of Future Manufacturing Concepts at INVITE, says that telemanipulation is crucial for keeping people out of the sterile environment. “No matter how much effort you put into automation, there comes a time when something unexpected happens and requires you to utilize the unmatched flexibility of a human,” he explains. “Only telemanipulation will allow you to rectify the situation at that moment without sending a human in and breaking sterility.”

One of the challenges for telemanipulation is having enough space inside the isolator available for greater use of robots. In current designs, the isolator space is kept small, which allows people to reach spaces with a glove. In addition, automation systems increasingly use actuators and material guides to increase reliability and avoid incidents, specifies Coulon. Both of these trends limit space. “In my view, the biggest roadblock [to telemanipulation] is the necessary disruptive rethink to build systems differently and isolators significantly larger,” he says. Coulon suggests the effort to automate can be reduced by programming only the expected standard functions and using telemanipulation of robots for anything outside of standard. “[In these rare cases],” he remarks, “you combine the flexibility and ingenuity of a human with the physical presence of the robot on site from a distance.”

EC. Annex 1 Manufacture of Sterile Medicinal Products. 

IMA. Bayer Chooses Injecta for the Production of Parenteral Medicines. Case Study, 

®
Vol. 48, No. 9
September 2024
Pages: 22–23

When referring to this article, please cite it as Markarian, J. Advancing Robotic Automation. 

Articles

New technologies improve efficiency and remove operator intervention.

Advancing Robotic Automation

Feliza Mirasol is the science editor for 

Adventitious agent testing remains critical in biomanufacturing to help ensure product purity. As such, testing protocols from monoclonal antibody (mAb) manufacturing may be transferred to gene therapy manufacturing, as the optimization of testing practices are applicable to gene therapy manufacture. 

Editor’s note: this article was published in 

For instance, in conducting tests to confirm a biological product’s safety, it is necessary to use multiple assays to ensure that various contaminants are identified. Several assays are commonly used in combination to test for adventitious agents, which is required by regulatory bodies, including the US Food and Drug Administration (FDA) and the European Medicines Agency. The two main types of assays for identifying adventitious agents are 

 assays are utilized when mammalian cell lines are used to produce biopharmaceuticals, while 

 tests to detect viruses that are not able to be grown in cell culture (1). 

Of more immediate concern is the fact that more complex modalities of biopharmaceuticals are prevalent in the industry pipeline. These complex modalities typically require more complex manufacturing processes, which means each product in development is a more significant investment of time and energy as well as patient trust. The current climate makes thorough biosafety testing procedures more crucial for biopharma developers (2).

Adventitious agents comprise a broad range of contaminants, which are unintentionally introduced into the biomanufacturing process. These agents include bacteria, fungi, viruses, mycoplasma, parasites, and mycobacteria, among others. A common way that adventitious agents enter the biomanufacturing process is via starting materials that are animal or human origin. These materials include cell substrates, bovine serum, or the cell lines themselves, or may be introduced by the manufacturing operators, such as where manual handling or processes are concerned (2).

Inadequately tested biopharma products that end up with contamination run the risk of investigation, corrective action, and downtime in manufacturing that ultimately costs the manufacturer—and developer—millions of dollars or more. Therefore, having preventative strategies and comprehensive testing in place is imperative in biologics manufacturing. Another issue to consider is that contamination can happen at any point in the process between securing the cell bank to the fill/finish stages. To mitigate contamination risk and ensure efficient workflow, it is necessary to test for adventitious agents at multiple timepoints. It is also worth it to note that testing and detecting any contamination earlier in the manufacturing workflow, rather than just relying on testing prior to final product release, can better ensure that tainted product does not reach the market and can save time, cost, and effort (2).

For virus detection, methods include traditional culture-based methods as well as electron microscopy studies, 

 molecular and antibody assays, sequencing methods such as massive parallel or next-generation sequencing, and degenerate polymerase chain reaction (PCR). Methods for detecting bacteria also include culture-based approaches and PCR but can also employ biosensor-based methods. Meanwhile, for other adventitious agents such as mycoplasma, detection can include PCR—this includes specific PCR kits, microbiological culture methods, and enzyme-linked immunosorbent assays (3).

Similarly, the adventitious agent testing requirements for viral vectors are consistent with the requirements for other modalities of biotherapeutic products, including selection of appropriate testing methods. However, a direct transfer of testing strategies used in recombinant proteins and mAbs may not necessarily be feasible or practical for viral vectors. Biological differences between viral vectors and large-molecule proteins hinder direct adoption of testing strategies (4).

Because viral vectors are themselves viruses, standard assays may need to be modified or alternative methods used for testing them. That factor can interfere with virus detection methods during adventitious agent testing. Other complications arise if cell-based assays are used to test live-virus vaccines, replication-competent gene therapy vectors, or vectors that exhibit the cytopathic effect. The issue stems from the fact that human cell lines are primarily used to develop cell-based assays, which are susceptible to human viruses. Adenoviral products, which are lytic viruses, will, for example, infect both human and primate-derived cell lines, which would invalidate the assay. On top of that, there is always the risk that cellular toxicity may occur (4).

