Surveying Pharma Workers on Employment Trends

Drug Solutions

Appreciating the full impact certain select technologies will make on the industry by 2026.

Six Approaches Significantly Impacting in the Future

Pharma workers appear ready for flux, change, evolution, and expanding molecular diversity.

Crossing the Same River Multiple Times

Experts weigh in on trends in the biotechnology market, psychedelics, and India.

Predicting Pharma’s Future

Inhaled vaccines must resist degradation and penetrate the mucosal lining in the airways and lungs.

Inhalation Vaccine Development

Analytical techniques for cleaning validation must evolve with the therapeutic landscape.

Cleaning Up in Bio/Pharma

Pharma Trends Dissected by 3 PR Agency Luminaries

FDA announced on Jan. 27, 2023, that it has granted accelerated approval to Eli Lilly and Company for Jaypirca (pirtobrutinib) as a treatment for relapsed or refractory mantle cell lymphoma (MCL). Patients who have had at least two lines of systemic therapy, including a bruton tyrosine kinase (BTK) inhibitor, are eligible for the treatment.

Efficacy for pirtobrutinib was evaluated in an open-label, multicenter, single-arm trial (BRUIN [NCT03740529]) of pirtobrutinib monotherapy that included 120 patients with MCL previously treated with a BTK inhibitor. Pirtobrutinib was administered orally at 200 mg once daily and was continued until disease progression or unacceptable toxicity. The main efficacy measures were overall response rate (ORR) and duration of response (DOR). In the results, ORR was measured to be 50%, median DOR was 8.3 months, and the estimated DOR rate at six months was 65.3%.

According to the agency press release, the recommended pirtobrutinib dosage is 200 mg orally once daily until disease progression or unacceptable toxicity. Prior to this accelerated approval, pirtobrutinib received priority review, fast track, and orphan drug designations.

Articles

FDA granted accelerated approval to Eli Lilly and Company’s pirtobrutinib for treatment of relapsed or refractory mantle cell lymphoma.

FDA Grants Accelerated Approval to Lilly Cancer Drug

On Jan. 27, 2023, FDA announced that it had approved Stemline Therapeutics’ Orserdu (elacestrant) as a treatment for postmenopausal women or adult men with estrogen-receptor (ER) positive, HER2-negative, estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. In addition to elacestrant, FDA also approved the Guardant360 companion diagnostic assay to identify patients with breast cancer for treatment with elacestrant.

Efficacy for elacestrant was evaluated in a randomized, open-label, active-controlled, multicenter trial (EMERALD [NCT03778931]) that enrolled 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer. Additionally, 228 patients in this population had ESR1 mutations. Patients were randomized (1:1) to receive elacestrant 345 mg orally once daily or the investigator’s choice of endocrine therapy.

The major efficacy outcome measure was progression-free survival (PFS). According to an agency press release, a statistically significant difference in PFS was observed in the full population and in the subgroup of patients with ESR1 mutations. In patients with ESR1 mutations, PFS was 3.8 months for patients treated with elacestrant vs. 1.9 months in those treated with a different endocrine therapy.

The recommended elacestrant dose is 345 mg taken orally with food once daily until disease progression or unacceptable toxicity. Prior to this approval, elacestrant was granted priority review and fast track designation.

FDA approved Stemline Therapeutics’ elacestrant for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer.

FDA Approves Novel Breast Cancer Treatment

Gerresheimer presents its new Clinical Trial Kit at Pharmapack in Paris on Feb. 1-2, 2023. The kit consists of sterile Gx RTF vials in nest and tub or tray with matching closures and is tailored to requirements to support the development of new drugs, vaccines, and biologics in early phases.
The kit is suitable for small batch manufacturing from first line trials to validation and clinical batches. It can be ordered in six different configurations of Gx RTF Glass Vials. Kits including Gx Elite and Gx RTF COP vials will follow soon.

“There are currently more than 3000 injectable drug programs in pre-clinical and clinical phases. With our clinical trial kits and supportive services, we want to proactively support our customers by providing them with first-class primary packaging solutions,” said Jean-Edouard Rabier, sales development manager and director project management/pharmaceutical services and member of the Gx Biological Solutions Team, in a company press release.

Gerresheimer is presenting its new Clinical Trial Kit to accelerate drug development at Pharmapack in Paris. 

Gerresheimer Presents New Clinical Trial Kit at Pharmapack

Marina Necdina has more than 10 years of exerience as a bench scientist specializing in the areas of biochemistry, cell biology, and drug manufacturing.

