SPECIAL FEATURE – Analytical Testing – Contractors Take on the Challenge of Complex Molecules
The global pharmaceutical analytical testing outsourcing market could reach $9.6 billion by 2025, with services to include cleaning validation, analytical standard characterization, and peak identification. Additionally, clinical bioanalytical testing will witness growth during this period, owing to the increasing number of clinical trials and increased regulatory guidelines aimed at improving drug discovery and development.1
Additionally, there is an increase in the number of deadly diseases such as cancer. This has created a need to increase the production of drugs and develop new drugs to reduce the burden on existing ones. These factors are also increasing the demand for high-quality analytical services2, for example, the desire for analytical and bioanalytical methods that address the growing market for complex compounds and biologics. Added to this complexity is the quickened pace at which service providers are expected to help progress these products into the clinic. To this end, contractors are enhancing their knowledge base.
This annual Drug Development & Delivery report highlights some of the analytical testing services that leading contractors offer aimed at the increasing complexities of today’s pharmaceutical pipelines.
Alcami offers a range of services with extensive experience in development and validation utilizing various detection techniques. For peak identification specifically, mass spectrometry and NMR equipment, as well as standard characterization, are deployed. Moreover, Alcami has cleaning validation experience, particularly in its oral solid dose and sterile manufacturing facilities. Alcami also provides complete environmental monitoring and water analysis services. Alcami assists with API structural characterization, drug product formulation, and full-on method development/validation work in support of a product’s lifecycle and production. At present, Alcami has more than 265 products in its portfolio. Alcami’s API portfolio includes more than 90 clinical and 20-plus specialty commercial and generic products, and its drug portfolio encompasses more than 90 clinical and 65-plus specialty commercial and generic products.
Alcami’s current contribution to the bioanalytical and biopharmaceutical space focuses primarily on antibody, protein, and peptide evaluations featuring cell-based bioassays, residual DNA analysis, particle identification, and extractable/leachable programs. “In the biotech area, we have invested in technologies and capabilities, including new qPCR equipment,” says Director of Biotechnology for Alcami Vernon K. Dailey.
In the past year, one of Alcami’s standout achievements, according to Jason T. Spacek, Director of Commerical Development for Laboratory Services, Alcami, was an analytical testing partnership that led to a client’s successful submission of an opioid product. “As the opioid abuse epidemic worsens and becomes more prevalent in our communities, Alcami works to combat the crisis by employing an experienced abuse-deterrence team. This highly skilled unit ensures opioid products formulations can stand up to the harshest abuse conditions and regulatory scrutiny.”
Extractable and leachable evaluations are becoming increasingly more vital to patient safety considerations and gaining regulatory approval. Heightened requirements necessitate manufacturers to seek subject matter experts who are aware of these industry trends and changes in the regulatory landscape for medical device evaluations and container qualification. Across its suite of discovery, development, and analytical and solid state capabilities, AMRI offers bioanalytical methods for the extraction and quantitation of drugs and metabolites in biological fluids and tissues including, but not limited to, biological sample preparation, rapid selection and method development, quantitative bioanalysis, radiometric detection, and structural characterization of metabolites by LC/MS/MS, LC/NMR, capillary NMR.
There is also growing interest toward biologics, controlled substances, and more chemically complex compounds. “It is AMRI’s intent to ensure that the company’s global analytical services have the expertise and technologies to serve this increasing demand from customers and meet the evolving requirements for healthcare professionals and patients,” says Pamela A. Smith, PhD, Vice President of Analytical and Solid State Services, AMRI. “As the market for complex compounds and biologics continues to grow, there is a significant need for established analytical and bioanalytical methods that can help improve discovery and development.”
Recently, AMRI introduced ultra-high resolution Q-TOF mass spectrometry services for large and small molecule analyses. Using state-of-the-art instrumentation enhances the company’s capabilities in analysis and data interpretation for small and large molecules, including biologic drugs, metabolites, and polymers to meet the expectations outlined in the ICH Q6B Specifications.
