Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

Advanced analytical instruments, such as near infrared (NIR) and Raman spectroscopy, have revolutionized solid dosage manufacturing by enabling real-time measurements of critical quality attributes such as content uniformity. Content uniformity testing is an important assessment for oral solid dosage (OSD) forms. “It is one of two allowable tests to assess the uniformity of dosage units (UDU), the other being weight variance,” says Darren Andrews, Pharma Business Manager, Raman Spectroscopy, Cobalt Light Systems, part of Agilent Technologies. “UDU is a test of the variance of the active ingredient over the batch manufacturing process.”

	Content uniformity is an important quality measure of the final solid dosage product, notes Ian Robertson, spectroscopy applications specialist at PerkinElmer. It ensures that a consistent dose of the API is maintained between batches so that the patient receives the correct dose. Robertson points out that content uniformity is particularly important where tablet splitting is used. “The active ingredient needs to be evenly distributed throughout the tablet to ensure that if the tablet is split in half, each half of the tablet has an equal dose,” he says.

	Content uniformity testing sets a limit on the variance of API within each tablet or capsule. “The intention is to make sure that OSDs do not have an abnormally low or high amount of API, which may arise because powder is blended and processed before being tableted or encapsulated,” Andrews says. “Blending will cause natural variations in the level of a dosage amount.”

Causes and consequences of non-homogeneity in blending 

	Blending a large amount of bulk powder such that each small amount has a total API content within a few percent of the target concentration is a significant challenge, observes Andrews. “A tablet is often tens or hundreds of milligrams in weight and is pressed from a small amount of a powder blend that can weigh more than one tonne. Although the processes that make the blend are designed to minimize variance, it can’t be eliminated completely,” he says. “The bulk material may change as it is transported, which can change the composition of the blend in the container as a function of powder depth. Sometimes, the beginning and end of a batch run can be out of specification because of this composition change and are, therefore, discarded.”

	“The aim of blending is to produce a homogenous blend of a sample that accurately represents the ratios of the components within it,” Robertson underlines. “Proper blending is essential to ensure consistent dosage and performance of solid dosage forms.” He highlights that each different blend will require unique blending conditions.

	“Non-homogeneities can be caused by many factors and can be related to the materials to be blended, the type of machinery used, and the processing parameters used for the blending,” Robertson explains. “The most common problems are insufficient blending time and overblending. For any given blend, under any given processing conditions, there will be an optimum blend time. With insufficient blending time, the materials do not have the possibility to achieve a homogenous mix. The obvious thought would be to just continue blending for a much longer time. However, this would greatly increase manufacturing costs and can also lead to overblending, which can cause demixing and segregation of the mixture.”

	According to Robertson, the type of blender needs to be appropriate for the materials being blended and whether it will be a batch or continuous process. “The size and shape of the blender must be appropriate for the blend being processed,” he says, emphasizing that the processing parameters of the blending process play a crucial role in avoiding non-homogeneity. “Non-homogeneity of the blend will lead to inconsistent dosage in the final product and could lead to product rejection, which will result in significant financial losses. Re-blending of a non-homogenous product is generally unfeasible, and the product needs to be scrapped.” Robertson recommends testing the blend during or after blending to prevent inhomogenous blends from being processed further.

	Once a suitable type of blender has been selected, it is important that the formulation and processing variables are optimized for that particular blend. “The major processing variables are mixing time, speed of mixing, and powder fill volume,” says Robertson. “Each of these parameters will, individually, have an effect on the blending efficiency.”

	“In rotational blenders, the mixing time is the product of the number of rotations and the speed of rotation of the blender,” Robertson explains. “The speed of mixing (or speed of rotation) will affect the quality of the blend. For free-flowing materials, the speed can be quite high and the materials will efficiently mix. However, for cohesive materials, the speed needs to be considerably slower to allow the ingredients to mix well.” He notes that it is also important to determine the optimum powder fill volume within the blender. “Too large a fill will prevent mixing during the blending process,” he says. 

	Robertson stresses that during the blending process, it is necessary to determine the blend homogeneity to determine completeness of blending. “This has traditionally required a sampling strategy to determine where and how often samples are taken for measurement,” he says. “Sampling was primarily performed using sample thieves, which have their own shortcomings.” Thief sampling is not instantaneous, produces little data, and has many sources of error and bias.

 2.9.40 (2), and other pharmacopeia chapters have set out the requirements for UDU by content uniformity testing. Generally, only 10 tablets from a batch have to be tested, Andrews notes. “These samples are assayed individually and a calculation using the individual values is made to find an acceptance value,” he says. “This method spreads the allowed variance over the test samples, and depending on the variance of the samples, an individual may have >10% deviation from the nominal value and the batch could still pass the test.”

	According to Andrews, using 10 samples to describe the batch variance is a limited number to assess the UDU of a large batch. He explains that if the test fails with n=10, taking an additional 20 samples to make n=30 is allowed, and the content uniformity test may pass as a result. “Taking more samples from across the batch routinely would give greater confidence in the batch process,” he says. “Some regulators are expanding the options for testing a larger number of samples, which becomes more feasible using spectroscopic technologies. 

2.9.47 (3), for example, provides options for testing 100–10,000 individual samples.

	Robertson points out that the biggest challenge in content uniformity testing for solid dosage forms is the sampling strategy, “namely, how do you ensure you are getting representative samples that reflect the whole batch?” They note that the results from 

 <905> lack confidence because the method does not use a statistical sampling plan, and therefore, provides limited assurance that the batch meets specifications and quality control criteria. In fact, FDA no longer supports the use of 

 <905> for product release testing. FDA also withdrew, in August 2013, its guidance document, 

Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment

 (4), because it no longer reflected the views of the agency (5). In response, a group of individuals from industry, academia, and FDA formed the Blend and Content Uniformity (BUCU) team, within the International Society for Pharmaceutical Engineering (ISPE) organization, to come up with alternative approaches and best practices for assessing blend and content uniformity. The team has developed modifications to the withdrawn FDA draft stratified sampling guidance and proposed sampling plans based on the application of two ASTM methods: E2709 (6) and E2810 (7).
	The US Pharmacopeia Convention has invited the BUCU team to advise on the preparation of the new chapter 

 <1905> on sampling considerations for batch release (8). ISPE has launched a section on its website to make available to the industry the BUCU team’s output.

	For OSDs, there needs to be a suitable sampling strategy for content uniformity testing, Robertson highlights. “The most common sampling plans suggested by the BUCU team are: simple random sampling, stratified sampling (partitioning the batch into sections, then sampling from each section), and systematic sampling (at regular intervals throughout the batch),” he says.

Analytical methods to assess content uniformity

	The most common method for assessing content uniformity in OSDs is high-performance liquid chromatography (HPLC), observes Andrews. “HPLC has the advantages of flexibility, sensitivity, and ubiquity, and many analytical chemists are trained to use HPLC methods,” he says. “The disadvantages, however, are the time and resources needed to prepare samples.”

