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Closing the Gap in Modern Process Control and Automation for QC/QA

Drug Digest December 2025

How It Helps Avoid Facility and Equipment Problems

A “Plan, Prevent, Prove” Approach

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

Question mark background | Image Credit: © Leigh-Prather - © Leigh Prather - stock.adobe.com

Q: According to our standard operating procedure (SOP), we perform supplier audits during the selection process and as part of ongoing oversight. Although we try to perform as many of these audits ourselves, we do need to rely on third parties to manage the volume of good manufacturing practice (GMP) audits. Is there an international standard for third-party GMP audits?

A: Interestingly, there isn’t such a standard. There are a large number of articles and presentations freely available on the subject, but these may give you conflicting advice, leaving you perhaps confused. This lack of standardized approach has been realized, and a working group (VDI EE 6306, 3rd Party GMP-Audits) under the auspices of The Association of German Engineers (VDI) was formally established in 2023, with the aim of establishing precisely such a standard. That work has already progressed well, and the document is currently under review by regulators and other interested parties. Its publication in German and English is just a matter of time.

Meanwhile, you could verify that your SOP covers all the key elements relating to audits performed by your third parties, namely:

Contractual agreement: each audit should be covered by a legal contract and a quality agreement (these can be combined in one document). The scope of the audit and the deliverables should be unambiguously described. Very likely, confidential disclosure agreements between all parties will be required.

Auditor qualifications: the competency of the auditor or auditors are decisive for reaching the goals of the audit. The competency assessment should address the technical/scientific knowledge and the social competence (e.g., cultural awareness) of the auditors. Additional requirements apply to audit team leaders. Anyone involved in the audit should certify that they have no conflict of interest.

Types of audits: third parties could be used for on-site, remote, or hybrid audits. Each type should be addressed in the SOP.

Audit preparation: as audits are typically of a very short duration, planning them is of utmost importance. The aims and the scopes of the audits should be fully aligned with the audit approach, the available resources, and the time available for the audit. The agenda should be agreed between all involved parties.

Conducting the audit: most audits follow a standard sequence of opening meeting, site tour, and documentation review, followed by a close-out meeting. Provisions should be made if it becomes necessary to deviate from the agenda for whatever reason.

Audit follow-up: as soon as possible, the third party should provide an update on the audit outcome, whether certain information is still outstanding or if anything else is pending.

Preparing audit reports: Invariably, an audit report is required, and it should follow the style of the contract giver’s documents to achieve consistency.

Audit close-out: in all cases (i.e., whether there were observations during the audit that require follow-up or not), there should be formal close-out of the audit. It has to be clear up to what point in this process the third party has to be involved.

The actual standard will of course provide much more detail on each of these aspects, and it will hopefully provide you with exactly what you need.

Siegfried Schmitt is vice president, Technical, at Parexel.


Vol. 47, Number 11
November 2023
Pages: 42

When referring Schmitt, S. Using a Third Party to Perform Audits. 

Articles

There are key elements that should be covered when dealing with third-party auditors, according to Siegfried Schmitt, vice president, Technical, at Parexel. 

Using a Third Party to Perform Audits

Emerson’s Fisher FIELDVUE DVC7K Digital Valve Controller

Emerson’s Fisher FIELDVUE DVC7K Digital Valve Controller is a new digital valve controller featuring Emerson’s Advice at the Device technology. Digital valve controllers are accessories for control and on-off valves are used to provide local analysis of valve data and digital communications with host systems, as well as other features. These features improve uptime by alerting personnel to developing problems, reducing maintenance costs by providing information required for proactive rather than reactive maintenance, and cutting troubleshooting time in the event of an issue by providing recommended corrective actions.

The DVC7K ‘s Advice at the Device technology contains embedded computing and real-time analytics that convert raw data into information with Bluetooth capability. This allows maintenance personnel to receive data via their phone, tablet, or computer wirelessly without having to be in a control room at the plant location. Information can be accessed wirelessly from one or more digital valve controllers from up to 30 ft, and the local user interface displays detailed information via LEDs.

