Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

The purity (aggregates, host-cell proteins, host-cell DNA, etc.) and structure (sequence of amino acids, post-translational modifications, folding, etc.) of proteins directly impact the safety and efficacy of any formulated drug product based on them. Because proteins are generally produced as a mixture of similar but different biomolecules using living cells and subjected to extensive purification steps, variations in their structure and purity can occur from batch to batch.

	The International Council for Harmonization (ICH) guidance Q6B, 

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

 (1) established guidelines for setting specifications for biologic drug substances, including determination of their composition, physical properties, and primary and higher-order structures, using appropriate methodologies. Comprehensive characterization of proteins is often challenging, however, given their complexity. In many cases, singular analytical methods cannot provide the complete picture for specific attributes. Orthogonal methods-different methods intended to measure similar attributes-are often necessary to provide independent confirmation of protein properties. Protein particle characterization is no exception.

	The key when selecting orthogonal analytical methods is to choose technologies that overlap in complementary ways to provide a complete characterization of the protein in question, according to Kent Peterson, president and CEO of Fluid Imaging Technologies. The first step is to identify the information that is required for protein characterization and which techniques can provide that information-and the information that each cannot provide. “It is important to keep in mind that different techniques may provide the same information, but produce different results due to their varying technologies,” Peterson says.

	Proteins, as well as all types of monoclonal antibodies and gene and cellular therapeutics, differ in terms of their structures, biological activities, and purity profiles. Consequently, while different sets of orthogonal technique strategies may be used for different biologics, true “toolbox” approaches or platforms may not be completely successful, according to Mike Merges, director of strategic growth for Catalent Biologics.

	As a result, Catalent, when developing strategies for assay or method development and optimization, considers a combination of one factor at a time (OFAT) to define individual factors, at least initially, and design of experiment (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 development of a set of orthogonal methods,” Merges adds.

	When it comes to particle analysis, Peterson notes that different techniques rely on different detection principles ranging from fairly basic (visual/microscopic inspection) to high-tech methods (resonant mass measurement [RMM], analytical ultracentrifugation [AUC]) and cover a wide range of particle sizes. “No single technique provides all of the answers. Two different techniques provide more data than just one,” he observes.

	Effective sets of orthogonal methods “follow-the-molecule,” according to Merges. Timeliness, cost-effectiveness, and accuracy are other important factors, according to Peterson.

	In addition, Merges notes that the ability to validate the techniques and transfer them from the development phase/lab to the quality control phase/lab or even to an outside contract research organization are essential.

	“Validation is accomplished in a phase-appropriate manner,” Merges continues. The overall guidance for all phase-appropriate levels is ICH Q2 (R1) (2),

	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 and/or other pieces of guidance, such as 

	“The establishment of appropriate validation acceptance criteria should be based upon data-driven decisions. Those data are best generated via a pre-validation exercise conducted prior to the drafting of each phase-appropriate validation protocol,” he explains.

	Orthogonal techniques for particle characterization

	When it comes to particle characterization, Petersen points out that collection of imaging data is one of the accepted techniques for acquiring size, shape, and other morphological information used to differentiate protein aggregates from other particles in the formulation. “The nature of the particles in protein formulations and the small sample volumes pose a challenge in that throughput, accuracy, and specificity are met by very few technologies, however,” he comments.

	Different techniques have different strengths and weaknesses for addressing these challenges. “For example,” Petersen observes, “particle count can be obtained by various particle analyzers, including single-function particle counters, light obscuration (LO) instruments, and flow imaging microscopes (FIMs). However, only some FIMs offer light and dark pixel thresholding that enables the detection of translucent proteins, while these proteins go undetected by other technologies.” 

	More specifically, LO provides particle count and concentration for large sample volumes. It provides the ability to analyze large volumes relatively quickly, has been around for a long time, and is seen as the first step in particle analysis, according to Peterson.

	It does not capture morphological information about the particles contained in the sample, however, nor does it accurately detect or record translucent to semi-translucent particles, according to Peterson. “In LO, the signal from each particle is converted to a sphere of correlative size, and what is actually measured is the equivalent spherical diameter (ESD) of the generated sphere. We know, however, that not all protein particles are spherical in shape, so this method does not produce the most accurate size distribution,” he explains. LO is an inexpensive and quick method that has been in use for decades despite these limitations due mostly to the fact that it remains a USP compendial method.

