Improving Aseptic Processing and Manufacturing Needs

Drug Digest

Laboratories are focusing on more automated processes while also trying to maintain quality with each analytical test.

Testing Innovative Analytical Waters

Quality Quartets may be used to achieve knowledge-driven, risk-based approaches to commissioning and qualification that are consistent with ICH Q9(R1) principles.

Quality Quartets in Risk-Based Qualification: ICH Q9(R1) Considerations

The biggest hurdle is developing palatable formulations that are efficacious and patient friendly.

Overcoming Challenges to Formulation Development for Pediatric Medicines

A comprehensive understanding of what makes mRNA vaccines tick is crucial in charting the future of the market.

Charting the Future of Vaccines

Interoperability difficulties resulting from discrepancies in preferred programming languages can be resolved via statistical computing environments.

Exploring the Skills Gap in Statistical Programming Organizations

Drug Solutions

Feliza Mirasol is the science editor for 

On Oct. 2, 2023, Advent International (Advent), a global private equity investor, and Warburg Pincus, a global growth investor, announced that they have completed their previously announced acquisition of Baxter International’s BioPharma Solutions (BPS) business for $4.25 billion in cash, subject to certain closing adjustments.

With the acquisition, the business will now be a standalone contract development and manufacturing organization (CDMO) and will operate under the name Simtra BioPharma Solutions (Simtra). Simtra will continue to offer the same solutions and capabilities that were available under the BPS name to ensure ongoing supply of critical pharmaceutical products worldwide, according to a company press release.

Simtra will continue to operate sterile contract manufacturing solutions, parenteral delivery systems, and customized support services to the pharmaceutical and biotech industries. Under a partnership with Advent and Warburg Pincus, Simtra will become a fully independent, end-to-end CDMO providing a range of services, from clinical development to commercial fill/finish. The team of approximately 1700 employees will also continue to operate manufacturing sites in Bloomington, Ind., and in Halle, Germany. New corporate headquarters will be established in New Jersey.

“I am thrilled to lead Simtra through this exciting time, augmenting the strong legacy that the team has built as part of Baxter,” said Franco Negron, who was announced as CEO of Simtra in August 2023, in the press release. “I look forward to collaborating with Advent and Warburg Pincus—two highly experienced investors within the healthcare space—to continue to grow Simtra’s mission-critical services across a variety of therapeutic areas. I am committed to delivering exceptional quality, service, and technical capabilities for our global customer-base, and am excited to partner with our dedicated Simtra team members as we begin this new chapter.”

“In partnership with Franco, the Simtra leadership team, and Warburg Pincus, we will strive to build on Simtra’s specialized capabilities and drive further product expansion that will ultimately benefit more patients with critical needs,” said John Maldonado, a managing partner at Advent, in the release.

“Simtra is well-positioned to accelerate its go-to-market strategy under the new brand, expand its drug development offering, and execute on capacity expansion,” said TJ Carella, managing director and head of Healthcare at Warburg Pincus, in the release.

Articles

The newly established business under Advent International and Warburg Pincus will be named Simtra BioPharma Solutions.

Advent International, Warburg Pincus Complete $4.25 Billion Acquisition of Baxter’s BioPharma Solutions Business

Chris Spivey is the editorial director of 

Peter Marks, MD, PhD, director, Center for Biologics Evaluation and Research, FDA

It is common knowledge that messenger RNA (mRNA) advances saved lives and limited the extent of the COVID-19 pandemic. Far less recognized, even in the science and technology community, is the decade-long nurture and support governmental organizations provided the mRNA ecosystem and the remarkable range of therapeutic advances that mRNA (and mRNA coupled to other platforms) could solve for, going forward.

On Aug. 23, 2023, the latter was made explicit when, as part of the Biden administration moonshot initiative, the Advanced Research Projects Agency for Health (ARPA-H) announced the launch of “Curing the Uncurable via RNA-Encoded Immunogene Tuning” (CUREIT) project. This effort, led by a team at Emory University in Atlanta, Ga., with up to $24 million in new funding, has the goal of developing “… generalizable mRNA platforms that can be harnessed to train the immune system to more effectively fight cancer, … other applications could extend to autoimmune disorders, transplants, and infectious diseases” (1).

As mRNA and RNA approaches surge in investment dollars and drug candidates moving into clinical trials, the Alliance for mRNA Medicines (AMM), initiated its “DC Day” meetings with a discussion with Peter Marks, MD, PhD, director, Center for Biologics Evaluation and Research, FDA. Top of mind for Marks was the possibility that public and political resistance to advanced therapies could be an obstacle to therapeutic efficacy, saying “We don't want the benefits of mRNA technology wasted due to poor uptake. We need to help people understand how well-established this technology is, and how it is not altering the human genome.”

On the side of production expedience, economics, and workforce efficiencies, Marks avers that, “mRNA vaccines have already shown tremendous capabilities which demonstrate a strong value proposition,” compared to more traditional approaches.

In relation to why there was the need for a new advocacy group, such as AMM, Marks says that while recognizing “When a group such as [AMM] is formed, it floats all boats,” he particularly emphasizes, “it’s very helpful to have a single unified voice to streamline engagement of expert working groups, build consensus, and relay authoritative guidance, fundamental facts (and constraints), to both the general public and also the pertinent governmental agencies. I look forward to regular working discussions with AMM—and other participants—in this field.”

Excellent and exhaustive communication was a hallmark for vaccine strategy during the past pandemic. Taking hard-won lessons forward, groups such as AMM will doubtless play a central role in coordination and consolidation for future efforts. Government agencies such as FDA, the Biomedical Advanced Research and Development Authority, the Office of Science and Technology Policy, and the US Army Medical Research Institute of Infectious Diseases, deserve to take a bow for having helped establish the necessary pre-conditions to allow pharmaceutical sciences to move smoothly between discovery, development, and deployment stages. As for the next generation of life saving medicines, AMM and partners should provide that clear voice to this shared vision for innovative mRNA and RNA therapies.

1. The White House, As Part of President Biden’s Unity Agenda, Biden Cancer Moonshot Announces Launch of ARPA-H’s CUREIT Project Led by Emory University to Develop New Tools to Strengthen the Immune System and Save Lives. Press Release, Aug. 23, 2023.

Government provides a spoonful of sugar, and genuine leadership, for good medicines.