RNA-based therapeutics have been in development for decades. The RNA drug development trend was on the rise in early 2000s; however, its popularity went down due to unique challenges. The COVID-19 pandemic helped to bring a spotlight on RNA molecules and their therapeutic potential.There were also lessons learned in terms of drug delivery, manufacturing, logistics and storage. This is the silver lining of the pandemic, where necessity and emergency need for vaccine and therapy highlighted potential solutions. Hopefully, it also opens the door for novel RNA therapeutics.

Historically, RNA research began from discovery of nucleic acids by Watson and Crick and later studies on messenger RNA (mRNA) molecule in the 1960s. However, it took decades for RNA biology to “explode” in the 1990s and early 2000s leading to discovery of variety of novel RNA molecules for therapy: antisense oligonucleotides, small interfering RNAs, aptamers, and more (1). RNA drug development, however, proved to be a challenging pathway for commercialization. Currently, only a dozen of RNA-based medicine are approved and available in the market.

The first RNA drug on the market was fomivirsen (Vitravene). It is an antisense antiviral that was used for treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients. It was approved by FDA in 1998; however, by 2006 Novartis withdrew it from the European Union and the United States markets due to lower cases of CMV and consequently no further need for such medication (2).

It took another decade for another antisense drug, Kynamro, to be approved in 2013. Overall, in addition to antisense platform, small interfering RNAs and mRNA drugs were approved in the past five to seven years (3). This is not surprising because RNA research is known to be challenging and costly.

Indeed, in spite of being considered a “winner”” in RNA therapeutics space, Alnylam company is a textbook example of how challenging development of RNA drugs can be (4). Formed in 2002, Alnylam spent more than $2 billion in its pursuit of an approved drug. The road to successful approval of the first RNAi therapeutic Onpattro in 2018 was not only rocky but very costly.Onpattro treats polyneuropathy in patients with hereditary transthyretin amyloidosis and its list price for an annual course is $450,000.

Due to these challenges in efficient drug delivery, stability, and cost, RNA therapies were a bit on the backburner in Big Pharma’s pipeline. However, the COVID-19 pandemic brought the RNA approach back into the spotlight.

In 2021, the market for RNA therapeutics was valued at more than $5 billion with projection to expand to more than $20 billion by 2030 (5). Analysts attribute this impressive growth to newly rising interest in RNA therapeutics after the pandemic, as well as development of new technologies.

The RNA therapeutics market has a growing number of companies that bring remarkable innovation to this space. The following companies can be considered as leading stars and innovators in this field.

After the success of mRNA vaccines to prevent COVID-19 infection, Moderna and BioNTech became household names. During the pandemic, Moderna’s revenues multiplied almost exponentially from approximately $60 million in 2019 to almost $18 billion in 2022 (6). Currently, Moderna has 48 programs in development. In addition, its board has approved a significant increase to R&D investments, with a budget for 2023 of around $4.5 billion (7).

Alnylam is a long-time player in the RNAi space. This company has several commercial products including ONPATTRO (patisiran), GIVLAARI (givosiran), OXLUMO (lumasiran), AMVUTTRA (vutrisiran) and Leqvio (inclisiran), which is being developed with Alnylam’s partner, Novartis (8).

Ionis Pharmaceuticals, founded more than 30 years ago, is focused on antisense therapy development. As of today, the company has three commercially approved medicines: Spinraza (Nusinersen), Tegsedi (Inotersen), and Waylivra (Volanesorsen), and more drugs are in development (9). In 2021, AstraZeneca and Ionis signed a deal to commercialize eplontersen, a liver-targeted antisense therapy for the treatment of transthyretin amyloidosis (10).

Overall, Big Pharma companies, such as AstraZeneca and Novartis, tend to collaborate with innovative RNA companies or acquire biotech with newly developed technology for further development into clinic. For example, in December 2022, Eli Lilly and Company expanded its RNA editing collaboration with ProQr using its Axiomer RNA editing platform to target disorders of the liver and nervous system (11).

Although leading companies continue to do innovative research, small biotech ventures also bring breakthrough methodologies. New trends include transfer RNA (tRNA), circular RNA, and self-replicating RNA.

Alltrna and Shape Therapeutics are both working on tRNA molecules that can correct for errors in the genetic code that would otherwise impair protein production.

Laronde and Orna Therapeutics are working on therapeutics based on circular RNA. This type of molecule can be found naturally in cells and is considered much more stable than mRNA. Unlike 

mRNA, they don’t produce proteins. Laronde’s and Orna’s technological platforms are to synthesize circular RNAs with specific genetic codes (12).