	FIM, on the other hand, enables the detection of particle sizes ranging from 300 nm-5 mm and reveals morphological characteristics of the particles imaged. In addition, FIM can detect translucent, semi-translucent, and opaque particles and allows for the differentiation of protein aggregates and non-proteinaceous particles.

	Currently, light obscuration and membrane microscopy are required by USP regulations, and flow imaging microscopy is being rapidly embraced globally, according to Peterson. The combination of technological advancement and the industry’s acceptance of the need for a better method to fill the gap where methods like LO left a lot of unanswered questions-specifically for smaller micro- and nanoparticle analysis-have paved the way for newer methods to become widely accepted, he explains. “Better data from imaging flow microscopy provides morphological characteristics of the particles analyzed and answers these questions while providing a more detailed analysis,” he says.

	Nanoparticle analysis lacks many orthogonal components. Historically, imaging in flow could not address this size range, according to Peterson, so information on size and shape and transparency through the imaging of nanoparticles had been missing. Newer technologies such as nano-flow imaging from his company are addressing this need. Automated membrane microscopy from HALO Labs and hyperspectral imaging from Spheryx are also offering promising solutions. “Until recently, there has been no imaging capability for flow imaging microscopy of particles in the nanometer size range. The FlowCam Nano imaging instrument from Fluid Imaging Technologies is an oil immersion flow microscopy technique that provides optical resolution down to the hundreds of nanometers,” Peterson says.

	The breakthrough technologies described herein are examples of solutions being developed by instrument manufacturers in response to the needs of formulation development scientists for orthogonal analytical techniques for protein characterization. Bringing them to the market is increasingly difficult, however, according to Peterson. “There seems to be a growing lag time between commercial implementation and regulatory acceptance and requirements. These delays may be jeopardizing the timely, widespread use of technologies that can significantly contribute to the safely and efficacy of biotherapeutic drugs,” he asserts.

Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

, Step 4 version (ICH, 1999).
	2. ICH, Q2(R1) 

Validation of Analytical Procedures: Text and Methodology

, Step 4 version (ICH, 1994) (Complementary Guideline on Methodology dated 6 November 1996 incorporated in November 2005).
	3. 

 General Chapter <1033>, “Biological Assay Validation” (US Pharmacopeial Convention, Rockville, MD, 2010).
	4. 

 General Chapter <1034>, “Analysis of Biological Assays” (US Pharmacopeial Convention, Rockville, MD, 2012).

Vol. 42, No. 4
	April 2018
	Pages: 56–58

	When referring to this article, please cite it as C. Challener, "Multiple Views Deliver Complete Characterization of Protein Particles" 

Articles

Complex protein formulations require multiple analytical techniques to achieve full characterization.

Complete Protein Particle Characterization from Multiple Views

Biologic drug substances are large, complex molecules prepared from living systems via complex cell-culture or fermentation processes. Given this complexity, it can be difficult to achieve consistent and predictable performance, with numerous factors from raw material variability to operator training to equipment selection influencing process outcomes. Biopharmaceutical manufacturers continuously seek new manufacturing technologies and approaches to improve process robustness and enhance product consistency and quality. Recent pursuits include continuous processing, the implementation of process analytical technology (PAT) and automation systems, the adoption of single-use equipment, development of enhanced modeling capabilities, and leveraging advances in data management and analysis. In the end, however, maximizing the benefits of these new approaches and technologies requires extensive collaboration within multifunctional teams.

	Uniform production of biologic drug substances from batch to batch requires consideration of three key attributes, according to Elise Mous, director of sales and marketing and business development for Capua BioServices: the people involved, including their training, know-how, experience, and flexibility; the process itself, because each has its own unique challenges, characteristics, and requirements; and the desired product, for which the final specifications determine the end-game.

	 “The first step is to find the right approach needed to orchestrate all of the necessary requirements in the right manner to ensure a successful, scalable, and robust recipe,” she says. Those requirements include expression strain requirements/characteristics; raw material requirements; plant/equipment design needs; automation needs; training requirements; utilities requirements; key process parameters; regulatory constraints/requirements; and environmental, health, and safety constraints/requirements. For contract development and manufacturing organizations (CDMOs), much of this information can be learned either from past experience at the plant or from the client.

	Attention to details can also make a significant difference in the robustness of a process, according to Mous. “It is important to analyze the potential risks and uncertainties upfront and define a custom onboarding trajectory for transfer, development, scale-up, and manufacturing campaigns, which includes definition and agreement of the joint objectives and journey required to achieve them,” she observes. Development of scalable, robust technologies as early as possible and establishment of a sampling plan and analytics are also important. Finally, attention should be paid to continuous improvement so that learning from the process and the data is ongoing. “Of course,” she adds, “safety and quality requirements can never be compromised.”

