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Drug Digest

Reaction Biology Corporation announced on December 2, 2022 that their closure on a definitive agreement for Reaction to acquire Bioassay Labor für biologische Analytik GmbH (Bioassay GmbH), including its wholly owned subsidiary, Peptide Specialty Laboratories GmbH (PSL), located in Heidelberg, Germany.

Bioassay offers good manufacturing practices (GMP)-accredited potency assays and functional bioassays, good laboratory practices (GLP)-compliant services, and through PSL, peptide synthesis services, including peptide-specific antibody production and neoantigen synthesis.

In addition, personnel, equipment, and facilities from the acquired companies will expand Reaction Biology’s presence in Germany while enabling its global customers to leverage Bioassay’s expansive portfolio of regulated clinical and commercial services.

“Market demand is increasing globally for large-molecule services as biopharmaceutical companies search for new treatment options for patients suffering with cancer and other serious diseases,” said John H. Johnson, chief executive officer of Reaction Biology, in a press release. “This transaction enables Reaction Biology to add Bioassay GmbH’s impressive clinical phase and post-approval infrastructure, which includes large molecule capabilities, as well as its GMP and GLP accreditations, to our expanding suite of drug discovery and development services. We can now provide our customers with even broader offerings to meet their research and development goals.”

Articles

Reaction Biology Acquires Bioassay GmbH for Increasing Large Molecule Capabilities 

Chris Spivey is the editorial director of 

It’s a useful end-of-year exercise to take stock of our industry—and more specifically the stock of the publicly traded companies that comprise what must, by now, approach $6 trillion in stock value (

) (1). The ‘From the Editor’ commentary on page 10 of this issue, reveals that the value of messenger RNA (mRNA) publicly traded companies shot past the $300 billion mark in a little over 12 months from around $15 billion in 2019 (2). Within the same layer of financial intensity sit cell and gene therapies, clustered regularly interspaced short palindromic repeats (CRISPR), and other gene editing approaches.

 Industry breakdown of publicly traded companies.

Interestingly, the lion’s share of the growth in value has been somewhat democratized (

) (1) since the golden awakening and acceleration of biotech. Next year, follow up on early conversations about organ-on-a-chip approaches will gain coverage, as these approaches are likely to shorten both cost horizons and shrink drug development timelines, amounting to getting better working drugs to market faster, with less cost and unintended side effects.

: Changing nature of composition of pharmaceutical industry.

On the machine side of things conversations at CPHI in Frankfurt made clear that a long standing dual tiered system still operates. Lower value more commodity-oriented products are produced on less expensive equipment, which is less well supported by the original equipment manufacturers (OEM) and sell into a more relaxed regulatory environment. These types of OEM equipment often come from Asia. Higher performance, higher cost equipment caters to a different type of customer with more stringent contract times, with far less flexibility regarding potential machine failures and project delays. This has been the case for many years and is not expected to change anytime soon.

What might be less visible surrounding this equipment is the emergence of the “junior” sized enterprise—big enough to have deep industry know how, but small enough to act decisively when unmet opportunity presents itself. This development is truer for contract manufacturing organizations (CMOs), contract development and manufacturing organizations (CDMOs), raw material suppliers, and analytical tool providers, than equipment manufacturers per se. But the trend is proliferating generally.

Rapidly changing patient expectations combined with increasing biological complexity drives some of this trend because large-scale legacy enterprises find adaption an inherent challenge. The need for speed is obvious and can sometimes trump a strong preference to have only one external manufacturing partner who can take a project the full distance through approval and ahead into commercialization and distribution. Most companies prefer to deal with only one other company, if at all possible, but will jettison that requirement if substantial speed advantages are included in discussions. And this is where a junior pharma company can often shine.

“Across various product groups, we have seen the demand for agile suppliers who can customize raw materials in a timely fashion. For this reason, finished drug manufacturers are looking to mid-sized organizations to supply such materials with the scale and quality standards of a large organization, but with the agility of a small organization. This level of service is critical to help meet their commercialization objectives and ensure they are first-to-market,” says Paul Staunton, global communications manager at Actylis.

When specifically discussing APIs, Scott Mohler, director of Business Development at Actylis, points out, “While many of the top pharmaceutical companies run their own operations to develop and manufacture the APIs for their own approved drugs and drug candidates, they only account for roughly one-third of all New Drug Applications (NDAs) (3). The trend, especially for clinical phases, continues to skew toward smaller biopharmaceutical developers who don’t have the full internal teams and facilities to develop and manufacture their drug candidates. This shift has led to an increased demand for outsourced R&D and manufacture with mid-sized organizations who can help them both though clinical phases and full-scale manufacturing as quickly as possible.”

Marching to the same drummer as Mohler, Marc Sauer, chief science officer, at BioVectra, comments that “many large CDMOs have facilities spread all over the globe, which can require external technical transfers, depend on a vulnerable and widespread supply chain, and slow down production.”

As a very new entity ten23 health has been gaining both traction and visibility for handling an array of challenging fill finish assignments. Swiss business consultant Michael Petersen describes ten23 health as being focused on development and flexible clinical manufacturing offering agility and flexibility. “They have examples of customers receiving material within a few weeks after signature [through] flexible changes in the production schedule based on customer requirements.” He continues they can be proud of “resolution of unexpected observations and root cause investigations by inhouse experts—because the whole team is one purpose-driven company and not split up in business units and departments.”

Similarly, Sauer goes on to highlight the way in which BioVectra functions, which is with all the facilities operating within the same region. “This localized form of operations means that all the facilities can share a single system for quality management, document control, inventory, procurement finance, and ERP [Enterprise Resource Planning]. Therefore, thanks to this way of operating, the company can decrease decision time and be nimble when moving processes from chemistry into biologics, or combining chemical synthesis with fermentation, without needing to adapt any of the processes or documentation,” Sauer specifies.