Replicate Biosciences is focused on self-replicating RNA that can be a vector for vaccines and immunotherapies (13).

There are also companies that offer a new approach to RNA-based drug manufacturing. Nutcracker Therapeutics develops ACORN: a microfluidic platform that functions as a computer-controlled RNA manufacturing system that starts with a nucleic acid sequence of interest and produces optimized nanoparticle-encapsulated RNA therapeutics on specific, single-use biochips (14). The advantage is that all steps are performed in an automated, fully isolated microfluidic path, enabling efficient manufacturing of high-quality products within smaller footprint facilities with reduced operating costs compared to conventional bioreactor manufacturing.

All these exciting novel trends open new venues for R&D.

It is quite remarkable that the discovery of mRNA in 1960s led to a whole new world of RNA molecules. RNA research holds untapped potential for drug development especially for unmet needs, such as rare diseases.

However, R&D in the RNA space also highlights challenges and limitations of almost every drug development process: stability issues, drug delivery aspects, cost, logistics etc. Approval of new RNA therapeutics in the past couple of years proved true value of this platform.

The pandemic definitely highlighted the importance of novel science especially in the times of emergency needs. It also brought to attention the quality of research and showed that new therapies can have positive and negative sides.

More importantly, it forced the public to learn and appreciate what science and research can do for us as society and that future investment in research and biotech are necessary to forward and improve our lives and health.

Damase, T. R. The Limitless Future of RNA Therapeutics. 

Bradley, C.A. First Antisense Drug Is Approved with Fleeting Success. 

Kim, Y-K. RNA Therapy: Rich History, Various Applications and Unlimited Future Prospects. 

PharmTech Editors. FDA Approves First-of-its-Kind RNA Therapy. 

Moderna. Moderna Reports Third Quarter 2022 Financial Results and Provides Business Updates. Press Release. Nov. 3, 2022.

Moderna. Moderna Announces Advances Across mRNA Pipeline and Provides Business Update. Press Release. Jan. 9, 2023.

Alnylam Pharmaceuticals. Alnylam Announces 2023 Product and Pipeline Goals and Provides Program Updates at R&D Day. Press Release. Dec. 15, 2022.

AstraZeneca. AstraZeneca and Ionis Sign Deal to Develop and Commercialise Eplontersen. Press Release. Dec. 7, 2021.

Eli Lilly and Company. Lilly and ProQR to Expand RNA Editing Collaboration. Press Release. Dec. 22, 2022.

Zhou, W-Y. Circular RNA: Metabolism, Functions, and Interactions with Proteins. 

Aliahmad, P. Next Generation Self-replicating RNA Vectors for Vaccines and Immunotherapies. 

Paunovska, K. Drug Delivery Systems for RNA Therapeutics. 

Owens, J. The Challenges of Vaccine Transport and Storage. 

Marina Necdina is a business development manager, former pharma analyst, and research scientist.

The COVID-19 pandemic helped to showcase RNA molecules and their therapeutic potential.  There were also lessons learned in terms of drug delivery, manufacturing, logistics, and storage. 

The COVID-19 Pandemic and Its Positive Impact on RNA Drug Development

Feliza Mirasol is the science editor for 

Bioassays play a crucial role in biologic drug development as a means to determine potency, toxicity effects, pharmacological activity, stability, purity, and other product qualities. The complexity of biological molecules, however, requires a wide range of analytical procedures to adequately characterize the product. In particular, the concern over immunogenicity in the use of biologics is driving the need to develop more highly sensitive assays. Because of this concern, there is a continual need to refine biological assays to increase accuracy and reproducibility. There is a specific need to replace 

 bioassays are important tools employed during drug discovery/drug development, according to Weihong Wang, PhD, director of Technology Development, Eurofins BioPharma Product Testing. 

 bioassays use cell culture and offer the benefit of low cost and high throughput, both of which are essential during early development. An 

 bioassay also has the necessary robustness needed for use as a lot-release assay for product quality control later in the drug development life cycle, Wang explains.

 bioassay is a more efficient method that allows researchers to clearly characterize product mechanism of action in a controlled environment, says Catherine Liloia, director, Cell & Microbiology, PPD clinical research, Thermo Fisher Scientific. “This approach is scalable and reproducible across production and can assess product stability,” she states.

 bioassays (non-clinical) use animal models and are considered more relevant to potential clinical outcome, says Wang. 

 bioassays are often costly, however, and are less robust and subjected to strict regulations and compliance standards. “Regulatory agencies across the world have been encouraging sponsors to replace, reduce, and refine (the three Rs) dependence on animal studies by advancing development of, and evaluating new, fit-for-purpose methodologies,” Wang explains.

 bioassays are more representative of the full biological complexity and pharmacokinetics of the human body; they can, therefore, more broadly assess potential patient safety impacts stemming from metabolic changes and other side effects. The downside, however, is that 

 bioassays require high investment, strict animal care protocols, and are not as conducive to high-level analytics, according to Liloia.