	Because CDMOs work on both long-term commercial and short-term clinical and commercial projects, the amount of available process data can vary significantly. Fujifilm Diosynth Biotechnologies tailors its approach to uniformity- and consistency-control based on the amount of data that is gathered, according to Abel Hastings, director of process sciences at the company’s North Carolina facility.

	 “For processes with long histories and substantial data sets, we can leverage traditional statistical control. For processes with smaller datasets, we aim to improve early responsiveness to process control and consistency monitoring by applying a logic-based, piece-wise approach,” he explains. This methodology requires three main steps: process parameter to attribute linkage, development of an ideal distribution of expected data, and comparison of data against expectations.

	Mapping out the expected process parameters to attribute linkage can form the basis for determining which data are most valuable to not only confirm that the process is running reliably, but also ultimately lead to tighter process control, even in circumstances where data are limited, according to Hastings. “This approach can also help teams focus on ways to capture the most informative information,” he adds.

	Once parameter-attribute linkages are established, Fujifilm’s teams discuss and document the expected data results distribution. For example, they consider whether a normally distributed histogram or a sine-wave distribution should be expected, and whether the data might be skewed. “Developing expectations based on the factors and control elements can help teams establish a basic understanding of what ‘normal’ should look like,” Hastings explains. Once actual data are generated, they are compared to the expectations. “Even in the absence of statistical significance, this approach can allow processes to move toward increased process control and uniformity early in their lifecycles,” he observes.

	Effective application of that actual data is essential to enabling meaningful interpretation, Hastings adds. “Most major equipment manufacturers have developed strong and deep data systems that gather information to help ensure reliable operation. In some instances, however, more data does not lead to more knowledge,” he asserts.

	Because CDMOs work on both long-term commercial and short-term clinical and commercial projects, the amount of available process data can vary significantly.

	To ensure the right interpretation can be made, Fujifilm recommends assessing each data acquisition against the corresponding parameter-attribute pair. “Teams should aim to identify any points of ambiguity. Common points of concern can result from misalignment between parameters and attributes, limits of resolution in data, and data acquisition frequency,” Hastings explains.

	An example of a parameter/attribute misalignment would be the difference between a temperature requirement for a shake flask operation and data recording of the temperature of an incubator. “While the temperatures may be the same, they are not the same element,” he says. Issues with data resolution can arise with many digital read-outs, which may clip or round data, potentially resulting in over-interpretation or under-appreciation of the degree to which the data may be skewed.

	Finally, Hastings notes that it is important for users to recognize that automated data systems recorded at intervals may not give an accurate reflection of processes that change at higher frequency. “Teams should consider the rate of change of a process step before selecting a sampling frequency,” he says. To avoid these problems and similar risks, Fujifilm strongly recommends a cross-functional review of processes--from scientist to automation engineer--in order to ensure all data risks are considered.

	Automation helps to ensure consistency by minimizing human errors and enabling repeatability and reliability of operations from one batch to another.

	In addition to types and amount of data and the way they are collected, the selection of biomanufacturing equipment can have a substantial impact on process robustness. Which aspects are most important can vary from one process to another, according to Gerald Hofmann, head of technology development at Capua BioServices. In addition, design attributes to be considered should not be limited to the performance during the actual cell-culture or fermentation process. “The hygienic design of the equipment, its maintenance needs, and what is required for an effective cleaning regime must also be well understood,” he says.

	Perhaps most importantly, selecting the equipment design that will provide the most robust process cannot be achieved without proper understanding of the full process requirements, according to Hofmann. “Making sure that these process requirements, and the needs of the user, are also well understood by equipment manufacturers can also have a measurable impact,” he comments. New equipment should therefore be selected to fit for a defined purpose in accordance with user requirements and critical process parameters.

	When working with existing equipment, it is important to understand the opportunities and limits presented by the design and the potential for any modifications that can make the equipment more fit-for-purpose. Appropriate installation qualification, operational qualification, and process qualification protocols should also be prepared, reviewed, approved, and followed; and a proper maintenance plan should be developed and implemented, according to Hofmann.

	Automation helps to ensure consistency by minimizing human errors and enabling repeatability and reliability of operations from one batch to another. Increasing adoption of automation and PAT in biopharmaceutical manufacturing is intended to reduce drug variability, increase yield, drive down costs, and maximize safety.

