New assays, as well as advances in mass spectrometry and chromatography, give analytical testing laboratories tools to provide drug sponsors with additional information.
Analytical instruments and methods are producing more information, enabling more rapid development drug therapies. Experts from contract testing laboratories and service organizations shared their perceptions of analytical testing advances, and challenges still ahead with Pharmaceutical Technology.
Mass spectrometry demand growsPharmTech: What emerging technologies or practices do drug sponsors expect your organization to provide?
Holl (Catalent Pharma Solutions): In addition to developing clinical candidates that do not have special regulatory designations, drug sponsors expect us to be able to execute accelerated development programs to support their clinical development candidates that have expedited, breakthrough, or orphan designations while maintaining the highest quality standards. In terms of emerging technologies or practices, drug sponsors expect some degree of familiarity with the use of bioavailability and solubility enhancement approaches and an expertise in dry-granulation processes.
Skultety (Xcelience): Several analytical areas have been evolving over the past few years that our sponsors look for us to understand and put into practice. One area is cleaning verification and making sure we are up to date with all of the global regulatory requirements. Another area is the use of Phase-specific analytical method qualification/validation and being able to do analytical work following the quality-by-design principles.
Connolly (Frontage Labs): Sponsors expect CROs to lead implementation of technology and best practices that help them stay current with changing regulatory requirements. Within the past year, older elemental wet chemistry methods were replaced with ICP-MS [inductively coupled plasma mass spectrometry] and ICP-OES [inductively coupled plasma optical emission spectrometry] for United States Pharmacopeia monograph testing per the ICH Q3D [Guideline for Elemental Impurities] revised requirements on specific quantification of heavy metals. Other growth areas (sponsors expect expertise, working practices, or instrumentation) are extractable/leachable testing, following new regulations on container closure; and in-vitro release test (IVRT).
Brandley (PPD): Mass spectroscopy capabilities are increasingly expected to be a more commonly available asset in contract analytical labs for supporting routine stability or development/validation studies, and not just for characterization studies. Quantitative mass spectrometry, in particular, is required for these services.
Development/optimization of analytical methods, particularly when performed for bioassays, is expected to include experimental design to test/define method limits, reduce variability, and support a conclusion of method robustness.
Rogers (SGS Life Science Services): It is very important for a service provider to maintain existing technologies but also to keep up to date with developing equipment and methodologies. Mass spectrometry, for example, has evolved from a research tool to a technique that is often now expected in QC [quality control] environments. Quality is perhaps the single most important aspect of all practices demanded by drug sponsors.
New test methods deliver more informationPharmTech: What scientific or technical advances have positively or negatively impacted drug-development processes in this market segment?
Rogers (SGS Life Science Services): Generally, the ability to automate analytical processes has made significant impact on precision and speed. ;A move towards UPLC technology allows for increases in the rate of analytical testing in the field of liquid chromatography, although, due to the increased efficiency, such development can lead to an often unwanted re-evaluation of the product composition.
Connolly (Frontage Labs): Industry acceptance of IVRT has reduced the number of in-vivo studies used to demonstrate bioavailability or bioequivalence and has helped drug developers better predict the outcome of product release attributes in vivo. Enhanced chromatography technologies improving method sensitivity and selectivity have allowed drug developers to identify potential degradation products and impurities earlier in the development process.Technology advancements have helped formulators to develop better delivery systems earlier in the product development lifecycle.
Brandley (PPD): Growing application and acceptance for using reporter gene assays that improve the generation of signals relevant to a product’s mechanism of action has expedited the ability to develop and validate potency assays for biological products. This results in improving the sensitivity in assessing product comparability, whether across lots or in determination of stability, as well as in demonstrating the degree of sameness between an innovator and a proposed biosimilar.
Skultety (Xcelience): Sponsors would like to have one month of stability on the clinical batch to be filed in their IND [investigational new drug application] and they do not want this to slow down their submission. To accomplish this, the goal is to put the CTM [clinical trial material] batch on stability as quickly as possible, which in a number of projects puts analytical method qualification on the critical path. Formulators have become more proficient at developing final clinical drug product, which in turn puts more pressure on analytical work.
Stutzman (Catalent Pharma Solutions): On a positive note, a renewed interest in the use of bioavailability and solubility enhancement in formulation development has allowed drug substance candidates that previously would not have been considered for clinical development to achieve sufficient bioavailability to be advanced into further development.
A need for new studiesPharmTech: Are you seeing shifts in demand for particular types of services?
Skultety (Xcelience): Xcelience is seeing a shift in certain service areas. In particular, sponsors desire a better evaluation and understanding of their active drug substance. They want to have a full understanding of what properties of their API are critical to their drug product. This also applies to excipients that will be utilized in the drug product. The concept of quality by design should now be a focus of the analytical work and not just a focus of formulation development.
Brandley (PPD): One trend is a continued demand for extractable/leachable (E/L) studies for broad array of dosage forms and products as a requirement for drug development and commercialization. In addition, E/L studies now are being extended to manufacturing process equipment and intermediate storage containers. Service requests performed by our biopharmaceutical services department are growing rapidly, particularly in support for follow-on biological and biosimilar products. Included in this is an increasing emphasis on a product’s functional characterization.
