Parenteral drug development and manufacturing within the bio/pharma industry is growing, due, in part, to the rising number of therapeutic biologics being developed and approved. As a result of this market trend, lyophilization services for bio/pharmaceuticals are also experiencing greater demand (1,2).

Lyophilization, or freeze-drying, has been used for healthcare products for over eight decades and enables the preservation of aqueously unstable products (3). “Freeze-drying or lyophilization in pharma requires the removal of water from a frozen drug as dry powder,” confirms Shaukat Ali, PhD, FAAPS, senior director, Scientific Affairs and Technical Marketing at Ascendia Pharma. “[The technique] is required for maintaining the stability, structure integrity, and a longer shelf life and efficacy of [numerous drug] products.”

“Lyophilization holds several promising applications in the biopharmaceutical sector, significantly enhancing the stability and usability of products,” adds Greg Sacha, associate director, Research & Development at Simtra. “One of the most promising applications is the ability to significantly extend the shelf-life of biopharmaceuticals. When correctly formulated, biopharmaceuticals can be frozen and dried without compromising their efficacy. This process stabilizes the product, preventing degradation over time, which is a common issue with liquid formulations.”

Prolonging the shelf life and ensuring the stability of biologics and biopharmaceutics is key, continues Ali. “Lyophilized formulations help enhance the product stability of biologics both for therapeutics and vaccines including proteins, antibodies, enzymes, polypeptides, DNA, siRNA [small interfering RNA], mRNA [messenger RNA], oligonucleotides, antibody-drug conjugates, liposomes, polymeric and lipid nanoparticles, among others,” he says.

Additionally, Sacha points out that lyophilization can help to reduce the need to store products at low temperatures. “This [application] is particularly advantageous for global logistics, as maintaining a cold chain can be both costly and complex. Freeze-dried biopharmaceuticals can be stored and transported at room temperature, simplifying the supply chain and reducing costs,” he notes.

“Overall, lyophilization offers significant benefits in terms of stability, storage, and logistics, making it a vital process in the development and distribution of biopharmaceuticals,” Sacha specifies.

Not all molecules can be lyophilized, however, and there are specific limitations associated with the technique, Sacha warns. “[For example], some molecules, like certain cephalosporins, degrade during freezing and drying,” he says.

Another limitation can be the requirement of long drying times and precise temperature control as a result of very low molecular critical temperatures, Sacha adds. This limitation is particularly difficult at full scale, he highlights.

“Longer primary and secondary drying time could be an impediment in mass production of lyophilized products,” agrees Ali. Additionally, scale-up of lyophilization can be challenging as a result of the stringent requirements for freeze-dried processes and products, he states.

Volatility is a further limitation to lyophilization, notes Sacha. “Some molecules are volatile under the shelf temperature and vacuum conditions used during freeze-drying, meaning they can be removed as a vapor from a solid during the process,” he specifies.

Furthermore, achieving uniformity and quality of a lyophilized product can be limiting, Ali remarks. “The product’s uniformity depends upon multiple factors and is often controlled by fine tuning the process parameters,” he says.

A lack of control over the uniformity of lyophilized products can impact the potency of certain drug products, Ali asserts. For example, in a study by Bennett 

 (4), the potency and stability of live varicella-zoster virus (Oka strain) vaccines were found to be negatively impacted by a longer controlled vacuum preparation method, Ali states.

Interfaces should be kept in mind for lyophilization, Sacha continues. “Biopharmaceuticals can interact at the container/solution, solution/air, and ice/solution interfaces, leading to unfolding and aggregation,” he says. “Aggregation results in the loss of the active molecule and, consequently, a loss of potency.”

The use of cryo- and lyoprotectants is also crucial, Sacha stresses. “These protectants, such as amorphous sugars, provide necessary water and hydrogen bonding, preventing the unfolding and aggregation of the biopharmaceuticals during freezing and drying,” he says.

Excipients play an important role in stabilization of drugs and are commonly used as cryoprotectants, adds Ali. “Sugars, amino acids, surfactants, and polymeric excipients are commonly used as stabilizers and lyoprotectants,” he specifies.