	“In blending operations, the sample is removed using a sample thief and analyzed by HPLC using a calibration curve for the active ingredient(s),” says Robertson. He explains that the method involves dissolving the tablet in a suitable solvent and analyzing the amount by HPLC against a calibration. Although accurate and repeatable, the disadvantages with HPLC are that measurements are offline, samples have to be removed from the blending process, it is destructive for tablets, and analysis can take several minutes per sample, Robertson highlights.

	Ultraviolet/visible (UV/Vis) spectrophotometry is another technique that can be used as an assay for content uniformity measurements. “The absorption at a known, given wavelength for a material will be directly related to the concentration of the material present,” Robertson says. “Using this correlation requires the material being analyzed to have a suitable absorption within this spectral range and for the other materials present not to have interfering absorptions, although spectral overlap can generally be accounted for by spectral deconvolution or appropriate curve-fitting quantitative methods.” He, however, points out that like HPLC, UV/Vis spectrophotometry is an offline and destructive method.

	Over the past decade, there has been an increasing emphasis on quality by design (QbD) and the use of process analytical technology (PAT) to monitor and control pharmaceutical manufacturing processes. “FDA encourages the use of new technologies and PAT techniques, such as NIR spectroscopy, for content uniformity analysis,” says Robertson. “NIR spectroscopy can be used throughout the manufacturing process in online, at-line, and offline modes of operation.” He explains that one such application involves the online monitoring of the blending process with small NIR instrumentation fitted directly onto the blender, or NIR instrumentation connected to the blender using fiber optics probes. “This set-up allows for real-time measurement of the blending process without the requirement to remove samples for measurement, which is a significant advantage over other techniques, such as HPLC,” Robertson says. “Different mathematical approaches can be applied to the spectral analysis to determine when the blend is optimized, without the requirement for quantitative calibrations.”

	Robertson adds that NIR spectroscopy can also be applied to the measurement of content uniformity of solid dosage tablets. “The measurement can be performed non-destructively directly on the tablet using reflectance or transmission after suitable quantitative calibrations, typically against reference values from HPLC measurements,” he says. “No sample preparation is required, and the measurement does not require solvents or other hazardous chemicals.”

	As is the case for NIR, Raman instrumentation enables non-destructive, online measurements of the pharmaceutical process, including blending and content uniformity measurements of tablets. “Raman spectroscopy can be used as a PAT tool for content uniformity applications,” says Karen Esmonde-White, senior marcom specialist at Kaiser Optical Systems. “The sampling flexibility of Raman lends itself to an offline measurement using a Raman microscope or sampling compartment and an in-process measurement using sampling probes.” She points out that in-process Raman measurements are beneficial because they provide real-time process understanding without needing to collect samples for offline measurements.

	“The real-time process understanding provided by Raman enables in-process corrections, improves efficiency, ensures quality, and can form the basis of automated feedback control,” Esmonde-White explains. “The specificity of Raman spectra, sampling flexibility, and compatibility with aqueous media are advantages over other spectroscopic techniques. Raman spectroscopy allows quantification of the API within the excipient matrix, and customers have reported API quantification to sub % levels using Raman.”

	Robertson concurs that Raman has the advantage of being extremely specific in terms of the spectral profiles of different materials present in formulations, whereas NIR spectra typically contain significant spectral overlap of the ingredients. He highlights that Raman, however, does have the disadvantage of being a weak scattering technique and is not suitable in cases where the samples fluoresce. 

	According to Robertson, a limitation of Raman spectroscopy for content uniformity measurements has been the limited spot size of the laser, with only a small fraction of the complete tablet being analyzed. “However, recent advances using raster scanning of the laser allow the entire tablet to be sampled,” he say. “Further advances have been achieved using Transmission Raman Spectroscopy (TRS), in which the Raman signal transmitted through the whole tablet is measured, thus measuring a much larger sample volume.”

	TRS is an alternative spectroscopic technique to quantify ingredients in a dosage form that has been available for approximately eight years, according to Andrews. “It is fast and flexible and can analyze hundreds of samples per hour,” he says. “TRS works with a wide variety of tablets and capsules and is suitable for high-volume testing, with significant impact on resource savings.”

	“It is Raman spectroscopy and so is complementary to infrared spectroscopy; both have information-rich spectra,” Andrews explains. He adds that by testing intact tablets, the solid-state form (e.g., polymorph type) can also be quantified.

	TRS is not an absorption technique, Andrews points out, hence, it is less sensitive to sample thickness than NIR. “A single measurement contains the data needed for analysis, allowing multiple APIs, excipient concentrations, and more to be determined with no additional effort.” TRS is currently used to release tablets and capsules with regulatory-approved tests for content uniformity, assay, and drug product identification.

	Having in place control procedures to monitor the blending process is key to ensuring consistent and efficient production of OSDs. PAT tools, such as NIR and Raman, provide an alternative to sample thieves by enabling online analysis of content uniformity.

(US Pharmacopeial Convention, Rockville, MD).
	2. EDQM, 

 General Chapter 2.9.40 Uniformity of Dosage Units (EDQM, Strasbourg, France).
	3. EDQM, 

 Chapter 2.9.47 Uniformity of Dosage Units Using Large Sample Sizes (EDQM, Strasbourg, France).
	4. FDA, 

Guidance for Industry, Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment

 (Rockville, MD, October 2003).
	5. J Bergum et al., 

 34 (2) (March/April 2014).
	6. ASTM Standard Number E2709: 

Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure,

 September 2009.
	7. ASTM Standard Number E2810: 

Standard Practice for Demonstrating Capability to Comply with the Test for Uniformity of Dosage Units, 

October 2011.
	8. ISPE, “ISPE Group Working on Blend and Content Uniformity Launches Website,” Press Release, Sep. 16, 2014.


	Vol. 42, No. 2
	February 2018
	Page: 16–21

	When referring to this article, please cite it as A. Siew, “Analyzing Content Uniformity,” 

Articles

New technologies, such as NIR and Raman, enable online measurements of blending and content uniformity in the production of solid dosage forms.

Analyzing Content Uniformity

Impurities can have a negative impact on the stability, safety, and efficacy of protein therapeutics. “Aggregates are of particular concern, either in soluble dimer/oligomer form or subvisible particle form,” notes Jay Kang, director of analytical and formulation development at Patheon, part of Thermo Fisher Scientific. “It is well documented that even a small amount of aggregates can cause a significant and sometimes life-threatening immunogenic reaction.”

	“Impurities may interact with the therapeutic protein in a way that blocks and/or compromises the activity and potency of the therapeutic protein 

 hence, reducing its efficacy,” explain Michael Sadick, principal scientist, Catalent Biologics Analytical Services, and Michael Merges director of strategic growth, Catalent Biologics. “On the other hand, the impurity may exaggerate or enhance the therapeutic protein’s bioactivity in an uncontrolled way, leading to adverse events. Some impurities (especially host cell proteins) may add an immune-stimulating or adjuvant behavior to the therapeutic, causing the patient to generate antibodies or cell-mediated immunity against the protein.”

	“Host cell proteins co-extracted with the therapeutic protein can contain enzymes such as oxidases and lipases that will break down the protein over time, affecting the stability of the product,” adds Niall Dinwoodie, Edinburgh biologics site lead at Charles River Labs (CRL). “Other host cell proteins and binding agents carried over from purification columns may mimic the action of the therapeutic protein in assays, leading to mis-formulation of the product outside the therapeutic window.”

