Behind the Headlines Episode 27

Ask the Expert

Small Molecules, APIs, and Excipients—Trends, Challenges, and Opportunities

Drug Digest September 2025

Artificial intelligence, machine learning, and novel instruments are helping drug developers.

Enhancing Bioanalysis and Drug Development with Advanced Tools and Technologies

J.P. Morgan Report Lists Biologics, Obesity, China

Top Trends Reshaping Pharma R&D

Feliza Mirasol is the science editor for 

® at AAPS PharmSci 360, Dujuan Lu, PhD, global leader—E&L, SGS Health Sciences, summarizes some of the points in her presentation at the conference, mainly about the differences and similarities between extractables and leachables (E&L) study design between ISO and USP standards.

For instance, she points out that for E&L studies being conducted on medical devices, then the standards from ISO 10993-18 for the chemical characterization of medical devices, whereas E&L studies being done on pharmaceuticals will typically follow USP <1663>/<1664> guidance for pharmaceutical packaging, such as the finished packaging/container closure system, and USP <665>/<1665> for the pharmaceutical manufacturing component.

The major difference between the two, she emphasizes, is that there are different extractables that may be tested. For instance, for a medical device, ”you might need to do an exhaust extraction for implants, while, for the pharmaceutical, you don't really need to do that,” Lu states. In addition, a different type of solvent may be used on a medical device, such as some harsher solvents (e.g., hexane, isopropanol, etc.).

However, in terms of analytical testing between ISO and USP, Lu says that they are similar, such as gas chromatography with mass spectrometry (GC–MS).“There is GC–MS for volatiles; there is direct injection GC–MS for semi volatiles, LC–MS [liquid chromatography with mass spectrometry] for the nonvolatiles, and the ICP–MS [inductively coupled plasma mass spectrometry] for elemental impurities,” she says.

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

Regulatory Expectations in Extractables and Leachables Testing of Combination Products

.” In her talk, she discussed chemical characterization, per ISO 10993-18, which has become important in biocompatibility testing for medical devices. One of the key points in her talk was on the differences and similarities of E&L study designs between medical devices (based on ISO standards) and drug product ( based on USP standards). She also discussed the need for understanding the recent regulatory expectations on E&L testing of medical devices and combination products.

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

 and the distinction between E&L testing for combination products vs. conventional drug products.

Articles

Dujuan Lu, PhD, global leader—E&L, SGS Health Sciences, discusses the differences in how E&L study design should be approached based on whether the study  is following ISO or USP standards. 

Discussing E&L Study Design Between ISO and USP (AAPS PharmSci 360) 

® at AAPS PharmSci 360, Dujuan Lu, PhD, global leader—E&L, SGS Health Sciences, gave her views on what key extractables and leachables (E&L) issues pharma manufacturers should keep in mind, from a regulatory standpoint, when formulating a pharmaceutical that requires a medical device for drug delivery.

She points out that, for any drug product that uses a device as a drug delivery system, a pharma manufacturer will need to consider extractable/leachable testing for both aspects. “You need to conduct your extractables and leachables study for your container closure system for the drug product, but, on the other hand, you need to work out your extractables and leachables for your drug delivery device,” she says.

That that end, a pharma manufacturer may need to consider the regulations in place for that device and then design its E&L study that is applicable to that portion. “You need to consider both aspects in that case,” Lu recommends.

Dujuan Lu, PhD, global leader—E&L, SGS Health Sciences, recommends some key issues that pharma manufacturers should consider when formulating products that require a medical device.

Key E&L Issues to Consider During Formulation (AAPS PharmSci 360)

Science laboratory test tubes, laboratory equipment | Image Credit: © BillionPhotos.com - stock.adobe.com

On Oct 31, 2023, Novartis announced FDA’s approval of Cosentyx (secukinumab) as a treatment for adults with moderate to severe hidradenitis suppurativa (HS). As reported by Novartis, Cosentyx is the only FDA-approved fully human biologic that directly inhibits interleukin-17A (IL17A), a cytokine (a small signaling protein) believed to be connected to the inflammation of HS. Secukinumab is the second biologic approved to treat HS.