“Without proper protectants, biopharmaceuticals can be over-dried, leading to destabilization and reduced potency. Amorphous sugars help maintain the structural integrity by preventing over-drying,” states Sacha. “Proper formulation and the use of appropriate protectants are essential to maintain the potency of drug products during lyophilization.”

However, advancements in the field of lyophilization have emerged that are helping to enhance efficiency and product quality, Sacha asserts. “One significant advancement is the implementation of quality by design (QbD) in the development of primary drying cycles,” he says. “This approach involves applying fundamental principles of heat and mass transfer to comprehensively understand the freeze-dryer and the thermal characteristics of the product. By doing so, it removes the guesswork from the development process, ensuring that primary drying conditions keep the product temperature well below its critical threshold.”

Controlled ice nucleation techniques represent another notable advancement for Sacha. “By controlling the nucleation of ice during the freezing step, variability between vials on a shelf and across different shelves is significantly reduced. This innovation is particularly impactful for amorphous products, as it can dramatically shorten primary drying times and improve product uniformity,” he explains.

“Recent advancements in freeze drying technology and process optimization parameter using controlled devices and equipment designs have been made for more efficient and to achieve reliable pharmaceutical dosages,” agrees Ali. “For instance, in improving the refrigeration system, state-of-the-art condensers are designed to handle high vapor loads to facilitate the efficient vapor flow during lyophilization. In addition, sterilization methods, automation, and isolators are all considered for improving the lyophilization process.”

Companies have also innovated with lyo beads, which are spherical freeze-dried solids, that have proven useful with products that are difficult to freeze in conventional vials, Sacha continues. “The spherical shape of lyo beads provides excellent flow properties and efficient freeze-drying due to their relatively small size,” he says.

“Moreover, there have been advancements in microwave-assisted freeze-drying,” Sacha asserts. “This technique can substantially reduce primary drying times without adversely affecting the product. By integrating microwave energy, the drying process becomes faster and more efficient, preserving the product’s integrity.”

Sacha expects that a few key advancements will form the future focus for lyophilization. One such advancement will be reducing the footprint of lyophilization systems, he says. “Developing more compact lyophilization systems to handle smaller volumes of biopharmaceuticals efficiently is increasingly important for personalized medicine and small-batch production,” Sacha confirms.

The implementation of continuous lyophilization processes will also be important in the future, Sacha specifies. “This approach aims to streamline production and improve efficiency,” he says.

There has been a recent emphasis on continuous freeze-drying technology that allows real-time monitoring, confirms Ali. “Process analytical tools (PAT) such as near-infrared spectroscopy (NIR) and Raman spectroscopy are very promising methods for monitoring inline quality attributes. Both techniques are highly sensitive and complementary to each other,” he states.

Through automation, it will be possible to reduce contamination risks and remove the potential of human error, Ali continues. “For example, advanced freeze-drying sensors and PAT allow better control of the process in primary and secondary drying processes under controlled nucleation regime by QbD for robust continuous manufacturing of lyophilized drug products,” he remarks.

“Ongoing improvements to make lyophilization more efficient, such as optimizing energy use, reducing cycle times, and enhancing automation and control systems [will be explored],” summarizes Sacha. “[All] these advancements will help meet the evolving needs of the biopharmaceutical industry, enhancing both scalability and efficiency.”

Biologics Market Size, Share and Trends Analysis Report by Source (Microbial, Mammalian), by Product (mAbs, Recombinant Proteins, Antisense and RNAi), by Disease Category, by Manufacturing, by Region, and Segment)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2024–2033

. Market Report, April 2024.
2. The Insight Partners. 

Lyophilization Services for Biopharmaceuticals Market Report 2023–2028

. Market Report, September 2023.
3. Trappler, E.H. Application and Insights for Lyophilization of Parenteral Products. In 

Practical Aseptic Processing Fill and Finish, Volume 1

, Lysfjord, J. Ed.; Parenteral Drug Association, 2009; pp. 31.
4. Bennett, P.S.; Maigetter, R.Z.; Olsen, M.G.; et al. The Effects of Freeze Drying on the Potency and Stability of Live Varicella Virus Vaccines. 