Furthermore, Sauer stresses that the entirety of the company’s increase in size has stemmed from organic growth, without acquisition of target companies as a path to business growth, one of the typical means through which big companies just keep getting bigger. “Over the 50 years since we first started manufacturing small molecules and enzymes for diagnostic reagents, we have steadily grown into new markets, including complex chemical synthesis, the production of highly potent APIs and PEGylation reagents, microbial fermentation of biologic drug substances, and drug product manufacturing capability. For more than 20 years we have been capable of all the upstream and downstream processing requirements and the purification of biologic drug substances. Our clients are pleasantly surprised, for example, when we onboard them for a large molecule fermentation, and they learn that we also have extensive chemical synthesis capabilities. They realize that we can make custom mPEGs and linkers for conjugation with their biologic, we can ferment small molecule metabolites for their process, or we can synthesize lipids for their lipid nanoparticles—all using GMP,” says Sauer.

A similar account about the state of the market is pointed to by Gearoid O’Rourke, VP of Global Marketing, Actylis. “In the biologics market, with high demand for critical raw materials with low impurity levels, there is a need for mid-sized organizations to fill the void that currently exists for such products,” he states.

O’Rourke reveals that for biopharmaceutical applications it is common to find that many of the existing product monographs require additional endotoxin and bioburden testing be performed. “Many such [large-molecule] products are used in smaller quantities than with small-molecules, thus the need for alternative mid-size manufacturers with the capability to GMP-manufacture in specific packaging formats with additional testing requirements,” he says.

“There is also a trend for outsourcing of downstream buffers, where there is a large number of buffers required for one finished drug product,” O’Rourke continues. “Some buffers will be large volume, but some will be quite small and may not fit a large manufacturer’s business/profitability strategy.”

Instead of the traditional role of producing large amounts of drug product for one-size-fits-all medications, many biologic drugs, for example, require smaller doses for a limited number of patients or even a single patient. These drugs need to be made and shipped much more quickly because the turnaround from diagnosis to treatment is measured in weeks, not the usual months. Now, modalities are calling for entirely new skill sets, the types of skills and organizational structure that allow performance at junior pharmaceuticals to shine.

The Pharma 1000 Top Global Pharmaceutical Company Report

2. W. Xie, B. Chen, and J. Wong, “Evolution of the Market for mRNA Technology,” Nature Reviews Drug Discovery, 

3. S. Mohler, “Meeting the Need for Innovative Small Molecule APIs,” 


Volume 46, Volume 12
Dcember 2022
Page: 16-20

When referring to this article, please cite it as C. Spivey, "Shining a Light on Junior Pharmaceuticals" 

Overall industry growth conceals growing numbers of smaller, faster-paced, adaptable corporate structures.

Shining a Light on Junior Pharmaceuticals

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Oligonucleotide drug substances generally are unstable at room temperature, and some are also degraded in the presence of certain enzymes. That is why, in part, they are formulated using special delivery solutions such as lipid nanoparticles (LNPs). (These delivery technologies also facilitate entry of nucleotide APIs into target cells.) Degradation can occur via loss of terminal nucleotides or certain functional groups, oxidation, and other mechanisms. Oligonucleotide–oligonucleotide interactions that can occur at higher concentrations are an added concern. These instability issues must be managed throughout the entire manufacturing process.

The challenges are particularly great for messenger RNA (mRNA), which can be degraded by enzymes found commonly in the environment, temperature, and due to the overall shear sensitivity of the long-chained molecule.

Variety of oligonucleotide drug substances

The landscape of nucleotide-based therapeutics is based on more than half a century of research and development in these modalities, according to Julian Mochayedi, strategic marketing manager for mRNA solutions with MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany. This knowledge translates to the clinic and beyond, with several approved therapeutic products on the market.

The different types of nucleotide-based therapeutics can be broadly classified by the type of nucleic acid, Mochayedi continues, such as those with DNA or RNA as a basis. Alternatively, they can be differentiated by their functional design, which determines the mode of action. “One can cite DNA-based adeno-associated virus (AAV) vectors for gene delivery, antisense oligonucleotides (ASOs), small-interfering RNAs (siRNAs) for gene expression disruption, and most recently, mRNA to express a protein of interest such as for immunization purposes, as the successful mRNA-based COVID-19 vaccines have demonstrated,” he explains.

mRNA instability particularly challenging

DNA-based oligonucleotide drug substances, such as AAV vectors and plasmid DNA, share the relatively stable characteristics of DNA, Mochayedi notes. The stability of shorter chemically synthesized RNAs such as ASOs and siRNA can be improved through chemical modifications during synthesis. Particularly long biologically synthesized mRNA molecules, however, are inherently unstable, and thus require additional management during manufacturing.

All nucleic acid-based platforms, however, must be formulated using delivery technologies that protect the therapeutic from degradation. Unique solutions such as LNPs help ensure stability in the patient setting, API stability and, ultimately, the efficacy of the therapeutic approach.

There are several reasons why mRNA is inherently unstable. The physiochemical properties of single-stranded mRNA molecules that lead to their instability include their very large size, high negative charge, sensitivity to rapid degradation by omnipresent enzymes such as endonucleases, shear sensitivity, and high viscosity through the formation of secondary structures in solution, according to Mochayedi.