Fisher FIELDVUE DVC7K combines patented technology with real-time analytics to provide real-time awareness of valve health. 

Digital Valve Controller

Charles Ross & Son Company's PD-40-gallon PowerMix Mixer

ROSS Mixers are high-performance mixers that are designed for durability and efficiency. The company’s original equipment manufacturer (OEM) team has reconditioned ROSS Mixers to restore them to “like new” working condition. These reconditioned mixers are intended to enhance existing equipment or expand production and are designed to perform at the same standard as brand-new equipment while offering cost savings and expedited shipping. Purchasers of the reconditioned machines receive the same standard warranty as a new ROSS Mixer: one year from the date of shipment.

Reconditioned equipment may utilize existing components to minimize waste, without compromising quality and value. A recent example is the pictured ROSS PD-40-gallon PowerMix, recovered through the ROSS Buy Back Program wherein owners sell mixers no longer in use back to ROSS. The PowerMix is a patented hybrid planetary mixer featuring a planetary stirrer blade and a High Speed Disperser, designed for heavy-duty mixing of high viscosity formulations up to 2 million cP. Reconditioning entails a thorough inspection of each part of the mixer, all of which are tested, cleaned, repaired, replaced, repolished, or modified as needed.

ROSS’ reconditioned mixers are restored to “like new” working condition by the ROSS OEM team and are designed to perform at the same standard as brand-new equipment while offering cost savings. 

ROSS Reconditioned Mixers

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

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

Encapsulating active ingredients within microspheres has proven to be an effective approach to drug delivery. Not only does the coating of the API provide protection against degradation, but it is also possible for developers to control the release of the active ingredient over a set amount of time.

A spin-off company from the University of Twente in The Netherlands, IamFluidics, is pioneering a new technology called in-air microfluidics, which is precise and scalable, as well as being more sustainable than traditional microencapsulation approaches. At CPHI Barcelona 2023, 

 spoke with Dr. Tom Kamperman, co-founder and chief technology officer of IamFluidics, to learn more.

“We work on microfluidics, and the microparticles are difficult to see; they are very small,” Kamperman said. “The active ingredients [are] not stable [and so] we want to stabilize them by encapsulating them, creating a protective shell, like wearing a coat.”

However, once the product is administered, the ‘coat’ should come off to allow the functional ingredients to perform their jobs, Kamperman explained. “Basically, that is what we do.”

Microencapsulation can also help formulators to overcome issues such as poor solubility, Kamperman remarked. “Hydrophobic components can be encapsulated in a hydrophilic shell to make them compatible with a hydrophilic base, or vice-versa,” he said.

As an example, Kamperman highlighted a proof of concept with curcumin as a hydrophobic antioxidant. “[Curcumin] is very difficult to solubilize and to put into formulations,” he stressed. “But, when we encapsulate it, [curcumin] can be easily mixed throughout aqueous formulation and also absorption is much better.”

IamFluidics have developed a few products that are ready to be commercialized, but to develop further, the company is seeking out partnerships. “We are looking for partners to further develop and bring to market the air microfluidics technology that we have,” Kamperman confirmed. “It's a microfluidics microencapsulation technology that has a lot of potential and we need people to collaborate with us to make it big.”

IamFluidics was featured at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023. CPHI Barcelona ran from Oct. 24–26, 2023.

Videos

Pharmaceutical Technology Europe® spoke with Dr. Tom Kamperman from IamFluidics, a Dutch high-tech company that develops customized microencapsulation solutions, at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023.

Gently Encapsulating APIs with IamFluidics at CPHI Barcelona

Biologic drug products are becoming ever more present in the development pipeline, with healthy growth anticipated in the sector over the next few years (1). However, delivery of these complex molecules is not always straight-forward; in particular, when trying to deliver high doses of viscous biological drug products, common delivery devices that patients rely on to be able to self-administer their therapies are not always suitable for use.

