Susan Haigney

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On Jan. 8, 2024, FDA announced that Leiters Health is voluntarily recalling 33 lots of products, including vancomycin intravenous (IV) bags, phenylephrine IV bags, and fentanyl IV bags, because of the potential for superpotency. The products may contain twice the labeled amount, according to the company, because “the semi-automated IV bag filling equipment used to fill the recalled batches may not eject the IV bags properly when compressed air tanks become low or a leak was detected, causing the recalled IV bags to be dosed twice.”

Fentanyl packaged in an IV bag under codes F3355 and F3342.

Phenylephrine packaged in an IV bag under codes F3360 and F3352.

Vancomycin packaged in an IV bag under codes F3206 and F3208.

The recalled products were distributed to hospitals nationwide, and details can be found at FDA.gov.

The company states in the press release that the use of defective vancomycin and fentanyl IV bags may result in life-threatening adverse events. According to the company, twice the infusion rate of vancomycin, which is used for endocarditis and staphylococcal infections, may cause acute kidney injury, ototoxicity, low blood pressure, wheezing, shortness of breath, hives, itchy skin, and skin redness. Higher doses of fentanyl may cause respiratory depression that could result in hypoxia and may also cause cardiac adverse events. Higher doses of phenylephrine, which is used for perioperative hypotension, hypotension during anesthesia, and shock, may cause high blood pressure.

The company states it has not received any reports of adverse events related to the recall as of the date of the press release. Adverse events may be reported to FDA via the agency’s MedWatch program. Consumers may contact the company at recall@leiters.com for more information.

Articles

The potential for superpotent drug initiated the voluntary recall.

Leiters Health Recalls Vancomycin IV Bags, Phenylephrine IV Bags, and Fentanyl IV Bags

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On Jan. 8, 2024, WuXi AppTec, a contract research, development, and manufacturing organization (CRDMO), announced it is expanding its manufacturing facilities with two new peptide manufacturing plants—one at the company’s Changzhou facility and the other at its Taixing site, both in China. The expansion will boost solid-phase peptide synthesis total reactor volume to 32,000 L. The plants will use digital operation systems with automated solvent delivery that optimize production and minimizes human errors, reducing production cycle time.

The new peptide plant at Taixing spans a total area of 169 acres and will facilitate the manufacture of synthetic molecules, including small molecules, peptides, oligonucleotides, and conjugates. Phase one of construction, which will be operational in 2025, includes nine plants with a total reactor volume of more than 1000 m

. The facility will include a dedicated plant for API cleanrooms. After completion, the expansion will increase WuXi AppTec’s total reactor volume for small-molecule API and intermediate manufacturing to more than 4000 m

“The launch of our new peptide manufacturing plants and the development of the new Taixing site are important milestones for WuXi AppTec. Our expanded capacity is essential for accelerating drug development and ensuring a reliable supply chain for our global partners. WuXi AppTec will continue to focus on enhancing our capability and capacity, accelerating innovative therapies to patients globally,” stated Minzhang Chen, co-CEO of WuXi AppTec, in a press release.

WuXi AppTec’s TIDES CRDMO platform features services for API and drug product from discovery to commercial stages for oligonucleotides, peptides, and conjugates. The company supported approximately 50 preclinical- to commercial-stage peptide projects in 2023.

The expansion will boost solid-phase peptide synthesis total reactor volume to 32,000 L.

WuXi AppTec Expands Peptide and API Manufacturing

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QurAlis, a clinical-stage biotechnology company located in Cambridge, Mass., announced on Jan. 3, 2024 the opening of its European Union (EU) headquarters in Leiden, The Netherlands. The location will serve as a European hub for operations that include clinical trials through commercialization of the company’s products. QurAlis’ product pipeline includes therapies to treat neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). QurAlis focuses on treatments for “patients who have a loss of Kv7.2/7.3, patients who have loss of STATHMIN-2, as well as patients with loss of UNC13A and impairment in synaptic signaling.”

“The expansion of our operations into Europe represents a new chapter for QurAlis, building upon the tremendous momentum of our organization,” said Kasper Roet, CEO and co-founder of QurAlis, in a press release. “In a short period of time, QurAlis has made significant progress with regulatory approvals for our clinical programs in the EU, Canada, and the UK [United Kingdom]. The successful completion of the quality systems inspection by the Dutch regulatory agency will allow us to directly leverage our world-class ASO manufacturing expertise and control our end-to-end production supply chain. With our new European headquarters, and the skilled talent network in Leiden and the region, we will further strengthen our position as we bring breakthrough precision medicines to patients with ALS, FTD, and other neurodegenerative diseases.”