Manufacturing strategies for managing mRNA instability

One of the main culprits causing mRNA degradation is the enzyme RNase. Avoiding it is difficult, however, because this enzyme is ubiquitous. “It is very difficult for mRNA to move freely in the environment,” Christian Cobaugh, CEO and founder of Vernal Biosciences, comments. “Extreme precautions must therefore be taken to avoid introducing this enzyme into manufacturing spaces or enclosures,” he stresses. This issue can often, he notes, be a barrier to entry into the mRNA market for laboratories not experienced in mRNA production.

Use of qualified processes, including sterile single-use technology, should be applied to mitigate contamination and carryover of endonucleases, Mochayedi says. Liberal use of RNase degrading chemicals for cleaning equipment surfaces, operator gloves, and so on is also essential, Cobaugh adds.

The instability of mRNA at room temperature creates further challenges, as the time available for holding generated mRNA sequences at room temperature is fairly restricted, according to Cobaugh. The drug substance must be moved seamlessly to downstream purification and formulation or quickly frozen.

“The choice of adopting a seamless manufacturing approach or having unit operations separated by controlled freezing and subsequent thawing steps must be considered early on, as the decision will impact the design and operation of the mRNA manufacturing facility, and once implemented, that design will essentially be locked in,” Cobaugh contends.

“Ideally, it is best to limit the number of freezing and thaw steps, as they can impact the quality of the mRNA drug substance and formulated mRNA-LNP products,” Cobaugh adds. Furthermore, gentle techniques must be employed. Continuous movement of the mRNA drug substance to purification and then LNP formulation avoids all but the final freezing step. “It is possible, though, with the right engineering solutions and validation procedures to surmount the challenges presented by either approach to mRNA manufacturing,” he concludes.

In addition, stringent optimization of reaction conditions and the process parameters for key unit operations, such as the synthesis step (in vitro transcription) and filtration (via tangential-flow filtration), can overcome viscosity challenges and ensure low shear during processing to maintain the stability of the mRNA at each stage of the manufacturing process, Mochayedi remarks. “Bespoke process development and optimization are necessary for each unique mRNA sequence to address and overcome the highlighted challenges,” he concludes.

While the concept of leveraging mRNA for the prevention or treatment of various diseases is straightforward, the safe and effective delivery of these fragile nucleic acids into cells where their message can be translated into proteins has proved to be a huge challenge, Mochayedi observes. “For the COVID-19 mRNA vaccines, the solution to this problem came through the development of LNPs. These particles, typically composed of four different lipids (ionizable lipids whose positive charges bind to the negatively charged backbone of mRNA, pegylated lipids that help stabilize the particle, and phospholipids and cholesterol molecules that contribute to the particle’s structure), provide a protective bubble for the delicate mRNA molecules, enabling their safe and efficient delivery into cells,” he explains.

The structure of the nucleotide API has a strong impact on the selection of the excipients for the formulation. The manufacturing process must, in addition, be highly controlled. “The buffer solution containing the mRNA drug substance used to produce the LNPs is of low pH (typically aqueous sodium citrate) that places additional stress on the nucleotide’s stability, leading to even more rapid breakdown than occurs at neutral or slightly basic pH,” Cobaugh says.

A low pH of approximately 4.5 is needed to ionize the mRNA so that it forms nanoprecipitates with the lipids. The use of stabilizing process aids is, Cobaugh adds, generally avoided because they would interfere with the ionization of the mRNA and could also potentially end up in the product. Most molecules that would stabilize mRNA against pH-mediated degradation would, furthermore, likely be hazardous chemicals.

The key to successful LNP production, therefore, is minimization of the time required for the LNP manufacturing process. That, Cobaugh emphasizes, requires extensive understanding of the process from a quality-by-design basis combined with thorough process validation. “It is absolutely essential to have a deep awareness of what levers can be pulled from both process and engineering perspectives to minimize the time for all aspects of the formulation process,” he states.

With respect to fill/finish of mRNA therapeutics and vaccines, the strategy is generally no different than that of any other biological API, according to Mochayedi. The goal, agrees Cobaugh, is to fill the product—whether drug substance in sterile single-use plastic bags and containers or formulated drug product into sterile glass vials—and then freeze them as rapidly as possible but in a controlled manner. In this case, the challenges are largely engineering and equipment-related.

For storage and shipment of mRNA, the requirement to maintain the cold chain to ensure its stability and integrity all the way to the patient is of utmost importance, Mochayedi says. “Central storage is usually performed at very low temperatures (-80 °C). Similarly, formulations containing nucleotides require shipment at low temperatures, which is typically achieved using dry-ice packaging,” he notes. In some cases, mRNA drug products may require the addition of a cryoprotectant to protect the particles. The adjustment of excipients to protect the nanoparticles may also enable some formulations to be shipped at approximately 4 °C.

The production of mRNA-LNP formulations that are stable at warmer temperatures is a key focus of developers of candidate therapeutics and vaccines. One approach noted by Cobaugh involves the development of higher-quality DNA templates that are free of breaks (commonly referred to as nicks) that result in the shorter, more unstable mRNA sequences. Mochayedi points to new types of modified nucleotides and new capping technologies to physically altered forms of mRNA, such as circular RNA. “These new approaches may overcome some of the stability issues and enable a broader application of mRNA as a technology platform,” he believes.

Lyophilization of mRNA products as an alternative to freezing is the other main area of investigation. “Theoretically, there is no reason why freeze-dried mRNA products cannot be stored at room temperature as long as water is kept out of the storage containers,” Cobaugh says. He notes that there has been preliminary success in this area, and he is hopeful that lyophilization will be applicable for mRNA products in the not-too-distant future.

Mochayedi agrees, noting that significant investigations into formulation optimizations to overcome the ultra-low temperature requirements of mRNA drug products during shipment and storage are underway across the industry, with lyophilization of formulated mRNA-LNPs as an extremely promising alternative for liquid-based products. “The complete drying of formulations afforded by freeze-drying would unlock the possibility of much more easily providing mRNA therapeutics in countries with higher temperatures,” he remarks. 

