Susan Haigney

Ask the Expert: Enhancing Out-of-Specification Procedures

Welcome to the Ask the Expert video series. This series is an extension of PharmTech’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. Have a question you would like answered? Send it to 

, and it may appear in a future episode or print column.

Why do pharmaceutical companies continue to receive regulatory observations regarding out-of-specification (OOS) procedures despite clear guidance from regulators?

The issue is rarely the regulatory process itself, but rather how companies apply and interpret it, according to Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel.

A significant challenge is the creation of overly restrictive internal procedures that cause problems with the procedure, such as requiring the original analyst to complete an investigation before taking leave, which results in a delay in the investigation. To move past these bottlenecks, the experts advocate for robust trending instead of treating OOS results as isolated events. Trending helps identify recurring issues with specific methods, personnel, or aging equipment, which is often neglected in budget cycles.

Furthermore, trending should serve as a key performance indicator focused on the quality and timeliness of the investigation, rather than an unrealistic goal of having zero OOS results. Schniepp and Schmitt emphasize that investigations must extend beyond the laboratory. They recommend process mapping the entire chain of events—including sampling, which is frequently performed by manufacturing personnel without sufficient lab or quality assurance department oversight. By performing a risk assessment on the entire process, companies can predict where human error is likely to occur, allowing for faster root cause identification.

For manufacturing environments involving contract partners, it is vital that all parties operate under the same OOS procedure to ensure the integrity of the investigation. The discussion concludes that a robust OOS program requires holistic training for all staff on the entire procedure, combined with electronic systems that provide immediate access to necessary data. By focusing on process transparency and trending, manufacturers can move from reactive troubleshooting to a defensible, controlled operation.

Watch the video above to find out how Schniepp and Schmitt answer the question, “We have routinely gotten regulatory observations on our out-of-specification (OOS) procedure? What can we do to make that procedure more robust?”

Investigating Out-of- Specification (OOS) Test Results for Pharmaceutical Production. Guidance for Industry. 

https://www.fda.gov/media/158416/download

MHRA. Out of Specification Guidance. March 2, 2018. 

https://mhrainspectorate.blog.gov.uk/2018/03/02/out-of-specification-guidance/

Susan J. Schniepp is distinguished fellow at Nelson Labs and a member of 

Siegfried Schmitt, PhD, is vice president, Technical at Parexel and a member of 

Videos

Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, provide advice on creating a robust out-of-specification procedure. 

Patient Access to Radiopharmaceuticals, Part 1

Radiopharmaceuticals merge the precision of targeted therapy with the systemic cytotoxicity of radiation. These products often pair diagnostic and therapeutic functions, facilitating real-time biodistribution assessments and personalized dose optimization through dosimetry, according to Nicholas Richardson, vice president of clinical development at Precision for Medicine.

The primary challenge for manufacturing and supply chain operations is the inherent nature of radioactive decay. The just-in-time delivery moves away from traditional inventory models. Success depends on seamless, rigorous coordination between isotope production facilities, radiolabeling sites, and distribution networks to ensure the therapeutic reaches the clinical site within its strict window of activity.

Infrastructure requirements are also demanding. Manufacturing and clinical sites typically need to have nuclear medicine licensing, specialized radiopharmacy capabilities, and advanced radiation safety infrastructure. Furthermore, the industry currently faces a shortage of trained personnel equipped to handle the complexities of radiopharmaceutical production and administration.

Developers must navigate a very complex regulatory system that integrates traditional drug regulatory frameworks with nuclear and radiation safety oversight. This combination adds significant layers of compliance and operational oversight compared to conventional oncology drug products.

Entering this space requires a robust understanding of nuclear medicine infrastructure and the ability to execute high-precision logistics under tight time constraints. By aligning these technical and operational components, manufacturers can support the delivery of personalized, highly effective treatments to cancer patients.

 interview with Richardson in the above video.