®
Vol. 48, No. 7
July 2024
Pages: 16–17

When referring to this article, please cite it as Thomas, F. The Rising Iceberg of Lyophilized Innovations. 

Articles

Manufacturing

The increased demand for biopharmaceutical products is increasing the demand for lyophilization innovations and services.

The Rising Iceberg of Lyophilized Innovations

The analytical testing of drug substances is a critical aspect of development and manufacturing within the bio/pharma industry. These comprehensive tests are used throughout the drug development lifecycle to ensure each product used within a therapy is safe and effective for use, and of the highest quality. To learn more about drug substance testing, 

® spoke with Pavan Kumar Kunala, global biologics lead, Almac Sciences, and Sander Kok, PhD, director Analytical Sciences at Ardena.

 Could you run through the role of drug substance testing for bio/pharmaceuticals and the types of tests generally used?

 The analytical methods for drug substances play a pivotal role in the journey of biologics development, from the early clinical phase to commercialization, ensuring that the product meets the highest standards of quality, safety, and efficacy for therapeutic use. Moreover, some of the drug substance [DS] methods are instrumental in testing in-process samples, providing insights into process development and ensuring that manufacturing remains consistent and robust during the early phases of product development. The characterization of the [DS], which involves understanding the critical quality attributes (CQAs) and selecting appropriate orthogonal analytical methods to assess them, is another vital application of these methods. Additionally, these methods are employed in the release and stability testing of the bulk [DS], thereby ensuring consistent quality across different batches. (See 

 for a link to a detailed review of drug substance test categories.)

 Typical tests in a drug substance analytical laboratory consist of in process control, release, and stability testing of DS batches. In the pre-clinical phase, analytical methods are developed, including forced degradation and robustness tests. In terms of methodologies, DS tests include at least the methods to verify identity, assay and impurities following [the] ICH [International Council for Harmonisation] Q6A guideline.

Technological advances and novel approaches

 Have there been any technological advances or novel analytical approaches that are helping to improve efficiencies in drug substance testing?

 For many years, ultra-high pressure liquid chromatography (UHPLC) has brought the pharmaceutical analytical community additional separation power and reduced analysis time. Particularly the strong improvement in resolution compared to conventional HPLC enabled a further and detailed characterization of drug substances with a complex impurity profile.

 Certainly, the advent of advanced analytical techniques is boosting the testing efficiency of biologic drug substances. For example, the use of next-generation sequencing (NGS) in identity testing of mRNA [messenger RNA] therapeutics brings significant improvements in efficiency. Traditional methods for identity testing often involved time-consuming and laborious processes such as Sanger sequencing or mass spectrometry. In contrast, NGS can process millions of sequences concurrently, drastically reducing the time required for comprehensive analysis. This high-throughput capability allows for rapid identity confirmation, accelerating the pace of mRNA product development and production.

Similarly, the use of nucleic acid testing (NAT) methods for mycoplasma testing have shown significant benefits over traditional culture methods in terms of efficiency for cell and gene therapy products. NAT-based methods are highly sensitive, specific, and can provide results within few hours, whereas culture methods often require weeks to grow and identify mycoplasma colonies. This rapid turnaround time is particularly advantageous for cell and gene therapies, where time is of the essence. It enables prompt detection of contamination and immediate intervention. Furthermore, the timely identification of mycoplasma contamination can prevent substantial financial losses.

 What are the main challenges in terms of drug substance testing nowadays given the evolving therapeutic landscape?