FDA Gets Its Arms Around Advanced Therapy Medicinal Products Early

On Sept. 28, 2023, Sartorius and UK-based startup SPARTA Biodiscovery (SPARTA) announced that they have entered into a partnership for SPARTA’s analysis platform. The platform helps speed the development, manufacture, and quality control of nanoparticles (small polymer or lipid capsules that act as carriers to deliver active agents to target cells) for biopharmaceutical drugs, including gene therapies, vaccines, and cancer drugs.

Under the agreement, Sartorius will invest up to £3.5 million (US$4.3 million) in a minority shareholding in SPARTA through Sartorius Ventures, its corporate investment unit. SPARTA, which was spun off from Imperial College London, developed its core technology, the single particle automated Raman trapping analysis, and developed a prototype for the platform at the college. The technology was established in the group of co-founder Professor Molly Stevens Fellow of the Royal Society, Fellow of the Royal Academy of Engineering. Single particle automated Raman trapping analysis uses spectroscopy to quickly and automatically analyze populations of individual nanoparticles at high throughput. Its mode of action helps accelerate nanoparticle development and optimize quality control during production, according to a company press release.

“The SPARTA platform will help customers optimize the design of nanoparticles at an early stage, even before the drug candidates move on to the clinic. We have teamed up to bring additional product commercialization and application expertise to the table to facilitate a swift transitioning from prototype to launch,” said Oscar-Werner Reif, head of corporate research and chief technology officer at Sartorius, in the press release.

“Often the challenge in bringing new therapies to life is not the development of new active agents, but safe and robust delivery of such agents into the body, e.g., through nanoparticles. We see an unmet need in R&D, manufacturing, and quality control in analyzing the composition of these nanoformulations. Together with Sartorius, we will be able to bring this technology to customers faster,” said Jelle Penders, CEO and co-founder of SPARTA Biodiscovery, in the release.

Under the partnership, Sartorius will leverage SPARTA Biodiscovery’s technology to accelerate development of nanoparticles used for drug delivery.

Sartorius and SPARTA Biodiscovery Partner on Novel Nanoparticle Analysis Platform 

TOP NEWS on grunge world map | Image Credit: © Sean K - stock.adobe.com

On Sept. 27, 2023, Gritstone bio, a clinical-stage biotechnology company, announced it has been awarded a contract by the Biomedical Advanced Research and Development Authority (BARDA) for the randomized Phase IIb study of its self-amplifying mRNA (samRNA) vaccine. The samRNA vaccine contains Spike antigen (similar to first-generation COVID-19 vaccines), as well as other viral targets to defend against COVID-19. The contract, valued at up to $433 million, is part of ‘Project NextGen’, a US Department of Health and Human Services (HHS) initiative that aims to push forward new and innovative vaccines and therapeutics providing larger and more long-lasting defenses for COVID-19.

As agreed upon in the contract, Gritstone bio is set to run a 10,000-participant, randomized Phase IIb double-blinded study that will compare its next-generation COVID-19 vaccine candidate against an approved COVID-19 vaccine. The study will test the immunogenicity, safety, and efficacy of the candidate, and it will be run in the United States alongside the COVID-19 Prevention Network (CoVPN). The CoVPN, which is supported by the National Institute of Allergy and Infectious Diseases (NIAID), is a network of clinical trial sites located at Fred Hutchinson Cancer Center with experience conducting large-scale COVID-19 vaccine trials.

This new vaccine candidate is a part of Gritstone bio’s CORAL program. The CORAL program uses self-amplifying mRNA and novel immunogens containing Spike antigen and additional viral targets to enhance B and T cell immunity. As of the publication of this article, the program has conducted three Phase I trials across a variety of patient populations and settings, including vaccine-naïve healthy and HIV+ subjects in South Africa, and healthy volunteers after primary series of approved COVID-19 vaccines. The results of these studies have showed high neutralizing antibody levels for at least six months and wide T cell responses. The CORAL program is supported by BARDA, NIAID, the Coalition for Epidemic Preparedness Innovations, and the Bill & Melinda Gates Foundation.

samRNA is a quickly emerging platform technology that can be used to develop multiple vaccines by changing the sequence of the antigen encoded in the vector RNA and delivered in a lipid nanoparticle. samRNA vaccines, much like traditional mRNA vaccines, use the translation system of the host to change mRNA to protein target antigens, encouraging immunity. But unlike mRNA, samRNA makes multiple copies of the antigen RNA once in the cell, which can lead to longer and amplified antigen expression.

The contract is part of US Department of Health and Human Services’ ‘Project NextGen’ initiative, aimed at pushing forward new and stronger COVID-19 vaccines and therapies.

BARDA Awards Gritstone bio $433 Million Contract for Phase IIb Study of Next-Gen COVID-19 Vaccine

Editor of Pharmaceutical Technology Europe

Developing the ideal dosage form for pharmaceutical products has long been a priority for drug companies. A poor dosage form decision can lead to costly commercial errors and potentially low medication adherence by patients—an aspect that can be particularly important in the rising numbers of chronically ill patients. Not only should consideration be made to the therapeutic characteristics and potential manufacturability of the finished drug product; but also, whether the dosage form will ultimately be patient-centric and, hence, ensure optimum adherence of a treatment regimen.

“Drug dosage forms have evolved in recent years due to several factors, including the growing demand for custom drug delivery solutions, the increasing complexity of new therapeutic entities (NTEs) entering the development pipeline, and the aggressive competition in the pharmaceutical market,” reveals Ishani Maharaj, Application Development Specialist, Pharma Ingredients, Univar Solutions. “While oral solid dose (OSD) forms remain the preferred choice due to convenience and cost-effectiveness, applying innovative delivery approaches is essential to meet the unique needs of the target patient population.”

“The pharmaceutical sector is propelled by radical innovations, accelerating the pace of the therapeutic process achieving the transformative shift from life science to healthcare. From personalized medicine, advanced nanotechnology to sustainable formulations, 3D printing, combination therapy, and smart drug delivery, the landscape is undergoing a profound transformation,” asserts Jnanadeva Bhat, vice president, head—Formulation R&D at ACG-Worldwide. “The growing attention to rare diseases has catalyzed a revolution in the field of drug development, reflecting the industry’s responsiveness to unmet medical needs while setting the stage for pioneering advancements.”