	According to Dinwoodie, some impurities have less insidious effects, but can still render the therapeutic unacceptable. “For example, trace levels of rapidly oxidized materials cause significant color change,” he says. “Historically, contamination with trace amounts of metals was a problem leading to aggregation of therapeutic proteins, which can cause significant changes in efficacy, but understanding of the phenomena has led to improved, metal-free production processes.”

	In general, impurities come from two major sources, observes Bérangère Tissot, general manager, SGS Life Sciences, West Chester, Pennsylvania: product-related impurities and process-related impurities. “Product-related impurities can be categorized as product variants, and basically correspond to any undesired modification of the protein amino-acid sequence or post-translational modifications,” she highlights. “Variants also include forms of the therapeutic proteins in solution that are different from the intended drug product (i.e., different conformation or aggregation state). They can also be identified as a sub-form of the therapeutic protein, possessing a biological activity either higher or lower than the one of the drug product.”

	The second type of impurities are mostly related to the production processes, says Tissot. Dinwoodie adds that the materials used in the production process to support cell growth, extract, and purify the therapeutic protein must be removed from the final dosage form. “Residual amounts of these materials can be carried through the production process to become impurities in the final form,” he points out. “Examples include growth selection agents, surfactants, purification column binding agents, and viral inactivation agents.”

	“The use of cells and growth media in the production process also presents risks of adventitious agents, such as viruses, entering the production system,” says Dinwoodie. “Whilst removal or inactivation of these agents is considered under the production process validation as a safety issue rather than tested in the final product as a quality concern, these agents can also be considered impurities in the product.”

	Process- and product-related impurities should be carefully monitored and controlled in the production of therapeutic proteins. In this roundtable discussion, industry experts share insights on the various methods used for purity and impurity analysis of therapeutic proteins.

What is the right approach to method development and validation for therapeutic proteins?

 Two concepts are key to approaching method development and validation for therapeutic proteins: ‘fit-for-purpose’ and ‘phase appropriate.’ A ‘fit-for-purpose’ strategy means a method should be suitable for its intended use and phase of development. The requirement to establish an analytical method depends on whether it is for an identity test, content test, or purity/impurity test; whether it is for release, in-process testing, or characterization. For example, the only requirement for an identity test is specificity, while specificity, linearity, range, precision, robustness, and sensitivity are mandatory for the purity test. Determining whether the method is for early-phase development or for biological license application (BLA) filing is also crucial because it will dictate the size and thoroughness of the validation data package.

The underpinning to this response is the knowledge that each protein therapeutic is quite different from any other protein therapeutic, whether in terms of its final tertiary or quaternary folding, biological activity, or purity profile. This is true even when considering different monoclonal antibody therapeutics. Consequently, while similar strategies may be used for different protein therapeutics, true ‘toolbox’ approaches/platforms may not be completely successful. In the strategies for assay or method development and optimization, we consider a combination of ‘one factor at a time’ (OFAT) to define individual factors, at least initially, and ‘design of experimentation’ (DOE) to look at multiple and interacting factors. The use of fractional factorial DOE as soon as is practical allows for a more rapid and robust method development.

	Validation would be accomplished in a phase-appropriate manner. The guideline for all phase appropriate levels would be the International Council for Harmonization (ICH) Q2 (R1) (1), although different technical platforms (e.g., enzyme-linked immunosorbent assay [ELISA] or bioassay potency tests) may have specific levels of adherence to the ICH guidelines, in addition to other guidelines, for example 

 General Chapters <1033> and <1034> (2, 3). Validation for an investigational new drug or at Phase I level would have the more basic requirements, with fewer tests to be executed, a smaller number of repetitions, and wider acceptance criteria. Late-phase (Phase III/BLA-enabling) validation will include all appropriate test categories, as well as robustness, with an increased number of sample repetitions along with more stringent acceptance criteria. The establishment of appropriate validation acceptance criteria should be based upon data-driven decision. Those data are best generated via a prevalidation exercise conducted prior to the drafting of each phase-appropriate validation protocol.

 This is not straightforward, as validation approaches will depend on the nature of the method, its intended use, the development stage of the product, and the type of therapeutic proteins. In all cases, the method should be evaluated, prior to its validation, through a risk management process that will dictate which parameters to validate, which acceptance criteria to aim at, and all other necessary components of a validation study. These considerations include nature and number of replicates for each of the parameters, robustness conditions, and intermediate precision details among others.

 The extent of development needed for a new analytical method will depend on the purpose of the method and the body of knowledge available on the product to which it will be applied. Physicochemical methods can be largely based on compendial procedures and require little development, and parameters for platform techniques such as size-exclusion high-performance liquid chromatography (SE–HPLC) can be established from an understanding of the protein’s molecular weight.

	Binding or potency assays, however, require the selection of suitable antibodies or modification of detector cell lines. Non-therapeutic host cell proteins can also present a considerable challenge to method development in ensuring that the polyclonal sera used provides full coverage of the range of proteins that may be extracted from the production cell line. 

	Method development also must consider the robustness of the approach and ensure that reagents and consumable items, such as columns, are readily available and consistent in the results they generate. Validation of the method will then serve to confirm the robustness of these elements and assess the variability introduced by different analysts and equipment.

	Both the number of replicates run for the determination of repeatability and intermediate precision, and the number of batches of the product tested in each run are affected by the product’s stage of development. They also must be defendable in covering all possible options for how the method will be used in the future. Other aspects of method validation are more easily derived from the guidance given in ICH Q2 (R1).

What are the commonly used analytical methods for characterizing therapeutic proteins?

 The main document used by anyone characterizing a therapeutic protein remains the ICH Q6B guidelines (4). Now these guidelines are a little outdated, mainly with regards to biophysical methods but they still remain a good basis for the design of a characterization method panel. There are many ways to address some of the key elements that need to be evaluated during a characterization study, but some of the most commonly used are listed in the following:

		Liquid chromatography–tandem mass spectrometry (LC–MS/MS) following digestion for primary amino-acid sequencing, which could be completed by N-terminal sequencing using Edman degradation. The same type of methodology can be applied to the evaluation of the most common post-translational modifications

		Liquid chromatography–mass spectrometry (LC–MS) or electrospray ionization–mass spectrometry (ESI–MS) for intact molecular weight when the therapeutic protein does not present any major challenge for ionization (such as heavily glycosylated proteins)

		Amino-acid analysis and extinction coefficient estimation

		A combination of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI–TOF MS), LC–MS, and other liquid chromatography with ultraviolet detection (LC–UV) or high-pressure anion exchange chromatography coupled to pulsed amperometric detection (HPAEC-PAD) methods for the quantitative and qualitative analyses of N- and O-glycosylation

		Liquid chromatography or electrophoresis methodologies to evaluate product heterogeneity (charge variants, size variants, hydrophobicity variants etc.)