If adventitious agents are detected, an important step is to identify the species and the origin(s) of the contamination. It is then important to evaluate the agents’ potential to infect humans (5). Some adventitious agents still find their way into the end product despite extensive detection efforts. Examples of these occurrences include the presence of porcine circovirus 1 found in a commercial rotavirus vaccine and a novel rhabdovirus in a Spodoptera frugiperda (Sf9) cell line (6–8).

 adventitious agent testing methods are usually sufficient, but they have their limitations. For one thing, test sensitivity may not be high enough to detect certain contaminants or too-low concentrations of contaminants. Some assays require lengthy times to perform. What’s more, different testing methods inherently have different sensitivities for detecting different contaminants, and each method has its own limitations. Fortunately, these different methods can complement each other and, when combined, can offer greater understanding of detecting adventitious agents (4).

The delivery times for some adventitious virus test results can be challenging, regardless of which testing methods are used. Some assays may take several weeks to generate results. On top of that, certain biotherapeutics, such as gene therapies, have short shelf lives, so waiting on results for adventitious agent testing may come too late. This is a concern for autologous cell therapies that are dependent on gene-modified components and must be administered to the patient soon after they are produced (4).

On the positive side, detection technologies for adventitious agent testing continue to evolve, with a focus on higher sensitivity, rapid methods, and broad detection ranges. The downside is that new technologies take time to develop, and they must be thoroughly validated to demonstrate their suitability and applicability before the bio/pharma industry and regulatory bodies will accept them for implementation into the testing strategies for adventitious agent control in biomanufacturing (9).

 (accessed 10 July 2024).
2. Thermo Fisher Scientific. Improving Adventitious Agent Testing in Biologics Manufacturing. 

, 9 Feb. 2023 (accessed 10 July 2024).
3. Morris, C.; Lee, Y. S.; Yoon, S. Adventitious Agent Detection Methods in Bio-Pharmaceutical Applications with a Focus on Viruses, Bacteria, and Mycoplasma. 

, 105–114. DOI: 10.1016/j.copbio.2021.06.027
4. Challener, C. Adventitious Agent Testing for Viral Vectors. 

 (9), 40-44.
5. Klug, B.; Robertson, J. S.; Condit, R. C.; et al. Adventitious Agents and Live Viral Vectored Vaccines: Considerations for Archiving Samples of Biological Materials for Retrospective Analysis. 

 (51), 6617–6625. DOI: 10.1016/j.vaccine.2016.02.015
6. Victoria, J.G.; Wang, C.; Jones, M. S.; et al. Viral Nucleic Acids in Live-Attenuated Vaccines: Detection of Minority Variants and an Adventitious Virus. 

 (12), 6033–6040. DOI: 10.1128/JVI.02690-09
7. Dubin, G.; Toussaint, J. F.; Cassart, J. P.; et al. Investigation of a Regulatory Agency Enquiry into Potential Porcine Circovirus Type 1 Contamination of the Human Rotavirus Vaccine, Rotarix: Approach and Outcome. 

 (11), 2398–2408. DOI: 10.4161/hv.25973
8. Ma, H.; Galvin, T. A.; Glasner, D. R.; Shaheduzzaman, S.; Khan, A. S. Identification of a Novel Rhabdovirus in Spodoptera frugiperda Cell Lines. 

 (12), 6576–6585. DOI: 10.1128/JVI.00780-14
9. Playter, G. Examining Next-Gen Technology for Adventitious Agent Testing. 

®
Volume 36, No. 8
September 2024
Pages: 29–30

When referring to this article, please cite it as Mirasol, F. Meeting Adventitious Agent Testing Needs for Complex Modalities. 

Viral vectors and other complex biologic modalities require more specificity and higher sensitivity to detect and distinguish contaminants.

Meeting Adventitious Agent Testing Needs for Complex Modalities

Researcher holding tablet, conducting medication quality control, effectiveness | Image Credit: ©motortion - stock.adobe.com

Independent of the type of medicine or dosage form, whether it be a solid-dose pill for treating headaches or a pre-filled biologic to treat autoimmune disorders, the materials that create drugs are the building blocks for treatment. These materials must meet certain qualifications in order to be used in a medicine. Manufacturers and providers of these ingredients, be they APIs or excipients, also must meet qualifications to ensure a safe and effective final drug product.

Contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs), especially those offering end-to-end services to sponsors, play a role in the sourcing, testing, and qualifying of drug materials and the companies that manufacture them.

Qualifying suppliers of raw materials is an important step in the supply chain and assures regulators that the materials used in drug products are safe and effective for patients.

“CDMOs use APIs, intermediates, excipients, and other inputs to manufacture and supply the finished product to sponsors. Their quality performance is determined by the quality of these input materials,” says Sundar Narsimhan, chief procurement officer at Neuland Labs. “CDMOs may set up robust quality systems that address the quality and regulatory requirements of the end markets. These include audits and inspections of their material suppliers, incoming testing, and release.”