In addition, AMRI offers a range of analytical technologies to characterize biologics and biosimilars, such as HPLC (RP, IEX, SEC, IC), gel electrophoresis (SDSPAGE/Native PAGE; IEF) for separation and purity evaluation, N-Terminal Edman Sequencing and amino acid analysis for protein identification, MALDI-TOF mass spectrometry for molecular weight determination, dynamic light scattering, SEC MALS, and SEM for aggregation state evaluation, and a variety of spectroscopic techniques (NMR, UV/VIS, IR and Raman) for fingerprinting of macromolecules. In addition, ligand binding and activity assays together with LAL endotoxin testing are provided to support batch release of biologicals and biosimilars.
“Having advanced analytical technologies that provide important information from different dimensions is essential to probing the physical and chemical attributes of these increasingly complex systems, such as drug-conjugated antibodies,” says Dr. Smith.
AMRI also sees growing interest for advanced formulation characterization approaches, patient-centered innovations, and emerging modalities for oncology. “This is particularly exciting for AMRI as we continue to strengthen our analytical and solid-state services, expertise, and technologies to support a variety of complex needs for our customers through our pre-formulation, material science, particle engineering, and analytical testing services,” Dr. Smith says.
The analytical services arena has increased within the past few years in the area of specialized testing. When manufacturing of a drug product, analytical prudence is premium, leading to a need for a cleaning validation procedure and to be in full compliance with regulatory agencies.
“This will confirm that the production equipment is prepared to perform its duty for the required manufacturing method,” says Alvin Persad, PhD, President/Cofounder, Aztech Sciences Inc.
Dr. Persad says that the cleaning validation method is analyzed by HPLC/GC, depending on the product’s physicochemical properties. Specialized stainless steel (ss) plates give a representation for the surfaces of the production equipment. These plates will be the platform for the wet chemistry reconstitution analysis and sampling, followed by HPLC/GC. These results will provide the specification criteria to be set.
HPLC/GC, among others, can generate a partial Certificate of Analysis (CoA) from an API. Standard characterization and peak identification using analytical methods can be very lengthy, depending on the stage of early development and emphasis on the client’s request. “As an example, our lab designed and prepared a formulation product, along with successful HPLC development, to confirm the analytical testing results within one week,” says Dr. Persad. “The client was able to get these results to a preclinical testing site for animal dosing.”
Catalent Biologics has acquired state-of-the-art frontline analytical capabilities and equipment to offer comprehensive analytical testing services for biologics. These range from early-phase screening to later-phase product characterization, and encompass chemistry, biochemistry, and biological techniques.
“Analytical standard characterization and peak identification are set to show tremendous growth in the next few years,” says Abhishek Mathur, Director, Biologics Analytical Services, Catalent. “We have invested heavily in supporting these services and in making sure we have the right capabilities to help characterize the standards thoroughly and pedantically.”
Unique challenges have arisen with the rapid growth of biologics analytical demand, and ICH, USP, and FDA regulations are evolving to address new biologic entities. “The new biologics are more complex, and the pace to see them progress into the clinic is faster than ever previously seen,” says Dr. Mathur. Concurrently, the biosimilar market requires the comprehensive analysis of molecules faster than ever before. Sponsors are competing to be the first to market with new original biologics or biosimilars.
The need to bring drugs to market faster, at minimal expense is driving the increased demand for high-quality GMP analytical services and outsourcing characterization work. The increase in biologics characterization to understand the product from the beginning of development is, in turn, driving the need for strategic partnerships. “The partnerships that Catalent is forming ensure that the understanding of the product is built over time, consistently and coherently,” says Michael Merges, Director of Strategic Growth, Biologics, Catalent.
Mathur adds that characterization of drug functionality and efficacy beyond cell-based potency assays is being increasingly requested. As a result, Catalent is adopting rapid cell-based functional assays for early screening before the drug is put into humans. “The advent and rapid rise of quantitative mass spectrometry with supporting technologies and instrumentation in the last decade has been instrumental in pushing the limits of characterization further,” says Mathur.