 More and more highly potent drug substances are of interest to our clients. This brings a challenge to create a safe work environment: not only to prevent cross-contamination towards subsequent manufacturing campaigns, but of even importance is the containment of these highly potent materials from the operators and analysts. Patient and employ

Another important and challenging subject is the quantification of potential genotoxic impurities (PGI). As PGIs are frequently highly reactive, a careful approach is needed in the development of a reliable, quantitative analytical methodology. Detection of low levels [of PGIs] are required, and this [necessitates] analytical creativity in sample preparation, separation, and advanced detection techniques to meet the strict [regulatory] r

 The evolution of newer biologic modalities is transforming the landscape of treatment options available to patients, offering more effective and targeted therapies for a wide range of diseases. This is a significant step forward in the pursuit of personalized medicine and improved patient care. However, this changing therapeutic landscape presents its own challenges.

For example, analytical ultracentrifugation (AUC) is a widely used analytical technique for determination of empty and full capsid ratios in adeno-associated virus (AAV)-based gene therapies. AUC is favored for its high-resolution capabilities and minimal sample preparation requirements. However, the deployment of AUC in a good manufacturing practice (GMP) environment for the release of AAV therapy drug substances present considerable challenges. These [challenges] include limited availability of instrumentation models that could be used in a quality control laboratory, instrumentation software which may not be fully compliant with current data integrity standards, and the complexity involved in training analysts in the comprehensive workflow of data analysis.

[Additionally], the diversity of biologics, ranging from long-peptides and proteins to complex monoclonal antibodies and gene therapies, complicates the establishment of universal standards for characterization of impurities. The lack of specific limits for the reporting and identification of impurities in biologics presents a significant regulatory challenge, given the potential impact of these impurities on the safety and efficacy of the biologic.

As we continue to innovate and develop new dosage forms and therapeutic modalities, the analytical techniques and tools we use to test these substances must also evolve to comply with current regulations.

®
Vol. 48, No. 7
July 2024
Pages: 18–19

When referring to this article, please cite it as Thomas, F. Advancing Analytical Testing Techniques. 

Analytics

Although advancements in analytical drug substance testing are being made, the increasing diversity of the therapeutic landscape is necessitating further innovation.

Advancing Analytical Testing Techniques

In biologics production, biomanufacturers need to demonstrate clearance of impurities and contaminants during the manufacturing process. Host cell impurities (HCPs) are a major class of process-related impurities (1) that must be monitored, and their presence must be documented throughout the development and manufacturing process of a biologic.

“The presence of HCPs beyond a permissible regulatory limit can potentially result in adverse immune response, toxicity, possible biological activity, [and] hence, interfere with the potency and stability of the drug as well as cause disruption during the purification process,” states Anis H. Khimani, PhD, senior strategy leader, Life Sciences, Revvity, a Waltham, Mass.-based provider of health science solutions, technologies, expertise, and services. “It is therefore important to monitor and control the presence of HCPs in large-molecule drug formulations all along upstream through downstream processes.”

Olaf Stamm, PhD, technical business development director, Biopharmaceutical Testing Solutions, Charles River Laboratories, highlights several reasons why monitoring the presence of HCPs during biologic drug manufacture is critical:

 HCPs can cause adverse immune reactions in patients, even in small amounts. These proteins can trigger allergic responses or other immune-mediated effects, which can compromise patient safety.

 HCPs can interfere with the biological activity of the drug, such as by degrading the drug product, altering its function, or inhibiting its intended biological activity, thus reducing the biologic’s efficacy.

 HCPs can affect the stability of the biologic by, for example, inducing aggregation, oxidation, or other forms of degradation. These effects can reduce product shelf life and affect product quality over time.

 Consistent monitoring of HCPs ensures consistency from batch-to-batch in the manufacturing process. Variability in HCP levels can signal an issue in the production process, such as changes in cell-culture conditions.

 Regulatory agencies such as FDA and the European Medicines Agency have stringent guidelines for HCPs in biologic products. Therefore, manufacturers must demonstrate that HCP levels are within acceptable limits in their product to gain approval for that product’s purification inefficiencies, which then needs to be addressed to maintain product quality.

“Overall, monitoring HCPs is essential to ensure that biologic drugs are safe, effective, and of high quality, meeting both regulatory standards and patient needs,” Stamm says.