In concurrence, Filipe Gaspar, vice president of Technology Intensification at Hovione highlights the growing proportion of orphan drugs—and the need for leaner and accelerated drug development paths along with it—as an important trend. “The change from large volume to small volume drugs, namely by the increased prevalence of rare/orphan drugs and precision medicine, is driving substantial changes in the pharma industry and driving innovation in many areas such as drug discovery, clinical design, supply chain management, development, and regulatory paths,” he says. “A very lean, API-sparing, and accelerated CMC [chemistry, manufacturing, and controls] development approach becomes critical to prevent being the bottleneck in drug approval.”

Therefore, Gaspar continues, continuous manufacturing is being more widely adopted as it provides a more streamlined approach, avoids the need for scale-up, and facilitates debottlenecking pharmaceutical development. However, he warns that despite the advantages brought about by transitioning from batch to continuous manufacturing, there are also challenges, such as a lack of access to continuous manufacturing technology for smaller pharma companies and biotech companies.

“Most small pharma and biotech [companies] do not have [continuous manufacturing technology] as a captive technology and the limited CDMO [contract manufacturing and development organization] network is still developing the expertise and expanding their capacity,” Gaspar adds. “By relying on batch processes, these innovators may incur on additional development costs and, most importantly, delay their drugs to market, sometimes many months, which can be critical to success of many drugs.”

Focusing on manufacturing, Lisa Caralli, senior director, Scientific Advisory, Catalent, raised the matter of spray drying for biologics as an efficient and scalable alternative to the traditional lyophilization technique. “The use of more modern techniques such as spray drying has been investigated as a way to formulate lipid nanoparticles with biologic payloads into a dry powder for oral delivery, as well as optimizing particle attributes for inhalation. While additional research is still needed to validate these approaches, they represent true innovation with a potential high impact for patients,” she says.

For Arnaud Verhaeghe, marketing director Pharma Oral Dosage at Roquette, the most influential trend over recent years has been the expanded focus on patient-centricity. “This [trend] has manifested itself in producers putting user needs first—devising innovative ways to help patients start and adhere to treatments,” he explains. “The popularization of dosage forms like functional gummies and jellies, orodispersible powders and tablets, orally administered vaccines, and more is the best example of this attitudinal shift in action.”

Additionally, Verhaeghe notes that due to the fact the success of such oral dosage forms, as mentioned earlier, hinges on a pleasant taste and texture, there have been good strides forward in the field of taste-masking as well.

“Continuous improvement in elevating traditional dosage forms to increase therapeutic efficacy, improve patient compliance, and enable more patient-centric options are becoming more practical with advanced technologies, innovative medical device designs, and new functional excipients,” Maharaj specifies. “From a formulator’s perspective, tablets and capsules are tunable and can achieve different release profiles, including immediate or modified release, fixed-dose combinations (FDCs), orally disintegrating tablets (ODTs), and other types of release profiles. This [flexibility] creates a lot of opportunity to develop oral dosage forms that are adapted for certain patient groups. ODTs have gained significant traction as they eliminate the need to swallow a pill and offer ease-of-use for the elderly and pediatric population.”

Commenting further on FDCs, Uwe Hanenberg, head of Product Development in Oral Solid Dose, Recipharm, iterates that this dosage form option has gained substantial popularity in recent times. “These formulations combine multiple APIs into a single dosage form, often utilizing advanced modified-release technologies,” he says. “By controlling the release of each API into the bloodstream, these combinations minimize side effects and extend the therapeutic effect in patients—reducing the number of daily doses required, which minimizes patient burden and enhances patient compliance with therapy.”

“The growing interest in oral medication has highlighted the importance of both personalized medication and FDC therapies as influential trends in the development of drug dosage forms,” confirms Manali Dalvi, lead white paper and articles at ACG-Worldwide. “[Additionally], FDC has provided the option to develop potential proprietary drugs, which offer greater savings compared to the NCE or their generic version. This strategic approach not only provides manufacturers with reinforced intellectual property support but also empowers them to prolong their market exclusivity.”

Repurposing existing active ingredients can also be leveraged to improve patient-centricity is enabled by FDA’s 505(b)(2) pathway, remarks Nick DiFranco, MEM, Global Market Manager, Oral Drug Delivery, Lubrizol. “The 505(b)(2) pathway accelerates drug product development by allowing companies to leverage the existing safety/toxicity data of a drug when developing improved formulations or changing dosage forms. This might include developing extended-release formulations that reduce the pill burden on a patient or creating smaller-sized tablets or granules that can be dosed directly for either a child or geriatric patient with difficulty swallowing,” he says. “Alternatively, it could be creating a long-acting injectable or utilizing altnernative excipients with reduced side effects. Particularly for poorly soluble APIs, the desire for patented formulations and advancements in delivery technologies, create opportunities for differentiated and optimized dosage forms.”

The movement of the industry toward a more patient-centric model has been key in driving innovation in dosage form design, stresses Caralli. “However, as a formulator, this puts a spotlight on bioavailability enhancing formulations, which often need to do more than improving aqueous solubility,” she states.

Overcoming solubility and bioavailability issues

“Approximately 60% of APIs under development, and more than 40% of those in reformulation, are poorly water soluble—meaning the pipeline is full of insoluble drug products,” emphasizes DiFranco. “If we want to continue bringing small molecules to market, we need new tools for formulation because traditional excipients aren’t always going to yield viable products. This is especially true in the oncology field, where the pipeline comprises many challenging classes of APIs, such as proteolysis-targeting chimeras (PROTACs).”

Ramesh Subramanian, chief commercial officer, Aragen Life Sciences, points to the investments being made into the development of novel drug delivery systems, such as liposomes, nanoparticles, and microspheres. “These systems help overcome the challenges of drug solubility, bioavailability, and targeted delivery, improving therapeutic outcomes,” he adds.

In Gaspar’s experience, amorphous solid dispersions (ASDs) are becoming the predominant platform to overcome poor bioavailability, leveraged by spray drying. “In turn, this has led to significant advances on the formulation of amorphous materials, namely in material and analytical sciences, the development of novel (sometimes enabling) excipients, and the need for appropriately formulated dosage forms,” he says.