		Circular dichroism (CD), Fourier transform infrared spectroscopy (FTIR), intrinsic/extrinsic fluorescence for the analyses of secondary and tertiary structures

		Sedimentation velocity analytical ultracentrifugation (SV–AUC), size exclusion chromatography coupled to multi angle light scattering (SEC–MALS) or dynamic light scattering (DLS) for the analysis of quaternary structures.

		Surface plasmon resonance (SPR) or bilayer interferometry (BLI) for binding activity.

	Then we have to consider what are now called the emerging techniques, at least for their application to complex biologics in an industry context, which in a couple of years will become as common as the techniques previously listed. These techniques include:

		Hydrogen-deuterium exchange–mass spectrometry (HDX–MS), ion mobility-mass spectrometry, and nuclear magnetic resonance (NMR)

 As protein therapeutics commonly have complex structures and are generally produced and/or modified by the host cell in several functional variations, analyses of these molecules require an orthogonal approach with multiple analytic modalities.

	Process-related variants can be identified, quantified, and differentiated from process-related impurities of cellular origin via techniques such as SEC–HPLC, hydrophobic interaction chromatography (HIC), ion-exchange HPLC, and isoelectric focusing (IEF) capillary electrophoresis. Process-related impurities and residuals such as Protein A can be detected and quantified with ELISA assays, whereas host cell residual DNA can be quantified via quantitative polymerase chain reaction (qPCR) assays. Functional activity of the protein therapeutic can be assessed and quantified with cell-based bioassays, or, in some cases, ELISA potency assays. Process-related variants and impurities may then be more fully identified and defined using mass spectrometry-dependent analyses. Host cell derived residual protein may be assessed and identified with a combination of ELISA assays (commercial assays at early phases, and then custom assays at later phase), one-dimensional and two-dimensional Western blot analyses, and more recently, MS-based analyses.

To characterize a protein, we need to understand its content, primary and higher order structure, potency, heterogeneity, purity, and impurity. The commonly used analytical methods for characterizing these proteins include UV spectroscopy for concentration; SEC, analytical ultracentrifugation (AUC), and field flow fractionation (FFF) for aggregate measurement; capillary gel electrophoresis (CGE) for fragment measurements; capillary isoelectric focusing (cIEF) for charge heterogeneity, biochemical/cell-based assay for potency measurement; mass spectroscopy for primary structure; FTIR, CD, or HDX for higher order structure.

How do you ensure that the final drug product is free from impurities that affect safety and efficacy?

Designing the production process to minimize the materials introduced during manufacturing, as well as installing appropriate purification steps, are simple sounding methods for ensuring a final drug product is impurity free. In practice, additives are required for cell growth, non-target proteins will be extracted, and downstream processing will occur, so purification steps are paramount. Control of these steps must be demonstrated by validation and/or quality control checks on the bulk drug substance. Control of impurities that could arise from the fill/finish process are then assessed for the final product.

 It is very challenging to completely remove all the impurities, but the industry can make sure that the level of impurities in the final drug product are at a safe and consistent level. A key factor to ensuring this is to develop a sensitive and robust analytical method, so all the impurities can be accurately measured and the impurity-removing capability of the downstream process can be demonstrated. For example, ELISA is the gold standard and work horse for host cell protein measurement, but it only measures the total HCP and can’t give detailed information on the level of each individual host cell protein. Mass spectroscopy can fill the gap, and is, therefore, an excellent supplemental method for host cell protein analysis.

A ‘pure’ protein is one that is free from any quantifiable amounts of impurities, so implementing several orthogonal methods together is necessary to assure this is the case. The complex structural properties of the protein, the nature of the potential contaminants (host cells, viruses, genetic variants, purification process), and the accuracy and appropriateness of any one given method all influence the selection of the methods used to perform the purity/impurity analysis. A subset of these analyses is executed during the purification process to assure that each purification step is performing as expected/required. The full panel is performed upon both the drug substance and the final drug product. In this way, effectiveness of and purity at each stage of processing is evaluated and assured.

 Having a product entirely free of impurities is a very arduous task, if achievable at all.

	For process-related impurities, control procedures to follow the clearance of some of the process-related impurities are designed during the very early stage of the finalization of the manufacturing processes, and are refined as the processes are locked down. The use of ultra-sensitive mass spectrometry has been increasing in that very particular field, offering a greater ability to monitor such small molecule impurities at a parts per million to parts per billion level. Such methods are also commonly validated as either process-validation-related methods or even product-release methods.

	For product-related impurities, the pre-IND or equivalent panel of assays, at the very early stage of the product development, includes some of the methods that will be further refined to monitor these impurities. Complementary chromatographic and electrophoretic methods using UV detection have been used to monitor therapeutic protein variants for decades, but these methods are on the verge of being replaced by multi-attribute methods (MAMs) using primarily mass spectrometry as a detection tool. The ability to not only monitor but characterize several of these variants or impurities using a single LC-MS or LC-MS/MS method will not only bring to this field more discrimination power but it is also expected to decrease the level of detection for these undesired components.

 What are the analytical methods used for purity and impurity analysis of therapeutic proteins?

 The analytical methods used to determine the levels of impurities within a therapeutic protein are those that have both the discriminatory power to separate the impurities and the sensitivity to detect and quantify low levels of the analytes. For impurities that are not closely related in structure to the therapeutic agent, such as surfactants, for example, the method can use this difference to maximize the sensitivity. Analysis of these impurities will include steps to remove all proteinaceous material to maximize the signal for charged aerosol detection or alternative measures. Sequence and glycosylation variants are closely related, or even part of the therapeutic protein; therefore, they require highly discriminatory techniques for their quantification. Capillary electrophoresis and HPLC or ultra-high-performance liquid chromatography (UHPLC) are commonly applied to resolving these variants from the more common form of the protein. Aggregates are readily separated by SE–HPLC when the aggregation is robust. Less stressful techniques such as analytical ultracentrifugation may be required where the aggregation is more fragile. For non-therapeutic host cell proteins, cell-line specific ELISA are often used though mass spectrometry techniques can provide the discriminatory and quantification power required for these complex mixtures of impurities.

Validation of Analytical Procedures: Text and Methodology,

(US Pharmacopeial Convention, Rockville, MD, 2011).	

Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products,


	Vol. 42, No. 2
	February 2018
	Page: 22–26

	When referring to this article, please cite it as A. Siew, “Impurity Testing,” 

Experts share insights on the various methods used for purity and impurity analysis of therapeutic proteins.

Impurity Testing

As the pharmaceutical industry faces increasing pressure to accelerate drug development, many contract development organizations are recommending early development programs. In this Q&A, Mark Egerton, chief executive officer of Quotient Sciences, discusses current roadblocks in the traditional drug development process and explains how productivity can be improved and timelines shortened by implementing a new approach the company refers to as Translational Pharmaceutics.

What can delay novel therapeutics from getting to market?

 There are many factors that can delay the development and eventual commercialization of novel therapeutics. One of the most intractable factors is the conventional trial-and-error approach to new drug development, under which the drug developer typically decides upon a fixed formulation type and two to three dosage strengths in the preclinical phase, often before completion of toxicology studies.