Effective HCP clearance starts in the upstream processing stage, where optimization of cell-culture conditions with respect to optimal viability helps to reduce the load of HCP in the harvest material, notes Stamm. He explains that this approach works mainly for expression systems (e.g., Chinese hamster ovary [CHO] cells), which secrete their product. In the case of critical HCPs that might co-purify with the product protein, however, some production cell lines have been genetically engineered by knock out or silencing of such particular HCPs, he points out.

Khimani adds that, “Although most monoclonal antibodies and Fc-fusion proteins are expressed extracellularly, particularly from CHO cells, cell lysis and cell debris result in HCP contamination within the cellular milieu.” Therefore, various factors during cell growth and protein expression influence the level of HCPs, such as media composition, culture feeding, bioreactor controls, length of incubation, and even cell viability, all of which impact the profiles of HCPs as well as their detection and clearance.

In the downstream process, several tools can be implemented to manage the elimination or minimization of HCPs, Khimani says, while Stamm points out that the power horses for HCP removal are capture/affinity chromatography steps such as Protein A/G, which typically result in >95% of HCP removal; although, this clearance level is applicable for antibodies only.

“Additional [downstream processing] steps, such as hydrophobic interaction chromatography, ion exchange chromatography, size exclusion and mixed-mode chromatography, aid in the removal of HCPs,” Stamm adds.

Khimani emphasizes that, “optimization of each step is critical to achieve a robust workflow resulting in efficient removal of HCPs. To monitor the levels of contaminating proteins, it is critical to utilize analytical tools that offer sensitive and reproducible detection.”

HCP identification and profiling is a designated critical quality attribute (CQA), Khimani points out. Therefore, covering this CQA is key to the development and production of biological drugs. Khimani explains that HCP detection has evolved from traditional techniques to next-generation technologies that offer greater sensitivity, reproducibility, and higher throughput.

“Immunoassays have been considered the gold-standard method for monitoring HCPs along upstream and downstream workflows of large-molecule drug production. ELISA [enzyme-linked immunosorbent assay] has been one of the most commonly used assays to identify and measure total HCP in large-molecule drug preparations; however, it is unable to provide a uniform comparison across various types of drugs where the HCP content from each cell type may differ and their related immune specificity may be undefined. Therefore, ELISA is limited by providing a coverage analysis of HCPs,” says Khimani.

On the other hand, detection using two-dimensional gels resolves proteins by size and charge followed by transfer onto membranes and subsequent Western blot detection. However, this method is challenged by the gel size, protein population complexity, and lower throughput, Khimani states.

Stamm says that the advantages of ELISA are high sensitivity, ability to handle multiple samples simultaneously, quantitative results, unexpensive equipment, ease of use, and good manufacturing practice (GMP) compliance. However, he also points out its disadvantages, the main one being that the performance of ELISA rests entirely on the quality of the antibodies generated for this assay. “The challenge is to generate polyclonal antibodies against several hundred to thousands of proteins which vary in size, immunogenicity, and physio-chemical properties. As these are critical reagents, those antibodies need to be thoroughly characterized before they can be used in the ELISA development. The entire process from the antigen generation to the immunization and qualification need to get thoroughly documented as such information is reviewed by the authorities and might be required a couple of years later to replenish antibodies of equal quality,” Stamm explains.

Khimani, meanwhile, points to mass spectrometry (MS) as an alternate or orthogonal technique that is more powerful in profiling HCPs because it has greater sensitivity and specificity. However, MS is limited by throughput due to complexity, requirements, and higher cost, he adds. Ultimately, the choice of methods to detect HCPs depends upon the complexity of the host cell lines’ protein profiles, regulatory requirements to monitor HCP levels as a CQA, and risk management strategies during large-molecule drug development, he states.

“Each technique varies in its sensitivity, specificity, and suitability for different stages of the purification process,” Stamm adds. He also states that the advantages of techniques such as liquid chromatography with tandem mass spectrometry (LC–MS/MS) is a high specificity and ability to identify individual HCPs in complex mixtures, such as bulk harvest, as well as in drug substance. The disadvantages of LC–MS/MS lay in the fact that it requires sophisticated equipment along with deep biochemical and bioinformatics expertise.