Catalent’s experience suggests there is a rising need for drug sponsors to engage early in the process to learn about the product. Recently, Mathur’s team worked with a large biotech drug manufacturer on a new and specialized program that was not typical for its conventional line of drugs and pipeline. The need was for successful engagement during pilot runs to ensure that the product had the desired quality attributes before full-scale production commenced. These requirements included method validation and rapid turnaround (~five days from sample availability to test results) for the analytical testing, which primarily required mass spectrometry characterization.
“With the drug candidate being a novel modality, additional challenges existed in terms of peak characterization and data processing,” says Mathur. “The work required seamless and frequent communication between Catalent and our partner to maintain streamlined operations and stick to the tight timelines. Data processing took much longer than anticipated due to the novelty of the product, and our partner acknowledged the “extra fuel” that was required to drive the project to success. Frequent communication between the scientists at Catalent and at our partner’s lab formed the key to the success of the project, which was realized to have strong flavors of ‘a new scientific learning opportunity.’ This is an excellent example of science excelling through a successful scientific collaboration.”
Analytical testing for biologics usually require an array of methods to elucidate the multifaceted aspects of structural, physicochemical, and functional properties. Frontage Laboratories has a range of capabilities to conduct testing release, stability, and comparability testing of the biologic products. To that end, Frontage scientists perform analysis of the critical quality attributes that need to be clearly assessed based on the potential impact on the manufacturing process, and clinical and regulatory requirements.
Large molecules, such as proteins, usually contain hierarchic levels of structures: primary, secondary, tertiary, and quaternary structures. Degradation of these structures can potentially impact the quality, potency, stability, and clinical outcome of the protein therapeutics, and can occur at all levels of the structure. The degradation pathways of a protein can often cause changes in charge, size, and mass. Frontage deploys several analytical methodologies, such as chromatography, electrophoresis, and mass spectrometry to detect these changes.
“Our analytical scientists can also develop protocols to monitor changes of charge variants or size (aggregates) species using chromatographic or capillary electrophoretic methods,” says Min Zhao, PhD, Director, Analytical Services-Biologic Product, CMC Services, Frontage Laboratories. “The icIEF/CE-SDS methods based on our new Maurice system enable separation of charge/size variants in a stable pH gradient established by ampholytes in a capillary, and detected by whole column imaging with UV absorbance or native fluorescence.”
Similarly, cIEF/CE-SDS methods can be established using the CESI 8000 Plus ESE-MS Instrument. Another method that is commonly used by Frontage scientists for analysis of charge variants is CZE method. The CZE separation, based on CESI 8000 Plus ESI-MS, has a significant advantage in that it can directly interface with the electrospray ionization (ESI) mass specrometer, Dr. Zhao explains. “The new CESI system offers an unprecedented analytical method to detect the charge variants by CE separation directly with a mass spectrometry.”
With regard to the advent of novel therapeutic modalities for cancers, such as engineered CAR T-cell therapy and cancer gene therapy, there is increasing demand for developing new and unconventional methods for analyzing these therapeutic agents. Frontage Laboratories is at the forefront of these techniques, Dr. Zhao says. For example, CAR T-cells are produced using genetic modification of the blood cells harvested from patients. The CAR T-cells are tested for identity based on cytochrome oxidase or short-tandem repeat profiling and DNA fingerprinting, while the viral vectors are analyzed by sequencing of transgenes and restriction enzyme digestion.
“There is also a need for quick assays to assess the sterility and microbial growth so as to provide real-time release of the CAR T-cells,” says Dr. Zhao. “In the next decade, it is expected that significant increase in demand for the unconventional and quick tests are required to support testing of safety, quality, and efficacy of the novel therapeutic modalities.”