The issue of delivering high dose, large volume, highly viscous biologics is what Congruence Medical Solutions, a start-up company incorporated in 2015 and based in the United States, specializes in. To learn more about the company and how it is tackling the issue of delivering viscous biologics in high doses, 

 spoke with CEO and founder, Gautam Shetty, at CPHI Barcelona 2023.

"We are a US-based drug delivery device company that’s engaged in the design, development, and supply of innovative drug delivery devices," revealed Shetty. "We work on addressing the unmet needs, emerging needs, and really hard to solve problems in injectable drug delivery."

The company focuses on three key areas: “microliter dosing; injection of high-dose biologics or viscous formulations; and minimizing drug waste at the point of injection,” Shetty added.

Shetty pointed out that some biologics can have a viscosity greater than 1000 centipoises, but despite this, he stated that most biologics can be addressed so long as it is possible to inject at a viscosity of 100 centipoises or lower. “We have worked on applications, maybe, as high as 1500 centipoises,” he specified.

In terms of their approach to drug delivery problems, Shetty pointed out that Congruence Medical Solutions are not the same as traditional drug delivery suppliers. “We really bring something to the table that traditional suppliers of drug delivery devices don’t,” he said. “We often joke that we work on things that other won’t or cannot do.”

Biologics Market Size, Share, and Trends Analysis Report by Source (Microbial, Mammalian), by Product (mAbs, Recombinant Proteins, Antisense, and RNAi), by Disease Category, by Manufacturing, by Region, and Segment Forecasts, 2023–2030. 

Congruence Medical Solutions was featured at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023. CPHI Barcelona ran from Oct. 24–26, 2023.

Pharmaceutical Technology Europe® spoke with Gautam Shetty from Congruence Medical Solutions, a US drug delivery device company, at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023.

Addressing Delivery Needs with Congruence Medical Solutions at CPHI Barcelona

Feliza Mirasol is the science editor for 

® at AAPS PharmSci 360, Sara Fathollahi, PhD, product application specialist, DFE Pharma, gives a summary of the takeaway message from her presentation at the conference.

“My main point … was [about] how excipient suppliers (taking DFE Pharma as an example) can support a smooth transition from batch to continuous manufacturing. I believe that the pharma industry is like a big complex puzzle. Each of us—excipient suppliers, manufacturers, machinery suppliers, universities, research centers—we are pieces of this puzzle, and we are individual pieces, but, together, we make the big, impressive image of innovation,” Fathollahi explains.

In her talk, Fathollahi showed how her company supports its customers by using excipients to de-risk the manufacturing process. “What we do is that we share [internal] … data. We have historical data of all batches that we produce and that support us [in showing] which variation the customer can expect from our material. Then, we can also select batches for them, and with [those] batches—in addition to experiments that they do on their end—they can prove robustness to the regulatory bodies,” she states.

“To give you a more specific example, let's say that the manufacturer received one, five, or ten batches from us; even though, after conducting really complete characteristics on the batches they received from us, thedata that they have [are] limited to those batches. As a supplier, we have historical data, we can really provide much more information and can give insight about which variation can be expected from our product in the next five years, for example,” Fathollahi emphasizes. In addition, DFE Pharma can also select batches that are representative of the variation that can be expected from a specific product, and those batches can be tested by customers.

“This is the way that we … support a smooth transition from batch to continuous manufacturing—by addressing the challenge of raw material variability,” Fathollahi adds.

Fathollahi was featured as a speaker at AAPS PharmSci 360 where she gave her talk, “

Impact of Raw Materials Variation On Continuous Feeders Performance

.” Her presentation centered around gaining a better understanding of the natural batch-to-batch variability of raw materials; understanding the link between raw material variation and the manufacturing process; understanding which variation is present in a given raw material and what that specific variation means for the manufacturing process; assessing the risk of using raw materials (with their natural variation) on process robustness and consistency of the final product; and understanding how to derisk the use of excipients in continuous manufacturing processes.