Cynthia A. Challener, PhD has been a freelance technical writer for over 20 years, leveraging her education from Stanford University (BS) and University of Chicago (PhD) and 10+ years of industry experience. She currently focuses on pharma/biopharma topics, writing technical articles, white papers, blogs, and other content for a variety of clients in addition to contributing regularly to BioPharm International and Pharmaceutical Technology.


Vol. 46, No. 12
December 2022
Pages: 22–23, 27

When referring to this article, please cite it as C. A. Challener, “Managing mRNA Instability During Formulation, Manufacturing, and Shipment,” 

Unique solutions are required to protect inherently unstable messenger RNA.

Managing mRNA Instability During Formulation, Manufacturing, and Shipment

Feliza Mirasol is the science editor for 

An understanding of the pharmacokinetics (PK) of monoclonal antibodies (mAbs) is important so that potential patient responses to treatment can be predicted. Both PK and pharmacodynamic (PD) studies are necessary in the development of a new mAb drug candidate. 

PKPK/PD modelling is already widely used in pre-clinical and clinical drug development; these studies are important for characterizing drug candidates quantitatively as well as aiding go/no-go decisions and informing future trial design and optimal dosing regimens (1). However, what is less well known is that PK/PD modelling can also be an effective tool in the earliest stages of drug development, such as in target selection and lead candidate selection. The same modelling techniques can be used to predict and illuminate the drug candidates that have the necessary characteristics for potentially successful development, or, conversely, can help pinpoint which drug development programmes may be less successful, before too much time and cost are accrued on that specific programme.

In particular, mAbs, which are an important therapeutic class, have complex pharmacology and interdependent PK/PD properties. Understanding the PK and PD of mAbs and their biological activity as well as their mechanisms of action are crucial factors in enabling their design and selection. Understanding these factors allows for the design of appropriate studies to characterize the mAb’s efficacy and toxicity, the translation of PK/PD parameters to humans, and the optimization of a dose and regimen for maximizing success in clinical development (2).

Meanwhile, the practice of characterizing the relationship between PK and PD is an important tool in the drug discovery phase. PK/PD strategies should be implemented in the early phases of research during drug discovery projects because these studies can enable a successful transition from discovery phase to development phase (3). An effective PK/PD study design, as well as proper analysis and interpretation can help researchers characterize the PK–PD relationship. Understanding the relationship would enable understanding of the mechanism of drug action and help identify PK properties that can help improve and optimize the design of the drug compound (3).

To learn more about the necessity of PK/PD studies in early mAb development and the most reliable ways to conduct these studies to generate data compliant with investigational new drug application (IND) filings, Pharmaceutical Technology Europe spoke with Maotian Zhou, PhD, Principal Scientist—DMPK Services Department, at WuXi AppTec.

 In the early development of a new mAb, what role does PK play in the development lifecycle?

 PK plays an important role in the early development of mAb therapeutics. This is even more apparent when the antibody is designed against a novel target, or if the antibody aims to be a ‘best in class’ drug in an already competitive arena with well-studied targets (i.e., HER2, PD1 [programmed cell death protein 1]/PDL1 [programmed cell death ligand 1], etc.).

This may differ from past views on mAb drug development. It is usually assumed that, for humanized monoclonal antibodies, the 

 absorption, distribution, metabolism, and excretion (ADME) characteristics share more significant commonality than small-molecule drugs. Thus, the importance of PK studies in the early phase of mAb development is diminished. The efficacy (or pharmacodynamics) appears to be more significant in the leading-candidate mAb selection.

The importance of PK studies increases with a better understanding of mAb drug mechanisms. Many factors can affect mAb exposure–response relationships 

, the affinity between the mAb and its ligand, the association between the mAb and different Fc receptors, and the modifications and physicochemical characteristics of the mAb. These factors form the basis for the continuous refinement of current mAb drugs. The mAb PK properties act as a bridge between its design philosophy and ultimate efficacy and safety. Fully understanding candidate mAb PK parameters can provide support for leading-mAb drug selection.

In summary, the PK studies significantly impact whether a mAb moves forward, and should happen early in discovery. Pushing a mAb toward an IND submission without fully understanding its PK could waste time and resources and/or result in programme failure.

 I always see the terms PK and PD together when discussing drug candidate screening or in drug discovery. What is the importance of both in mAb development, and is it necessary to have both PK data and PD data (can you have one without the other)?

 Simply put, PK is ‘what the body does to the drug’, whereas PD is ‘what the drug does to the body’.Explicitly, PK quantitatively describes the process of absorption and disposition of the drug in the body. PD evaluates the time course of the pharmacological effects of drugs.

For mAb drug development, the PK and PD always communicate, because mAb drugs generally have long-acting PD effects, and PD will have a direct impact on PK. PK and PD are mechanistically linked (unlike small-molecule drugs). Having both PK and PD data for mAb development is strongly recommended. PK/PD studies serve distinct roles at different stages of mAb drug development.

 What is a ‘best practice’ approach to conducting PK/PD studies, and do these studies necessarily need to be compliant with regulatory standards?

 PK/PD studies should adapt to the different requirements of each research stage. In the discovery phase, the PK/PD assessments facilitate an understanding of the biology by validating and confirming target engagement. For the leading-mAb selection stage, PK/PD studies should help to select the most ‘potential’ mAb, along with efficacy and toxicity evaluations, to minimize the risk of off-targeting. At the IND stage, systematic PK/PD studies, along with safety studies, play a vital role in translating pre-clinical knowledge to first-in-human clinic studies. In the clinical phase, further in-depth PK/PD studies can identify the covariates and potential sources of population variability, establishing exposure–response relationships in different cohorts. And finally, these studies support proper dose selection, regimen optimization, and biomarker tools establishment.