, generate valuable data needed for regulatory filings, such as investigational new drug (IND) applications. 

 bioassays support determination of product potency, for instance, says Liloia. “When included in analytical panels during release and stability testing, potency data can demonstrate lot-to-lot consistency and long-term stability of the product,” she says.

In addition, bioassays provide data to better understand the impact of manufacturing process changes through process development. “Early 

 methods may be needed to help discern true product mechanism of action in biological pathways that are complex or not well characterized. These methods can sometimes be consolidated or replaced on a product release panel as data [are] collected to determine a single method’s capability to reliably determine product potency across production samples,” Liloia explains.

 method cannot by itself model the biological response in a reliable manner, as is the case with immunogenicity and other safety testing, Liloia adds.

IND-enabling studies, including pharmacology/pharmacodynamic, pharmacokinetics, and toxicology studies, are typically done through both 

 assays, states Wang. She adds that additional 

 assays to address product safety and quality, such as viral testing, and potency testing, are also necessary later on for product licensing.

Cell-based bioassays have also become an important tool in the analytics arsenal for biologics drug development. According to Wang, cell-based bioassays measure relevant physiological responses in cell cultures, but unlike 

 bioassays, cell-based bioassays do not involve the use of live animals and often have different types of assay readouts/endpoints. “Nevertheless, the physiological responses are reflective of mechanism of action, and, therefore, cell-based assays are considered necessary components of product characterization, in addition to other biophysical/physiochemical analytical methods,” she states.

Cell-based bioassays utilize biologically relevant cell lines to measure product potency, says Benjamin Ziehr, senior group leader, PPD clinical research, Thermo Fisher Scientific. He notes that there are several types of cell-based bioassays that vary depending on what is being measured. “The classic cell-based bioassay compares the response of cells treated with drug sample or reference standard. Typically, sample and standard are diluted in a manner suitable to produce a four-parameter response curve in the target cell line. Well-defined response curves are critical for maintaining and demonstrating control of the assay and drug product in these assays,” he explains.

Ziehr further explains that the relative activity of sample drug material to reference standard drug material is reported as the relative potency of the drug product. In comparing cell-based bioassays to other types of bioassays, the key distinction lays in the fact that cell-based bioassays allow mechanism-of-action-dependent measurements, whereas other bioassays measure physical characteristics of the drug product, such as epitope binding or receptor occupancy. “Therefore, cell-based bioassays allow measurement of the cellular processes responsible for a drug product’s effects on the patient,” says Ziehr.

Meanwhile, there are several other modes of cell-based bioassays that provide information about other attributes of the drug product. Ziehr points out two common examples of these other modes from cell and gene therapy product testing: infectivity and replication competency assays. “These assays measure the infectious potential of the drug product and the presence of replication-competent viral particles, respectively,” he states.

In other words, rather than measuring a cellular response, these infectivity and replication competency assays measure the accumulation of viral genetic material following infection of permissive cell lines. “While these assays don’t measure product potency, they do provide critical process and safety data and detect lot-to-lot variability of products,” says Ziehr.

Cell-based bioassays become a clear front runner in this movement, where applicable, remarks Wang, who points out that, in other circumstances, sponsors may be able to eliminate certain 

 assays based on risk analysis. For example, per the International Council for Harmonisation Q5A(R2) (2), 

 testing is no longer necessary for well-characterized cell lines such as Chinese hamster ovary, non-secreting murine myeloma, and SP2/0 (a standard mouse myeloma cell line), based on cell-line history, prior knowledge, and other risk-based considerations, notes Wang.

Despite their advantages, however, cell-based bioassays are limited in their ability to represent more complex, distal biological responses in a patient, cautions Liloia.

Meanwhile, the challenges in working with cell-based bioassays include not only the fickleness of working with certain cell lines, but also the fact that the day-to-day variability is much higher in terms of assay performance, observes Ziehr. The state in which cells enter the bioassay affects their response in the bioassay.

“Cellular state is dictated by many factors, notably metabolic stimuli, cellular density—both in culture leading up to a bioassay and in the bioassay itself—and cellular age. Stable transfections, optimized banking, and robust maintenance controls are needed to minimize cell variability,” Ziehr says.