	As CDMOs, both Fujifilm and Capua BioServices have a unique perspective because they work with a spectrum of processes, including products undergoing their first at-scale batches, decade-old processes being relocated to another facility, and commercial processes with a long history of continuous improvement. “The strategy necessary to ultimately implement automation ideals can often be challenging for processes striving to simply produce clinical batches,” says Hastings. “It is beneficial to find the right balance between manual versus automated operations; continuously evaluating investment versus added value,” adds Mous.

	“When installing new processes into our facility, we aim to consider the full lifecycle of the process while also meeting the short-term goals of the project. To do so and overcome some of the challenges with implementation of automation, we design our process development work to simulate what can be both implemented as a manual operation and be transitioned into an automated step,” says Hastings.

									In response to the growing complexity and globalization of biopharmaceutical manufacturing, in 2017 FDA’s Office of Pharmaceutical Quality (OPQ) established the Manufacturing Science and Innovation Center of Excellence (CoE) “to promote internal and external scientific collaboration in manufacturing science, facilitate research communication and management, and advance OPQ’s research culture and capabilities in manufacturing science” (1). The CoE is intended to build on FDA’s history of research on bioprocessing issues, particularly viral clearance, quality by design, bioreactor control, and unit operation linkage.

									The CoE’s mission is to “promote biopharmaceutical science and innovation by addressing cross-cutting science and regulatory issues in bioprocessing through research that supports guidance and policy development,” which it will accomplish by identifying technology gaps in bioprocessing methods and directing research to address them, with a focus on improving robustness and eliminating potential failure modes association with common unit operations. Some currently perceived gaps include real-time monitoring of protein critical quality attributes, adventitious agent control, viral clearance robustness, and the linkage between upstream and downstream processes.

									FDA also believes that the CoE can help address industry competitiveness. In addition, because advances in manufacturing technologies can simultaneously improve efficiency/productivity and create regulatory challenges, the CoE will enable FDA scientists/reviewers to better understand new technologies as they are being developed. As a result, the agency will be better positioned to evaluate their potential impacts on quality and safety.

									1. K. Brorson and S. L. Lee, “

OPQ Establishes Manufacturing Science CoE

	Underlying all activities related to the development of robust processes for the production of biologic drug substances is the need for collaboration among scientists and engineers involved in all aspects of a project. “Selection, training, and coaching of the project team, from the operators to the process engineers to the plant engineers to the analytical scientists, is essential to achieving effective processes. Success is not possible without such a multidisciplinary approach,” asserts Mous.

	In many cases, finding the right solutions requires a bit of creative thought and collaborative work between the process development teams and manufacturing and/or quality-control operators, agrees Hastings. “We strongly recommend that cross-functional teams spend time in one-another’s area in order to build a solid understanding of flexibility needs, constraints, and long-term opportunities,” he comments.

	Through this type of collaboration, it is possible for teams to find the right balance between speed, risk and reward, and cost, according to Mous. “In some cases, a project can be started quickly with a higher risk, while in others, investment in proper preparation upfront is the more appropriate approach,” she explains. Cross-functional teams are also better able to determine whether making facility or process modifications is more practical. “These teams know how to look for the best fit in terms of not only the best fit with the process, but the best fit with the budget,” Mous concludes.

	When referring to this article, please cite it as C. Challener, “Consistent API Quality Calls for Collaboration" 

Bioprocess understanding, the right equipment, and automation help, but multifunctional teamwork is the key to API production success.

Consistent API Quality Calls for Collaboration

Access to multiple analytical techniques is essential for fully characterizing complex protein formulations.

Multiple Views Deliver Complete Characterization of Protein Particles

Global government regulatory agencies are paying increasing attention to the contract manufacturing space, with increased inspections particularly of overseas contract manufacturing/contract development and manufacturing organizations (CMOs/CDMOs) supplying the US market. At the same time, most pharmaceutical companies are focusing on supply chain diversity as a risk management/mitigation strategy. The increasing complexity of APIs and drug delivery technologies is also leading sponsor firms to seek service providers with demonstrated expertise in complex chemistry, high-potency API production, and small-volume manufacturing. Manufacturers of APIs are crucial links in the pharmaceutical industry supply chain. Selecting the right API supplier has become essential for the success of any new drug development or commercialization project.