HS is a chronic, systemic, and painful skin disease whose symptoms include recurring boil-like lumps which can burst into open wounds, often in sensitive areas, causing irreversible damage. Many patients seeking treatment have a more developed form of HS, as it can take them up to 10 years to get a correct diagnosis. For those individuals, HS can significantly impact their quality of life.

The FDA approval was based on evidence from, as reported by Novartis, the largest Phase II program in HS as of the publication of this article. Cosentyx has been studied clinically for more than 14 years and has treated more than 1 million patients worldwide since 2015.

“Cosentyx can offer effective, lasting relief from HS symptoms so that people with HS have a chance to live every day with confidence,” said Victor Bultó, president, Novartis US, in a Novartis press release. “With this sixth indication approval for Cosentyx—along with ongoing studies in numerous other conditions—we are reaffirming our commitment to reimagine medicine for those living with immunological diseases.”

This is the second biologic approved to treat HS, a painful and reoccurring skin disease. 

New Biologic Treatment for Hidradenitis Suppurativa Receives FDA Approval

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On Nov. 3, 2023, the European Commission announced it was launching a selection procedure for experts looking to join the European Medicines Agency’s (EMA’s) independent Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Orphan Medicinal Products (COMP). 

The six PRAC experts will be appointed to a three-year term that starts on July 2, 2024 and will have an active role in supervision of medicines in Europe. Members of PRAC are independent scientific experts and are expected to actively contribute to PRAC discussions.

COMP is looking for three new committee members to represent patients’ organizations for a three-year term that begins July 1, 2024. Members participate in COMP procedures and attend monthly meetings. They also contribute to scientific discussions, examine documents, and speak for their target group. COMP members are also members of EMA’s Pharmacovigilance Risk Assessment Committee, Paediatric Committee, and Committee for Advanced Therapies.

“The COMP has a strong tradition of involving patient representatives in its work. Its main task is to examine applications sent by companies and decide whether their medicines can be designated as 'orphan'. An orphan medicine is used in the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition that is rare, which means it affects no more than five in 10,000 people in the European Union (EU). The role of a patient organization representative in the COMP is to give a voice to patients and ensure their needs are taken into account in the Committee's decision-making process. Although a medical background is not required, candidates may benefit from a sound knowledge of medical and, to a certain extent, regulatory issues related to medicines in the EU,” the agency stated in a press release.

Submissions for applications for either commission are due Dec. 7, 2023 at 12:00 CET. Current members may also re-apply.

The EC is calling for interested parties for their safety and orphan drug committees.

European Commission Searches for Committee Experts

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

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

Demand for intranasal drug delivery methods has been spurred on by various factors, such as the rising prevalence of allergic rhinitis cases and asthma. As a convenient, non-invasive, alternative route of administration, continued growth in the sector has been forecasted by market researchers (1).

Dr. Ferrer BioPharma—a Florida, US-based company that was founded in 2020—is focused on innovation in the field of intranasal medicines through the use of nanoparticle technology. During CPHI Barcelona 2023, 

 spoke with Dr. Ferrer BioPharma’s CEO, Gustavo Ferrer, to learn more.

“Dr. Ferrer BioPharma is a company that was originated by a group of clinicians/doctors and the whole idea was to look into how we can improve the medications that are delivered into the upper airways—the nose and the respiratory system,” Ferrer specified.

Over a decade ago, Ferrer explained that he and his colleagues started looking into specific things that were bothering patients and clinicians around treatment. Collating the information that was gathered into a book, it became apparent that with over-the-counter medicines that were being consumed, neither the patient nor clinician fully understood what they were using, Ferrer continued.