PK/PD studies must comply with regulatory guidance, both during and after the IND phase of mAb drug development. It is also helpful to reference the regulatory standards in the early phase of drug development. Given that regulations are often adapted based on the lessons learned from many actual drug development cases, items rooted in regulatory guidance are often representative of key points in drug development. For example, a mAb PK bioanalysis in the discovery phase, using a partially validated method (validating specific parameters such as selectivity and stability) will make the mAb quantification more reliable in an unconventional matrix.

 What role or impact do PK/PD studies have on an IND filing for a new mAb?Are they even relevant at that stage?

 PK/PD studies are essential materials for an IND filing. PK/PD studies serve the following purpose in the IND phase for mAb development: integrate pharmacology and toxicology data and help correlate pre-clinical knowledge to first-in-human clinical study; bridge toxicology studies to define maximum tolerated dose (MTD) and select first-in-human dose; design a dose escalation scheme; and project efficacious dose in clinical.

 What currently are the major analytical/technical challenges in conducting PK/PD studies on new mAbs?

 Several challenges currently exist within PK/PD studies for mAb drugs. First, the assumptions used to simplify the exposure–response relationships in PK/PD modelling may not always be appropriate. For example, in the past, the PK/PD model assumed the drug concentration in tumor cells was related to the cell-killing effect. However, in the absence of an actual measurement of the distribution cascade, the validity of this assumption is uncertain.

Second, the translation from animals (pre-clinical) to humans (clinical) based on PK/PD modelling is also challenging. Furthermore, existing PK/PD modelling assumptions are usually based on prior experience, as such studies are needed to understand the applicability of new mAbs.

Third, the reliability of PK/PD data depends on the selection of a proper analytical method/platform, which may be a challenge in some instances. The bioanalysis should always follow a fit-for-purpose principle. Based on the ligand properties (such as solubility and endogenous concentrations), the availability of critical reagents, and desired sensitivity, a suitable assay format needs to be designed.

There is an ongoing effort regarding PK/PD analytical strategy optimization. The ability to accelerate research and develop safe and effective mAbs rely less on tools and more on an investigator’s skills, knowledge, and expertise. Drug developers and sponsors that do not have the time, capacity, or expertise to conduct these investigations in-house should consider working with a testing partner.

 77 (5) 740–745 (2014).
2. A.V. Kamath, 

 21–22, 75–83 (2016).
3. T. Tuntland, et al., 


Vol. 34, No. 12
December 2022
Pages: 16–17

When referring to this article, please cite it as F. Mirasol, “The Power of PK/PD in mAb Development,” 

Although well known in R&D, PK/PD studies are an equally powerful tool for promoting successful biologic drug development.

The Power of PK/PD in mAb Development

Somnath Mishra, Somnath.mishra@shabas.net, is president at Shabas Solutions LLC.

William Hauck is senior associate at Shabas Solutions LLC.

Zachary Royal, is senior consultant at Shabas Solutions LLC.

Robert Michalik is advisor (Quality and Corporate Compliance) at Shabas Solutions LLC.

Disclaimer: This article was not written by the FDA, and it does not necessarily reflect the views of the agency.

In recent months, FDA has begun championing Quality Management Maturity (QMM), a new quality surveillance initiative intended to raise awareness at all levels of management in the pharmaceutical industry as to how to best achieve quality objectives and improve manufacturing site quality and supply chain reliability in drug manufacturing processes. QMM follows a maturity modeling paradigm first developed and adopted by other high technology industries. The nexus between a clearly articulated mature quality culture, technical processes, and corporate-wide business practices that are integrated with quality objectives has crystallized into a viable roadmap for enhancing a drug manufacturer’s operations, while satisfying patient needs and corporate goals.

Since first introducing the proposed initiative, FDA has conducted two QMM pilots to measure quality management maturity levels at an establishment—one for domestic finished-product manufacturing sites and another aimed at overseas API manufacturing sites. Shabas Solutions LLC (Shabas) was selected to run the QMM pilot for overseas API manufacturers in which eight sites—of various sizes, location, age, and product focus—participated voluntarily (1). The Shabas team (including the authors of this article) collaborated with FDA to develop a comprehensive QMM assessment tool to inform FDA’s vision for the QMM program. The tool is characterized by four pillars and 15 practice areas, more than 60 QMM questions with accompanying interview guides, a 5-level rating system, and a scoring and reporting process.

The pilot program yielded findings that helped FDA and industry participants better understand what impact the QMM initiative might have to enhance quality management for a drug manufacturer, both at its corporate level and specific manufacturing site, and how adoption of QMM could eventually benefit the industry.

In this article (first of a multi-part series), the authors leverage insights gained from the FDA QMM pilot to explain what QMM means in practice to a firm’s management, trace its evolution, and explain the benefits of adopting it.

According to FDA, QMM is the state attained when drug manufacturers have consistent, reliable, and robust business processes to achieve quality objectives and promote continual improvement (2). FDA mentioned QMM in its 2019 report, Drug Shortages: Root Causes and Potential Solutions, which pointed to a lack of manufacturer incentives to improve their quality management beyond the minimum required for current good manufacturing practice (CGMP) compliance (3).

In an earlier article, FDA officials noted: “A drug manufacturer is responsible for implementing dependable daily operations that assure consistent drug quality. Management’s daily decisions on myriad issues involving equipment, materials, maintenance, staff qualifications, supervision, process control, and investigations will ultimately determine the quality of the drugs that are shipped from a given facility” (4).