“It is an old but true saying that quality cannot be tested into a product because by the time a sample is in the QC [quality control] laboratory, the quality is already determined! But the good news is that CMOs and CDMOs can do a lot to help ensure the quality of APIs and excipients,” says Iain McGhee, vice-president of Quality at Ascend Advanced Therapies. “Externally, this will require clear oversight of any suppliers and the supply chain. Internally, this includes maintaining control of the manufacturing process and keeping good records.”

Contract organizations can assist sponsors to select and qualify material suppliers by understanding what the materials are being used for, understanding regulations and markets, and performing robust onboarding and qualification, according to Kim Arsenault, Quality Compliance manager, BIOVECTRA. “Both the CDMO and the client need to clearly understand and document the intended use and processes involving the material, including the end product’s phase and timeline,” says Arsenault. “[Both parties should know] the regulatory requirements of the target market ensure all material attributes and sampling needs are defined and met, while avoiding any compliance issues that could arise during or after product launch.”

“To ensure the quality of pharmaceuticals in the final product it is important to have an up-front understanding and alignment of critical quality attributes (CQAs)/specifications from customers,” says Josh Hoerner, general manager and executive vice president, Purisys (part of the Noramco Group). “Many factors may play into a customer’s quality requirements, including information only the customer may have, such as that derived from toxicological studies, feedback from regulatory authorities, dosing strategy and other information that is important to patient safety. Incorporating this information into the API or excipient process design requirements is critical to developing products that are safe for patients. As a CDMO, we also need to consider and provide input on CMC [chemistry, manufacturing, and controls] aspects of the API or excipient such as chemical manufacturing process capability, analytical method capability and limits, compendial quality standards, control of impurities (such as genotoxic impurities and nitrosoamines), etc.”

CMOs/CDMOs also assist in ensuring the quality of materials in other ways, including storage and handling, quarantine processes, and testing, according to Mayank Nagar, vice-president and head of Tech Services & New Product Launches, North Americas, and Himanshu Joshi, director, New Product Launches, North Americas, at Dr. Reddy’s Laboratories. “Analyst training is equally an integral part of ensuring consistent quality,” says Nagar. “As the adage goes, ‘The quality of the input material dictates the quality of the final product’.”

When selecting a supplier of raw materials, quality compliance is ensured through an audit and qualification process, says David Shell, head of Quality, Andelyn. CDMOs and CMOs offer sponsors assistance in this endeavor. And a phase-based approach may be the best way to select such a supplier, according to Adelyn, depending on what the CDMO/CMO’s client requires and the phase of the program. “A balanced approach may be considered based on the specific regulatory requirements for each program, for current needs and having flexibility to be forward-looking if additional quality standards are needed, if cost or timing considerations are a key factor. Having a clear and concise definition for critical versus non-critical materials and classification is also important. It can be important to categorize suppliers based on risk: how critical the component or service is to the process and final product,” says Shell.

“When selecting materials suppliers, it is critical to ensure that ingredients are fit for purpose for pharmaceutical use (e.g., GMP [good manufacturing practice] grade),” says McGhee. “Normally, the grade will increase as a product gets closer to commercialization (research grades during process development and pharmacopeial grades for GMP manufacture). With gene therapies, this approach is not always the best. And while GMP compliant suppliers will be more costly, sourcing from non-GMP suppliers or using low grade materials for less cost can be catastrophic.”

Often, says McGhee, contract organizations already have relationships in place with suppliers. McGhee also states CMO/CDMOs can also ensure contract negotiations include all quality levels and chemistry, manufacturing, and controls (CMC) information needed for regulatory filings.

Arsenault agrees, stating, “leveraging existing relationships and industry expertise can support sponsors, especially those new to the industry, in navigating material sourcing. A sponsor who is new to the industry may not have an extensive supplier network to draw from. Alternatively, a small/mid-size CDMO may need to leverage existing supplier relationships between a larger/more established sponsor and their supplier network in some instances.”

According to Arsenault, a strong, systematic onboarding process should be in place, as well as processes for qualifying, approving, and documenting the use of raw materials. “It must be capable of accurately identifying how/where materials are used and the lifecycle stage of these processes to manage material requirements effectively as they evolve,” Arsenault stresses. Onboarding and qualification processes should ensure that suppliers have solid quality systems, and performance should be monitored by quality audits and notification/approval processes. Supporting material statements should also be in place, says Arsenault, to verify quality, traceability, and safety.

Ensuring the quality of materials used in developing and manufacturing drug products is a crucial step for sponsors. CMOs and CDMOs can provide supplier qualifications as part of the sponsor/client quality agreement, says Cyrill Kellerhals, COO at Andelyn. Qualification requirements, according to Kellerhals, include manufacturing/production capabilities, quality standards and certifications, quality regulatory and compliance requirements, technology, customer service standards, delivery and cycle times, and lifecycle management.

Supplier qualification should align with current good manufacturing practice (CGMP), say Nagar and Joshi, with quality agreements that define roles and responsibilities. “Additionally, based on the historical usage of materials and prior experience with suppliers, a risk-based approach can be matured, considering the criticality of the API and excipients,” says Nagar.