Using the collected data, it was then possible to start working on optimized medications and associated delivery systems, Ferrer stated. “And, [we are] looking into ways of integrating the delivery service more as well,” he said.

The inaugural Start-Up Market at CPHI Barcelona 2023 has been a great success, according to Ferrar. “[The market] gave us access to presenting our information on our data, discussing with big companies, big tech companies that are looking into new innovations that are coming to CPHI,” he asserted.

Next year’s start-up area should be even more well attended in Ferrar’s opinion. “This is the first time that CPHI has done this [start-up area], and I think it has been highly successful,” he said. “I think, next year, in Milan, you’re going to see a lot more [start-ups].”

In the future, Ferrar noted that Dr. Ferrar BioPharma will continue to optimize drug delivery, providing solutions for medicines to be available with less side effect, so, the pathway to the consumer is shorter. “Our goal in the next few years is to get into the European market,” he revealed.

Nasal Drug Delivery Technology Market Report 2023–2033.

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

Videos

Pharmaceutical Technology Europe® spoke with Gustavo Ferrer from Dr. Ferrer BioPharma, a US company focused on innovative intranasal medications, at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023.

Improving Intranasal Treatments with Dr. Ferrer BioPharma at CPHI Barcelona

The US Pharmacopeia (USP) announced on Oct. 30, 2023 that ATCC and USP have collaborated to create a set of joint products to advance quality control of biological therapies and vaccines. The six products include highly characterized and pure genomic DNA (gDNA) from cell lines. The cell lines can be used to measure residual host cell DNA; gDNA can pose a safety risk if not removed from the product.

These six products allow for the testing of drug substance and process intermediates to determine if residual gDNA has been cleared, using analytical reference materials derived from an authenticated cell line. Derived from host cell lines commonly used in the manufacture of vaccines and biologics, the products support the following platforms:

“Developing cutting-edge medicines in the biologics space requires trusted reference materials and standards to ensure quality, consistency, and safety,” said Amanda Cowley, general counsel and senior vice president Legal, Strategy and People of USP, in a press release. “With increased demands around the globe for new biological medicines on accelerated timelines, it’s essential that there are products and solutions that can be used to address and advance quality assessment and bring confidence to the development process. By focusing on the detection of gDNA, this first set of ATCC and USP products is significant for the future of biological development as it addresses a common concern when it comes to quality and mitigating risk.”

“This initial set of gDNA products are the first of many that will help ensure the quality and safety of biologic therapies which is of utmost importance not only to biopharmaceutical developers and manufacturers, but ultimately patients,” said Ruth Cheng, PhD, ATCC senior vice president and general manager, Research & Industrial Solutions, in the press release. “They trust us to provide them with reference materials and standards that produce reliable, reproducible, and comparable results, so they can deliver the next generation of high-quality and safe treatments to patients.”

ATCC, a global biological materials and standards organization, and USP are planning to release additional product portfolios that provide materials and standards for the development of biological therapies.

According to USP, the products will advance quality and reduce risk in the development and manufacture of biologics and vaccines.

ATCC and USP Launch Six Products Used to Detect Residual Host Cell Genomic DNA

Throughout many industries, continuous manufacturing has proven to be advantageous when compared with traditional batch processing, providing a faster, cheaper, and more flexible option. Within the pharmaceutical industry, there has been some adoption of continuous manufacturing processes; however, a fully end-to-end continuous pharmaceutical process is still challenging (1).

For CONTINUUS Pharmaceuticals—a spin out company from a multi-year collaboration between MIT and Novartis—producing drugs effectively and at a lower cost has been the primary mission. To learn more about the company and how it is enabling end-to-end continuous manufacturing, 

 spoke with the company’s senior marketing manager, Leonardo Vincenzi, at CPHI Barcelona 2023.

"We specialize in process development,” explained Vincenzi. “We have developed, over the years, a plethora of enabling technologies to allow the continuous manufacturing of pharmaceuticals.”