In other words, site management’s proficiency in governing a site’s business processes as well as their level of integration with quality objectives, influence the performance of the quality management system and technical processes involved in developing a product and, therefore, impacts product quality and availability.

In a competitive market, reliable delivery of high-quality product and reduced quality-related shortages sustainably over the long-term—the essence of QMM as identified by FDA—is a management concern in all industries, in which their lessons learned are also applicable to pharma. Shabas researched the pharma and other industries to identify key foundational competencies (“four pillars”) that undergird QMM for an organization aspiring to be “quality management mature”:

Compliance management: ability to consistently meet and/or
exceed compliance with applicable laws, regulations, and industry best practices

Risk management: ability to identify and manage organizational risks and build resilience

Quality culture: ability to develop and maintain an organizational mindset and behaviors that value continuous learning and improvement, and customer satisfaction

Sustainability: ability to successfully secure and manage appropriate technology, infrastructure, human capital, suppliers, customers, institutional knowledge, and other resources to
sustain the operations.

Achieving site QMM starts with understanding where an organization is in terms of QMM—thus the need for an assessment. Increased site maturity would be evident through improved quality metrics and other relevant, but carefully, chosen indicators. But a prerequisite to achieving an optimized site maturity is for site management to invest in establishing systematic business processes that are well integrated with quality objectives and committing to developing the culture—the two key facets of an “operations excellence” program. Such a demonstrated intent of management’s willingness could serve as useful evidence to a QMM assessor.

By integrating continuous improvement in the business processes as the focus of the organization as QMM seeks to do, management may successfully realize the potential of achieving long-term growth in line with corporate strategy.

A QMM assessment is not an FDA quality audit of an organization’s quality management system or products but should rather be viewed as an alignment check between an organization’s planned strategy and its actual execution. An independent pharmaceutical site QMM assessment would therefore inform site management with a “snapshot in time” as to its institutional capacity, culture, and knowledge related to manufacturing medicines, how well the organization is able to leverage them to guide the design and governance of the site business processes to produce high quality medicines reliably, and how committed the site management is to institutionalize a quality culture.

Brief history of quality management and its maturity

The fundamentals of modern quality management practices can be traced to innovative principles developed by Joseph Juran and Edward Deming. Juran’s model of quality, referred to as Total Quality Management (TQM), focused on prospective quality practices employed throughout a manufacturing process, rather than reactively weeding out non-conforming products during finished product quality control (QC) inspection (5).

By the 1960s and 1970s, manufacturers and regulators in various industries began to take notice of the impact that TQM practices were having on product quality and productivity in Japan (6). In 1978, FDA embedded TQM principles into GMP regulations (e.g., prospectively defined product and process specifications driven by written standard operating procedures [SOPs]). Globally, TQM practices were adopted by International Organization for Standardization (ISO 9000 series) and International Council for Harmonisation (ICH) in their pharmaceutical best practices related to technical and quality standards (Q, S, E, and M series). By 2000s, ICH became a leading standards organization for the development and manufacture of pharmaceuticals globally (e.g., Q7 through Q12 guidance) (7,8).

Beginning in the late 1980s and into 1990s, the US Department of Defense and military contractors engaged with the Carnegie Mellon Software Engineering Institute to propose a Capability Maturity Model assessment tool (now, CMM-Integration [CMMI] with 5-level maturity scale) to illuminate subtle issues at the senior management level which stymied TQM effectiveness (9). CMM assessments enabled management at companies in high-tech industries to discern whether its quality mission statement was effectively being communicated throughout the organization (10). In 2017, FDA’s Center for Devices and Radiological Health endorsed CMMI for their Voluntary Manufacturing and Product Quality Pilot Program aimed at medical device manufacturers (11,12).

Given the success of quality maturity modeling assessments seen in other high-tech industries—and driven by FDA’s Congressional enabling legislation (13) and its own policy initiative to address drug supply chain problems—in 2016 (3), FDA sponsored researchers at the University of Gallen’s Institute of Technology Management to conduct a study of Operational Excellence (OPEX) metrics to identify root causes of quality system problems that could lead to drug shortages for vulnerable patient populations.

A series of three reports issued by St Gallen Pharma OPEX Study demonstrated a remarkable correlation between the “assessed” level of quality management maturity and quality system effectiveness, or “operational excellence” (14). It addressed an important question: “To what extent does a pharmaceutical manufacturer’s quality management maturity affect its ability to convey a culture of quality throughout its organization?”

Not surprisingly during the QMM pilot assessment, sites that received higher QMM scores generally performed well in similar key performance areas as noted by Juran in 1946 (corporate culture, quality messaging, and communication throughout the organization).

Today, with the advent of the digital revolution and artificial intelligence (AI) machine learning capabilities, the quality landscape is once again being transformed. Conducting a QMM assessment becomes more critical than ever as a means to inform site management of their organization’s current maturity level and its ability to integrate changes.

Site management decisions related to various business processes often create a de facto quality culture that impacts product quality and availability. While FDA provides oversight of the site quality management processes and product quality via CGMP inspections and other surveillance methods, there are currently no comparable regulatory tools that examine a site’s business processes and how well they are integrated with quality objectives. QMM fills that much needed gap, as illustrated by 

Figure 1. Quality Management Maturity and Shabas Assessment Approach. Figure courtesy of the authors.

In a future article, the authors will cover typical symptoms of low and high QMM that were encountered while conducting the FDA QMM pilots.