	Before the selection of API suppliers begins, it is important to conduct an internal needs assessment in order to understand the expertise needed to support a company’s entire API portfolio, according to Janel Firestein, life-sciences lead at Clarkston Consulting. “Understanding the technologies your project requires is a good first step,” agrees Eric W. Smart, president of Fountainhead Pharmaceutical Consulting. “If there are special capabilities required, for example the ability to handle a potent compound or perhaps energetic reactions, it is best to seek out companies that specialize in that technology,” he says.

	In addition to having the right technical capabilities and resources to support production needs both today and in the future based on the pharma company’s organizational strategy, the right supplier will be able to demonstrate compliance, flexibility, and costs for any existing, established APIs it produces, as well as have a proven track record for hitting regulatory milestones successfully, according to Firestein. She adds that the ideal CMO/CDMO will also have the ability to partner in support of other portfolio and pipeline projects, have innovative technical capabilities in early-phase formulation development, and have developed a roadmap that shows commitment to keeping their facility compliant and efficient.

	Smart uses web searches, but also seeks advice and recommendations from people he trusts. “Just because a company lists a capability online, doesn’t necessarily mean they are good at it or easy to work with,” he says. He also finds it useful to create a fairly detailed request for proposal (RFP) that includes the project objectives, quantity, timeline, process description, etc. “The more detailed you can make the RFP, the more consistent the resulting proposals will be (if you get that far with a particular supplier), and the easier it will be to compare multiple proposals,” Smart explains. Compliance history should be gauged through review of recent inspections and their outcomes.

	The selection process, according to Firestein, should include a self-evaluation questionnaire, interviews, an onsite evaluation, and a thorough review of any supporting documentation. With regard to on-site audits, Smart usually advocates waiting until a supplier has been chosen, because it is a time-consuming process for both the supplier and the pharma company. Proposal acceptance can be made contingent upon a successful audit.

	The criteria by which API suppliers should be judged can vary depending on the requirements of each project. For instance, Smart notes that if difficult or specialized chemistry is involved, finding a supplier with these capabilities should be the focus. If the chemistry/technology requirements are of a more general nature, then he recommends focusing on compliance and whether the supplier appears to communicate well and will be easy to work with. “While it can be hard to assess in advance of beginning work, matching a pharma company’s project management expectations with the CMO’s way of doing things is important,” he observes.

	Firestein points to six key considerations, including manufacturing quality, capacity, culture/compatibility, cost (accuracy of the cost estimate, approach to cost-containment), data integrity, and facilities (protocols, location of raw material receiving, sampling, testing, etc.). Product quality can be gauged by comparing the CMO’s/CDMO’s regulatory history against industry standards. The percentage of clients that are repeat customers also gives an indication of client satisfaction, according to Firestein. The number and types of molecules a company has produced-and at what scale-gives an indication of manufacturing sophistication and supply chain diversity.

	Data integrity is increasingly important due to the greater emphasis being placed by FDA on this performance aspect, according to Firestein. “Data integrity issues will inevitably create regulatory challenges, but there are also impacts to communication and integration,” she notes.

	Smaller sponsor firms should also assess the CMO’s/CDMO’s roster of active clients and consider asking potential suppliers how smaller projects are not orphaned as resources are allocated to bigger-budgeted projects.

	“Ultimately, pharmaceutical companies should be looking for CMOs/CDMOs that will treat their molecules as though they were their own,” Firestein asserts. Smart adds that while geographic proximity, price, and the like can sometimes play important roles, in his experience they take a back seat to technical competence and the ease with which the sponsor can work with the supplier. 

	To an extent, the same criteria should be continuously met throughout the lifecycle of the sponsor/supplier relationship, according to Firestein. “There should be a partnership scorecard established and shared on both sides of the relationship that measures key performance criteria (e.g., on time delivery, number of deviations, batches right-first-time, etc.). It may also include volumes that need to be tracked each year, such as consumption for Drug Enforcement Administration controlled substance licenses,” she observes.

	Evaluation of CMO/CDMO performance should be ongoing, with the pharmaceutical company providing honest and timely feedback throughout a project, according to Smart. “Suppliers may not always like what they hear, but they should appreciate it because it is not in anyone’s interest for clients to be unhappy. If feedback isn’t provided, particularly when it is negative, it is hard for a supplier to improve its performance,” he says. 

	Changing suppliers is usually difficult, because institutional knowledge tends to be lost in the process. Sticking with one supplier all the way through clinical trials and into commercial production is not always possible, but is a good goal, according to Smart. “Even if a project doesn’t go smoothly, a supplier will usually learn important lessons every time a given product is manufactured,” he notes.