Ziehr explains that, typically, robust maintenance controls involve the use of well-defined and controlled culture protocols, qualification of critical reagents, and substantial system suitability criteria in the bioassay. “Consistency of technique is challenging, even with clear procedure, so robust training with clear connection between biological processes and cell handling technique remains important,” he remarks.

Because cell-based assays utilize live cells, they are subjected to intrinsic assay variability that are often larger than that of physiochemical methods, says Wang. Thus, the selection of an appropriate cell line that is not only relevant to product mechanism of action, but also able to support a robust response in a dose dependent manner, is the single most critical factor for successful method development, she emphasizes.

“Many details need to be considered and optimized to produce a robust assay suitable for quality control. In addition, for products that may have multiple mechanisms of action, a carefully selected matrix containing multiple cell-based assays may be necessary to fully characterize the product,” Wang says.

Wang also points out, however, that it may yet be difficult to develop a cell-based bioassay for some products that either have not known defined mechanisms of action or have complex mechanisms of action. Furthermore, some cell-based assays still require extended testing time, which can be a cause for concern regarding products that require rapid factory-to-patient delivery. In such cases, Wang suggests that development of surrogate assays and/or orthogonal assays may be beneficial, though subject to discussions with the relevant regulatory agency.

In terms of advantages conferred, compared to 

 bioassays, cell-based bioassays often offer the advantages of a more streamlined testing procedure, higher assay throughput, quicker turnaround time, and less assay variability, according to Wang. “It is generally easier to develop a cell-based assay with an accurate quantitative endpoint than an 

 assay, which is particularly essential when the method is intended to be used for quality control,” she states.

Liloia notes that cell-based methods are quite challenging in many areas. Solutions such as liquid handling automation helps in providing accurate and precise sample dilution pipetting and transfers to the low concentrations and small volumes often needed in a cell-based assay. She also notes, however, that analytical workflows have become more complex because of the diversity of analytical readouts needed to support expanding product areas.

The growing complexity of analytical workflows has resulted in a greater need for coordination across functional areas, broadened cross-training, and design changes to laboratory spaces to maintain efficiency while also maintaining process flows that consider biosafety and contamination prevention, Liloia says. “Data analysis expectations continue to evolve as laboratories and agencies gain experience with newer products, requiring strong statistical support and the ability to apply industry best practices in a new way,” she states.

Overall, cell-based bioassays are considered a critical tool to predict quality and safety of drug products in the patient. “When established early in the development process, cell-based bioassays can provide early indicators of lot-to-lot variability in manufacturing, drug potency stability, and impact from process changes,” states Ziehr.

“Bioassays have an essential role throughout the life cycle of product development of biologics.Many aspects of product discovery, development, characterization, and quality control require careful construction and implementation of bioassays in order to thoroughly assess product safety, efficacy, and stability,” Wang adds.

1. Mire-Sluis, A.R. Progress in the Use of Biological Assays During the Development of Biotechnology Products. 

, 18, 1239–1246. DOI: 10.1023/A:1013067424248.
2. ICH, Q5A(R2) 

Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

As the development of increasingly complex biologics grows, more robust bioassays are required to accurately characterize these molecules.

Robust Bioassays Needed for Increasingly Complex Analytical Workflows

Editor of Pharmaceutical Technology Europe

Within the bio/pharma industry, there is a certain expectation for companies to maintain required levels of cleanliness within their facilities to ensure products that are manufactured are at minimal risk of contamination. All cleaning processes must also be validated for effectiveness and reproducibility.

As drug products become more complex and sensitive to potential contaminants, there is an increasing demand for cleaning validation throughout industry. According to market research, the cleaning validation market is forecasted to grow by a compound annual growth rate of 5.7% between 2021 and 2027 (1).

Of course, the requirement for manufacturing equipment to be clean is nothing new; as Andrew Kolbert, PhD, senior leader, Technical Solutions, Element, points out, this facet of drug production has been a necessity for 70 years since the introduction of the 21 Code of Federal Regulations (CFR) 210 Part 133.4 (2). “Early efforts [in this field] were focused on avoiding microbiological contamination or just filth, as seen at food manufacturers,” he states.

“In 1978, the GMPs [good manufacturing practices] were amended to 21 CFR Part 210.67, which specifically addressed the issue of cross contamination, as opposed to mere unsanitary conditions, with particular focus on manufacturers that made penicillin and other pharmaceutical products on the same equipment train,” Kolbert continues. The issue of cross contamination was brought to the fore by a case in 1988, he highlights, where a drug product, Cholestyramine Resin, was recalled due to contamination with pesticides as a result of insufficient cleaning of solvent drums (3).