Based on the authors’ experience from administering the FDA QMM foreign pilot, industry participants of any company size would benefit from adopting QMM by moving toward greater systemization and optimization of their business processes and their integration with quality objectives. This will result in improved investment decisions, risk-based redundancies, and enhanced operations in terms of resiliency, workforce efficiency and collaboration, customer and supplier relationships, management oversight of quality, and ultimately a robust quality culture at the site thereby paving the way to achieve targeted strategic objectives. As an example, the QMM assessment tool developed by Shabas demonstrated to the pilot participants how systemization can provide greater visibility of business processes and remove barriers to collaboration between different functional areas, ways to improve supplier and customer collaboration processes, and how to progressively fit quality into a site’s strategic plan.

The QMM initiative is squarely aimed at operationalizing the vision laid out in the FDA’s report on Pharmaceutical Quality for the 21st Century: “a maximally efficient, agile, flexible manufacturing sector that reliably produced high-quality drug products without extensive regulatory oversight” (7). It is a logical evolution in the history of pharma quality management to adopt principles of operations excellence to systematically link management proficiency, business process maturity including digitalization, corporate culture, and continuous improvement ethos to achieving long-term growth, quality goals and strategic corporate objectives.

Shabas Solutions LLC sincerely acknowledges the FDA CDER QMM team for their support and guidance during the QMM Pilot and for reviewing this article. We also wish to acknowledge and thank Major General (retired) John Handy, Mr. Joseph Delukey, and Dr. Clyde Schultz for their invaluable contribution to the FDA QMM Pilot project.

Shabas Solutions LLC (www.shabas.net), based in Fairfax, Virginia, USAis a small business provider of scientific and management consulting services to multiple US federal government agencies. Our experts and staff members bring decades of experience in Defense and Health Supply Chain Management, Pharmaceutical Quality Management, Pharmaceutical Research and Development, Federal Policy and Regulatory Operations, and Technology Integration.

 “Quality Management Maturity for Active Pharmaceutical Ingredients Pilot Program for Foreign Facilities; Program Announcement

“Quality Management Maturity: Essential for Stable U.S. Supply Chains of Quality Pharmaceuticals

Drug Shortages: Root Causes and Potential Solutions A Report by the Drug Shortages Task Force 2019

J. Woodcock and M. Wosinska, “Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages,” 

American Society for Quality, The History of Quality available from asq.org [accessed Nov. 14, 2022].

INC Magazine, “Total Quality Management,” Article, Jan. 5, 2021.

Pharmaceutical Quality for the 21st Century: A Risk-Based

ICH, Quality Guidelines available from ich

Software Engineering Institute, CMMI: A Short History, Brochure, 

M.C. Paulk, et al., Capability Maturity Model for Software, Version 1.1, Technical Report, 

FDA, “Fostering Medical Innovation: Case for Quality Voluntary Medical Device Manufacturing and Product Quality Pilot Program,” Notice, 

FDA, Fostering Medical Device Improvement: FDA Activities and Engagement with the Voluntary Improvement Program, Guidance Document, 

FD&C Act, sec. 301(a); 21 U.S.C. 331(a);see also 

FDA Quality Metrics Research Final Report Year 1

,
University of St. Gallen (Switzerland), November 2017.

Somnath Mishra, Somnath.mishra@shabas.net, is president, William Hauck is senior associate, Zachary Royal, is senior consultant, and Robert Michalik is advisor (Quality and Corporate Compliance), all at Shabas Solutions LLC.


Vol. 46, No. 12
December 2022
Pages: 30–33

When referring to this article, please cite it as S. Mishra, W. Hauck, Z. Royal, and R. Michalik, “Introduction to Pharmaceutical QMM Model: QMM Assessment to Promote Pharmaceutical Operational Excellence,” 

QMM is an evolutionary advancement in FDA’s quality management maturity initiative that provides industry with a viable methodology to assess and improve manufacturing quality and supply chain reliability. 

Introduction to Pharmaceutical QMM Model: QMM Assessment to Promote Pharmaceutical Operational Excellence

Editor of Pharmaceutical Technology Europe

Agilent Technologies opened the doors of its new Dissolution Centre of Excellence (CoE) based in Craven Arms in the United Kingdom on 12 Oct. 2022 (1). The facility, which has been modernized, will house the company’s dissolution activities under one roof.

The new CoE will be Agilent’s hub for dissolution testing. “The company is bringing all the business functions back under one roof,” said Dan Spisak, marketing manager for the Dissolution Division at Agilent Technologies, during an interview with 

 at the opening of the company’s Dissolution CoE facility. “With a lot of investment happening in the dissolution business, it just makes sense right now.”

In terms of geographical location, the UK provides access to multiple different time zones, remarked Steve O’Donohue, director of Agilent Technology’s Craven Arms site, in the interview. It is possible to connect with the United States, Europe, and Asia, with reasonable ease, for example. “Apart from the time zone benefit, then the choice of location comes down to the expertise of the staff,” O’Donohue continued.

“There are many centres of excellence within Agilent,” added Tom Van de Goor, director R&D, Agilent Technologies during the interview. “Each product family has some home somewhere in the world. It is more that all these functions are together in one place because that’s where the centre of knowledge is and that is where decisions can be made on these products.”

Infrastructure has been put in place at the new facility in Craven Arms to facilitate expansion. “We’ve got the expansion space for production, and we’ve got lots of expansion space to house R&D and support staff required to bring that full centre of excellence together,” stated O’Donohue.

However, a key area that needs to be considered from day one of any new facility design is how to make the facility more sustainable, O’Donohue emphasized. “Facility design has definitely moved on from product-centred initiatives to now have sustainability considerations built into the concepts of new designs,” he said.

And sustainability is also driven by the customer who is asking more questions of companies on their initiatives in this area, explained Van de Goor. “The whole sustainability topic, environmental sustainability, is going to play a big role in the coming years,” he summarized.