	Due to the costs and timelines required to onboard a new CMO/CDMO, Firestein adds that establishing a long-term partnership is advantageous. “We advise our clients to catalogue partners’ capabilities, determine partnership goals, regularly review partner results, and continuously evaluate opportunities to invest to extend the value of the partnership. These partnerships are especially beneficial in building out multi-year contractual minimums, where you can agree to dollar minimums across multiple APIs with the ability to rebalance needs as demand fluctuates.”

	While switching is difficult, in some cases a project outgrows a supplier’s capacity. In fact, some CMOs/CDMOs aim to serve only clinical needs, while others only work on commercial products. “Shifting from a clinically-focused CMO to a commercial supplier is a pretty easy decision when its necessary. If it is a decision being made because of poor performance, that can be more difficult,” Smart says.

	Clarkston Consulting clients have switched in the past due to supply or quality issues with their current CMOs/CDMOs. Others have made a change after reevaluating their supplier bases, making the decision to move from tactical to more strategic relationships with a select group of preferred partners, according to Firestein. “When pharmaceutical companies perform a risk assessment of their entire supply chain for a given product, they often discover that the risk profile is too great for their CMO/CDMO. In addition, as government agencies continue to tighten regulations across the globe, more and more CMOs/CDMOs are finding it difficult to meet the more stringent regulations, so we’re seeing more audit findings (i.e., 483s), which creates risk for pharmaceutical companies and often causes them to pursue new partners,” she observes.

	When sponsors do choose to make a change, it is important to get a good technology transfer package put together and, if possible, the assistance of the previous supplier, according to Smart. The practicality of achieving this goal often depends, however, on the circumstances surrounding the need for the change.

	CMOs/CDMOs can take steps to make themselves attractive to potential clients. First, according to Firestein, they can differentiate around a core competency in the increasingly consolidated industry, whether through quality, flexibility, or a proprietary expertise. Demonstration of a commitment to the future of their facilities is also important. “Suppliers should make it clear how they will remain compliant and efficient while leveraging industry best practices and new technologies,” she says. CMOs/CDMOs can also prove their dedication by acting as extensions of their clients’ strategic imperatives and showing that their organizations will be aligned through good times and challenges.

	For suppliers looking to establish new relationships, the sales team plays an important role in conveying what it would be like to work with them, according to Smart. “Some CMOs/CDMOs never really get a chance at a new project if their business functions aren’t easy to work with,” he observes. Smart also believes it is important for CMOs/CDMOs to get key technical personnel involved during the early phases of the sales process in order to provide prospective clients a good window into their organizations. “Being perceived as a company that is easy to work with and responsive to client needs is, all other things being equal, a key factor in the selection process,” he concludes.

Vol. 42, No. 4
	April 2018
	Pages: 26–29

	When referring to this article, please cite it as C. Challener, "Unlocking the Best Solution for API Sourcing" 

CMOs/CDMOs that are easy to work with, have demonstrated performance track records, and plan for the future are preferred.

Unlocking the Best Solution for API Sourcing

The switch in emphasis in the pharmaceutical industry from the development of blockbuster drugs to therapies that treat rare diseases and smaller patient populations has led to the need for small-volume current good manufacturing practice (cGMP) API manufacturing capabilities. These APIs must meet the same regulatory requirements as larger-volume drug substances, except at smaller scale and with less-but much higher value material-available for analytical testing, and often under accelerated timelines. In addition, the APIs used to formulate these products are typically highly complex, requiring multi-step syntheses using unusual reagents. Managing multiple projects can be a challenge for contract development and manufacturing organizations (CDMOs).

	CDMOs often manage at any one time numerous small-volume API development projects involving a wide range of chemicals targeting a broad array of therapeutic indications. As a result, they must deal with many different challenges simultaneously. “These molecules tend to by highly complex, and most have never been synthesized before except perhaps at small scale in the laboratory. They also typically require the application of specific, sophisticated technologies, some of which must be engineered for the first time,” says Ed Price, president and CEO of PCI Synthesis.

	Practical syntheses must be developed that can be transferred to cGMP processes that consistently meet quality requirements. Even though commercial processes for these APIs involve smaller volumes than those of APIs intended for blockbuster drugs, scale-up issues must still be addressed. Understanding critical process parameters (CPPs) and their impact on critical quality attributes (CQAs) is essential to understanding the process and conducting risk evaluations for unit operations and equipment to ensure “right-first-time” technology transfer, according to Shyam Vispute, general manager of tech transfer at Neuland Labs.