“Cleaning validation is a subject that receives a great deal of attention within biopharmaceuticals, not least due to the risks presented in terms of product adulteration from cross-contamination and, hence, patient harm from improperly cleaned surfaces (and noting additional concerns such as operator protection),” specifies Tim Sandle, head of microbiology at Bio Products Laboratory (BPL) in Elstree, UK.

Sandle also highlights microbial proliferation as an area of importance because of the risk it poses in terms of the numbers of organisms adhering to surfaces and the release of microbial toxins. “Under the least desired conditions, a combination of organic residues and the presence of microorganisms can lead to a biofilm developing,” he says. “Biofilms are difficult to detect, and they are challenging to remove.”

Therefore, it is expected, by the regulatory bodies, such as FDA, that a drug manufacturer has a cleaning process in place for all equipment to ensure that no drug residue exceeds the maximum allowable carryover (MACO) level—a level that is determined based on toxicological risk—and that there are no cleaning agent residues and so forth, Kolbert asserts. “The cleaning process must also be validated to ensure it is consistently reproducible and effective. The exact form of this validation depends on the nature of the equipment as well as the cleaning process,” he says. “If cleaning is to be done manually, the reproducibility across workers will be need to be explored. If solvents or detergents are used, reduction to an acceptable level must be demonstrated.”

“Approaching cleaning validation should always begin with a risk assessment,” emphasizes Sandle. “To be effective, the risk assessment needs to be built upon a thorough understanding of the equipment to be cleaned and the cleaning reagents and mechanisms.”

Additionally, any residue(s) that needs to be removed must be identified and the optimal method to remove the residue(s) must be considered, Sandle continues. “For example, some residues are best cleaned by either an alkaline or acidic cleaner (or both types of cleaning agent may be required). To ensure the designed process has a greater chance of being effective, it is also important to understand how the residue is actually being removed (which requires detail of the residue chemistry),” he states.

“The next step is whether to use product residues or an alternative soil to challenge the designed cleaning process,” Sandle adds. “Users need to assess whether product residues are suitable for the cleaning validation because some process soils pose little challenge to the cleaning system, and it may be more appropriate to use a surrogate with greater viscosity and binding characteristics.”

Furthermore, Sandle points out that consideration should be made to how much residue may be permitted to be left, which will impact the level of cleaning that is required. “This [consideration] means selecting appropriate sampling methods, typically based on rinsing and swabbing, and the appropriate test methods for microbial and chemical analysis,” he says. “With methods, there needs to be an understanding about the metrology of the test instruments and the likelihood they can quantify the minimum acceptable residue. In addition to typical analytical method validation parameters (specificity, accuracy, linearity, limit of detection, precision), the actual sampling procedure must be qualified.”

For Kolbert, swabbing all of the drug product contact surfaces along the manufacturing train using the simplest analytical finish that will achieve an appropriate limit of detection is the most common approach. “If the drug product has a chromaphore, HPLC [high-performance liquid chromatography] or even UV [ultraviolet]/vis [visible] may be sufficient,” he says. “It is important to detect not only the drug product but any degradants or by-products that may be created.”

Also, if a detergent mix or solvent is required for the cleaning process then merely analyzing the rinsate does not suffice, Kolbert admonishes. “The product path components must also be tested for residue by direct swabbing,” he states. “A commonly used metaphor is if you are cooking in a pot, it is not enough to analyze the water rinse, you also need to look at the pot for old product residue that may break off over time.”

Increasingly, companies are utilizing highly potent drugs in biopharmaceuticals, which is creating challenges in terms of cleaning validation, asserts Kolbert. These drugs have extremely low MACO, which has driven analytical limits of detection to barely achievable levels, he adds. As a result, it is becoming necessary to use liquid chromatography coupled with tandem mass spectrometry to hit the toxicologically driven thresholds, Kolbert states.

In Sandle’s opinion, the main challenges in cleaning validation are in relation to residue removal, which is partially dependent upon the required level of cleanliness and the level of cleanliness that can actually be achieved—which relates to the design of the equipment. “Ideally, equipment selection will have embraced quality-by-design and there will be no inaccessible parts,” he continues. “However, in reality, some areas of large items of equipment are easier to clean than others and the main challenges that arise are often cantered on developing cycles that can reach challenging locations [such as] narrow pipes, u-bends, valves, and so on.”

Another area that is sometimes neglected is consideration of the age of equipment, Sandle specifies. “Manufacturing activities have the potential to induce abrasion and corrosion,” he says. “Hence, consideration must be given to ageing equipment with any aspect of cleaning.”