“More lipid-based delivery solutions, solubility, and permeability increasing excipients are coming onto the market to enable formulators to improve the solubility profile of those lipophilic, hard-to-formulate APIs within an oral dosage form,” notes Maharaj. “This [market dynamic] alleviates numerous challenges with formulating Class II/IV drugs, resulting in increased therapeutic efficacy, but improved manufacturing efficiency, shortened development timelines, and reduced overall costs.”

Another option to help overcome bioavailability is nasal administration, Maharaj continues. “Nasal dosage forms such as nasal sprays, powders, suspensions, and gels have been on the market for years. However, this dosage form type can offer an ideal route and improved bioavailability for some drug types, particularly for central nervous system disorders. This offers immense potential for nasal dosage forms with innovation focused on delivery devices,” she states. “Excipient and process selection to produce the desired API particle size is critical for optimal deposition and absorption via the nasal cavity route.”

“The rise of biopharmaceuticals and biosimilars has led to innovations in formulation development,” specifies Subramanian. “These complex molecules require specialized formulations to maintain stability and ensure consistent therapeutic performance.”

Growth within the biologics sector is expected to continue at an impressive rate, which, according to Hanenberg has also spurred further advancements in OSD technology. “Although biologics have traditionally been administered parenterally due to the sensitive nature of their active ingredients, recent development work on some of these molecules, such as insulin, has allowed them to be formulated for oral delivery,” he says. “This shift enhances patient centricity by offering the convenience of OSD while introducing new formulation challenges for large-molecule drugs. As a result, we can expect more developers to turn their attention to such advancements in drug delivery.”

The notable shift in industry’s focus toward the development of protein and RNA therapies has been apparent over recent years, Caralli adds. “The investigation of nanoparticle delivery exploded after the COVID-19 pandemic: one such method involves using nanoparticles to deliver mRNA vaccines via the gastrointestinal tract, as researched by Robert Langer and his team at the Massachusetts Institute of Technology (1). These vaccines would not be constrained by the cold-chain restrictions of the injectable versions, allowing for the easier distribution of drugs to developing countries and rural areas,” she remarks.

Orally administered and other non-parenteral vaccines are great examples of ways in which patient compliance can be improved by pharma companies, stresses Verhaeghe. “Not only do these dosage forms remove the meticulous cold chain required for the use of liquid biologics—making them less susceptible to supply chain disruption—but they have been shown to be more attractive to patients, not least because of the elimination of off-putting needles.”

It is estimated that one in six people will be over the age of 60 years by 2030 (2), meaning that there will be a greater proportion of patients who may have difficulties with dexterity and swallowing, asserts Hanenberg. “OSD developers will have to reformulate their drugs to cater to these evolving patient needs, designing their tablets to be smaller and easier to swallow and packaging to be more accessible. They must also consider the needs of pediatric patients, catering their administration to counter bitter-tasting medicines with more palatable flavors and mouthfeel,” he says.

Assessment of whether or not a dosage form is appealing and satisfactory to the target patient population impacts drug adherence, which is just as important as ensuring the right excipients for the active are selected to facilitate optimal drug delivery and product stability, Maharaj confirms. “Patient-centricity is a trend that will continue to be a key driver in developing novel drug dosage forms in the future,” she emphasizes.

“The industry has witnessed a remarkable evolution in drug dosage forms, driven by a convergence of scientific breakthroughs, patient-centric approaches, and regulatory incentives,” concludes Bhat. “As we stand at the intersection of innovation and healthcare, it has become exciting to delve into the trends that are shaping the future of drug delivery.”

1. Kim, H.; Kirtane, A.R.; Kim, N.Y.; et al. Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles. 


Vol. 47, No. 10
October 2023
Pages: 12–16

When referring to this article, please cite it as Thomas, F. Driving Dosage Form Developments. 

Dosage forms are being shaped by numerous factors, with patient-centricity continuing to be an important driver of decisions in development.

Driving Dosage Form Developments

Emma Ramnarine, PhD, is Executive Director, Product Management & Development Operations, US Biopharma Operations at Boehringer Ingelheim Fremont, Inc.

woods block step on table with icon Action plan, Goal and target, success and business target concept, project management, company strategy | ©Smile Studio AP - stock.adobe.com

Control is the ability to direct, regulate, limit, or manage something. For a pharmaceutical product, that something is product quality. It is essential that the required quality of a pharmaceutical product is clearly specified and produced consistently for every unit of medicine, in every single batch manufactured.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) defines product lifecycle as “All phases in the life of a product from the initial development through marketing until the product’s discontinuation,” in ICH Q8(R2), Pharmaceutical Development (1), and laid out the following three primary objectives throughout the product lifecycle in ICH Q10, Pharmaceutical Quality System (2):

Achieve product realization (i.e., deliver products with the quality attributes appropriate to meet the needs of patients, health care professionals, regulatory authorities, and internal customers).

Establish and maintain a state of control (i.e., use effective monitoring and control systems for process performance and product quality, thereby providing
assurance of continued suitability and capability of processes).

Drive continual improvement (i.e., implement appropriate product quality and process improvements, variability reduction, innovations and PQS enhancements, thereby increasing the ability to fulfill quality needs consistently).

The concept of product lifecycle management implies that it is dynamic and must be directed, regulated, and managed—or in other words—controlled as product and process understanding (knowledge) evolves. This is illustrated in 

 and explained further in the sections that follow.

 The life of a product is dynamic. (Figure courtesy of the author)

A control strategy is expected to provide the overall basis for consistently directing and managing key elements necessary to deliver the specified and required quality of a product. These elements are not only directly related to the product, but also have important interdependencies with enabling infrastructure (i.e., facilities, equipment, materials, processes, test methods, and monitoring) for manufacturing, testing, and managing the product.

Quality risk management and knowledge management provide the backbone for designing, managing, and sustaining all elements of a control strategy, and thereby the lifecycle of a product. Hence ICH Q10 refers to quality risk management and knowledge management as enablers (i.e., “processes that provide the means to achieve an objective” [2]), the objective being consistently producing a product of the required quality.

The concepts of product lifecycle, control strategy, risk management, and knowledge management have been around for almost two decades; yet it remains unclear how these might be practically connected, implemented, and sustained all through the dynamic life of a product, such that they provide the foundational bedrock for achieving the objectives laid out in ICH Q10.