	Analytical methods must also be developed and validated, which can be challenging due to the complexity of the molecules. In addition, given the small quantities of high-value material being manufactured even at commercial scale, minimizing the quantity of material consumed in these activities is important. “Alternative protocols may need to be developed in some cases to allow for use of reduced quantities of these costly APIs,” Vispute says.

	The complex molecules being developed as drug candidates today require sophisticated technology for their production, such as advanced chromatography systems and specialized isolation techniques like tangential flow filtration, according to Price. PCI Synthesis has seen the need for low-temperature chemistry grow significantly. “Doing cryogenic chemistry is manageable at the lab scale but is much more challenging at the 1000-gallon scale,” he says.

	Often it is necessary to design suitable hardware for use in the laboratory and then transfer the technology to plant scale, according to Vispute. In some cases, existing equipment can be modified, but in others new systems must be purchased.

	Scale-up and optimization of small-volume processes can be challenging because for many there is little information available in the literature. “It is essential to consider all of the various process parameters-temperature, pressure, mass transfer, etc.-upfront,” Vispute observes. Risk analyses for each unit operation-reaction and purification (extraction, distillation, crystallization, filtration, etc.), drying, and powder processing-should be conducted to avoid problems at plant scale.

	Joshua Hoerner, senior director of research and development at Noramco Athens, notes, however, that solution mixing, pressure, and temperature challenges may actually be reduced on a small-volume basis due to the smaller surface areas involved.

	In some cases, the batch scale, which is determined from the dosage strength of the final formulation, will impact the choice of technology used in a synthesis. When developing peptides, for example, researchers must determine whether solid-phase, solution-phase, or hybrid technology is most appropriate, according to Partha Pal, head of custom manufacturing solutions and business development for Neuland Labs.

	Because most of these molecules have not been synthesized on any appreciable scale before, it is also necessary to develop practical purification strategies, according to Price. Poorly soluble compounds falling in Biopharmaceutical Classification System (BCS) classes II and IV can be particularly challenging. “Exploring all available techniques to improve solubility and bioavailability, such as employing suitable techniques to modify the physicochemical properties or increase the specific surface area of the API powder particles, is often necessary,” notes Girish Kavishwar, associate vice-president of R&D at Neuland Labs.

	Some isolated intermediates and APIs may be oily liquids, which can create handling and stability challenges, according to Hoerner. “Managing active ingredients that are predominately viscous oily liquids is a significant challenge, both from a handling and stability perspective. Noramco is working on dosage form solutions to help improve the processability of such substances while also enhancing their commercial shelf-life,” he notes.

	Crystalline powders, on the other hand, may have different polymorphs and crystal habits that can impact drug product manufacturing robustness and the bioavailability of the API, Hoerner adds. “Identifying and stabilizing the appropriate polymorph requires special skills and should be performed early on in the process to avoid problems late in the development cycle,” agrees Pal.

	Handling cytotoxic and highly potent compounds is yet another issue. Appropriate facility and equipment design is required for handling such compounds, and appropriate disposal facilities are also required based on their occupational exposure limits. Automation of process operations is also important for reducing the exposure of operators and the environment to hazardous chemicals, according to Pal. “A process hazard analysis (PHA) should always be conducted prior to implementing a small-volume cGMP synthesis to systematically identify and mitigate hazards that arise from innate chemicals or chemical reactions,” Hoerner asserts.

	One of the key technical and operational challenges associated with cGMP manufacturing of small volumes of intermediates and APIs is difficulty in obtaining reliable reaction yields and consistent quality, according to Hoerner. Noramco tackles this issue with thorough process development efforts to maximize process knowledge and understanding. In-process controls for monitoring reaction completion, crystallization, drying, and other critical steps are also used to ensure completion.

	“Overall, we emphasize a company culture that focuses on the patient/customer and ensures our products are of optimal quality and produced in a safe and compliant manner,” Hoerner comments. From a technical perspective, Noramco begins at the R&D stage, selecting and developing a phase-appropriate route and evaluating critical raw material sources, reagents/solvents, equipment, and analytical controls to ensure robust delivery of cGMP material. In addition, Hoerner says that scale changes between development and cGMP supply are modeled with advanced software; process analytical technology (PAT) or advanced offline analytical technologies are applied to synthetic steps that are highly complex or have significant risk to impact product quality.