A supplier qualification typically involves seven steps, according to Narsimhan. These include ascertaining the criticality of the material, developing a procurement strategy, using due diligence to identify suppliers, floating RFP [request for proposal] to the shortlist [of potential suppliers], performing a pre-qualification audit, conducting a techno-commercial environmental, social, and governance (ESG) evaluation, and then awarding the contract. “In addition, CDMOs can assist their sponsors by performing their gap analysis and critical evaluation of sources and recommending risk mitigation pathways,” says Narsimhan.

Hoerner suggests having a pre-filled standard questionnaire that details supplier qualifications regarding quality systems and inspection history. “As a CMO/CDMO, it is also important to be open to a customer audit before business is contracted to build confidence between a sponsor’s quality unit and a supplier’s quality unit,” says Hoerner. “Before and during any CMO/CDMO audit, it will also be important to align and ensure the scope and extent of qualification of facilities, buildings, and production equipment and/or laboratory instruments to be used in manufacturing the customer/sponsor’s materials.”

When developing a quality risk management (QRM) plan for qualifying materials suppliers, Narsimhan recommends the following elements:

Determine the quality objectives, criticality factors, end-use, and specifications.

Assess the material’s quality vulnerabilities and variability by looking at the manufacturing process, quality culture and track record of the supplier, and traceability.

Compare the supplier’s performance and capability against established criteria during site visits, audits, checking of documentation and quality control infrastructure, and reviewing supplier feedback.

Continually assess the supplier’s performance through tracking, corrective and preventive actions/process improvements, and tracking quality indicators.

Arsenault stresses that both quality and business risks should be considered with managing risk in suppliers. “We categorize suppliers based on the type of materials supplied, their criticality to the overall process, and the process/phase where they are used. Additionally, we evaluate business risks such as single vs. multi-source availability, geographical location, political climate, industry reputation, and EHS [environment, health, and safety]/safety/ethics practices,” says Arsenault.

Documentation provided by the supplier should be reviewed, according to Arsenault, as well as change control and notification policies, previous adverse events or regulatory notices, and the type of supply (single source vs. alternative source).

“For critical suppliers, we include a detailed assessment of the associated processes, validation status, quality audits, and any out-of-specification events. For software providers, we evaluate the software validation status and associated risk score,” says Arsenault.

Supplier and vendor audits may be performed based on risk assessment has stated in the International Council for Harmonisation’s (ICH) Q9 document, according to Betsy Torres, QA compliance manager at Andelyn. Assigning a risk score will allow the determination of the frequency needed for requalification and future audits, according to Torres.

“Having a transparent process with proper documentation and compliant quality systems is critical in order to provide proper visibility into the manufacturing and quality processes, so the client is assured that supplier risk is mitigate[d] [to] the best extent possible,” Torres says.

“You have to have a [QRM] approach that is (ideally) stepwise and follows the principles outlined in ICH Q9 for risk identification, analysis, evaluation, reduction, acceptance and review,” Hoerner concurs. “During discussions with a supplier, you need to establish compliance with ICH Q9 and what tools a supplier uses to manage risk (e.g., FMEA [failure modes and effects analysis], FTA [fault tree analysis], PHA [process hazard analysis], etc.). To ensure alignment of roles and responsibilities between a supplier and customer in terms of communication, a quality agreement can serve the purpose of defining a supplier’s responsibility to report and communicate risks and issues.”

Monitoring a supplier for potential future problems is crucial, according to McGhee. This includes manufacturing and delivery status. “If any delivery timelines are shifting, could there be an underlying issue at the manufacturing site?” McGhee asks. Restructuring, mergers, or any changes in leadership at the supplier should be identified. These changes would impact experience at the supplier, says McGhee. Suppliers should have strict cyber security. “This is particularly important for organizations that have electronic quality systems or are using any type of AI [artificial intelligence] or VR [virtual reality] technology,” says McGhee. Finaly, McGhee suggests having secondary sources validated.

“Continuous monitoring through regular audits, performance reviews, and material testing is essential, alongside maintaining open communication channels for prompt issue resolution,” Nagar and Joshi agree.

“Comprehensive documentation of all evaluations, audits, and quality assessments is crucial to ensure traceability and compliance, ultimately ensuring consistent material quality and regulatory adherence,” they conclude.

®
Vol. 48, No. 9
September 2024
Pages: 31–33

When referring to this article, please cite it as Haigney, S. It’s All About the Small Things. 

Qualifying material suppliers is a crucial step in ensuring safe and effective drug products.

It’s All About the Small Things

Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Behind the Headlines: Weight Loss Drugs; Price Controls; and Free COVID Therapies

This Behind the Headlines news roundup panel discussion covers news items such as the weight loss drugs battle between Novo Nordisk and Eli Lilly, entering new territory through Lilly’s partnership with HAYA Therapeutics and long non-coding sequence mining. It was questioned whether HAYA would have turned its platform toward obesity without that market commanding so much commercial attention at present.