AAPS PharmSci 360 ran Oct. 22–25 in Orlando, Fl.

redesign concepts for continuous manufacturing

Sara Fathollahi, PhD, product application specialist at DFE Pharma, makes the case of how excipient suppliers can support the transition from batch to continuous manufacturing.

A Look at How Excipient Suppliers Can Support Adoption of Continuous Manufacturing (AAPS PharmSci 360)

® at AAPS PharmSci 360, Sara Fathollahi, PhD, product application specialist, DFE Pharma, discusses one of the major challenges in the adoption of continuous manufacturing: variation in raw materials.

There is variation in raw materials, including both excipients and active pharmaceutical ingredients. Variations can include particle size, white density, etc., and these variations may impact the quality of the final product, Fathollahi states.

“This is very important to consider, and the manufacturers that want to enjoy the benefits of continuous manufacturing, such as faster production, more efficient production, and lower cost, [should] plan to overcome this challenge,” says Fathollahi.

Typically, manufacturers manage this challenge by, first of all, selecting a reliable raw material supplier to ensure consistent delivery of raw material with high quality. “[Manufacturers] work closely with excipient suppliers to understand the variation in their raw materials that they receive from them, and also, in line with what is designed for continuous manufacturing, they assist this variation in what it means for their process and what is the impact on the final product,” she says.

excipient suppliers supporting continuous manufacturing adoption

Sara Fathollahi, PhD, product application specialist at DFE Pharma, discusses a major challenge in the adoption of continuous manufacturing.

The Challenge of Raw Material Variation in Adopting Continuous Manufacturing (AAPS PharmSci 360)

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FDA released a draft guidance on Oct. 25, 2023 explaining the agency’s procedures for how it requests and conducts voluntary remote interactive evaluations at drug manufacturing facilities and facilities that operate under FDA’s Bioresearch Monitoring (BIMO) program. According to the guidance document, the agency may decide to perform remote interactive evaluations based on mission needs and travel limitations. These types of evaluations may be conducted for preapproval inspections; prelicense inspections; postapproval inspections; surveillance inspections; follow-up and compliance inspections; and BIMO inspections.

As part of FDA’s oversight, the agency conducts inspections of FDA-regulated products and manufacturing facilities. The agency may choose to conduct Remote Regulatory Assessments (RRA) before or instead of an onsite facility inspection. “For instance, if a program office determines that an inspection is not necessary, feasible, or practical, FDA may instead conduct an RRA. An RRA is an examination of an FDA-regulated establishment and/or its records, conducted entirely remotely, to evaluate compliance with applicable FDA requirements. RRAs may consist of (or include) a request to conduct voluntary remote interactive evaluations,” the guidance states. The guidance describes remote interactive tools used to conduct RRA evaluations and refers to use of a combination of these tools as a remote interactive evaluation.

According to the document, FDA will use risk management tools to determine if a facility will be participating in a remote interactive evaluation. However, the agency will not be accepting requests from companies asking FDA to perform a remote interactive evaluation. “Such decisions depend on many factors and information not always known to applicants or facilities, and it would be unduly burdensome on all parties to establish a request-based program,” FDA states in the guidance document.

Facilities will be notified by electronic correspondence or a phone call if they are chosen for a remote interactive evaluation and request the company to confirm willingness to participate in the evaluation. The agency will then work with the company to plan and coordinate evaluation activities. “Declining FDA’s request to perform a remote interactive evaluation could impede our ability to make a timely regulatory decision (e.g., regarding adequacy of a clinical trial used in support of a pending application or adequacy of a drug manufacturing operation described in the application),” the agency states in the guidance.

The guidance describes the agency’s procedures for performing remote interactive evaluations at drug manufacturing and bioresearch monitoring facilities. 