	To advance the molecule into first-in-human (FIH) clinical trials, the drug developer then must invest significant quantities of drug substance, which may be in scarce supply, in preparation of large batches of each of these dose strengths as a means to provide sufficient quantities and flexibility of drug product to cover the early development program. When that molecule fails toxicology, or if the selected drug product format turns out to be suboptimal following clinical dosing, the drug developer must start all over again, which will require obtaining regulatory approval for a redesigned trial with a modified formulation or dosage strength. Each iteration of redesign, resubmission, and re-evaluation can significantly delay marketing authorization and commercialization.

What are the challenges in developing novel therapeutics?

 One of the biggest challenges in today’s environment is the sheer competitiveness of the marketplace, in which it is imperative for innovator companies to deliver first- and/or best-in-class medicines. That pressure has increased the emphasis on new molecular targets and disease mechanisms that offer the potential to deliver breakthrough therapies. However, due to the very nature of translational science, the majority of investigational programs will fail at or before proof of concept (POC), resulting in high attrition rates in Phase II.

 What are the current roadblocks in the traditional drug development process? What strategies can be implemented to remove these roadblocks?

 Some of the most significant roadblocks in the traditional drug development model are of an organizational nature. Current organizational structures and processes are such that many innovator companies and service providers have consolidated into two vertically integrated supply chains: one focused on the making of test materials (drug substance and product) and the other focused on testing of those materials (preclinical and clinical). This strong demarcation of ‘make’ and ‘test’ functions, which has given rise to the contract development and manufacturing organization (CDMO) and contract research organization (CRO) industries, is suboptimal in terms of supporting early development because the transfer of drug product(s) between the two channels can be cumbersome and complex. For example, generation of sufficient stability data to achieve an extended shelf life and to accommodate the logistical inefficiencies between manufacture and dosing can result in significant delays.

	Early development also requires considerable investment to manufacture a range of dose strengths at quantities to cover all eventualities in a clinical trial. In an outsourcing situation, the provision of drug product may require up to four different suppliers to cover drug substance supply, formulation development, clinical trial manufacturing, and packaging. The resulting siloed supply chain thus presents a significant management burden and timeline risk, especially when the chain breaks down and the incumbent suppliers are not focused on devising a solution.

	Fortunately, horizontal integration of the ‘make’ and ‘test’ supply chains-by which these functions are outsourced to a single supplier-can enable the rapid and seamless manufacturing-to-clinic transfer of drug product, with manufacturing often completed within a 24- to 72-hour period prior to dosing. This approach, which we call Translational Pharmaceutics, can reduce development timelines and expenditures, in some cases by up to half of those of conventional approaches. More importantly, horizontal integration can encourage innovative thinking in the early stages of development, especially for processes preceding FIH studies or for subsequent optimization of the drug product prior to full development.

	Another notable early-stage obstacle is the difficulty of forecasting the pace and location of patient recruitment. This can be especially challenging in the orphan and rare disease space, as well as for pediatric indications requiring small-scale, innovative POC trials. Rather than pursue the conventional approach of producing a large batch of product with an extended shelf life, horizontal integration can overcome this obstacle by enabling the manufacture of drug product on a per-patient basis. Under the Translational Pharmaceutics approach, a recruiting physician can contact the drug developer as soon as an eligible patient is identified, whereupon the manufacturer can produce the product for that patient, and deliver it to the physician for dosing within 14 days of patient identification.

	Additionally, drug development programs can be derailed by poor solubility, an issue that affects more than 70% of small molecules in the industry pipeline. Under the conventional approach, a drug developer must make a judgment call as to which formulation technology to apply in the clinical setting based upon laboratory or preclinical data. However, horizontal integration of the ‘make’ and ‘test’ functions provides the flexibility to take multiple technologies into a trial, allowing the drug developer to choose the most appropriate technology to take forward, based on thorough analysis of clinical data.

How do you accelerate the drug development process and how can productivity be improved?

Horizontal integration of the ‘make’ and ‘test’ supply chains allows for the adaptation and fine-tuning of the manufacturing process to the specific needs of a clinical trial. That is a key benefit that can yield significant reductions in the amount of drug product that must be manufactured (and, by extension, in the amount of resource, including drug substance, which is consumed in a trial), as well as in the lead time for manufacturing, ultimately condensing the drug development timeline.

	A major advantage of horizontal integration is that the drug product dose and formulation can be adaptive in real time in response to clinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Armed with the timely analysis of those data, the outsourcing partner can go back to the manufacturing unit to produce the modified drug product, dose to subjects in the trial, and evaluate the clinical data anew. By repeating that cycle as often as every 14 days, the outsourcing partner can use the clinical data to intricately adjust the formulation such that by the end of the early development program, the customer has a drug product that is optimized for progression to the later stages of development and commercialization. Indeed, implementing the 14-day ‘make-test’ cycle can shave six months or more off a typical formulation development timeline.

 What are the drivers and advantages of outsourcing drug development to CROs and CDMOs?

 To a great extent, the current wave of outsourced drug development has been driven by mega-mergers that in many cases have resulted in R&D budget cuts, site closures, and loss of in-house R&D personnel and know-how. Many large pharmaceutical organizations have recently entered into multi-year, multi-compound strategic outsourcing partnerships by which major elements of operational responsibilities and resources are transferred to a service provider, sometimes in conjunction with R&D facilities. For an innovator company, a major advantage of outsourcing to CROs and CDMOs is that the company can direct its investment toward attainment of key development milestones, rather than toward an internal infrastructure that may be underutilized.

Formulation development and adaptive GMP manufacturing 

How do you optimize and validate a formulation?

The conventional approach to the development of improved drug product formulations uses separate CDMO and CRO providers to develop candidate formulations of a drug that can then be screened in preclinical and ultimately clinical studies. This approach results in longer development times and requires acceptance of (poorly predictive) preclinical PK data to determine which systems to take forward into a human study.

	By contrast, Translational Pharmaceutics can accelerate access to clinical data more readily and allow accurate decision making in formulation evaluation. This application of Translational Pharmaceutics can also be used to optimize formulation composition by interrogating a formulation design space within a clinical study. This approach builds upon established International Council for Harmonization Q8 principles and allows products from any point within a continuous formulation composition space to be evaluated without having to submit multiple amendments to a regulatory authority.

Why is it important to integrate formulation development and adaptive GMP manufacturing with clinical research?

 Horizontal integration of formulation development, real-time adaptive GMP manufacturing, and clinical testing is especially advantageous in the early stages of drug development (defined as FIH through to POC). When a sponsor can outsource all these functions to a single partner that offers these capabilities under a single roof, with a single project manager, an integrated early development program can significantly ease the sponsor’s management and contracting burdens.

	The integrated approach also addresses a major shortcoming of the conventional, multi-vendor outsourcing approach: the lack of operational or ‘know-how’ synergy between vendors, which can stymie innovation. Rather, under the integrated approach, the formulation development and drug product manufacturing specialists understand exactly what the clinical trial personnel need, and vice versa, fostering a consistent exchange of information.

Can you give an example of how the Translational Pharmaceutics platform was used in a development project?

 In one example, a sponsor development team was challenged to identify a new oral formulation of one of their compounds. The new formulation needed to be able to overcome solubility-limited absorption to improve bioavailability compared to the formulation used for FIH trials.