Improving the monitoring of HCPs during the manufacturing process involves a combination of immunoassays and MS, says Stamm. Combining these techniques also enables HCP clearance in downstream processing. During early process development, generic ELISA kits are typically used for the quantitation of the HCP load in the cell harvest, process intermediates, and drug substance; however, instead of trusting such ELISA results blindly, Stamm emphasizes, the use of MS (e.g., shotgun LC–MS/MS approach) on the same samples will provide unbiased quantitative results as well as help identify potential critical HCPs that may be co-purifying (i.e., hitchhiking) with the product protein of interest.

Meanwhile, Khimani states that “a well-designed set of best practices that align with the type of cell line in use, the type of drug product in development with defined CQAs, the expected or previously defined profile of host proteins that may impact the drug preparation, and defined parameters for an optimal process should be implemented for greater efficacy and safety.”

1. Pilely, K.; Johansen, M.R.; Lund, R.R.; et al. Monitoring Process-Related Impurities in Biologics—Host Cell Protein Analysis. 

 (2), 747–758. DOI: 10.1007/s00216-021-03648-2

Feliza Mirasol is the science editor for 

®
Vol. 48, No. 7
July 2024
Pages: 32–33

When referring to this article, please cite it has Mirasol, F. The Importance of HCP Monitoring. 

Outsourcing

HCPs are major process-related impurities that must be monitored throughout biologics production for clearance.

The Importance of HCP Monitoring

On June 20, 2024, FDA announced that it had expanded its approval of delandistrogene moxeparvovec-rokl (Elevidys), a gene therapy for the treatment of Duchenne muscular dystrophy (DMD), to cover both ambulatory and non-ambulatory DMD patients of four years and older with a confirmed mutation in the DMD gene (1). This expanded approval will allow for a greater number of patients suffering from DMD, which is a rare and serious genetic condition that progresses over time, to be treated. In addition, the expanded approval will help to meet the urgent unmet medical need of this patient population.

The area of rare, difficult-to-treat diseases is where cell and gene therapies truly shine, offering treatment options where there have previously been none and in some cases, even the potential to eliminate the disease altogether. Given the promise of these advanced therapies, it is no wonder that the global market is expected to witness significant double-digit growth over the next few years (2).

However, as the cell and gene therapy sector continues to mature, greater attention is being paid to increasing therapeutic efficacy while also improving patient safety. This particular topic has been explored in this issue’s cover story on pages 10–12 (3), where experts reveal some of the strategic approaches being used to overcome constraints and challenges related to emerging therapies, such as reducing vector tropism to reduce liver damage or regulating the immunoreceptor complex with a dimerizing agent.

As researchers from all over the industry and regulatory bodies continue to focus on their investigations into approaches and strategies to improve not only the therapies themselves, but also methods to test these novel drugs, their efficacy and safety for patients will be optimized, and more unmet medical needs will be fulfilled.

1. FDA. FDA Expands Approval of Gene Therapy for Patients with Duchenne Muscular Dystrophy. Press Release, June 20, 2024.
2. Research and Markets. 

Cell and Gene Therapy Global Market Report 2024

. Market Report, February 2024.
3. Mirasol, F. Taking Stock of a Maturing CGT Sector. 

Mike Hennessy Jr is president and CEO of MJH Life Sciences®

When referring to this article, please cite it as Hennessy, M. With Age Comes Wisdom. 

From the CEO

A greater number of patients with Duchenne muscular dystrophy will be able to be treated after FDA's approval of a gene therapy.

Publisher's Note: With Age Comes Wisdom

Q: We received a warning letter (WL) from FDA, to which we provided a written response. Although we are confident that our reply is comprehensive, we would like to get confirmation from FDA. Is there a way to ask FDA to give us this feedback?