Generally dealing with large pharmaceutical companies, Vincenzi pointed out that CONTINUUS Pharmaceuticals provides process development technology that allows their customers to convert their batch manufacturing systems into continuous ones.

Recently, CONTINUUS Pharmaceuticals has worked with the United States government in response to the COVID-19 pandemic and to aid in the manufacture of some of the drugs that were in shortage, Vincenzi revealed.

“One of the class of drugs that were challenging for us and pushed us to develop new technologies were high-potency products and controlled substances,” Vincenzi said. “Therefore, we developed new technology and new labs for us to work on these kinds of products.”

For Vincenzi, the key differentiating factor for CONTINUUS Pharmaceuticals is the fact that they are offering an end-to-end solution, something that he hasn’t seen anywhere else. “We go from the raw material to your preferred drug product, all the way through your reaction, filtration, drying steps to the final tableting or vial filling,” he remarked.

1. Domokos, A.; Nagy, B; Szilágyi, B.; Marosi, G.; Nagy, Z.K. Integrated Continuous Pharmaceutical Technologies—A Review. 

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

Pharmaceutical Technology Europe® spoke with Leonardo Vincenzi from CONTINUUS Pharmaceuticals, a US company that specializes in process development, at the inaugural Start-Up Market on the show floor at CPHI Barcelona 2023.

Converting to Continuous Manufacturing with CONTINUUS Pharmaceuticals at CPHI Barcelona

Hollie Barton, senior director, Chromatographic Services, for the PPD clinical research business of Thermo Fisher Scientific, spoke with 

®) at AAPS PharmSci 360 on the need for training the current and the new generation of analytical experts for the bio/pharma industry. With the emergence and growth of newer modalities of therapeutics, such as cell and gene therapies, messenger RNA-based and other nucleic acid-based therapeutics, and more advanced forms of antibodies, to name a few, 

the industry has been feeling the void of a lack in technical and analytic expertise

 (1). Barton highlights at least one approach toward filling that void and ensuring the future of analytical expertise.

“It used to be, when folks joined the BioA labs, they went through what was referred to as a new hire training, where they were just exposed to safety, GLP [good laboratory practice], the basics. What we're seeing now is an [addition] of trainers directly associated with functional teams they're supporting. These trainers are actual lab scientists who are coming in, and the first things that they're doing is exposing our folks to protocols, methodology, therapeutic areas, and helping them to understand exactly what they're working on,” Barton explains.

By having these in-house trainers available to staff, she continues, the staff are being advanced at a much quicker rate. “We're also seeing a lot of mentoring and one-on-one training that is being provided to get everybody where they need to be as quickly as possible,” Barton remarks.

analytical challenges in meeting turnaround times

1. Mirasol, F. Biologics Testing Highlights Need for Analytical Skills. 

Hollie Barton, senior director, Chromatographic Services, for the PPD clinical research business of Thermo Fisher Scientific, highlights one approach to ensuring the continuation of analytical expertise.

Ensuring the Next Generation of Analytical Experts (AAPS PharmSci 360)

Jennifer Markarian is a contributing editor for 

Drug target identification and lead optimization of hit compound candidates for orphan diseases | ©HYUNGKEUN - stock.adobe.com

Although biopharmaceutical production today generally takes place in centralized manufacturing facilities, industry and regulators are taking a close look at the benefits of decentralized or distributed manufacturing, which involves smaller and flexible-volume manufacturing operations in multiple locations closer to the site of use and even to point-of-care (POC) locations. POC manufacturing is seen as essential for efficiency in producing personalized medicines. In the near-term future, POC production is likely to be in a controlled environment such as a hospital, clinic, or pharmacy, while in the long term, POC production could extend to other locations. Such a model could enable quality drug production anywhere, from the battlefield to remote villages or even outer space, experts suggest.

The impetus for POC manufacturing comes in part from its potential to alleviate pressing problems, such as drug shortages, pandemic preparedness, and equitable availability of treatments. It is also driven by technological advances that promise to allow efficient and consistently high-quality production using new equipment, analytical tools, and quality control paradigms.