This paper posits that a control strategy provides a practical framework for evidence-based risk management and knowledge management throughout a product’s lifecycle. The paper discusses what a control strategy is, including its components, why it is important to start its design during the first stage of the product lifecycle (pharmaceutical development), how it should evolve during the next stages of the lifecycle (technology transfer and commercial manufacturing), what does a control strategy look like for outsourced operations (i.e., contract development and manufacturing), how the control strategy can provide a feedback and feedforward mechanism for knowledge and risk-informed decisions, and, finally, how to manage the control strategy through a cGMP-compliant pharmaceutical quality system (PQS) in order to keep it “living”.

When established in such a manner, the practical framework of a control strategy can become the basis to maintain a state of control while driving continual improvement for any product through all stages of its lifecycle and maintain sustainable compliance.

Knowledge and risk tend to have an inverse relationship—as knowledge increases, it serves to reduce the level of uncertainty and unknowns, thereby reducing risk. Lipa, O’Donnell, and Greene developed a simple framework called the Risk-Knowledge Infinity (RKI) Cycle to link risk and knowledge, show how knowledge is both an input to and output from risk management, and illustrate how maximizing use of knowledge minimizes risk (3, 4).

An important goal of product lifecycle management is using the growing product and process knowledge (as a product moves from development to commercial manufacturing) to reduce risks to product quality and/or patient safety. Conversely, emergence of any new risks in the commercial manufacturing or technology transfer stages that were not known during product development add to the knowledge base and product understanding. This growing knowledge base allows risk-based and/or risk-informed decisions to be more data and evidence- based. The risk-knowledge flow dynamic is indeed an infinity cycle all through the product lifecycle and should be managed as such.

But how does one do this when knowledge and risks are dispersed and constantly evolving over drug substance, excipients, intermediates, container closure systems, and drug product operations? All these pieces that collectively constitute the “product and process understanding” for a product, should be available within a company’s PQS. But what can serve as a “hub” (i.e., an effective center of an activity or a network) to enable this dynamic flow between risk, knowledge, and lifecycle activities for a product?

A control strategy should function as a “hub” for the network of controls for a product

 Good manufacturing practices (GMPs) for pharmaceutical manufacturing are legally binding in most countries. However, while GMPs provide the foundation for producing quality product by assuring appropriate management of risks throughout the the product lifecycle, there has been recognition that further definition of approaches that optimize operational excellence in pharmaceutical manufacturing would be beneficial.

Over the past two decades, the ICH guidance documents—ICH Q8(R2), 

Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Managemen

t—while not legally binding, have introduced concepts that enhance assurance of GMP compliance and are necessary for producing quality product all through its lifecycle and achieving quality excellence in pharmaceutical manufacturing. Some key concepts introduced by the ICH guidance documents include product lifecycle management, pharmaceutical quality system, quality risk management, knowledge management, product and process understanding, design space, continual improvement (of process performance and product quality), and control strategy (1, 2, 5–7). The ICH guidance documents are integrative and have built upon each other in referencing these concepts as relevant.

Nevertheless, it is also important to acknowledge that practically connecting the implementation of all these concepts in product management, quality management, and manufacturing operations is not straightforward. In fact, there is limited guidance on how to implement all of these related concepts in an integrated manner for a single product, let alone to optimize sharing and use of knowledge across multiple products. ICH Q8(R2) is clear in that, while defining the design space for a product is optional, a control strategy is not.

Elaborating upon the concept of a control strategy, this paper focuses on how it can function as a powerful “hub” for product lifecycle management, risk management, product/process understanding and knowledge management, and continual improvement. The control strategy can function as this “hub” if one were to think of it as a core part of the nerve center that consolidates the set of controls that are necessary to consistently produce quality product.

Basics of a control strategy and how it can be a powerful “hub” for the entire set of product controls. ICH Q10 defines a control strategy as, “a planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control” (2).

So, a control strategy is not just end-product testing and specifications. The ICH Q10 definition is more encompassing and includes product-specific elements (drug substance, drug product, materials, components, in-process controls, product specifications, testing, monitoring) and non-product specific elements (facilities, equipment). Every product and process should have a control strategy including some site-specific aspects (e.g., multi-product cross-contamination facility, utilities, and environmental controls). It is important to note that a control strategy is essential, but it is not the only aspect necessary for a product batch release decision.

 was developed to pictorially depict the elements and objectives of a control strategy making it a “hub” for the consolidated set of controls necessary to consistently produce quality product.

 Objectives and elements of a control strategy. (Figure courtesy of the author)

The author’s choice of the term “hub” is deliberate in that:

A control strategy should not be thought of as a single document that lives within the PQS and contains all the relevant knowledge for a product. That would not be practically achievable simply given the dynamic nature of each of the elements and the growing volume of knowledge as a product moves through its lifecycle. An overall product control strategy is built from several different control strategies all working together to produce and manage the product in a state of control (e.g., control strategies for each unit operation, analytical testing control strategy, cross-contamination control strategy, monitoring strategy, raw materials control strategy, environmental control strategy, cleaning control strategy, microbial control strategy, etc.). It can be easier if conceptualized electronically, with each control strategy element being a distinct virtual e-document, and the consolidated set of e-documents form the control strategy “package” for a product. An example of a possible document architecture/package that can constitute a control strategy are provided in 

Each control strategy (consolidated set of controls for a product) provides a framework that allows it to serve as a feedback-feedforward nerve center or “controls hub” for effective risk-knowledge flow across the various constituent elements—all with the sole purpose of consistently producing quality product.

Such a consolidated mapping of all documents that constitute a control strategy for a product, as shown in 

, would be practically useful for timely product lifecycle management, knowledge management, and risk management. It is also important to note that not all elements of a control strategy may appear in a standard or common way across different products, even if the products might have some shared platform-based aspects. It is entirely possible to use different approaches to build a control strategy. For example, a control strategy with real-time release testing (RTRT) or process analytical technology (PAT) for a tablet will likely look quite different in terms of testing, monitoring, process parameters, and equipment controls compared to the control strategy for a tablet with conventional end-product testing. The result in terms of product quality may be exactly the same, though, for both tablets with their respective control strategies. This underscores the importance of strong product and process understanding, knowledge management, and risk management when designing, maintaining an optimal control strategy for a product, and continually improving it throughout the product’s commercial life.