“The partners will identify multiple regulatory genome derived RNA-based drug targets to address these chronic conditions. Under the terms of the collaboration, HAYA will receive an upfront payment, including an equity investment, and is eligible to receive up to an aggregate $1 billion in pre-clinical, clinical and commercial milestone payments, as well as royalties on product sales. HAYA’s proprietary regulatory genome discovery platform enables the identification of tissue-, disease- and cell-specific long non-coding RNA (lncRNA) targets and the development of RNA-targeting therapies, with potentially better efficacy and less toxicity than current treatments, to reprogram disease-driving cell states … This partnership with Lilly demonstrates the significant advances we have made with our revolutionary regulatory genome RNA-guided platform and validates the potential of targeting lncRNA for chronic conditions," said Samir Ounzain, CEO, HAYA Therapeutics, in a press release (1). "We look forward to working closely with Lilly, an established leader in developing treatments for metabolic diseases, to help bring patients novel disease-modifying therapeutics that could offer greater efficacy, safety and accessibility than currently available treatments” (1). 

The panel also discussed The Centers for Disease Control’s Director Many Cohen’s decision to make free vaccines available for those who otherwise couldn’t afford them ($62 M). Starting in late September 2024 from the 

 website, each household can order up to four free at-home tests, which will be delivered through the mail. This is a popular program that has sent out more than 900 million tests since 2021, according to Dawn O’Connell, Health and Human Services’ assistant secretary for planning and response. O’Connell said the government’s Paxcess program, which is run by drugmaker Pfizer, will continue to distribute free Paxlovid through the end of the year to people who test positive for COVID-19 and who are uninsured or who are on Medicare or Medicaid (2).

An advance in mitochondrial basic biological understanding with ramifications for potential disease etiology and diagnostics, alongside drug targeting was also discussed. A recycling system in self-repairing mitochondria has been reported by imaging scientists at the hospital for sick children (SickKids). A report by 

 stated, “their research demonstrates mitochondria can recycle a localized injury, removing damaged folds called cristae that contain proteins and molecules needed for energy production. The researchers believe this mechanism could present a future target for the diagnosis and treatment of conditions characterized by mitochondrial dysfunction, including infections, fatty liver disease, aging, neurodegenerative conditions, and cancer” (3).

The panel also discussed the Biosecure Act passage and re-shoring pharma manufacturing to North America. In a survey of small, emerging biotech firms in the United States, the Biotechnology Innovation Organization (BIO) found that 65% work with China-based contract development and manufacturing organizations in some capacity. Switching to new manufacturers, or manufacturing in the US, would temporarily halt production and potentially cost more in labor (4).

HAYA Therapeutics. HAYA Therapeutics Announces Collaboration with Lilly to Discover Novel Regulatory Genome Targets for Obesity and Related Metabolic Conditions Using Proprietary RNA Platform. Press Release. Sept. 4, 2024. 

https://www.hayatx.com/news-and-publications/haya-therapeutics-announces-collaboration-with-lilly

Goodman, B. Free Covid Tests, Treatments Will Return to Help the Country Cope Over Fall and Winter, US Officials Announce. 

https://www.cnn.com/2024/08/23/health/free-covid-tests-treatments-2024/index.html

Genetic Engineering & Biotechnology News. Recycling System in Self-Repairing Mitochondria Discovered. 

https://www.genengnews.com/topics/translational-medicine/recycling-system-in-self-repairing-mitochondria-discovered/

Vedantam, K. US Manufacturing Unprepared for BIOSECURE Act’s Repercussions. 

https://www.biospace.com/policy/us-manufacturing-unprepared-for-biosecure-acts-repercussions

Alex Philippidis, Senior Business Editor, Genetic Engineering & Biotechnology News

Benjamin McLeod, Director, Cell & Gene Therapy Segment, NanoMosaic Inc.

Chris Spivey, Director of Industry Relations and Strategic Partnership, MJH Life Sciences

Videos

This Behind the Headlines news roundup panel discussion covers news items such as the weight loss drugs battle between Novo Nordisk and Eli Lilly, entering new territory through Lilly’s partnership with HAYA Therapeutics and long non-coding sequence mining. There was much discussion on how the inflation reduction act and Medicare price controls may or may not pertain—given the uncertainty around the presidential election results, and subsequent policy directions. The Centers for Disease Control making cost free COVID-19 diagnostics and therapies available was also evaluated. 

Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Evaluating Aseptic Processing and Manufacturing

Delving into Biopharmaceutical Development and Manufacturing

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, and Feliza Mirasol, Science Editor, Pharmaceutical Technology Group, interview experts about aseptic processing and manufacturing. During the discussion, industry experts will evaluate the importance of aseptic processing and manufacturing, highlighting the challenges impacting industry, the intricacies of the regulatory landscape, the importance of understanding nuances between products and processes, the necessity of addressing QC/QA early on, best practices to ensure aseptic sterility, and potential future trends.