Regulators expect companies to conduct a risk assessment, Sandle points out. “With the risk process, it is good practice to use a multi-disciplinary team. The team should assess indirect product contact pars in relation to: the ability to build-up residues and the ability to transfer residues to product contact sites,” he explains.

Additionally, there is an expectation from regulators that all sample locations selected are represented and that potential ‘worst cases’ are indicated, Sandle notes. “I have seen several regulatory findings for cleaning validation that has been undertaken using locations that are not sufficiently challenging,” he says.

“A common regulatory issue also relates to manual cleaning,” Sandle continues, “especially around verification [as to whether] the operators can continue to undertake manual cleaning to a reliably high standard.”

Essentially, the cleaning process needs to be documented and demonstrated to be valid as per the regulatory bodies’ guidance, such as FDA outlined in Validation of Cleaning Processes (7/93) (3), confirms Kolbert. “There are a number of pitfalls that must be avoided, such as an overreliance on rinse analyses instead of direct observation of the equipment product contact paths; lack of sufficient evidence of reproducibility of any manual steps in the cleaning process; and verification of the absence of cleaning agents at the conclusion of cleaning,” he emphasizes.

“Perhaps the most important lesson from regulatory findings is the importance of running a risk assessment to manage the process, focusing on the proactive identification of hazards, selecting the optimal process to reduce the risk presented by these hazards, and with that ensuring there is a suitable measure of detection in place to verify the outcome,” Sandle says.

Sandle hopes that there will be increased use of rapid methods in cleaning validation that can provide real-time assessments in the near future. 

“Adenosine triphosphate (ATP), protein residue, and glucose residue swabs are among the more useful rapid methods, although further development is required to improve accuracy and repeatability,” he highlights. “Of the different ‘PAT [Process Analytical Technologies] methods’, ATP bioluminescence technology offers a higher sensitivity compared with colorimetric methods.”

In terms of management of cleaning validation processes, software developments are piquing Sandle’s interest, including some that are employing artificial intelligence. “Such packages can help to sort equipment into types where a matrix approach is preferred, as well as enabling scheduling and for setting re-validation targets,” he states.

At its very essence, cleaning validation will require greater consideration, simply as a result of the evolving therapeutic landscape, Kolbert asserts. “The increased use of biological therapeutic agents in pharmaceutical manufacturing will require increased complexity of analytical techniques as activity of the residue is as important as chemical presence,” he summarizes.

1. MMR. Pharmaceutical Cleaning Validation Market: Industry Analysis and Forecast (2021–2027) by Product Type, Validation Test, and Region. Report,.October 2021.
2. CFR Title 21, 210 Part 133.4 (Government Printing Office, Washington, DC).
3. FDA. Validation of Cleaning Processes (7/93), Inspection Guide. Aug. 26, 2014.

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

Analytical techniques for validating cleaning methods must evolve to match the pace of an increasingly complex manufacturing landscape for new therapeutics.

Validating Cleaning Methods in Bio/Pharma Processes

Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

FDA just announced that it will restart in-person, face-to-face meetings with industry sponsors of drugs and biologics, beginning Feb. 13, 2023, after a shift to all-virtual meetings during the COVID-19 health emergency for nearly three years. However, the 

that it has revised its definition of such formal meetings to include both in-person and virtual components utilizing IT platforms that allow for both audio and visual communication. The agency explains that a face-to-face (FTF) meeting between FDA and industry will be a hybrid session, with both in-person and virtual components using cameras.

This redefinition of “in-person” meetings was agreed on in the recently updated user fee agreements for drugs (PDUFA VII) and biosimilars (BsUFA III). FDA also plans to apply this process to formal meetings involving over-the-counter medicines, even though that new user fee agreement does not specify this policy. For now, the agency will limit face-to-face hybrid sessions to requests for Type A meetings, Biosimilar Product Development Type 1 sessions, and Type X meetings, with other meeting types continuing to be fully virtual, without an in-person component.

FDA says it is in the process of updating guidance documents for formal meetings to include this revised definition and is highlighting the new meeting policy on its website to “help reduce uncertainties” for all parties. This dual approach for in-person meetings reflects a hybrid workplace format at the Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER), where many staffers still work only a portion of the time at FDA’s White Oak facility. The agency is upgrading its conference rooms there in phases to better handle hybrid meetings, a process that limits the number of in-person sessions that can be accommodated at this time.