	A formulation development program was conducted that identified spray-dried dispersion formulations as ideal for the compound, which were confirmed as superior to the preceding formulation through discriminatory dissolution testing. A series of demonstration batches of candidate formulations was manufactured under GMP to provide data for submission to the regulatory authority. Approval to commence recruitment for the clinical study was received in 14 days.

	The candidate formulations were manufactured in real time and dosed to 10 healthy volunteers in a crossover trial, with significant improvements in bioavailability observed. In this program, the first subject was dosed with the new formulation just 20 weeks from commencement of formulation development. The total project duration from initiation to completion of the clinical phase was 28 weeks, minimizing the impact of the formulation program upon the development plan, thereby delivering both time and cost benefits.

	When referring to this article, please cite it as A. Siew, “Accelerating Early Drug Development with Translational Pharmaceutics,” 

Mark Egerton, PhD, chief executive officer of Quotient Sciences, shares insights on a new approach to accelerate drug development, which integrates formulation development, real-time adaptive GMP manufacturing, and clinical research within a single platform.

Accelerating Early Drug Development with Translational Pharmaceutics

	Prefilled syringes represent a win–win scenario for both end-users and manufacturers. This drug-delivery system is widely used across a range of therapeutic areas because of its broad acceptance among healthcare workers, patients, and caregivers. As a result, there is a lot interest in the development of biologic drug products in prefilled syringes within the bio/pharmaceutical industry. Graham Reynolds, vice-president and general manager, Global Biologics at West Pharmaceutical Services, Inc., shares with 

 the various aspects that have to be taken into account when developing a biologic drug product in a prefilled syringe.

 What are the formulation considerations for prefilled syringes?

 A drug product’s formulation is comprised of multiple raw materials, as are the components of prefilled syringes. It is ultimately the compatibility of these systems that will help to qualify the system for its intended use. Components of prefilled systems typically include pistons, syringe barrels, needles, and needle shields-all of which must be compatible as a system and with the drug product.

	In addition, formulators often struggle with the challenges of optimizing volume and viscosity to ensure an effective concentration of drug product. With larger molecules, it may be difficult to develop a dose below the 1-mL volume (to fit within a standard 1-mL syringe) without producing a high-viscosity product that may be difficult to handle and require high forces to inject. In such cases, the use of a larger dose volume, administered with a larger syringe (2.25 mL is typically the next larger size), will be required. There may be limitations to the volume that can be injected quickly, and many companies are now considering the option of a wearable delivery system, rather than hand-held, for volumes in excess of 2 mL.

 What are the functional considerations for prefilled syringes?

 The prefilled syringe component with the maximum drug product contact area is the syringe barrel, which can have a major influence on drug product quality. The compatibility of the drug product with the barrel’s contact surface is critical to the drug product quality, while the break-loose and glide forces are key to the administration.

	Conventional wisdom says that a better delivery system can lead to a better patient experience. Specifically, “better” means easier to handle, with plungers that move smoothly and with the same force, consistently, every time. Additionally, they should cater to the particular diagnosis-for multiple sclerosis patients, for example, the prefilled syringes should be designed to accommodate patients who may struggle with dexterity issues while handling smaller items.

 What about the importance of lyophilization?

 Because biologic drug products are often moisture and temperature-sensitive, they present new challenges around packaging and containment. To ensure optimized storage and moisture protection for their injectable drug products, biopharmaceutical companies are increasingly turning to the process of lyophilization for biologics and other drugs that are sensitive in liquid form or sensitive to their environment. Lyophilization is considered an ideal process for injectable drug products that may have a limited shelf life in solution. Typically, lyophilized products are packaged in a vial, although there are options to use a dual-chamber syringe in some cases. The use of prefilled syringes to contain diluents, combined with some form of vial adapter or transfer device, can be an option to ease the administration of lyophilized products.

Graham Reynolds, vice-president and general manager, Global Biologics at West Pharmaceutical Services, Inc., shares insights on key considerations when developing a biologic drug product in a prefilled syringe. 

Formulation and Functional Considerations for Delivering Biologics in Prefilled Syringes

The United States is facing an opioid crisis. FDA has expressed concern about the growing epidemic of opioid abuse, dependence, and overdose, and part of its action plan includes a call to pharmaceutical manufacturers to develop opioid formulations with abuse-deterrent properties (1). As a result, there is increasing interest in the development of abuse-deterrent formulations as the technologies to prevent abuse among patients and recreational abusers continue to advance rapidly. 

	“Generally speaking, abuse-deterrent formulations should prevent drug abuse, but maintain clinical benefit and patient compliance,” says Michael DeHart, associate director, Pharmaceutical Development, Metrics Contract Services. “In other words, incorporating excipients to prevent drug abuse should not alter the bioavailability of the API or increase the tablet/capsule size dramatically.”  

	According to DeHart, one of the biggest challenges in developing an abuse-deterrent opioid formulation is that formulators are sometimes formulating from a reactive perspective. “A similar comparison can be made to how antivirus software developers must sometimes react to, or address, hackers who have already released a virus,” he says. “Drug abusers are highly resourceful and can generally ‘hack’ a formulation to get what they want.” 

	Current products on the market that contain abuse-deterrent labeling approved by FDA fall into two categories, highlights Angela Moore, scientist, Analytical Development, Alcami. One is based on a physiochemical abuse-deterrent approach and the other combines the opioid with an antagonist. “Physiochemical abuse-deterrent properties include products that are formulated to resist crushing, chewing, and physical manipulation. They contain excipients that will gel upon contact with solvents to make them difficult to inject intravenously,” she explains. 

	One of the more common excipients used to impart abuse-deterrent properties is polyethylene oxide (PEO), observes DeHart. “PEO can be cured or processed through hot-melt extrusion so that it cannot be crushed,” he says. “Grunenthal’s abuse-deterrent Intac Technology is based on this approach.” Tablets produced using Intac Technology have higher mechanical strength and are, therefore, resistant to crushing (2). An additional advantage is the low extractability of the active drug from the tablet in a wide range of solvents (2). “This low extractability is because PEO swells when exposed to various solvents,” DeHart says. The gelling of the polymer creates a viscous mass that is difficult to draw into a syringe, hence, raising the hurdles to drug abuse. DeHart notes that Purdue Pharma uses PEO in their reformulated OxyContin tablets.

	“Opioid/antagonist products, on the other hand, contain the active opioid intended for therapeutic use as well as a sequestered antagonist, so that if the product is manipulated intentionally, it will release a chemical that will prevent the user from feeling the euphoric effects of the opioid,” Moore points out. 

	DeHart cites Pfizer’s Embeda as an example of an opioid formulation containing an antagonist. “In the case of Embeda, inactive naltrexone (i.e., the antagonist) is formulated with morphine sulfate in the capsules. If the capsules have been adulterated for potential abuse, the antagonist would become bioavailable and prevent any kind of abuse,” he says. “Opioid formulations may also include excipients such as sodium lauryl sulfate that can cause irritation when crushed and snorted.”  