Maik W. Jornitz, Founder and Principal Consultant, BioProcess Resources

Maik W. Jornitz, founder and principal consultant of BioProcess Resources, is a 35-year veteran of the industry. He is highly experienced in single-use bioprocesses, aseptic processing, and a subject matter expert in sterilizing-grade filtration and filter integrity testing. He has published multiple books, book chapters and over 100 scientific papers on various bioprocessing and facility design topics. He is the former chair of the Parenteral Drug Association (PDA) board of directors and science advisory board, and member of multiple PDA Task Forces, including the European Union Annex I response team. He is board member and senior business and strategy advisor of DIANT Pharma. As a faculty member of various training activities, including PDA Training and Research Institute, he trains members of the industry and regulatory authorities frequently. In his previous roles, he was the CEO of G-CON for 10 years, he worked 26 years for Sartorius, with his last role being the senior vice-president for Global Product and Marketing Management Bioprocess. He received his Master of Engineering in Bioengineering at the University of Applied Sciences in Hamburg, Germany, and accomplished the Program for Executive Development at IMD Business School in Lausanne, Switzerland.

Dan Strange, PhD, Chief Technology Officer, Cellular Origins

Dan Strange has been working at the intersection of engineering and biology for almost 15 years, and he is an inventor on 20 patents. After completing a PhD in regenerative medicine at the University of Cambridge, he moved to TTP where he developed complex drug delivery devices. He was instrumental in the creation of multiple technology platforms successfully licensed to large pharma in deals worth over $100 million. For the past four years, Strange has focused on cell therapy manufacturing equipment. Strange is an active member of various automation working groups and was a reviewer on the Alliance for Regenerative Medicines A-Cell report on cell therapy manufacturing.

Drug Digest is a tech talk video series with the 

® editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

Small Molecule APIs, Excipients, and Formulation

Solid Dosage Drug Development and Manufacturing

In this episode of Drug Digest, discussion with industry experts will highlight the challenges impacting aseptic processing and manufacturing, the intricacies of the regulatory landscape, and the necessity of addressing QC/QA early on, among other critical aspects. 

Drug Digest: Evaluating Aseptic Processing and Manufacturing

Rentschler Biopharma, a biopharmaceutical contract development and manufacturing organization (CDMO), announced on Sept. 3, 2024, that it has launched an expanded service offering at Stevenage, UK, the company's advanced therapies site. With the expanded offering, Rentschler Biopharma now offers a new lentiviral vector (LVV) manufacturing toolbox for producing advanced therapy medicinal products (ATMPs), which complements the company’s existing adeno-associated virus (AAV) viral vector services.

The Stevenage site offers customized solutions for accelerating viral vector programs and includes novel, license-free toolboxes for AAVs and LVVs, according to a company press release. The company’s proprietary human embryo kidney 293 (HEK293) cell line offers additional time and cost savings for advanced therapy projects. The company’s services contributed to nearly 25% of FDA-approved biopharmaceuticals in 2023, Rentschler Biopharma stated in the press release.

“We made a strategic investment in the cell and gene therapy sector, starting with adeno-associated viral vector services, so we could offer our development and manufacturing expertise and sector experience to support innovators in this fast-developing space,” said Christiane Bardroff, chief operating officer, Rentschler Biopharma, in the press release. “We are now pleased to build on our success and augment this offering with lentiviral vectors. Our company remains dedicated to evolving our portfolio to enhance the health and quality of life for seriously ill patients around the world.”

Growing research and positive clinical results across a range of therapeutic applications has increasingly brought LVVs to the forefront in the advanced therapy space. Using LVVs for gene transfer has been applied to treat several genetic diseases, including beta-thalassemia. LVVs have also been used introduce genes to T-cells to modify them and generate immunity against cancer (1).

“The new lentiviral vector manufacturing toolbox highlights our commitment to providing cutting-edge solutions that enable our clients to advance their viral vector programs from pre-clinical and clinical development to market. By integrating lentiviral vector process development and manufacturing to our services, we are better serving the market by meeting the growing needs of the evolving and vibrant global advanced therapies sector,” said Robert Panting, general manager, ATMP, Rentschler Biopharma, in the press release.

Manufacturing LVVs has traditionally been difficult because 

, which are more delicate and sensitive than non-enveloped viruses. LVVs are therefore more sensitive to temperature, pH, shear, etc. (2).

Because of their sensitivity, purification approaches for LVVs are typically gentler, often applying one single-step chromatography and one concentration/buffer exchange step; however, final sterile filtration is still a challenge and may impact titer and yield. Designing a manufacturing process must therefore consider how to mitigate yield loss all along the way (2).

1. Ghosh, S.; Brown, A. M.; Jenkins, C.; Campbell, K. Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges. 

 (1), 7–18.
2. Mirasol, F. Comparing Viral Vectors for Gene Therapy Delivery. 

Rentschler Biopharma has expanded its service offerings at its Stevenage, UK, site with a new lentiviral vector manufacturing toolbox.

Rentschler Biopharma Offers New Toolbox for LV Manufacturing

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - stock.adobe.com

Steriline, based in Lake Como, Italy, will display RVFCM11-S, its new, robotic vial filling and capping machine, in the company’s home country at CPHI Milan from Oct. 8–10, 2024, Steriline announced in a press release on Sept. 2, 2024 (1).