“QurAlis’ new location in Leiden is designed to not just meet our current needs, but also to scale with our business as we continue to grow,” said Hagen Cramer, chief technology officer of QurAlis, in the release. “Our new European headquarters will allow us to release ASOs and other products into the European market for our programs so that we can deliver innovative solutions and make a meaningful difference in patients’ lives.”

The new Europe headquarters will be the hub for the company’s European operations, including production of product.

QurAlis Opens European Headquarters in The Netherlands

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Validating the effectiveness of the cleaning of pharmaceutical manufacturing and process equipment is part of good manufacturing practices (GMPs) (1,2). Regulators expect manufacturers to be able to show that their cleaning process is sound. Analytical methods and tools assist in assuring that equipment is clean and ready for use. “An analytical method provides an independent assessment that the equipment [being used] for a client’s product is clean,” according to Wayne Goodwin, director, Quality Operations at BIOVECTRA.

Preventing cross contamination between manufacture of different products is of primary concern. Residue from a previous product must be reduced to acceptable levels before equipment can be used to manufacture a new product, remarks Goodwin. Regulators, and clients, need to be assured that this has been done. “[Regulators and clients] want the entire cleaning package, including work instructions for cleaning the equipment and results of rinse and swab testing. They routinely review the method validation reports which support the analytical methods,” he says. “[Manufacturers] also must show that [the] cleaning acceptance criteria are appropriate as [they] clean from Product A to go into Product B. The justification typically includes an acceptable daily exposure (ADE) limit for the outgoing product and also incorporates factors such as shared equipment surface areas and the rinse and swab recovery factors for the
outgoing product.”

Analytical procedures can be used to quantitate if residuals of a drug product or cleaning agent remain on equipment after it has been cleaned, asserts Shailesh Vengurlekar, senior vice president of Quality and Regulatory Affairs, LGM Pharma. “Determining or quantitating the left-over residues helps reduce the risk of cross contamination or adulteration of products,” he says.

When creating an analytical method to ensure cleaning validation, the type of residue being measured, the sampling method, and the residue acceptance limit (RAL) in the sample should all be considered, according to Vengurlekar. “The selection of an analytical method depends on the chemical nature of target residues and analytical limits established for those residues. A key element in the selection of an appropriate analytical method is that the method produces a result that has a logical, scientific link with the target residue,” he says. The method or procedure should confirm residue has been removed from the equipment during cleaning. “The analytical procedure is first developed and validated to ensure that the drug substance can be recovered/detected using that methodology,” says Vengurlekar. “The validation of a cleaning validation analytical method for product residue must be based on the RAL calculated for that material as defined in a cleaning validation plan. The method may be considered valid for any RAL within the validated RAL recovery range. If the RAL is outside this recovery range, the method must be revalidated with respect to the affected parameters/characteristics.”

According to Goodwin, an appropriate analytical method for cleaning validation includes limit of detection, quantitation of the method, specificity, and recovery studies from both the rinse and swab samples. “Data from the cleaning validation exercise demonstrate that the method is suitable for use,” he states. “If a product goes into [the] GMP equipment, then a cleaning method validation [is needed] regardless of the lifecycle status of the previous product.”

Analytical procedures should be meticulously designed, stresses Goodwin, to detect impurities and confirm cleanliness. “A ‘non-detect’ result may arise if our testing methods lack sensitivity for the target analyte,” he says. A method should attain the necessary specifications. “For cases when the preferred method for a particular product isn’t sensitive enough to detect low levels, we’re obligated to find an alternative method with sufficient sensitivity,” Goodwin confirms.

The method should also fit the needs of the production facility, Goodwin continues. “For example, our preferred method might use HPLC [high-performance liquid chromatography] with methanol as the diluting solvent. However, if that area of the production facility is not rated for flammable solvents, manufacturing teams cannot use solvent in the cleaning and cannot provide the QC [quality control] team with methanol samples,” he specifies. “Other factors such as material cost and reagent toxicity must also be considered.”

Analytical methods should meet detection limit requirements. “Regardless of what the cleaning is, we perform a product-specific validation of the analytical methods, such as TOC [total organic carbon], HPLC, or UV [ultraviolet]. This [product-specific validation] provides the data for the overall process cleaning validation,” continues Goodwin.

Goodwin also points out that analytics ensure cleaning process consistency. “The work instructions are coupled with automation and process analytical technology (PAT) to demonstrate that we are able to remove the previous product from the equipment consistently every time,” he says.

Analytical tools used in cleaning validation include HPLC (limit and quantitate test), gas chromatography (GC), spectrophotometry, TOC, microbial analysis, total protein analysis, and visual inspection. However, the analytical tool used for cleaning validation depends on the product used on the equipment, according to Vengurlekar.

Pre-approved test methods developed for a cleaning activity for a specific product should be compared for every quality control release, Goodwin agrees. “A one-size-fits-all approach is not feasible at BioVectra given the varied product mix,”
says Goodwin.