Nicholas Richardson is a hematologist oncologist and vice president of clinical development at Precision for Medicine, an oncology and rare disease-focused contract research organization. Prior to joining Precision, Richardson was formerly at the FDA for nearly 10 years as a prior FDA oncology, deputy director.

Nicholas Richardson, vice president of clinical development at Precision for Medicine, explains why radiopharmaceuticals are unique for patients with cancer and what makes them challenging to develop for those patients. 

Close-up Medical Injector Pens on Conveyor Belt at Modern Pharmaceutical Factory. Insulin Pen on Production Line. Weight Loss Medication Manufacturing. Medical Drug Production Plan. | Image Credit:  ©IM Imagery -stock.adobe.com

Injectable drug products often consist of a vial and syringe product. However, these drugs can also be delivered via a prefilled syringe combination product, which present specific challenges for visual inspection. 

 spoke with Deborah Smook, co-founder and co-owner of TurboFil Packaging Machines, to find out about some of the complications involved in prefilled syringe manufacturing.

PharmTech: How does the viscosity of liquids complicate the filling of prefilled syringes? How does it impact traditional vial/syringe delivery?

 Viscosity tends to complicate a variety of filling and delivery parameters. Depending on the particular viscosity, different methods of filling are necessary—and specific obstacles may arise. These include drips, stringiness, and air bubbles, the latter of which concerns how various viscosities differ in the ways they trap air.

In addition to filling methodologies, viscosity also may necessitate fine-tuning of both equipment and processes. For example, if a product is not only viscous but compressible, the product may ooze from the tip after the syringe and nozzle are separated, requiring pulling back on the plunger to prevent this untenable outcome. A low-viscosity product is more susceptible to leaks during the fill cycle; for that reason, an operator may want to alternate between pumps when switching between low- and high-viscosity liquid products.

Notably, syringes may require additional force at the start of activation—a phenomenon known as breakaway force. This is another reason why exercising the plunger may be recommended at the inception of the filling process.

Which parts of the filling processes are best suited to the addition of artificial intelligence (AI) into automated filling steps?

Obviously, the primary benefit of AI-enabled systems is an abundance of data. But it’s what is done with this depth and breadth of information that is critical.

For equipment operators, AI can pay huge dividends when it comes to predictive maintenance. Increasingly, AI-enabled systems can track not only the quality of products being produced, but also the overall health of the line itself. The goal is to understand not only how and when production goes out of spec, but when an individual production process is trending toward becoming out of spec. This allows for real-time, continuous adjustments that keep product flowing and machines running.

Batch data and changeover assistance are two other areas where AI can bring substantial value. With batch data, it is not a simple matter of ‘the more info the better.’ Rather, it is in choosing from and curating the troves of data systems can generate that make it far easier to identify key performance indicators of not only successive batches but individual items, providing unprecedented actionable insight for engineers and operators alike.

In terms of changeover assistance, one AI-relevant area that is steadily gaining steam is virtual reality-enabled changeover guidance. Such tools amount to interactive instruction manuals that clearly and expediently guide operators through the complicated task of switching between batches and components. This is especially valuable since downtime is frequently the result of human error. A properly executed AI-enabled setup brings the potential to mitigate or eliminate mistakes, optimally tune machines and, ideally, minimize costly machine downtime.

How do supply chain complications impact filling lines (eg, glass and stopper materials, plastics, suspension and other media)?

Prefilled syringes can be composed of exceptionally complicated mechanisms, comprising dozens of individual components. When the reliable supply of any one of these components is threatened or compromised, the result is a ‘weakest link’ scenario that adversely affects the sum of its parts.

For example, there was a recent shortage of pharma-grade glass tubing that created substantial challenges surrounding its procurement. This was a reminder that the issues that thankfully ebbed following the COVID-caused shipping crisis can still resurface at times.

Concerningly, when a manufacturer is planning a new filling line, it may have requirements for specific components that are appropriate in the near-term but unsustainable over the long-term, due to a risk of supply chain delay or disruption. Avoiding such tenuous scenarios requires manufacturers to carefully consider their syringe components from conception, to best ensure those parts are readily and reliably available in an increasingly volatile global trade market.