 Example of possible documents architecture/package for a control strategy. (QTPP is quality target product profile. CQA is critical quality attribute. CPP is critical process parameter. DS is drug substance. DP is drup product. QA is quality attribute. SOP is standard operating procedure.) (Figure courtesy of the author)

Product-specific elements of a control strategy.

 The pharmaceutical development of every product starts with prospectively defining the quality characteristics of the product that should be achieved to ensure the desired quality, safety, and efficacy; this is the starting point noted in 

. Aspects such as the intended use, route of administration, dosage form, strength, bioavailability, stability, etc. are considered. This summary of the desired quality characteristics for a product is known as the quality target product profile (QTPP) (1).

Product and process knowledge and understanding to achieve the desired QTPP—in terms of identifying, understanding, and adequately controlling relevant attributes (for drug substance and drug product materials and components)—starts being built from early on during pharmaceutical development. It continues to grow as more experience is gained through technology transfers and commercial manufacturing, as illustrated in 

All quality attributes (QA) of a product are desired, but not all are critical. Understanding the knowledge and risks associated with each QA helps determine its criticality to product safety and/or efficacy, and thereby the level of control necessary for that QA. A critical quality attribute (CQA) is “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality” (1). During development, it is expected that CQAs for the drug substance, excipients, any intermediates, and drug product are identified; a risk assessment is useful for this purpose. As an example, a risk assessment that ranks impact to safety/efficacy and uncertainty in terms of available data/knowledge can be used to relatively rank severity of each QA from most to least critical. The lesser the data and knowledge on a QA initially during development, the higher the risk associated with it. This should guide development studies to generate data and better understanding of the less-understood QAs. It is quite common for QAs with low understanding to be initially categorized as preliminary CQAs and be changed to non-CQAs when enough data has been accumulated to provide the supporting evidence for their recategorization. Several QAs require mandatory testing per regulatory requirements; these should be considered as CQAs by default.

Once identified, it is essential that limits, ranges, acceptance criteria, and/or tests for the CQAs are developed, well-understood, and controlled for the product. The other non-CQAs or less critical QAs can be evaluated too, just less frequently. Development studies are designed to generate knowledge on how to deliver the CQAs, what are suitable ranges for each CQA, what and how to design the process to best control each CQA within the appropriate ranges. It is also important to show clear relationships and linkages between a QA/CQA and the control strategy (e.g., characterization, comparability testing, process validation, in-process control, lot release testing, stability testing, monitoring, etc.). This becomes the starting point for the product related elements of an initial control strategy.

As mentioned earlier in this article, there might be various possible approaches for the design of a control strategy. Modeling different control strategies during development can provide useful knowledge on which approach might provide the most comprehensive controls coverage for a product.

trol strategy. Non-product specific elements of a control strategy involve aspects such as facility, utilities, equipment, cross-contamination controls, cleaning, general (non-product specific) microbial controls, general (non-product specific) analytical test methods, etc. These are applicable across products and are not unique to any one product. Risk assessments form the basis for identifying, assessing, and controlling risks that can impact product quality and/or patient safety. It may often not be straightforward to directly link non-product specific risks to each product, yet without assessing, controlling, and managing them, it is not possible to assure consistent delivery of quality product.

The non-product specific control strategy elements are mostly associated with a manufacturing facility, and are applicable regardless of product. They can be developed independent of the product-specific control strategy elements. A determination should be made for each manufacturing facility and general analytical testing controls on what non-product specific elements are important to control. Appropriate risk assessments should be used, and data generated even for these non-product specific elements, to guide the development of relevant control strategies (e.g., cleaning control, microbial control, facility and environmental control, cross-contamination control [for multi-product facilities], etc.).

To elaborate further upon this point, the following specific example would be useful. Most manufacturing facilities tend to be multi-product, and it is essential to avoid cross-contamination between products due to facility layout aspects, personnel, material, equipment and waste flows, common utilities and environment, shared areas, tools, instruments, consumables and supplies, etc. During the technology transfer of a new product into a multi-product facility, any risks specific to product and process fit in the new facility, cleaning, product-specific unit operations or equipment, analytical testing, etc. are assessed and mitigated as part of the transfer. However, all potential avenues of cross-contamination may not be comprehensively assessed for each new product introduction into a multi-product facility. Therefore, it is highly recommended that a multi-product cross-contamination risk assessment be performed and a cross-contamination control strategy be established. Each time a new product is introduced into the facility, it should be evaluated against the cross-contamination control strategy to identify and manage any new risks that might be introduced by the new product to other products in the facility, or vice-versa.

Control strategy for outsourced operations. It has become increasingly common for companies to outsource development, manufacturing, and/or testing operations to contract development and manufacturing organizations (CDMOs) or contract laboratory organizations (CLOs). The accountability for the product license and, therefore, product quality (and safety and efficacy), remains with the marketing authorization holder (MAH), even when aspects of product development, manufacturing and/or testing are outsourced to a CDMO or CLO at any stage of the product lifecycle.

The CDMO and/or CLO become responsible for those elements of the control strategy that are a part of the operations outsourced to them, whereas the rest of the control strategy elements may remain within the purview of the MAH. In such instances of outsourced operations, the MAH and CDMO/CLO should partner closely in developing, updating, and managing the elements of the control strategy that are within their respective scopes of work. Having said that, the MAH remains ultimately accountable for the product and therefore, the consolidated set of controls that form the control strategy for a product, even when the elements of the control strategy are fragmented between the CDMO/CLO and the MAH. This is why it is essential that outsourced operations are set up and managed as open transparent partnerships (as opposed to fee-for-service contractual relationships) between the CDMO/CLO and MAH in terms of timely interactions, communications, and decision-making when it comes to assuring product quality and availability.

The following example illustrates how the different control strategy elements may be fragmented between a CDMO/CLO and MAH and how it would need to be managed.

 Product and process development are performed by the MAH; product is manufactured by a CDMO; analytical method development, validation, and testing is performed by a CLO; final product release is performed by the MAH. In this example:

Development, design, and validation knowledge of the product and process, and, therefore, the product-specific elements of the control strategy, reside with the MAH.

The unit operations, and non-product specific elements of the control strategy (e.g., facility, equipment, utilities, multi-product
controls, cleaning, etc.) are owned by the CDMO.

The analytical testing control strategy elements are owned by the CLO.