Designed specifically for primary packaging of cell and gene therapies, RVFCM11-S measures 2.25 m by 1.65 m, contains nested vials in four different sizes, and can be configured to fill pre-filled syringes and cartridges, according to Steriline (1). The machine uses two robots for handling of primary containers with no glass-to-glass contact, and an integrated, double-wall isolator that minimizes contamination risk.

“Our new RVFCM11-S addresses the specific challenges associated with the production of cell and gene therapies, where sustainability is often determined by product loss,” said James Rorke, vice president of operations at Steriline North America, in the press release. “The entire supply chain can now benefit from a solution that ensures minimal loss, a high degree of sterility assurance, and compliance with [European Union good manufacturing practice] Annex 1 requirements.”

Vials are removed discretely by RVFCM11-S’s use of magnetic levitation, to move each vial to a robot arm. The vials then proceed to the filling station, with a check-weigh system integrated into the design to ensure precise filling (1). A second robot arm handles capping, and places vials back into their nests.

Overall, the machine has a production capacity of 15 nested vials, syringes, or cartridges per minute, according to Steriline (1). Additional software-based tracking features are deployed to ensure that temperature-sensitive materials do not exceed their time limit in the solution, therefore preserving pharmacological efficacy.

Steriline said in the press release that the RVFCM11-S would attract both pharmaceutical professionals, and other companies, that want to enhance their production efficiency while keeping in line with the stringent standards of the industry.

“Steriline remains committed to developing innovative pharmaceutical packaging solutions,” Federico Fumagalli, Steriline commercial director, said in the press release. “Our aim is to advance the industry by providing more efficient systems that optimize the production process for the greater good.”

Previous Steriline showcases at CPHI have included its RVFCM2, designed to integrate robotics and isolators with a zero-loss philosophy, at the 2023 conference in Barcelona (2). And in 2022 in Frankfurt, Steriline displayed the VCFM100, a vial filling and capping machine under double-wall isolator that had been developed for the purpose of increasing production capacity for a contract development and manufacturing organization that at the time was supplying COVID-19 vaccines throughout the world (3).

The RVFCM11-S will be on display during CPHI Milan at the Steriline stand, located in room A42, Hall 18, according to the press release (1).

1. Steriline. Steriline Unveils New Robotic Vial Filling Machine at CPHI Milan 2024. Press Release. Sept. 2, 2024.
2. Steriline. Robotic Vial Filling and Capping Machine (RVFCM2) Under Isolator. 

, Oct. 9, 2023.
3. Steriline. CPHI Frankfurt 2022: Steriline Leverages on Compactness and Versatility. Press Release. Nov. 1, 2022.

Among the design features of the machine is software-based tracking that is meant to ensure that products that are temperature-sensitive do not exceed their time limit in the solution.

Steriline to Show New Robotic Vial Filling and Capping Machine at CPHI Milan 2024

Mike Hennessy Jr. is the President and CEO of 

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On Aug. 14, 2024, the World Health Organization (WHO) declared mpox (previously called monkeypox) as a public health emergency of international concern (PHEIC) as a result of the increasing rates of infection that are being witnessed in African countries (1). The International Health Regulations Emergency Committee of independent experts had advised WHO on the level of concern about the spread of the virus and the potential for the virus to penetrate other continents.

Two years ago, in July 2022, the multi-country outbreak of mpox was also declared a PHEIC; however, after less than a year, in May 2023, that PHEIC was declared over as a sustained decline in global cases was seen (1). A new virus strain of mpox, clade 1b, has emerged and has been rapidly spreading.

When the first PHEIC was declared for mpox in 2022 for a less deadly strain of the virus, the bio/pharma industry went to bat quickly and utilized experience from the COVID-19 pandemic to work efficiently. One of the main players from the 2022 outbreak, Bavarian Nordic, is proving its worth once again, committing to donate 40,000 doses of its mpox vaccine to the Africa Centers for Disease Control and Prevention (2). “Mpox is spreading at an alarming rate in Africa, calling for further action from the international community,” said Paul Chaplin, president and chief executive officer of Bavarian Nordic, in a press release (2).

The 40,000 vaccines from Bavarian Nordic will form part of a larger donation of 215,000 doses that will be provided by the European Commission’s Health Emergency Preparedness and Response Authority (3). However, many more vaccines will be needed, and WHO has triggered the Emergency-Use Listing process for mpox vaccines and started working with countries and vaccine manufacturers on potential donations (1).

“The emergence of a new clade of mpox, its rapid spread in eastern DRC [Democratic Republic of Congo], and the reporting of cases in several neighbouring countries are very worrying,” warned Dr Tedros Adhanom Ghebreyesus, director-general of WHO, in his PHEIC declaration announcement (1). “On top of outbreaks of other mpox clades in DRC and other countries in Africa, it’s clear that a coordinated international response is needed to stop these outbreaks and save lives.”

1. WHO. WHO Director-General Declares Mpox Outbreak a Public Health Emergency of International Concern. Press Release, Aug. 14, 2024.
2. Bavarian Nordic. Bavarian Nordic Receives Order from HERA and Announces Significant Donation of Vaccines in Response to the Mpox Outbreak in Africa. Press Release, Aug. 13, 2024.
3. EC. Mpox: HERA to Donate Over 215,000 Vaccines to Africa CDC Amid Urgent Outbreak. Press Release, Aug. 14, 2024.