These technologies offer the benefit of making drugs much closer to where and when they are needed. “The advantages of making medicines on demand—to solve issues such as the difficulty of predicting demand and the complexity of the supply chain—are compelling,” states Govind Rao, professor at the University of Maryland, Baltimore County (UMBC) and director of UMBC’s Center for Advanced Sensor Technology.

FDA recognizes the need for flexible and agile manufacturing and sees the potential for portable, distributed manufacturing units to be used for POC manufacturing. In October 2022, the Center for Drug Evaluation and Research (CDER) published a discussion paper that highlighted areas to consider for drugs regulated by CDER as well as the Center for Biologics Evaluation and Research and called for public feedback (1). FDA and the Product Quality Research Institute (PQRI) also held a workshop in November 2022 to gather input from stakeholders. For advanced manufacturing technologies—particularly distributed manufacturing, POC manufacturing, artificial intelligence (AI), and end-to-end continuous manufacturing—seeking input is the first step in FDA’s new Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative, according to a presentation by Michael Kopcha, director of CDER’s Office of Pharmaceutical Quality (2).

The European Medicines Agency’s (EMA) Quality Innovation Group is focused on a similar list of advanced manufacturing technologies, which were discussed at a March 2023 focus group meeting (3). That decentralized manufacturing is being discussed is one reason for optimism regarding its uptake in Europe, suggests Celeste Lamm, director of Global Regulatory Affairs, CMC at Merck. In addition, she points to the European Commission’s proposed new directive (4) that includes a pathway for decentralized manufacturing within the European Union and provides an architecture for responsibility between a central site and decentralized sites. “However, the proposal limits decentralized manufacturing to applications where the central site is located within the EU, and it isn’t clear how the regulation would be applied if some of the decentralized sites were outside of the EU,” Lamm says.

Regulatory uncertainty is an ongoing challenge, with unanswered questions around how connected sites that are located in different regions will be regulated and a lack of global harmonization. Agencies in different regions are communicating with each other, and it is hoped that approaches will be similar. Because no final guidance has been released by any regulatory agency, any differences in requirements are still unknown, Lamm cautions.

Change will take time. Lamm sees similarities between the pace of adoption of distributed manufacturing and that of continuous manufacturing. “Both regulators and industry acknowledge the benefits, but adoption has been slow, because existing traditional manufacturing is frequently sufficient, and it can keep costs down to use existing facilities,” Lamm says. “Adoption of innovative manufacturing technology occurs gradually as there is opportunity to replace existing lines, where existing technology isn’t sufficient (for example, when local manufacturing is needed), and where there is enough clarity to calculate the long-term benefit to justify investment.”

A significant hurdle for distributed and POC manufacturing is how to ensure consistent quality of the drug product, but there is a growing availability of technologies that can meet this challenge. For example, prefabricated, portable cleanrooms and automated processes that fit in these spaces meet the need for standardization of equipment, process, and systems that is crucial to consistency. In addition, digital technology and cloud-based systems in use today make it easier to connect the data and quality systems of different locations. With these tools, distributed manufacturing can even reduce risk and contribute to consistency.

“Using enterprise quality systems across distributed sites is the natural extension of how we currently work in a global environment,” says Lamm. She says that regulators accept aspects of digitally connected quality system solutions, but they note that it is important to ensure that all personnel are similarly trained and are following the same practices.

“There are many flavors of distributed manufacturing for consideration when training personnel,” Lamm adds. Variations include the number of sites and the complexity of the manufacturing process. “The conversation regarding appropriate quality approaches for distributed manufacturing is ongoing, particularly for high volumes of sites or complex manufacturing processes. It is critical that we continue the dialogue between industry and regulators to address concerns.”