To better manage the in-person component of these hybrid sessions, FDA plans to limit the number of people in the room to “core participants” (i.e., those with “primary speaking roles”) and encourages industry to do the same. Other staffers from both parties will join the session virtually. As FDA gains more upgraded conference rooms, it will consider phasing in additional types of meetings for in-person scheduling, such as Type A and Type B (milestone meetings), BPD Type 1 and Type 2, and Type X and Type Y. Eventually, all FTF formal meetings may be eligible for the in-person format.

FDA will restart in-person, face-to-face meetings with industry sponsors beginning Feb. 13, 2023, after a shift to all-virtual meetings during the pandemic.

FDA Resumes In-Person Meetings with Industry … Sort Of

Ahead of Pharmapack Europe 2023, taking place on Feb. 1–2, 2023, the event’s panel of experts predict increased consolidations in 2023, driven by supply chain concerns and big pharma preferences. A report to be published at the show, foresees continued challenges ahead for smaller and medium-sized packaging companies that are likely to face significant competitive pressures. The report highlights that many companies are looking to sell products globally, with multiple regulatory burdens and divergent standards. Companies turning over €20 million or less are more likely to be potential acquisition targets.

“Pharma customers like to have suppliers they can reply upon for more than single components (e.g.. cap, bottles, etc.) and increasingly want providers that can provide complete solutions,” said Gregor Nischer, MP corporate finance GmbH managing partner, in a press release. “At the same time, regulations are becoming more complex, and small companies don't have the necessary resources, meaning the development of products is becoming prohibitively expensive.”

The event, which is at the center of pharma’s packaging and drug delivery devices industry, will take place at the Paris Expo, Porte de Versailles (Hall 7.2) and will see 5500 attendees and more than 300 companies.

Pharmapack Europe experts say smaller and medium European packaging companies to grow or be acquired.

Pharmapack Experts Predict Increased Packaging Consolidations in 2023

Thermo Fisher Scientific and AstraZeneca announced a collaboration to develop a solid tissue and blood-based companion diagnostic (CDx) test for osimertinib (brand name Tagrisso) on Jan. 24, 2023. The CDx is intended to help identify patients with non-small cell lung cancer (NSCLC) who may be eligible for treatment with osimertinib by identifying tumors that exhibit epidermal growth factor receptor (EGFR) alterations, including exon 21 L858R mutations, exon 19 deletions, or T790M mutations.

According to a company press release, the test will use the Oncomine Dx Express Test on the Genexus Dx System, a fully integrated next-generation sequencing platform. The platform features an automated specimen-to-report workflow and can deliver results after 24 hours.

“As part of our ongoing partnership with AstraZeneca, today’s announcement will help bring targeted oncology treatments to more patients in need of new care options,” said Garret Hampton, president of clinical next-generation sequencing and oncology, Thermo Fisher Scientific, in the press release. “By leveraging the Genexus Dx System’s unprecedented turnaround time, we can help ensure molecular testing results are more readily available to inform vital treatment decisions.”

AstraZeneca and Thermo Fisher will collaborate to develop a solid tissue and blood-based companion diagnostic test for osimertinib.

AstraZeneca and ThermoFisher to Collaborate on Companion Diagnostic Test

Be The Match BioTherapies, a provider of solutions for developing and commercializing cell and gene therapies, in conjunction with the Center for International Blood and Marrow Transplant Research (CIBMTR), is offering expanded clinical research organization (CRO) services. These services are designed to help companies reduce the time required to launch and execute clinical trials.

According to a Jan. 17, 2023 company press release, the new CRO Services provide turn-key solutions, including protocol development and approval oversight, project management, site selection, site start-up, data management, research sample/laboratory coordination, study monitoring, statistical analysis, patient-reported outcomes, and financial administration. Companies also have the option to only choose select services, including data analysis, surveys, site selection and management, and sample management.

The CRO services feature built-out clinical infrastructure, including a single institutional review board, a dedicated data safety monitoring board, master contracts, and 

 compliant software. Customers will also gain a direct link to the CIBMTR outcomes database, consisting of data from more than 575,000 patients.

“Be The Match BioTherapies and its partners have successfully supported bone marrow transplant and cellular therapy clinical trials for nearly 20 years,” said Erin Leckrone, senior director, Clinical Trials, CIBMTR, in the release. “Today, with our formal launch of CIBMTR CRO Services, the expertise and resources honed over decades of work by the leading experts are accessible to small-to-mid-sized biotechnology companies. These services, whether used in whole or as ad hoc support, will accelerate time-to-trial and bridge the transition from research to patients.”

Be the Match BioTherapies’ and CIBMTR’s expanded service offering is intended to aid in the design, implementation, and oversight of cellular therapy clinical trials.

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