The annual product review, monitoring, and overall product management is owned by the MAH, with the CDMO and CLO providing input into it from their respective control strategy elements.

As noted, overall, the MAH remains accountable for product quality, safety, efficacy, and availability. However, all three players—MAH, CDMO, and CLO—need to manage the risk-knowledge dynamic not only within the scope of their respective control strategy elements, but they also need to effectively manage this dynamic between and across their relevant control strategy elements, for instance, when a change is made, or a deviation or trend is observed. This is because the different elements of the control strategy tend to be inter-connected and an impact on one aspect of the control strategy may have an
influence on others.

The control strategy is inherently a risk management and knowledge management strategy

In addition to knowledge being developed through development studies, good risk management based on available knowledge along each step of process development is important for guiding development studies. This is a direct practical application of the RKI Cycle—the level of uncertainty and/or knowledge on a QA determines the level of risk—this helps determine the studies needed to fill the knowledge/understanding gaps and to determine if a QA is critical as a CQA or not—which then helps identify suitable process and/or testing controls for the CQA in order to reduce the risk/ impact to product quality—and the risk-knowledge cycle continues throughout the development stage. Thus, fundamental risk management and knowledge management collectively drive the build-up of data and risk-informed product and process understanding to ensure the design and optimization of a robust manufacturing process with well-defined controls that can consistently deliver product with the desired quality (including safety and efficacy).

The objective of process design is to define a commercial process that can consistently deliver safe, efficacious product that has all the required quality attributes. The expected output is a control strategy in addition to master production and control records.

 provides an example of a structured risk-based approach and successfully implemented to establish the product-related elements of a control strategy. Once the QTPP is defined, a risk-based approach can help determine which QAs are critical to product quality (i.e., CQAs) vs. not. As process understanding is gained through development studies, the ability of the process to control a CQA determines how best to control it. For CQAs associated with high and/or medium process impact, in-process control or release testing would provide the best assurance of control. For some QAs associated with medium- or low-process impact, monitoring the attributes, independent of batch release, could provide the appropriate level of control. Finally, for non-CQAs with low criticality, no testing is necessary. The interplay between knowledge and risk is evident when making these determinations.

 Example of a structured approach to establish a control strategy (product-related elements). (QTPP is quality target product profile. QA is quality attribute. CQA is critical quality attribute.) (Figure courtesy of the author)

This risk-based approach is relevant and useful even during the commercial life of a product. As more data and knowledge are gathered during commercial life, it can be the evidence that is used to re-assess if any QAs need to be reclassified as CQAs or non-CQAs, which in turn would trigger an update to the testing and monitoring controls that were established during the development stage.

Feedback-feedforward through the control strategy “hub”

ICH Q10 defines feedback as “the modification or control of a process or system by its results or effects” and feedforward as “the modification or control of a process using its anticipated results or effects.” It further states that “feedback and feedforward can be applied technically in process control strategies and conceptually in quality management” (2).

The approach to and content of a control strategy (product-specific and non-product specific elements) are expected to evolve during the product lifecycle. Scale-up, technology transfers, and manufacturing experience can lead to refinements for the control strategy, for instance in the following cases:

As knowledge grows (e.g., enough data and evidence are accumulated on a QA to change it from a CQA to a non-CQA or vice-versa).

New risks are identified (e.g., impact of increased variability of a process parameter requires its range to be controlled more tightly, new product introduction).

New technology becomes available (e.g., new PAT that allows in-line monitoring of a process parameter, QA, or CQA, so end-product testing is not needed any more, or a better analytical technology will improve sensitivity or speed of testing).

A new microbial contaminant is identified in a facility or a process (e.g., a new test needs to be added to detect it).

Raw material change or raw material supplier change introduces a new impurity (e.g., characterization and control of the impurity is deemed necessary and new test method needs to be developed and validated for the impurity.

Process changes need to be made to increase manufacturing yields.

New signals, trends, quality, or compliance issues are detected through the PQS (deviations, complaints/adverse events, annual product review, operational metrics review, management review, etc.).

A continual improvement opportunity is identified.

New regulatory expectations are added (e.g., testing for nitrosamines).

All these instances should function as feedback or feedforward triggers to evaluate current knowledge/understanding, determine if/how the current risk profile for a product might change because of it, and what updated or new controls might become necessary in order to maintain a state of control. It would also be useful to review the control strategy as part of the annual product review or when making changes to determine if any updates to the control strategy, including continual improvement, might be warranted. Completion of a production campaign also offers a good opportunity to at least consider any lessons learned or new knowledge that might be of relevance for a control strategy update.

Using the control strategy as a nerve center for the network of controls necessary for a product allows it to function as a feedback-feedforward “hub” for effective risk-knowledge flow across its constituent elements. The triggering event would determine what aspects of the control strategy need to be probed, considering the new knowledge, and changed risk profile. This would enable timely knowledge and risk-informed decisions for the product and the relevant elements of the control strategy. Without this dynamic and timely feedback-feedforward, it becomes impossible to attain the cGMP and ICH Q10 objectives of achieving product realization, establishing and maintaining a state of control, and facilitating continual improvement.

Lipa’s RKI Cycle provides a practical means to activate and operationalize the feedback-feedforward power of a control strategy all through a product’s lifecycle. Several case studies showing this application particularly during technology transfer and commercial manufacturing have been published by Lipa, Mullholand, 

 (8). The paper explains several nodes in the RKI Cycle and how different events during a product’s lifecycle can initiate the RKI Cycle at different nodes, based on the level of available information and knowledge and an understanding of associated risks; this is depicted in 

 (8). Some examples of such events include a change, failure or error, corrective action, preventive action, improvement, implementation of a new technology, tightening of a specification, process optimization, annual product review, data trends, etc.

 Potential nodes (entry points) in the RKI Cycle (8). (Figure courtesy of the author)

Application of the RKI Cycle in conjunction with the dynamic feedback-feedforward power of a control strategy “hub”, should trigger the following questions (this is not a comprehensive list):

What is the level of knowledge and understanding associated
with the event?

What prior knowledge or data might be available about this event from this product or another product?

What aspects of a product(s) might be potentially impacted?

Does it change (increase or decrease) any current risks for a product(s), or introduce new risks? If so, in what way?

What controls are in place to mitigate the risk(s)? What enhanced or new controls might be needed?