	According to Moore, there are many considerations for manufacturers developing abuse-deterrent opioid formulations. “Most importantly, the product must be considered safe and effective, and it must adhere to all FDA manufacturing and testing guidelines,” she stresses. “From a chemistry and biologic perspective, the product must resist dose dumping and abuse, but still release the active ingredient when ingested as intended. From a commercial viewpoint, one of the key considerations is to develop a product that has a competitive advantage over those already on the market.” She explains that a company must differentiate its product in such a way that doctors will want to prescribe the new product over other available alternatives. She adds that insurance companies must also be convinced that the new product is worth paying more money for compared to cheaper products that do not contain abuse-deterrent formulation properties.

Evaluating the effectiveness of abuse-deterrent formulations

	The current FDA guidelines (3) for determining the effectiveness of abuse-deterrence of a drug product involve four main studies, termed Category 1, 2, 3, and 4. “Category 1 testing involves laboratory manipulation and extraction studies,” says Moore. “In these studies, the product is evaluated and compared to currently marketed formulation(s) for the ability to defeat or compromise the abuse-deterrent properties. This testing is done 

 and provides the physical characteristics of the product and its ability to resist crushing, grinding, melting, and to resist nasal abuse. Extraction studies provide information on the product’s ability to isolate the antagonist, or resist abuse by injection, or, in larger volumes, resist abuse by ingestion,” she explains. 

	“Category 2 testing involves pharmacokinetic studies in healthy humans. The product’s 

 properties are evaluated by comparing an intact formulation against the manipulated formulation through one or more routes of administration. Comparator products are also evaluated for comparison,” says Moore. She adds that Category 3 testing evaluates the clinical abuse potential of the product. “These are large, complicated 

 studies that are generally conducted with recreational drug users as test subjects. These test subjects are screened prior to the study to ensure that they are able to distinguish between the active drug and a placebo in a drug abuse setting. In these studies, the test subjects are provided the drug product being developed and suitable comparators. The drugs are administered through the route of abuse that is being studied (i.e., oral or intranasal) and the patients provide not only pharmacokinetic data, but also subjective data on the drug liking (how high they are) and if they would take the drug again,” she explains.

	Moore highlights that Category 4 assessment is a post-approval study that determines if the product has resulted in meaningful reductions in abuse, misuse, or adverse clinical outcomes (addiction, overdose, and death). “These evaluations are conducted by the product manufacturer,” she says, pointing out that currently, there are no products on the market that qualify for the Category 4 label for abuse-deterrence.

	“Recently, one of the more common tests that we have seen being used to evaluate the effectiveness of abuse-deterrent formulations is its syringeability,” DeHart notes. “Syringeability looks at how much opioid can be extracted from a tablet using heat, agitation, and in small volumes of water to see if it can be pulled through a syringe.” 

	According to DeHart, drug products that are susceptible to snorting should be evaluated for crushability and particle size distribution. He adds that tablets should also be evaluated to determine if dose dumping can be prevented. “Dose dumping typically occurs when painkillers are consumed with alcohol,” he explains. “It is, therefore, important to evaluate opioid release from drug products in dissolution media with various concentration of ethanol.”

	While the pharmaceutical industry has a crucial role to play in developing opioid formulations that are more resistant to abuse and manipulation, the opioid crisis can only be tackled effectively if FDA, governments, policymakers, healthcare providers, patients, and their families to work together, as pointed out by FDA Commissioner, Scott Gottlieb (4). 

	1. FDA, “FDA Opioids Action Plan,” 
	

www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm484714.htm

,
	accessed Dec. 13, 2017.
	2. Grunenthal, Intac, 

Guidance for Industry: Abuse-Deterrent Opioids-Evaluation and Labeling

 (Rockville, MD, April 2015).
	4. FDA, “Statement from FDA commissioner Scott Gottlieb, MD, on the Trump Administration’s Important Efforts to Address the Opioid Crisis,” Oct. 26, 2017.


	Vol. 42, No. 1
	January 2018
	Page: 34–36

	When referring to this article, please cite it as A. Siew, “Tackling the Opioid Crisis with Abuse-Deterrent Formulations,” 

Abuse-deterrent opioid formulations generally fall into two categories: the first is based on a physiochemical abuse-deterrent approach and the second combines the opioid with an antagonist.

Tackling the Opioid Crisis with Abuse-Deterrent Formulations

As real game-changers in the treatment of diseases, biologics have a dominant share in the global pharmaceutical market today. EvaluatePharma has projected that by 2022, biologics will make up 52% of the top 100 product sales, overtaking small-molecule drugs (1). It is, therefore, not surprising that biologics are becoming a major part of drug development pipelines, especially for Big Pharma. The number of new biologics on the market has been growing steadily despite the highly complex production process; however, because of delivery challenges associated with non-invasive routes, most of these drugs will be developed for parenteral administration. 

	The focus of product development has evolved into making parenteral administration more convenient for the patient or healthcare provider while improving manufacturing, notes Martin VanTrieste, an expert and consultant in all aspects of quality in the pharmaceutical industry, who previously served as senior vice-president at Amgen, responsible for quality assurance, quality control, compliance, and operational excellence. “Packaging has thus become an integral part of the drug concept,” he says. “Besides contributing to patient safety, parenteral packaging should also allow for more flexibility, such as the use of different filling lines. It should facilitate manufacturing and contribute to a lower total cost of ownership, which can be achieved through standardization, for example.” 

	Pharma manufacturers are generally looking for smooth and reliable processes, observes Markus Hörsch, sales and marketing director at Bausch + Stroebel. “Due to increasing drug costs and the associated rise of unit value, pharma manufacturers are seeking to minimize product loss during the filling operation. There is a lot of interest in all kinds of process controls. We notice that such applications are being requested more and more to prevent rejects and raise process safety,” he says. 

Packaging solutions shaped by industry trends

	The challenges of parenteral packaging facing R&D-driven pharma companies arise from three significant trends shaping drug development and manufacturing activities. Firstly, the shift toward customized therapies that target smaller patient populations is driving the demand for more efficient and flexible fill/finish processing, VanTrieste observes. Smaller batches require small, flexible fillers, which are able to process multiple containers such as vials, syringes, and cartridges, Hörsch points out. “Pharma manufacturers want the flexibility to process different products and containers on the same machine and at the same time, while minimizing changeover times. Fast changeovers between different packaging containers are, therefore, important,” he explains. “Today, more and more containers as well as the components are supplied as ready to use, which means they are already washed and sterilized. Thanks to such formats, pharma manufacturers can focus on their core business of filling their product.” VanTrieste, however, adds that there is a need for standardization of ready-to-use packaging platforms.

	Secondly, there is an increasing number of highly concentrated, and thus, highly viscous drug formulations, which require high-dosage accuracy. “Extremely accurate container volume specifications (such as inner diameter and length) are needed for such formulations,” VanTrieste explains. Thirdly, the trend toward higher dosage volumes with longer administration times is triggering the need for device integration to enable convenient self-administration outside the hospital setting. “In this case, accurate dimensions for enhanced container/device compatibility are required,” VanTrieste says. 

	“Taking all these requirements into account and considering the huge number of already marketed therapies and existing drug/packaging configurations, it becomes evident that future pharma packaging has to be a modular concept,” VanTrieste highlights. “Thus, the most important question is: what is the most sufficient packaging solution per therapy, determined by patient, drug, and fill/finish requirements.”