Quality assurance/quality control (QA/QC) methods for distributed manufacturing will need to be different from those currently used in centralized manufacturing, says Rao. His group at UMBC recently patented a method for using machine learning (ML) to ensure consistent product quality in UMBC’s Biological Medicines On-Demand (Bio-MOD) system, which uses a cell-free method for end-to-end continuous manufacturing of biologic drug substances (5).

“With cell-free manufacturing, one gene produces one protein in a process that is almost more like chemistry than biology in that it can be consistent,” says Rao. “Our ML algorithm can extract enough data from the process sensors and analytic measurements to get a high degree of confidence that everything about the process is consistent. If the process is the same, the product should be same. The algorithm can also identify any deviation from the expected, such as an air bubble or impurity. This automated function raises the safety level to a much higher level than the current method of testing a product after it is made.”

The Bio-MOD system is currently suitcase-sized, but could be scaled-out to larger volumes, says Rao. He adds that the ML approach can also be used in cell-based manufacturing.

Decentralized, POC manufacturing is particularly helpful for autologous cell and gene therapies (CGTs), because it solves some of the problems of long-distance, cold-chain shipping of patient-specific raw materials and finished products. Various technology providers have created closed, automated CGT manufacturing systems that aim to provide scalable throughput to meet the growing demand for CGTs in centralized or decentralized locations (6).

Sterile compounding is already occurring at point-of-care facilities, some of which are regulated by FDA as 503B outsourcing facilities under strict quality and safety guidelines. James Rorke, vice-president of North American Operations at Steriline, predicts that this rigor will, in the future, extend to some or all patient-specific 503A sterile compounding, which often takes place in pharmacies, hospitals, and institutional settings. Steriline’s Intelligent Compounding System (ICS) meets the need for aseptic patient-specific compounding in a compact footprint, Rorke says.

In the ICS, check-weighing provides the data to prove that every single container has been filled to the optimal volume, explains Rorke. “Incorporating 100% check weighing while filling allows us to target the primary fill volume to the lower end of the acceptable fill range, such that variances in the fill volume are more likely to fall in the nominal range or under filled. If under filled, we add the additional volume of product to meet the requirement. This function practically eliminates over-filled rejects, and it tightens the process window to eliminate waste.”

Biotech company Orgenesis has targeted POC CGT manufacturing with its POCare Network and its Octomera Mobile Production Units and Labs (OMPULs). In June 2023, the company and one of its network partners, the University of California (UC), Davis, announced that OMPULs will be installed and operated by Orgenesis at multiple UC medical and academic institutions (7).

Decentralized and standardized manufacturing is crucial for getting CGTs to patients at a reasonable cost, says Vered Caplan, CEO of Orgenesis. She says that the OMPULs are standardized units that are operated with standard procedures.

“We have defined everything—raw materials, disposables, all the process parameters, cleaning parameters, the environment in and around the unit, all the equipment, and procedures,” Caplan explains. “The unit is not just a mobile cleanroom. It is a closed, automated mini-production facility with standardized, validated isolation units inside. These units can then be duplicated and located at different sites, either in a hospital or nearby. Because of their agnostic nature, we can augment them to many modalities and even applications such as apheresis, if needed, to complete the full value chain.”

Comparability testing of products from the different units will demonstrate that standardization produces comparability; the extent of testing is decided using risk analysis. Caplan adds that although product quality is built-in to the standard process, the decentralized sites will also have quality assurance oversight through centralized audits. “Our work is driven by compliance to the most current guidelines, and our flexible nature allows us to be responsive as we start to see [new regulatory guidance] come to fruition,” she says.

Caplan suggests that hospitals are driving demand for decentralized manufacturing so they can meet their patients’ needs. She says standardized manufacturing platforms like the OMPUL will provide consistent quality at lower cost than each hospital creating their own platform. Orgenesis is also working with solution and equipment providers to ensure that the team is aware of the latest technologies and that they can easily be incorporated into the platform, Caplan says.