FDA Provides Guidance on Remote Facility Evaluations

Excipients are a crucial component of a pharmaceutical finished dosage form, normally providing support to help produce an effective drug product. Galvita AG, a start-up company based in Basel, Switzerland, was founded in 2021 and its COO, Dr. Rainer Schmidt, was on hand at CPHI Barcelona 2023 to provide 

with an overview of the company's offerings.

"Galvita is an excipient manufacturer," explained Schmidt. "We are producing excipients as a platform technology to be loaded with active ingredients."

Schmidt highlighted that the company is working with as many active ingredients as possible, looking to load these ingredients into an orally dispersible tablet (ODT) form. "[These ODTs] are taken by the patient [orally] and disintegrate very fast," he said. "The microcapsules [then stick] onto the mucosa and transport the active ingredient to the body."

According to clinical studies performed by Galvita, Schmidt revealed that the onset of the active ingredients has been shown to be around 10 minutes. "So, [our platform is] very fast acting," Schmidt added. "It's a very nice product to [use to] implement emergency medicine, epilepsy medicines, and any medicine you would like to have."

Schmidt went on to highlight the fact that Galvita can also incorporate poorly soluble compounds within its offerings. "The loading capacity is about 30%, and we are using water solutions and ethanol at the moment, but also isopropanol is possible," he added.

Furthermore, ODTs provide a great option for specific patient-populations, such as geriatrics and pediatrics, Schmidt stated. If the patient has difficulty swallowing, then an ODT enables the patient to simply pop the drug product into their mouth and it can dissolve and administer the drug product. "So, because we do not need so much liquid to disintegrate the tablets, in the end you cannot feel [them] in the mouth," he specified.

Taste-masking is also a possibility, Schmidt confirmed, as the microparticles used "suck in the active ingredient" and protect it. So, Galvita's platform can also taste-mask bitter ingredients, which is again beneficial for pediatric patients, he remarked.

It is also possible to coat the tablets—so, they are no longer ODTs—but within this coated format, Schmidt pointed out that it is possible to transport the tablet to the colon of the patient. "In the colon you can also have these mucosa adhering effects," he said. An option particularly useful for diseases within the stomach-colon area.

"The active ingredients we use are only in combination with inorganic materials," Schmidt summarized. "Our microcapsules are pure tri-calcium phosphate, which is [stable in the mouth] as microparticles … so no problem in terms of toxicological effects."

Galvita AG was featured at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023. CPHI Barcelona ran from Oct. 24–26, 2023. 

Pharmaceutical Technology Europe® spoke with Dr. Rainer Schmidt from Galvita AG, an excipient manufacturer based in Switzerland, at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023.

Producing Excipients as a Platform Technology with Galvita at CPHI Barcelona

Jennifer Markarian is a contributing editor for 

The range of applications for twin-screw extruders as pharmaceutical manufacturing equipment—either as a stand-alone, continuous unit operation or integrated into a continuous manufacturing line—is growing. Hot-melt extrusion (HME), which involves melting and mixing polymeric excipients with APIs in a twin-screw extruder to produce an amorphous solid dispersion, is used commercially in multiple applications, including drug-loaded devices or as a solvent-free alternative to spray drying. Twin-screw granulation (TSG) uses a twin-screw extruder to make granules using dry granulation, wet granulation followed by drying either continuously or in a separate fluid-bed batch process, or melt granulation using a highly viscous binder.TSG was used in early powder-to-tablet continuous manufacturing lines, and commercial use continues to grow. Although direct compression can be used for some formulas in continuous manufacturing lines, TSG is important for others where direct compression isn’t suitable.

“In recent years, TSG processes have been advancing rapidly, particularly towards continuous manufacturing processes becoming standard in the pharmaceutical industry because of the potential benefits TSG offers,” says Hemlata Patil, senior manager for hot melt extrusion technology at Catalent. “Consequently, a thorough understanding of the impact of formulation and process variables on granule quality has become crucial.”