1. Agilent Technologies, “Agilent Opens Center of Excellence for Dissolution Products,” Press Release, 12 Oct. 2022.

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.

When referring to this article, please cite it as F. Thomas, “Agilent Sets Up Dissolution Testing Hub in UK,” 

Pharmaceutical Technology Europe got the scoop on Agilent's new Dissolution Testing Centre of Excellence in Craven Arms, UK.

Agilent Sets Up Dissolution Testing Hub in UK

Dissolution testing is an integral part of pharmaceutical development, providing drug companies with the analytical ability to determine the efficacy, bioequivalence, and bioavailability of the active drug substance, as well as control quality, stability, and consistency of the final drug product. “Dissolution is a very controlled, very precise, and required sample preparation technique,” specified Dan Spisak, marketing manager for the Dissolution Division at Agilent Technologies, during an interview with 

 at the opening of the company’s Dissolution Centre of Excellence (CoE) facility in Craven Arms, United Kingdom (see article 

). “The dissolution test is not going away; it is a required test in the pharmaceutical industry. Everyone making pharmaceutical products needs to run dissolution tests on their products prior to release.”

Thanks to a variety of market drivers, dissolution testing is, in some respects, undergoing change. Some of the expansion and refresh of instrumentation within the area of dissolution testing is being seen as a result of reshoring, a trend that has picked up over the past few years, Spisak stated. “This reshoring helps protect companies from unexpected issues—like pandemics—that could affect critical parts of the supply chain and drug release process,” he said.

But the generics sector is driving the bulk of growth in the field, Spisak stressed. “The lower-cost generics increase the level of healthcare to address the needs of the growing ageing population, especially in emerging markets,” he noted.

However, there is also a shift in focus to more novel and personalized dosage forms that is happening within the bio/pharma industry, requiring modifications to many different areas of drug development and manufacturing, including dissolution testing, Spisak added. “For that reason, it is becoming necessary to modify the capabilities of what can be done [in dissolution testing],” he said.

A prime example of how instrumentation is being updated could be seen within the modernized CoE facility (

), which incorporates multiple systems that have been designed to work with novel formulations, such as nanoparticles. Novel formulations can pose challenges when using standard apparatus; nanoparticles, for example, are not necessarily sufficiently separated from the dissolution medium with standard techniques. Therefore, modification of the instrumentation, such as that found in Agilent’s NanoDis system, is required to ensure an accurate prediction of 

 performance of the drug product can be made.

Dissolution lab at the new Agilent Dissolution Centre of Excellence in the UK. 

[FIGURE COURTESY OF AGILENT TECHNOLOGIES.]

Additionally, in instances where medical device companies need to perform dissolution testing, challenges can be encountered as a result of a lack of knowledge about the sample preparation technique—such companies can be unfamiliar with dissolution—Spisak continued. “We often encounter ‘homemade’ devices being used in the laboratory which can be very labour-intensive and difficult to transition into a quality control environment,” he stated. “Agilent has developed the 400-DS model specifically for these types of products. This instrument complies with United States Pharmacopeia and is ideal for products delivering small amounts of drug over weeks or even months, such as drug-coated stents or implants.”

Looking at the overarching dissolution environment, there is the obvious trend of automation, Spisak noted. In a dissolution lab, there are typically entry-level chemists at work, and so, automating processes can ensure that potential errors are avoided, he explained.

A primary aim for Agilent Technologies is to create a digital lab, free of paper and pens and, ultimately, easier to use while also limiting errors, Spisak asserted. “Then, on the back end, for the lab in general, there are data and traceability for all the actions performed,” he said. “So, when it comes to data integrity and compliance, when the lab gets audited for example, everything is readily available.”

Another facet to consider is the efficiency that automation can offer; although, this aspect is certainly not unique to dissolution, emphasized Tom Van de Goor, director R&D, Agilent Technologies during the interview. “It’s not that each business needs to invent the wheel again, but to build upon the infrastructure and automate the workflows already available,” he said. “This work is something that Agilent feels is very important because not only are customers asking for it, but if a company is not participating in automating processes, then at some point in time they will be left behind.”

Engagement with customers on a virtual platform has certainly become more acceptable in recent times, perhaps a change that has been accelerated as a result of the COVID-19 pandemic and the resultant necessity to continue operations in a virtual capacity. What virtual opportunities allow is for instantaneous connection, not just for sales, but also in instances where issues may arise and an expert can help to troubleshoot, explained Spisak.

“Even before COVID, Agilent had a very strong initiative to offer remote training and knowledge sharing,” said Steve O’Donohue, director of Agilent Technology’s Craven Arms site, during the interview. Through using a video room and virtual communication platforms, it is possible to improve efficiencies and share knowledge with the customer base, he stated.

“COVID has been a world leveller,” asserted O’Donohue. There was so much innovation being driven within Europe to tackle COVID that the region was able to advance forward in the ‘driving seat’, which has possibly left the region in a better place than some others to continue that momentum, Steve added.

“The pandemic was a driver for developments that would have taken much longer normally,” added Van de Goor. “New tools have come into play; in some areas, virtual reality is being used for demos or there are maybe more configurators for instrumentation. So, these things were more or less born in this time; although, they were probably in the planning already for a longer period of time but were accelerated because those were the tools needed to continue interacting with customers. A very positive outcome of this pandemic has been the acceleration of this whole digital transformation of how we work.”


Vol. 34, No. 12
December 2022
Pages: 27–29

When referring to this article, please cite it as F. Thomas, “Building Up to a Bright Future,” 

Dissolution testing is experiencing a refresh thanks to a variety of market drivers.