	The risks associated with packaging are often not at the forefront of early stage development, but for biologics particularly, the container can have a profound impact on the drug product. The industry now recognizes the importance of focussing on primary packaging in the drug development process. 

	For biologics, new drug products are often launched in vials or syringes, observes Professor Volker Rupertus, senior principal expert for Schott. “Given the complex and sensitive nature of these molecules, the compatibility of the packaging material with the drug product is an important aspect. But it’s also equally important to ensure that the packaging meets machine fill/finish requirements as well as patient requirements, such as the need for self-administration,” he says. 

	“It is unlikely that we will have one packaging solution that covers all drugs,” Rupertus points out. “Therefore, collaboration between the pharmaceutical company and its packaging suppliers (including the elastomer component suppliers), machine vendors, and fill/finish contractors is needed. In fact, it is important to develop the drug product and its appropriate packaging at the same time,” he says. 

	VanTrieste believes that the earlier all parties are brought to one table (at the latest, prior to clinical studies), the better. He adds that a close collaboration involving all parties will support pre-qualification of packaging combinations and platforms. “Such collaboration will also support the final packaging evaluation for a specific drug market launch,” he says. “Moreover, the close collaboration can pre-define packaging iterations during the lifecycle of a certain drug.” 

	Packaging suppliers are constantly working on new packaging solutions to meet the needs of more complex and sensitive drug product, notes Hörsch. “During the development process, the packaging suppliers will reach out to the machine vendors to get feedback about the processability of the new packaging on the existing lines,” he explains. “For the packaging supplier as well as the pharma company, this discussion helps later on when the new packaging is introduced into the market because there are already technical solutions to process the new packaging.”

	Hörsch points out that for machine vendors, it is a huge benefit to know what packaging might soon come to market and to have the opportunity to give feedback and proposals for minor changes. “This interaction allows us to create the best possible solution for the pharma customers and prevent difficulties or problems during the processing of the packaging,” he adds. “From a machine vendor’s perspective, we prefer the standard primary containers (e.g., like ISO formats defined for vials in ISO 8362-1) with tight geometric tolerances to enable stable and highly efficient processing. The same applies for ready-to-use configurations, with regards to the outer packaging, tubs, and nests.”

	“As the requirements for drugs are getting more and more diverse with the advent of new therapies, trying to establish one best solution that is applicable to all drug products is not helpful for an industry that wants to reach a cost/benefit optimum,” says Rupertus. “To give you an analogy, this would be like developing a car that has a tremendous acceleration and at the same time, can transport 30 tons of load.” He explains that the challenge is rather to find the best possible solutions for a specific application, and ideally bundle existing technologies into platforms.

	“The really interesting packaging solutions today are not about building new technologies, but rather combining technologies,” observes VanTrieste. “Examples are applying existing standards of syringe filling to nest-and-tub configurations for vials and cartridges, or applying proven toughening procedures to tried-and-true borosilicate glass instead of pushing for change in the glass type.” He adds that changing the glass type would come with high testing work for a holistic risk assessment as well as regulatory effort for re-registration.

	Despite interest in other novel materials, borosilicate glass is still regarded as the preferred primary packaging material for parenteral drugs due to its long track record and the large amount of available data. Schott asked customers what they consider as the most important aspects with regards to the packaging container of their drug products. “The vast majority underlined that they want to base any packaging decision on long-term scientific data to minimize any safety risk for the patient and that they want to keep regulatory efforts to the minimum,” says Rupertus.

	“An important aspect is the high quality of the glass surface to prevent damage and breakage,” Hörsch highlights. “During the whole process, various forces, such as heat and pressure impacts, can influence the stability of the glass object. Microcracks or scratches, which are already in the glass, can then result in potential breakage of the glass and compromised efficiencies of the processing equipment.”

	“The most important requirements I see for glass containers are glass strength, low particle counts, critical dimensions, and cosmetic appearance,” says VanTrieste. 

	According to Rupertus, cosmetic quality (i.e., accurate dimensions and flawless surfaces) is the most prevalent demand among its customers. The dimensions are important for several reasons. “First, the more accurate the vial, syringe, or cartridge, the more smoothly it will run on the production line,” he explains. “Second, tight tolerances, for example, in inner diameters, lead to improved container closure integrity and gliding force in the case of syringes, as the fit between the elastomer components (e.g., stopper) and the container is much better.” 

	“A flawless outer surface has, in fact, a huge impact on the reduction of breakage,” says Rupertus, who has undertaken extensive studies on glass surface characteristics. “Glass has a remarkably high internal strength. Its weak points are small cracks on the surface or edges. These micro-defects can spread inward as mechanical stress increases, leading to sudden fractures. Looking at it the other way around, vials of high cosmetic quality with an intact surface are already at least twice as resistant to breakage.”

	Rupertus points out that breakage is mainly a problem with old filling lines, considering that surface defects are mostly caused by production or handling. “Newer lines come with improved handling technologies, and with the switch to ready-to-use filling lines, where the packaging is safely fixed in a nest, we no longer have this problem,” he says. “A variety of technologies are available to improve existing lines. We know of a variety of cases where minor adjustments have already made a huge difference.”

	Rupertus highlights that for the vast majority of applications, improved cosmetic quality (and thus reduced breakage risk) plus line optimization are an adequate solution. “In cases that require stronger break resistance (e.g., toxic drugs), proven chemical toughening procedures can achieve compressive stress in the glass surface, hence, preventing cracks from propagating and making the respective glasses more break-resistant. This method is an industry standard. Schott and others, for example, have been offering chemically toughened borosilicate glass cartridges for some time. This procedure can also be applied to produce vials with higher break resistance,” he says.

	Rupertus explains that further improvements related to particles and/or pre-damages, such as scratches or chips, can be achieved with better forming technologies combined with automated camera systems/inspection technology. “Such technologies also help to avoid scratches and reduce particle load significantly,” he notes. “To further evolve this, packaging suppliers and machine manufactures can form close ties and work on improved glass handling, advanced transport and logistic concepts, standardized interfacing, and Big Data approaches to name a few.”

	“With more patients around the world gaining access to healthcare, supply chains are becoming more complex,” says Rupertus. “For suppliers, concentrating on their own processes no longer suffices. While this complexity certainly poses many challenges and calls for new ways of collaboration, there is also a positive side to it-working closely can indeed fuel supplier-enabled innovation. Packaging serves as the interface to the patient and is the key to achieving dosage accuracy and enabling self-administration. Therefore, working closely with packaging, filling line, and elastomer partners can help pharma companies to market drugs in a faster and safer way.”

	1. EvaluatePharma, “World Preview 2017, Outlook to 2022,” June 2017.


	Vol. 30, No. 1
	January 2018
	Pages: 14–17

	When referring to this article, please cite it as A. Siew, “Elucidating Parenteral Packaging Requirements for Future Drugs,” 

The development of new packaging solutions that are fit for drugs of the future requires close collaboration between the pharmaceutical manufacturer and its packaging suppliers and machine vendors.