How do aseptic/sterile manufacturing requirements impact the number of prefilled syringes that can be produced at one time?

Given their reliable revenue streams and comparably robust resources, major manufacturers are accustomed to producing high volumes of prefilled syringes without sacrificing quality control or overlooking aseptic guidelines. It’s the small and medium-sized producers that may experience pitfalls when attempting to maintain output under increasingly stringent sterility requirements.

One issue can become batch size limitations, since routine batch size production for commercial settings must align with the sizes submitted for validation. Here, a smaller manufacturer may not have the initial discretionary capital to invest in sterility solutions like isolators for larger batches. This dearth of resources can inadvertently paint manufacturers into a corner through validated batch sizes that are smaller than they could be. This sort of ‘limitation from conception’ may become more frequent in the short term, as heightened sterility gradually becomes the new norm.

Deborah Smook, co-founder and co-owner of TurboFil Packaging Machines

Deborah Smook is the co-founder and co-owner of TurboFil Packaging Machines, where she oversees all commercial and operational aspects of the business, including sales, marketing, strategic planning and business development. Smook works closely with customers to define practical, compliant solutions for aseptic filling and containment, helping bridge technical requirements with real-world manufacturing and regulatory considerations.

In total, Smook has more than 35 years of experience across the life sciences industry, including leadership roles at True North Partners, Pfizer, and The Wilkerson Group. She earned a bachelor’s degree in electrical engineering from Tufts University, and an MBA from The Wharton School.

TurboFil is dedicated solely to the design and development of liquid filling and assembly machines for the pharmaceutical and medical device segments. The company specializes in designing and constructing bespoke production solutions for challenging applications. It aims to set new benchmarks for filling precision and operational simplicity.

Articles

Prefilled syringe combination products introduce filling and inspection complexities that differ from traditional vial-and-syringe delivery. Liquid viscosity drives selection of fill methods and equipment tuning, with risks including dripping, stringing, bubble entrapment, leakage, and post-fill ooze requiring plunger pullback and attention to breakaway force. Artificial intelligence can convert high-density line data into predictive maintenance, curated batch analytics, and changeover guidance, including VR tools to reduce human-error downtime. Supply chain volatility and aseptic validation constraints can cap scalable batch sizes, especially for smaller manufacturers.

Deborah Smook, co-founder and co-owner of TurboFil Packaging Machines, explains some of the challenges involved with prefilled syringe manufacturing. 

Overcoming Challenges in Prefilled Syringe Manufacturing

PharmTech Weekly Roundup-May 15, 2026

The pharmaceutical landscape is currently defined by three intersecting trends: rapid technological integration on the factory floor, a strategic shift toward globalized development networks, and significant leadership upheaval at the regulatory level. As manufacturing lines adopt advanced automation and AI to meet stricter sterility standards, the industry is simultaneously navigating a period of unprecedented volatility within the FDA. Furthermore, the ongoing challenge of supply chain resilience is forcing a move away from reactive inventory management toward data-driven, clinical-centric strategies.

 resigned following industry pressure, leaving the agency in a state of regulatory flux, underscoring a period of significant turnover and potentially impacting the stability of drug review initiatives. The resignation followed earlier reports that said the 

White House was planning to remove the commissioner.

entered into an agreement this week that highlights the strategic use of China's accelerated development timelines to generate early clinical data and de-risk global drug portfolios.

Manufacturing trends discussed this week include the use of 

, which are increasingly utilizing isolator technology, automation, and AI-driven analytics to enhance sterility assurance and meet stringent global regulatory standards like EU GMP Annex 1.

 by prioritizing proactive communication with health systems and implementing end-to-end inventory visibility tools compatible with hospital automation.

, implementing validated electronic master production records with structured governance is essential for strengthening data integrity and ensuring GMP inspection readiness throughout the manufacturing lifecycle.

focused on clinical criticality and cross-hospital collaboration is necessary to move past reactive hoarding and ensure medications reach the patients who need them most.