Researchers continue to create new process analytical technology (PAT) for TSG that provides process insight and helps advance the science needed for product and process development using quality by design (QbD). QbD techniques will be especially helpful because the modular design of twin-screw extruders widens the range of possible variables.

“TSG and HME technologies provide a lot of promise for formulations, such as controlled release or poorly soluble drugs,” says Doug Hausner, senior manager of business development for continuous manufacturing at Thermo Fisher Scientific. “There is a large knowledge base in twin-screw granulation, but there is also a large design space. There are many options for screw configuration in the equipment, along with other input variables such as liquid-to-solid ratio. Process design requires know-how as well as statistical analysis for optimization.”

This knowledge is important for both individual and integrated operations. Hausner adds that while Thermo does not currently use TSG or HME in its integrated continuous process for final dosage forms, the continuous manufacturing team provides expertise in feeding and PAT for individual TSG and HME operations. “A multi-step continuous process will require a good stand-alone development activity on the TSG or HME step,” Hausner says.

Patil points out that Catalent can use TSG to create granules with various profiles, such as immediate release, sustained release, delayed release, and taste masking. Twin-screw dry granulation (TSDG) is effective for moisture-sensitive materials and useful for APIs that are not suitable for roller compaction, such as molecules that require higher shear for mixing and agglomeration, she adds. “In addition, TSDG has a unique application for APIs with needle-shaped crystal habit, which have low flow rate and bulk density. These poor physical and mechanical properties make them difficult to process via conventional methods such as roller compaction and slugging. The kneading action of the twin-screw extruder enhances consolidation of powders with needle-shaped API, resulting in better flow and compressibility. For high drug-loading products, this process yields superior granule quality and bulk density.”

TSG is beneficial for both high- and low-dose APIs. “In low-dose products, it is feasible to increase the uniformity by forming granules and preventing demixing,” explains Robin Meier, scientific director at equipment maker L.B. Bohle. In high-dose APIs, TSG offers the ability to improve compressibility. Meier says that a stable and compressible granule can be formed with minimal amounts of binder, in the range of 5%. He reports that compressible granules could be produced with all APIs tested so far on the company’s equipment, once a suitable binder was identified, depending on API solubility, particle size distribution, and partition coefficient.

To build the knowledge base regarding the behavior of materials in twin-screw extrusion equipment, Leistritz Extrusion Technology formed a consortium in 2019 of pharma companies, the University of Texas at Austin, and McMaster University.

“Equipment variables include the ratio of the outer diameter of the screw to the inner diameter, the length-to-diameter ratio, and the screw design,” says Stephen Post, product manager for Life Sciences at Leistritz. “We’re working on gaining more knowledge of the fundamental behaviors of materials and equipment, and we’re looking for trends in material behavior that can be extrapolated to similar formulations.”

For example, consortium researchers have investigated how screw design affects particle size distribution (PSD). Researchers are also performing scale-up experiments to replicate the PSD obtained from an 18-mm diameter screw on a 27-mm diameter screw. Although some drug manufacturers may choose to scale-out by using multiple 18-mm extruders, there are advantages to using a larger extruder to scale-up, such as lower facility footprint and lower utilities cost, explains Post. Better scale-up data are needed, he says.

“We are also developing material-sparing methodologies to assess the feasibility of TSG using various screening tools without running the twin-screw extruder” says Feng Zhang, associate professor in the College of Pharmacy at the University of Texas. “One of the key challenges in TSG is the process-induced chemical degradation and physicochemical transformation during processing.We have developed an in-depth understanding of how these undesired changes can be inhibited via rational selection of formulation composition and process design.”

PAT is being used in TSG processes to measure critical parameters in real-time. Moisture content and PSD, for example, are critical quality attributes (CQAs) of the intermediate product that affect CQAs of the final product.

Near-infrared (NIR) PAT has been evaluated to replace time-consuming loss-on-drying measurements to quantify moisture content in granules, says Patil. “NIR analysis allows for the adjustment of process parameters in real-time, resulting in significantly less material waste and improved process optimization within a shorter timeframe, even during the same extrusion run,” she says.