Mike Hennessy Jr is president and CEO of MJH Life Sciences®

When referring to this article, please cite it as Hennessy, M. Responding to Mpox. 

A coordinated and international response is needed to help control the latest mpox outbreak in Africa.

Responding to Mpox

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In 2024, the warmest day in recent history was experienced on Earth, with the daily global average temperature reaching 17.16 °C (1). In fact, over the past 13 months there has been a vast difference in temperature when compared with previous records, which is demonstrating the impact of climate change at an alarming scale.

Trying to stem the impact of global warming is something that is continually being assessed across many global industries, including the bio/pharma industry. Various initiatives and strategies have been put in place, such as 

 (2), aimed at helping economies and society in general become more sustainable. However, according to research, the healthcare sector contributes to 4.4% of global carbon emissions (3).

A report from NIRAS, a global manufacturing consultancy company, has set out a strategic framework for decarbonization and emphasized the importance of ‘future state planning’ for life sciences companies (4). Future state planning is a methodical approach whereby companies start by analyzing current practices in detail to see where change is needed and then develop a framework through which they can measure progress being made while also ensuring accountability.

However, future state planning, as with decarbonization in general, should not just be considered as a singular event, as specified in the report: “Future state planning is not a one-time effort; it is an ongoing process that requires regular review and adjustment […] Embarking on the decarbonization journey is a commitment to transformative change. It is a voyage that requires meticulous planning, steadfast determination, and the agility to adapt to new discoveries and innovations along the way.”

“As the world moves towards a more sustainable future, the process industries must take bold steps to decarbonize their operations,” said Lis Thodberg, sustainability director, NIRAS, in the report (4). “This transition is not just an environmental imperative but also a strategic business move, as stakeholders increasingly value sustainability.”

1. Copernicus. New Record Daily Global Average Temperature Reached in July 2024. News Release, 25 July 2024.
2. EC. COM(2019) 640 Final. Communication from the Commission: 

. Brussels, Belgium (December 2019).
3. Dehipawala, S.; Goldman, E.; Hwang, E.; et al. The Pharmaceutical Industry’s Carbon Footprint and Current Mitigation Strategies: A Literature Review. Poster Presentation at the 2023 ISPOR Annual Conference, Boston, MA, 7–10 May 2023.
4. NIRAS. 

Decarbonisation in the Process Industries: What Can Manufacturers Do Now?

When referring to this article, please cite it as Thomas, F. Strategic Decarbonization. 

Bio/pharma companies should be approaching their decarbonization journey as a strategic business move for the future as industry stakeholders are placing greater value on sustainability.

Strategic Decarbonization

Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Q: We are revising our audits and inspections programs and wanted some advice on best practices. How can we limit the number of on-site audits or inspections?

A: Companies need to find the right balance between the different types of audits, be it a questionnaire, a remote (virtual) or an on-site audit, or a combination of these. A number of reasons have to be taken into consideration, including criticality of the product or service, the feasibility of the type of audit, the regulatory expectations, and others. Here, the company is in charge of the decision making.

This is different in the case of inspections. It is at the discretion of the inspecting authority what type of inspection they will perform. The inspected company can greatly help such an inspection succeed if they are suitably prepared for the various scenarios, especially with regards to remote inspections.

Let us first address the audit program. It is essential to understand that there are fundamental differences between the different types of audits. The following examples shall exemplify this.

A third-party logistics (3PL) company with its own warehouses and fleet of transport vehicles is to be audited. The 3PL fills in a questionnaire sent by the customer. According to the answers, the company is in full compliance with all good distribution practice requirements. The customer decides to perform a virtual audit of the 3PL. This allows for a review of the actual documentation and a virtual site tour. Everything is clean, and there is sufficient space for performing the work. All seems to be fully compliant. However, the customer decides to perform an on-site audit. The documentation is the same; although, it is now possible to have several documents next to each other and cross-reference easily. Importantly, the premises and operations can now be seen firsthand, making it possible to see problems such as cracks in the concrete floor of the warehouse, paint peeling off the wall, insect traps that hadn’t been cleaned for too long, aisles blocked by pallets because there actually isn’t enough space, and electronic access controls being bypassed by doors that were propped open. Just be aware.

In reverse, if you the customer get inspected, you do not want to be the one who isn’t open and honest. You want to present truthfully what you do and how you do it. And this you want to do equally well, whether it is a virtual or an on-site inspection. Plenty has been published about preparing for on-site inspections, and companies are usually well prepared. The issues are still with preparing best for virtual audits. Specifically, can you share all documents electronically, including logbooks or other paper documentation? Can you show live video of all areas without a wobbling (handheld) camera? These are the two most challenging aspects of such inspections.

Updating your audits and inspections program gives you a chance to make sure you are as prepared for inspections as you would want your suppliers to be prepared for your audits.

Siegfried Schmitt is vice president, Technical at Parexel.

Updating your audits and inspections program ensures inspection preparedness, says Siegfried Schmitt, vice president, Technical at Parexel.

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