CDER. Distributed Manufacturing and Point-of-Care Manufacturing of Drugs, Discussion Paper. 

Kopcha, M. A Regulatory Perspective on Innovations in Pharmaceutical Manufacturing. Presentation at the FDA/PQRI Workshop of the Regulatory Framework for Distributed and Point of Care Pharmaceutical Manufacturing (Nov. 14, 2022).

Listen and Learn Focus Group Meeting Report

EC, Proposal for a Directive Of The European Parliament And Of The Council on the Union code Relating to Medicinal Products for Human Use, and Repealing Directive 2001/83/EC and Directive 2009/35/EC (April 26, 2023).

Rao, G. et al. US Patent 11,685,892 B2. “Methods to Incorporate Machine Learning Analytics for Optimizing Protein Purity, Potency, and Quality in an On-Demand Production System for Point-of-Care Delivery” (June 27, 2023).

Markarian, J. Automation Aids Cell and Gene Therapy Production. 

Orgenesis. Orgenesis and University of California, Davis Sign Partnership Agreement for Rollout of Cell and Gene Therapy Mobile Processing Units and Labs Throughout California. Press Release, June 7, 2023.

Jennifer Markarian is manufacturing reporter for 

Volume 47, No. 11
November 2023
Pages: 12–14

When referring to this article, please cite it as Markarian, J. Considering the Promises of Point-of-Care Manufacturing. 

Emergence of advanced manufacturing technology to ensure quality of biopharmaceutical drugs combined with efforts to identify a regulatory pathway indicate that a distributed manufacturing model is within reach. 

Considering the Promises of Point-of-Care Manufacturing

Prasanth Sambaraju is an independent researcher based in Hyderabad, India. 

Business data analysis and analytics of customers insights with charts. | Smart AI - Stock.adobe.com

Submitted: June 29, 2022
Accepted: July 5, 2023

Stability studies are carried out to study the impact on the quality of drug substance or drug product over a period of time under the combined influence of environmental factors like temperature, humidity, and exposure to light. One of the main purposes of stability testing is to establish shelf life for these drug products. The goal of this paper is to create an Excel spreadsheet, which can be used for statistical testing of more than three stability batches for poolability. The spreadsheet is designed to meet the poolability criteria as per International Council for Harmonisation Harmonised Tripartite guideline for evaluation of stability data, Q1E.

Stability studies in the pharmaceutical industry are intended to measure the degradation of drug product over time. These studies are conducted by taking random samples from a batch that is stored under specified conditions. By using data from these studies, degradation rate as a function of time is calculated. The shelf life is the point in time where the lower 95% confidence interval from the linear fitted regression line crosses the 90% labeled amount (1). The shelf-life estimation for a hypothetical single batch is shown in 

Figure 1. Shelf-life estimation for a single hypothetical batch. Where CI means confidence interval. (Figure courtesy of the author)

The International Council for Harmonisation (ICH) Tripartite Guideline, Q1E 

, describes the procedure for shelf-life estimation. The objective of statistical analysis outlined in the guideline is to determine variability among these batches and then estimate the shelf life accordingly (2).

When multiple batches are manufactured, data from these batches can be pooled for shelf-life calculation. According to ICH’s guideline (2), analysis of covariance (ANCOVA) is used to test statistical difference between both slopes and intercepts of regression lines generated from these multiple batches, using time as a covariate. A significance level of 0.25 is used as the criterion for pooling (3).

In a previous paper (4), the use of Microsoft Excel to test the equality of slopes and intercepts using ANCOVA for three batches was described. The goal of this paper is to test for equality of slope and intercepts using Microsoft Excel, when the number of test batches is greater than three. Two reported datasets each containing data from six batches will be used to demonstrate this approach.