Holl (Catalent Pharma Solutions): We are seeing an increase in demand for dry granulation services, especially in roller compaction, large molecular characterization, and an increased interest in the development of dosage forms specially designed for pediatric administration.
Connolly (Frontage Labs): Demand for heavy metal testing, extractable/leachable testing, IVRT for all types of products, and purity/characterization analyses for large molecules have increased. Since large molecules are difficult to characterize using singular analytical techniques, a variety of test methods, from size-exclusion chromatography, gel electrophoresis and Western Blot, to particle characterization using laser diffraction and fragmentation analysis using mass spectrometry may be employed. These challenges have increased demand for specialized analytical services.
Rogers (SGS Life Science Services): In the specific area of biopharmaceutical testing, there has been an unmistakable expansion into services that allow higher order structures to be defined. Such techniques are now applied in characterization of primary products as well as for comparability studies such as in the testing of in biosimilars.
Addressing technical challenges
PharmTech: What pressing technical challenges have you seen in this market segment? What actions has your company taken to resolve the challenge? What actions does your company suggest?
Connolly (Frontage Labs): Common technical challenges often relate to instrumentation limitations. The use of currently available instrumentation generally involves sacrificing sensitivity for broad application, or vice versa.
Most service providers actively attend relevant conferences and events (such as Pittcon) and engage frequently with instrument developers to stay current on instrumentation technology and attempt to employ these technologies to specific analytical challenges.
Holl (Catalent Pharma Solutions): Because of the aggressive development timelines associated with today’s drug product market and a renewed interest in drug-product candidates with expedited, breakthrough, and/or orphan designations, we have seen a decrease in the amount of time and effort available to fully assess their product and process design space to support process performance qualification (PPQ). To address this growing trend, we incorporate QbD [quality by design] into our development strategy and have established what we term “QbDLite,” which is an abbreviated yet thorough assessment of our client’s design space to support PPQ.
Brandley (PPD): One technical challenge is the increasing expectation for the contract lab to evaluate impurities at trace levels as instrumentation capabilities become enhanced. However, this is often thwarted by obstacles caused by product matrix complications. Another area is the growing interest in the effects of aggregates on product performance, particularly regarding the impact on a product’s potency. Both the generation and evaluation of aggregates and their effects on product performance promise to increase the technical demands on the biopharmaceutical services team. Evaluating various sample prep cleanup options and automation are two of the approaches we are taking to address this. We are recommending that our clients initiate earlier and more extensive characterization of degradation conditions, and investigate the changes to a product’s physicochemical characteristics, as well as performance changes that might occur.
Skultety (Xcelience): A challenge is the use of mechanical calibration for dissolution apparatus. This speeds up the process and provides for fewer failures than using the traditional tablets procedure for calibration. It takes some training to get analysts used to operating this way but is well worth the effort. Labs are being pushed to get the data faster whether it is for a batch release or for stability samples. To meet the ever-tighter timelines, it is necessary to evaluate all processes used in lab and become more efficient. The answer is not just [to] hire more people.
Rogers (SGS Life Science Services): One of the many technical challenges lies in definition of biotherapeutic impurities. Such studies often demand a multidisciplinary approach in terms of technology and expertise. SGS is able to respond to such requirements by maintaining a broad base of scientific experts and diversity within laboratory instrumentation, which is continually updated.
Analytical technology advances aheadPharmTech: What advances do you see developing in science or technology in this market segment in the next five years?
Brandley (PPD): In the next few years, it is foreseeable that we will see more seamless integration of mass spectrometry with biological samples in aqueous buffers. In addition, routine, bench-top NMR [nuclear magnetic resonance] for impurities identification and characterization will be more commonly used. Plug-and-play mass detectors will be more routinely applied to LC [liquid chromatography] and GC [gas chromatography] covering wide mass ranges.
Stutzman (Catalent Pharma Solutions): We see increased interest in anti-counterfeiting measures to address the growing global pharmaceutical manufacturing activities that can result in compromised global supply chain. In addition, we see the growing importance of assuring patient compliance through the use of advanced technology approaches, including those that can sense and signal the administration of dosage units to patients. There are also new advances in tablet presses that allow for unique dosage-unit configurations that were not possible even a few years ago. These advances can result in the design of bisected compressed powder tablets that maintain sustained release delivery even after bisection or the ability to form dry-coated dosage units containing multi-particulates.
Connolly (Frontage Labs): High throughput and sensitive analytical instrumentation will continue to advance. Using a combination of scientific expertise with the latest technologies will continue scientific advancement for analytical techniques. It is important for scientists to remain engaged in the development of new technology and ensure that the technologies developed are fit for the purpose they are intended.
Rogers (SGS Life Science Services): Traditionally, there has always been a demand for increased rate of testing and this will continue with advances in automation and application of technologies such as UPLC. In the biopharmaceutical-testing field, advances in sensitivity and miniaturization will become critical, particularly with the evolution of individual patient therapies. Techniques such as FTIR [fourier transform infrared spectroscopy] may also advance to allow non-destructive, continuous screening, which may find application in, for example, stability programs.