An increase in the number of deadly diseases has created a need to increase the production of drugs and develop new drugs, escalating the demand for high-quality analytical services. Metrics Contract Services is familiar with these therapeutic classes of drugs. “Our experiences have led us to understand that phases of development for such drugs can be much different than with medicines treating less-life-threatening conditions,” says Keith Moore, Vice President, Analytical Services. “It’s important to understand the regulatory pathway to ensures a balance of customer expectations. As an example, the path to approval for certain type of drugs can be much shorter and thus, the amount of data to support approval is much more limited than traditional drugs. Therefore, it is critical to leverage the limited amount of data to support their submission.”
As an example, a customer selected Metrics Contract Services to support a Phase II program for a drug addressing a unique medical condition. Phase I activities were completed by another CDMO, from which Metrics received the analytical methodologies and structural information of the active molecule. The previous CDMO utilized traditional RP-HPLC with UV detection set-up in developing an assay and impurities procedure. “The structural properties of the molecule lead us to question the detection selection as well as the potential degradation pathways,” says Mr. Moore. “After just a few experiments, Metrics chemists determined that the salt form of the drug was being detected on the UV instead of the drug itself. We instead used Charged Aerosol Detection to develop a new testing procedure and to analyze all previous Phase I supplies to provide accurate results of the chemical purity. We also utilized LCMS to confirm our initial hypothesis. Scientific technical competency and due diligence allowed us to successfully set up the proper techniques for the client’s Phase II program.”
While pharmaceutical scientists continually develop different formulations and newer classes of molecules, the foundation of analytical chemistry already firmly established in support of formulation development can be readily modified. “For example, we are seeing more polymer-based drug technologies, multi-particulate formulations, and dual-active formulations,” he says. “While these can be challenging to work with, analytical scientists know that component, material, and composition understanding is the key to finding the right approach to analysis. Whether it is related to the diluent/dissolution media solvent selection or appropriate extraction techniques, the foundational elements utilized within the analytical chemistry sector still can be applied to fully characterize the drug components.”
As the pharmaceutical industry continues to experience consolidation and downsizing, more aggressive outsourcing efforts are underway with regard to analytical services. UPM Pharmaceuticals is a CDMO that uses a Quality-by-Design (QbD) approach to method development to ensure that the most appropriate and robust techniques are developed for each specific application. This approach also ensures that analytical methods are developed from the start to transfer to commercial operations. UPM accomplishes this through the use of diverse array of technology platforms, including the latest UPLC/HPLC, GC and FTIR systems, particle size and TOC analyzers, UV spectrophotometers, and state-of-the-art software systems for data acquisition and document management.
“Not limiting itself to a specific platform makes UPM’s analytical services group highly versatile and capable of responding to a range of needs, including the development of methods for novel compounds and controlled substances,” says Daniel Dixon, Vice President of Quality Control, UPM Pharmaceuticals.
Collaboration between UPM and its clients is an important facet of the approach to analytical method development. Similarly, close cooperation with other fully qualified laboratories that have complementary capabilities ensures that UPM can provide the entire spectrum of analytical support required for drug development and commercialization, says Mr. Dixon. In addition, UPM has worked with outside contractors to develop specific HPLC columns for the chemical entities it tests. “As a CDMO, it is paramount to have an analytical group that is agile and aware of the trends in order to handle these more complex methods as they come along,” he says. “Specifically, we have increased our staffing and knowledge base to develop the more complex methods required for the complex drug substances in today’s pharmaceutical pipeline.”
1. Pharmaceuticals Analytical Testing Outsourcing Market Worth $9.6 Billion By 2025, Grand View Research, Inc., Jan. 2017, https://www.grandviewresearch.com/pressrelease/global-pharmaceutical-analytical-testing-outsourcing-market.
2. Key Aspects of the Global Healthcare Analytical Testing Services Market, Technavio, November 24, 2017, https://www.businesswire.com/news/home/20171124005027/en/Key-Aspects-Global-Healthcare-Analytical-Testing-Services.
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