A: It is understandable that you want to be certain that your response to FDA is complete and acceptable. You should stay in contact with the person(s) mentioned in your WL and to who you addressed your response letter. In addition, under the Generic Drug User Fee Amendments (GDUFA or GDUFA III Commitment Letter) (1), your facility may be eligible for a Post-Warning Letter Meeting, as described in section VII(D)(1) of the GDUFA III commitment letter (2).

You can only be granted such a meeting if you have “submitted to FDA a thorough and complete corrective action and preventive action (CAPA) plan that addresses all items cited in the warning letter, and reasonable progress has been made toward remediation” (2). As mentioned above, your facility needs to keep FDA informed regularly about progress with the remediation effort as detailed in the CAPA plan. As FDA must see what progress you made, they cannot grant a meeting earlier than six months from the date of a company’s initial response to a WL. In fact, you should be certain that you have reached significant milestones in your remediation program before applying for a Post-Warning Letter Meeting, or FDA may deny you such a meeting.

What can you expect from such a meeting with FDA? The meeting will allow you to present the remediation progress to date and the projected completion dates for any remaining CAPA activities. FDA will voice any concerns they may have regarding your roadmap back into compliance. The agency will tell you if you are on the right track or if additional efforts are needed. It will give you assurance that your planning schedule is appropriate. It should be noted that FDA’s advice is not binding. Furthermore, agreeing to a Post-Warning Letter Meeting “does not preclude FDA from taking any regulatory actions necessary, including a follow-up inspection at any time” (2). You can request a maximum of two Post-Warning Letter Meetings.

Success depends very much on good preparation. You should, therefore, study the FDA’s draft guidance (3) that provides information on how to prepare the Meeting Package and the Meeting Package Content. Should you be eligible for such a meeting, it is recommended that you include this in your overall communication plan with FDA. Returning to a compliant state of operations at your facility has highest priority. Leveraging all available tools to inform and convince the agency of your sincere intentions, actual progress, and estimated fulfillment dates of all commitments is a sensible and logical approach.

FDA. Post-Warning Letter Meetings Under GDUFA. September 2023, 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/post-warning-letter-meetings-under-gdufa

GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027

. https://www.fda.gov/media/153631/download

Post-Warning Letter Meetings Under GDUFA Guidance for Industry

https://www.fda.gov/media/171785/download

Siegfried Schmitt is vice president, Technical at Parexel.

When referring to this article, please cite it as Schmitt, S. Post-Warning Letter Interaction with FDA. 

Ask the Expert

Communication and meetings with FDA after receiving a warning letter 
demonstrates a serious response, says Siegfried Schmitt, vice president, Technical at Parexel.


Post-Warning Letter Interaction with FDA

Thermo Fisher Scientific has introduced the Thermo Scientific Heracell VIOS 250i AxD CO2 Incubators, first-of-their-kind CO2 incubators designed for integration into automated and modular laboratories to support future implementation of automated cell therapy workflows. The VIOS family of incubators are known for optimal cell growth conditions and minimal contamination risk. The new Heracell VIOS 250i AxD incubators have the added innovation of a patent-pending automated door control, allowing them to open automatically when integrated into a centralized lab automation platform. The added innovation allows for vessel loading and unloading through robotic control and supports continuous cell therapy production processes. Other important features include in-chamber high efficiency particulate air filtration; Thermo Scientific THRIVE active airflow for homogeneous culturing conditions throughout the incubator chamber; and the Thermo Scientific Steri-Run Cycle, which is capable of a 12-log sterility assurance level, eliminating more than one million biological indicators for both dry heat sterilization and autoclave sterilization in half the lethal time used in production models.

Product Spotlight

The VIOS family of incubators are known for optimal cell growth conditions and minimal contamination risk.

Pharmaceutical Technology, July 2024

The Rising Iceberg of Lyophilized Innovations

Advancing Analytical Testing Techniques

The Importance of HCP Monitoring

Publisher's Note: With Age Comes Wisdom

Post-Warning Letter Interaction with FDA

CO2 Incubators