For PSD, direct imaging is well established, but other PAT types are also being investigated.

“The discrete nature of moving particles makes it harder to understand what’s going on in the machine, because standard monitoring techniques like pressure and temperature monitoring are unreliable as indicators of deviating product specifications,” says Michael Thompson, associate dean and professor of Chemical Engineering at McMaster University, whose research group has studied twin-screw granulation for more than a decade. He adds that while batch granulation often produces a Gaussian PSD, twin-screw granulation typically has a bimodal PSD, which makes real-time analysis even more important. Thompson’s lab has developed an inline particle size analysis PAT using acoustic emissions (AE). The researchers created a digital signal filter to ensure that particles of any size would be represented (1). Next, they created a filter that would also account for inelastic forces by training an artificial intelligence model with an elastoplastic (Walton-Braun) contact force model and a dataset of acoustic emission spectra collected from a broad range of granulated pharmaceutical formulations. The prediction error was as low as 2%, demonstrating its applicability to monitoring particle size distributions in continuous twin-screw granulation (2).“I see the existing optical [imaging] methods and this acoustic method as complementary approaches to particle size analysis,” concludes Thompson. “Both have their strengths and weaknesses in a dusty production environment like the exit chute of a twin-screw granulator.”

In a continuous granulation and drying set-up, such as L.B. Bohle’s QbCon 1, Meier indicates it is most meaningful to measure the residual moisture after the drying process (rather than after granulation) to be able to control and feedback the dryer process parameters. “In this case, we usually apply NIR or microwave resonance measurements. The latter allows univariate calibration,” he says. In the granulation step, Meier explains that solid feeding rate and liquid feeding rate are the crucial parameters used to control mean granule size. He suggests that controlling these rates is more reliable than a method that measures in-line PSD and adjusts liquid addition. Meier reports that the QbCon 1 equipment, as part of a complete continuous manufacturing line, was recently delivered to a large German pharma company for clinical supply of new entities. This line is designed for small-scale throughputs up to 4 kg/h and is capable of handling APIs in occupational exposure band 5.

Twin-screw extrusion aids complex formulation

Researchers at Rutgers University are using a twin-screw extruder as a hot-melt coater and granulator in a unique, patent-pending solution to the ongoing challenge of manufacturing drug products with high doses of poorly soluble APIs. “Poorly soluble drugs are poorly soluble because they dissolve less, but this also is often because they are hydrophobic; they are difficult to wet and so they dissolve more slowly,” says Fernando Muzzio, distinguished professor of Chemical and Biochemical Engineering at Rutgers University. “We solved this problem by using a twin- screw extruder to coat the drug substance particles with a surfactant, which improves solubility. The particles are mixed with a low-melting point surfactant and fed into a twin-screw extruder operating at a temperature low enough to avoid decomposing the API but high enough to partially melt the surfactant and allow it to coat the API particles. The resulting granules flow and compress well, allowing us to make a high-dose (approximately 80% API), immediate release tablet.”

Muzzio says that this twin-screw granulation process is potentially less expensive to operate than more complex processes for high-dose, poorly soluble APIs, such as HME, nanomilling, or spray drying. The innovation is a result of understanding what happens to materials when their surface is modified, combined with an understanding of the twin-screw granulation process that allows accurate control of mechanical and thermal variables, says Muzzio.

Abdulhussain, H.A. and Thompson, M.R. Predicting the Particle Size Distribution in Twin Screw Granulation through Acoustic Emissions. 

Jennifer Markarian is manufacturing reporter for 

As new analytical technologies advance, insight into the twin-screw granulation process is growing.

Featured Content

Pharmaceutical Technology Is Now PharmTech: A Sharper Name for a Smarter Industry

Behind the Headlines Episode 28

Ask the Expert

Drug Digest December 2025

A “Plan, Prevent, Prove” Approach