What elements of the current control strategy (product-specific and non-product specific) need to be assessed?

Does the current control strategy address the potential impact of this event? If yes, how? If no, what activities or studies need to be initiated to acquire the data/evidence/knowledge needed to make decisions?

What does the new knowledge of the event and/or the data generated to understand it, indicate?

What updates are needed to the control strategy to mitigate the impact of the event?

Managing product risks and knowledge is ultimately all about assuring and maintaining a state of control such that product of the desired quality can be delivered consistently. If it is all about control, then what better means to assure this than to use the control strategy as the
“controls hub” for a product?

Once an initial control strategy is established during the pharmaceutical development stage, it will need to be refined, updated, and managed all through the product lifecycle.

As noted earlier, a control strategy should not be thought of as a single document that houses all controls for a product. Instead, it is a consolidated set of all controls necessary to consistently produce quality product, and these controls may be found in different quality and operational documents. For outsourced operations, some elements of the control strategy may even reside with a CDMO or CLO as discussed earlier.

This raises some logical questions, including: where does one find this consolidated set of controls? and how do you manage this dynamic set of controls in a timely manner based on the constantly evolving knowledge and risks for a product/process, such that product quality is assured at all times? The answer to both questions is within a cGMP compliant pharmaceutical quality system (PQS).

The ICH Q10 model for a PQS is structured and applicable across all four stages of the product lifecycle—pharmaceutical development, technology transfer, commercial manufacturing, and product discontinuation, in a phase-appropriate manner. The model includes four elements—process performance and product quality monitoring (PPPQMS), corrective and preventive action (CAPA), change management, and management review—as well as two enablers—quality risk management (QRM) and knowledge management (KM); all governed by clear expectations for management responsibilities across all lifecycle stages and across the four elements and two enablers (2).

All components of this ICH Q10 PQS model provide the structure necessary to document and contain all controls necessary to assure consistent product quality. The PQS also provides the structure to dynamically manage changes and updates to any of the controls, when triggered by an event as discussed in the previous section.

 described the different product-specific and non-product specific constituent elements of a control strategy. For each of those elements, based on the level of knowledge and risk, a list of controls will be identified. 

 depicts how these various controls identified within the product-specific and non-product specific elements of a control strategy may be documented and implemented via different components of the PQS.

 Implementation and management of the control strategy in the pharmaceutical quality system (PQS). (CPV is continuous process verification. CPP is critical process parameter. SOP is standard operating procedure.) (Figure courtesy of the author)

Three examples are described below to illustrate how the PQS would be used to document and manage the consolidated set of controls (product-specific and non-product specific) that form the control strategy for a product.

change to a product CQA. The initial list of CQAs, their ranges, and controls are defined and documented in development and characterization studies during process design and in process qualification and process validation reports. These documents typically reside in and are managed through a company’s document management system which is governed by the PQS.These documents lead to the definition and documentation of the initial product control strategy (i.e., CQAs, their limits, test methods, and specifications). Let’s assume during the commercial life enough data has been generated and assessed during annual product reviews (APRs) (documented in APR reports managed via the document management system) to demonstrate that a CQA is well-controlled and that the initial specifications defined during development can be tightened to better represent the commercial process variability. The product control strategy becomes the relevant element for this triggering event. The change management element of the PQS would be used to document an assessment of the change, provide all supporting data, assess any risks and associated controls, and capture any regulatory or product quality impacting considerations and decisions. The change management system would also document and trigger any actions needed (such as updates to product specifications, manufacturing batch records, batch release documents, trainings, need for any regulatory submissions, etc.) via the change implementation plan. The completion of those actions, any unintended consequences, etc. would be documented as well, and the change would be closed after satisfactory implementation of the change. The PQS would also be used to document any post-implementation reviews needed.

 a quality issue during product manufacturing. Deviations from approved procedures can occur during manufacturing, testing, release, or supply of a product. Any deviations are typically documented in a discrepancy (nonconformance) management system. For this example, let’s assume a deviation occurred during the blending unit operation for a tablet, so the unit operation control strategy becomes the relevant element for this triggering event. An assessment of the deviation, any potential impact to product quality for this (and other relevant products), actions needed to respond to the deviation including management of potential product impact, new studies or data needed, etc., are documented in the discrepancy management system. If a risk assessment exists for the blending unit operation, it would be reviewed to determine if an existing risk has changed or if a new risk might have been introduced, and what updated or new controls might be needed. All this information is included in the discrepancy record. The deviation is not closed until all relevant decisions have been made, including updates to the unit operation risk assessment, the need for relevant corrective and/or preventive actions, and any updates to relevant procedures, training, etc. The corrective and/or preventive actions identified are documented and their implementation managed via the CAPA system.

 continual improvement through implementation of a new analytical technology. A product can live in its commercial life for more than 20 years, and it is not unexpected that during that long lifespan new manufacturing and analytical technologies emerge. Let’s assume for this example that one of the analytical tests to ensure appropriate concentration is an in-process sampling and control by ultraviolet (UV) analysis. A new in-line UV analysis technology provides the opportunity to perform real-time concentration monitoring, thereby eliminating the need for in-process sampling and holding the process until UV analysis results are obtained to confirm concentration of the active ingredient. The product testing and in-process control strategy become the relevant elements for this continual improvement-triggering event. Development of the in-line UV test method, including generation of method comparability data, and method validation are performed and documented through method development, method validation, comparability studies, and reports via the document management system. Development, qualification, and validation needed for the new technology are performed and documented in suitable development, qualification, and validation reports. Implementation of the new UV analysis technology in-line is assessed and managed via the change management system, including the need for any regulatory assessments and/or submissions. Relevant SOPs, test method, calibration, and routine maintenance documents are established within the PQS via the change management system.

A control strategy can function as a powerful “hub” to gain a comprehensive understanding of the consolidated set of controls that are necessary to ensure consistent delivery of quality product.

Control Strategy: A Feedback-Feedforward ‘Controls Hub’ for Risk, Knowledge, and Product Lifecycle Management

Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

an automated production line manufacturing glossy luxury cosmetic packaging filled with amber liquid in a spotlessly clean and modern factory. generative AI | Image credit: © yj - stock.adobe.com

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.”

Twin-screw granulation process insight is growing as researchers employ new analytical technologies and investigate new ways to use the equipment.