These shifts in technology, policy, and supply chain strategy require manufacturers to remain agile and data-focused. For in-depth analysis on any of these topics, please refer to the full reports on PharmTech.com.

This week, the industry saw rapid technological integration on the factory floor, a strategic shift toward globalized development networks, and leadership upheaval at the FDA. 

PharmTech Weekly Roundup-May 8, 2026

This week, the industry saw a push for proactive risk management, the rise of advanced modalities, and the integration of flexible, tech-enabled infrastructure.

Whether it is navigating the complexities of genetic medicines or addressing skilled labor shortages, the industry is moving away from rigid, legacy systems toward modular, automated, and sustainable frameworks. The following stories highlight how the sector is evolving to meet modern clinical and commercial demands.

 of its Indiana manufacturing campus underscores a massive push for domestic capacity in advanced modalities, including genetic medicines and high-volume metabolic treatments for obesity.

 to learn more about IPEC-Americas’ Risk-Based Excipient Framework and the related workshop conducted at Excipient World, which was held from May 4-6 in Nashville this year. The new risk-based framework and decision-tree model from IPEC-Americas aims to streamline the development of new excipients by systematically evaluating safety, quality, and market acceptance risks.

Our coverage of INTERPHEX 2026 continued with interviews on lean and sustainable design, media and buffer strategies, robotics, and modularization.

Leslie Weaver and George Hunt of IPS talked about how integrating “

design for disassembly” and lean principles

 into capital projects allows pharmaceutical manufacturers to build more adaptable, sustainable facilities that can evolve with changing production needs rather than requiring total demolition.

 talked about how bringing media and buffer manufacturing on-site offers CDMOs a strategic way to de-risk supply chains, reduce lead times, and improve sustainability through increased productivity in cell and gene therapy production.

 explained how increasing regulatory expectations are driving the adoption of robotics in aseptic cores to minimize human intervention, thereby reducing contamination risks and improving the efficiency of environmental monitoring.

stressed that modularization and off-site fabrication are becoming essential construction strategies to mitigate the impacts of regional skilled labor shortages and enhance proactive risk management for large-scale pharmaceutical projects.

Dirk Schuster, sales director Pharma at groninger & co. GmbH

, provided his insights on how artificial intelligence is transforming the visual inspection of injectable drugs by linking complex process and image data to detect subtle deviations, particularly in sensitive, high-viscosity biologic formulations.

As this week’s news stories and interviews show, the future of the industry lies in balancing rapid innovation with robust, data-driven controls. By embracing these technological and structural shifts, manufacturers can ensure more reliable, scalable, and compliant pathways to the patient.

Be sure to join us again next week. Thank you for watching.

This week's roundup features coverage from Excipient World and INTERPHEX, including discussions on proactive risk management, the rise of advanced modalities, and the integration of flexible, tech-enabled infrastructure.

Automated pharmaceutical semaglutide ozempic injection pen filling line. Aseptic manufacturing of injectable drug delivery devices, insulin GLP-1 pens. weight loss drug production, medical automation | Image Credit: ©Corona Borealis -stock.adobe.com

Visual inspection of pharmaceutical products is part of quality control and quality assurance. The FDA provides guidance for the development of a risk-based approach to detecting, controlling, and preventing visual particulates in drug products, including injectables.

 Injectable drug products can be the typical vial and syringe products or prefilled syringe combination products. The nature of a combination product; however, creates specific challenges for visual inspection. 

spoke with Dirk Schuster, sales director Pharma at groninger & co. GmbH, to find out more about what goes into visual inspection of prefilled syringes and how artificial intelligence (AI) may be used in the process.

 The viscosity of a drug substance has a direct impact on the entire filling process. While synthetically manufactured small molecules are typically low-viscosity and relatively easy to handle, modern large-molecule drugs, such as biologics, place significantly higher demands on process stability and equipment performance. Highly viscous formulations flow more slowly and are more sensitive to external influences, such as temperature, pressure, shear forces, or pump speed. Filling therefore must be fast, highly precise, and at the same time, particularly gentle to preserve product integrity.