Two stability data datasets each involving six batches from Ruberg and Stegeman’s research (1) were tested separately using the aforementioned approach. The procedure involved regression analysis of stability data using in-built Excel functions and then creating an ANCOVA table using these values. For multi-batch stability data

 shows the possible scenarios for drug product degradation. The common intercept separate slope (CISS) model is used only in special circumstances (5). The other models used to describe stability studies are listed below:

Figure 2. Different models to explain stability studies.

*CISS model is only used in special circumstances. (Figure courtesy of the author)

Common intercept common slope (CICS) model.

 This model indicates that all the batches have a common intercept and slope. The values for common slope and intercept for dataset 1 are obtained by using regression analysis in Excel.

Separate intercept separate slope (SISS) model. 

This model indicates that different batches have different slopes and different intercepts. These values can be obtained by regression analysis from individual batches separately. Residual sum of squares is obtained by adding squared differences between observed and expected value. The expected value is calculated using slope and intercept from individual batches.

Separate intercept common slope (SICS) model.

 This model indicates that different batches have common slope and separate intercept. These values can be obtained by regression analysis using dummy dependent variables containing ones and zeros.

ANCOVA calculations for comparing the intercepts and slopes of stability batches were calculated as described (4) and are shown in 

. These tests make a comparison between two models, simple (reduced) vs. complicated (full) model (5). The P-value obtained for row C in ANCOVA table (

) was less than 0.25, due to which null hypothesis was rejected (SICS model) and alternate hypothesis (SISS model) was used for shelf-life estimation.

Table I. Slope and intercept for different models. Where CICS means common intercept common slope; SISS means separate intercept separate slope; SICS means separate intercept common slope.

Table II. ANCOVA calculations for dataset 1. Where CICS means common intercept common slope; SISS means separate intercept separate slope; SICS means separate intercept common slope; SSE means sum of squared errors; SS is the difference between the sum of squared errors of null and alternate hypothesis and df is the difference between degrees of freedom of null and alternate hypothesis.

The calculations comparing intercepts and slopes of stability batches are shown in 

) obtained for dataset 2, the P-value for row C was greater than 0.25, thereby failed to reject the null hypothesis (SICS model). In row B, the P-value was less than 0.25, due to which null hypothesis was rejected (CICS model) and alternate hypothesis (SICS model) was used for shelf‑life estimation.

Table III. Slope and intercept for different models. Where CICS means common intercept common slope; SISS means separate intercept separate slope; SICS means separate intercept common slope.

Table IV. ANCOVA calculations for dataset 2. Where CICS means common intercept common slope; SISS means separate intercept separate slope; SICS means separate intercept common slope; SSE means sum of squared errors; SS is the difference between the sum of squared errors of null and alternate hypothesis and df is the difference between degrees of freedom of null and alternate hypothesis.

The stability model selected at the end of analysis for both datasets matches with the model used for shelf-life estimation (1). The advantage of this Excel spreadsheet approach is that it gives the users an easy and convenient way to test for poolability of stability data. The procedure doesn’t involve any programming and can be used when the number of batches is greater than three. The limitation of this method is that it can be used only to evaluate data from one factor, batches.

Ruberg, S.J.; Stegeman, J.W. Pooling Data for Stability Studies: Testing the Equality of Batch Degradation Slopes. 

Lee, H.-y.; Wu, P.-c.; Lee; Y.-j. stab: An R Package for Drug Stability Data Analysis. 

LeBlond, D. Hypothesis Testing: Examples in Pharmaceutical Process and Analytical Development. 

LeBlond, D.; Griffith, D.; Aubuchon, K. Linear Regression 102: Stability Shelf Life Estimation Using Analysis of Covariance. 

Prasanth Sambaraju is an independent researcher based in Hyderabad, India.

®
Vol. 47, No. 11
November 2023
Pages: 24-27

When referring to this article, please cite it as Sambaraju, P. Pooling of Batches for Stability Data Analysis. 

One of the main purposes of stability testing is to establish shelf life for these drug products. The goal of this paper is to create an Excel spreadsheet, which can be used for statistical testing of more than three stability batches for poolability. 

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