“For complex chemistry and small molecules, product-specific analytical methods, like HPLC or GC, [are typically used] to detect trace amounts of the intact API. Often this means adapting the release assay method to detect 1000–10,000-fold lower concentrations in the cleaning samples, at levels approaching 1 µg/mL in solution,” says Goodwin. “For biologics, nonspecific methods, such as TOC and conductivity, [are generally applied], which are more appropriate to these sample matrices.”

Data collected from analytical laboratory testing can provide information on method sensitivity and determine recovery for rinse and swab samples, according to Goodwin. Cleaning solvent volumes, temperatures, contact time, and stir rate data can be obtained from production data. Coverage testing on equipment that uses spray balls can determine if there are dead spots, he says.

“The information collected on a given cleaning validation can certainly be used to inform subsequent cleaning activities for other products, though it is important that the development work is sound prior to putting any new product into manufacturing equipment,” Goodwin stresses.

Analytics can be used to develop a cleaning validation procedure and evaluate critical process parameters such as solubility, porosity and roughness, concentration of cleaning agents, water temperature and flow, contact time, and cleaning times, confirms Vengurlekar. “The level of drug product and cleaning agents detected through analytical methods after cleaning can be used to improve the cleaning procedure to ensure residuals/carryover to the next product are within allowable limits and prevent risk to consumers,” he summarizes.

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients


Vol. 48, No. 1
January 2024
Pages: 26–27

When referring to this article, please cite it as Haigney, S. Proving It’s Clean with Analytics. 

Analytical methods and tools play a pivotal role in cleaning validation.

Proving It’s Clean with Analytics

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The European Medicines Agency (EMA) announced on Dec. 20, 2023 that the midterm report of the European Medicines Agencies Network Strategy (EMANS) shows that the pandemic strengthened the network, allowing it to be on track to meet its goals and objectives regarding drug availability; data management; innovation; antimicrobial resistance; supply chain challenges; and sustainability of the network. EMA and the Heads of Medicines Agencies (HMA) published the network strategy in December 2020 to guide the delivery of operational, regulatory, and scientific output and shared goals for a five-year period.

EMANS sets out how the network provides supply of safe and effective medicines by adapting to industry developments and emerging health threats, such as a pandemic. Six priority focus areas in line with the European Commission’s roadmap for a pharmaceutical strategy in Europe were outlined, and EMANS identifies goals and objectives for each area. The midterm report provides a look at achievements by EMANS from January 2021 to June 2023. The report also takes a look at the original goals and the actions proposed to deliver those goals. The conclusion of the report is that the original proposal is valid and relevant, and delivery of the remaining actions will be delivered.

“Despite the unprecedented challenges presented by the COVID-19 pandemic and the resource that has been deployed across the medicines regulatory network in response, a lot of progress has been made in the six priority focus areas of our network strategy,” says Emer Cooke, EMA’s executive director. “The end of the public health emergency and the lifting of the business continuity planning means we will once again be in a position to focus more fully on delivering patient-relevant medicines and digital transformation while continuing to deal with health threats and supply issues.”

Karl Broich, chair of the HMA Management Group, said: “The European medicines regulatory network, with its unique way of collaborating and pooling scientific and regulatory expertise across Europe, has just emerged from three long years of the COVID-19 health emergency. Difficult periods often serve to stress test systems and reveal facture lines and valuable learnings. From the network’s point of view, this experience has strengthened the desire to continue building together a better regulatory system and all the priorities envisioned as part of the EMANS.”

The midterm report of the European Medicines Agencies Network Strategy finds that the network has strengthened and is on track to achieve its objectives.

European Medicines Regulatory Network on Track to Meet Goals

Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products

, to provide sponsors with direction for designing a new registry or using an existing registry to support regulatory decision-making about safety and effectiveness of a drug. It does not, however, discuss choice of study design or statistical methods used to analyze registry data.

The guidance document is in response to requirements in section 505F of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Section 505F created a Real-World Evidence (RWE) Program in order to evaluate the use of RWE to support approval of a new indication for a previously approved drug under section 505(c) of the FD&C Act.

The guidance document includes considerations about a registry’s fitness-for-use, linking a registry to other data sources for supplemental information, and supporting FDA review of submissions that incude data from registries. The agency discusses using registry data to support regulatory decisions, the relevance of registry data, and the reliability of such data.

The guidance defines a registry “as an organized system that collects clinical and other data in a standardized format for a population defined by a particular disease, condition, or drug exposure.” Real-word data are defined in the guidance document as “data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.” RWE is defined by FDA as “the clinical evidence about the usage and the potential benefits or risks of a medical product derived from analysis of RWD.”

The final guidance document provides recommendations for designing a new registry or using an existing registry to support decisions regarding safety and effectiveness of a drug.