Compared with traditional vial filling—where more robust products and larger fill volumes allow wider process windows—prefilled syringes with high-viscosity products operate within much tighter tolerances. As a result, product requirements directly affect line performance and output, making reliable equipment operation under demanding conditions a key success factor for quality, efficiency, and patient safety.

Which part of the filling processes is best suited to the addition of AI into automated filling steps?

Artificial intelligence delivers the greatest benefit where highly automated filling processes meet complex product and process requirements. This is particularly true in areas where large volumes of process, motion, and image data are generated, such as monitoring filling operations, material handling, or overall machine performance.

In our view, the value of AI lies not in replacing proven automation, but in intelligently analyzing and linking data to identify deviations, trends, or irregularities at an early stage— before they affect product quality or line efficiency. AI can also support operators by improving error detection and root-cause analysis, for example through guided, visualized, and validated format changeovers on advanced filling lines for sterile vials, prefilled syringes, or cartridges.

How do supply chain complications impact filling lines? (eg, glass and stopper materials, plastics, suspension, and other media)

Supply chain disruptions affect fill/finish processes in a fundamentally changed market environment. Historically, filling lines were designed for high volumes of robust formulations, with throughput and efficiency as the primary goals. Today, targeted therapies, biologics, and peptides—often developed as integrated drug-device combinations—are more sensitive, higher in value, and increasingly processed in prefilled syringes or

As a result, variations in glass, stoppers, or pre-sterilized components can no longer be considered in isolation; even minor deviations may significantly impact process stability. For fill/finish equipment, this means traditional compensation mechanisms reach their limits. From a machine builder’s perspective, the focus shifts to designing robust yet flexible systems that can reliably handle material variability without compromising quality or regulatory compliance.

The number of prefilled syringes produced per aseptic manufacturing run depends largely on the characteristics of the product itself. Robust, low-viscosity drug substances allow high output rates even under sterile conditions, as they tolerate wider process windows and deviations.

By contrast, sensitive peptides or biologics require particularly stable and gentle processes due to narrow tolerances, high product value, and sensitivity to mechanical or temporal stress. In such cases, it is not sterility requirements alone but product properties that limit the economically viable batch size.

For the machine builder, this means designing filling systems consistently around the product—for example through highly automated, isolator-based RTU concepts—and defining productivity through reproducible quality, process stability, and long-term controllability rather than speed alone.

Inspection of Injectable Products for Visible Particulates, Guidance for Industry.

. December 2021. Accessed April 29, 2026. https://www.fda.gov/media/154868/download

Dirk Schuster, Sales Director Pharma, groninger & co. GmbH 

Dirk Schuster is sales director Pharma at groninger & co. GmbH as well as a member of the company’s management board. He is responsible for global sales activities in the pharmaceutical sector, with a strong focus on aseptic filling, containment solutions, and fill-finish technologies for complex drug products. With many years of experience in the pharmaceutical machinery industry, Schuster supports pharmaceutical and biotech manufacturers in developing scalable, regulatory-compliant production concepts. His work focuses on aligning customer requirements with long-term, robust filling solutions that address increasing product complexity, automation, and lifecycle considerations.

Visual inspection is integral to parenteral QC/QA, and prefilled syringe combination products introduce distinct inspection and fill/finish constraints. High-viscosity, large-molecule formulations tighten process windows versus traditional vial filling because flow is slower and more sensitive to temperature, pressure, shear, and pump dynamics, necessitating fast yet gentle, highly precise dosing. AI is positioned to add value in data-rich, highly automated operations by correlating process, motion, and image data to detect deviations early and improve root-cause analysis and validated changeovers. Material variability from supply disruptions further stresses stability, shifting equipment design toward robust flexibility.

Visual inspection injectable products may be enhanced by the utilization of AI to analyze and link data to identify deviations, trends, or irregularities.