	Neuland uses quality-by-design (QbD) and design-of-experiment (DoE) approaches beginning at the development stage to identify relevant process parameters and identify the design space that will have minimal variations at the plant scale, according to Vispute. Use of simulation software, such as for scale up and mixing behavior studies, allows the evaluation of equipment performance prior to actual experimentation in the plant, leading to reduced costs and development times for Neuland. PAT tools are used for real-time measurement of CPPs, such as focused-beam reflectance measurement (FBRM) probes for particle size distribution, particle vision and measurement (PVM) probes for particle shape and polymorph determination during crystallization processes, infrared (React IR , Mettler-Toledo) for monitoring the real-time progress of reactions, and near infrared (NIR) probes to perform drying profile studies for determination of desired polymorphic forms of temperature-sensitive products.

	The internal protocol at PCI Synthesis places emphasis on doing a good job at building a practical process early on in a project. “Once the chemistry and analytics are locked in, if any changes are needed, a tremendous amount of work will need to be repeated. That is why it is so important to take the time upfront to choose the right raw materials (considering cost and availability), really understand the process, and build into the early stage chemistry what will be required down the road,” Price observes. Process optimization using a DoE approach allows efficient yet thorough exploration of the design space. Method development for in-process and final product testing and confirmation of process robustness and reliability at larger scale are then performed before moving to GMP production.

	Small-volume cGMP chemistry is clearly an area that can pose significant challenges. “The first focus should always be on safety and compliance during manufacturing and ensuring robust production of high-quality intermediates and active ingredients,” Hoerner says. That cannot be achieved if small-volume API manufacturing is treated as a commodity business, according to Price.

	 “We work with many different small companies, each with its own business model, culture, internal resources, and level of experience. Each project they bring us is unique, involving vastly different raw materials, equipment, and chemistry. Flexibility and the ability to respond to the different needs of our customers and their projects are crucial to success. We must be able to bring a significant number of differing resources to bear to create custom-tailored solutions to complex problems,” Price concludes.

Vol. 42, No. 3
	March 2018
	Pages: 22–24

	When referring to this article, please cite it as C. Challener, " Small Volumes, Big Challenges" 

Highly complex APIs developed to treat rare and orphan diseases present big technical questions for contract developers.

Small Volumes, Big Challenges

Excipients are crucial ingredients in final drug formulations with potential impacts on product quality, stability, tolerance, release profiles, local distribution and availability, and thus overall efficacy and safety. Recent regulations have increased the requirements for drug manufacturers and excipient suppliers with respect to ensuring the quality and safety of excipients. The emphasis continues to be on the use of risk assessments and the growing recognition that excipient producers and pharmaceutical companies have shared responsibility for ensuring excipient safety.

	Excipients are becoming a top priority among regulatory agencies. Regulatory bodies in the United States, European Union (EU), and Japan, as well as those in the ‘BRICK’ (Brazil, Russia, India, China, and Korea) countries, are modifying existing and/or introducing new regulations for finished pharmaceutical products that specifically address excipients, either directly or indirectly. Many of these regulations have an impact beyond domestic production of drug products, according to Priscilla Zawislak, global regulatory affairs advocacy manager with Dow Pharma Solutions. National pharmacopeias are also placing a greater emphasis on standards for excipients.

	Regulations on excipient risk assessment were issued by the European Medicines Agency (EMA) in 2015 (1) with implementation required by March 21, 2016. An update of the annex to the European Commission’s guideline on excipient labeling by EMA on Oct. 9, 2017 (2) included the expansion of safety warnings for 10 excipients and the addition of five new excipients to the list, according to Mario DiPaola, senior scientific director at Charles River Labs.

	“Recent draft guidance documents issued by FDA, such as the 

 guidances, are examples of why drug product manufacturers must have a better understanding of what’s needed to comply,” adds Zawislak. “Open communication with suppliers about the composition, functionality, and performance of excipients in a drug product is essential. Excipients are no longer regarded as inactive and it is no longer sufficient to simply provide excipient specifications in an investigational new drug application (ANDA). FDA now requires drug product manufacturers to tell the full story about the role and interaction of the excipients with the API in final drug products,” she continues.

	In China, “Bundling Review” requirements were included within the 

 2015 standards (3) and will be retained in its future 2020 version.

	Industry has also been active in updating voluntary guidelines on ensuring excipient quality and safety. The updated International Pharmaceutical Excipients Council (IPEC) 

 (4) by the IPEC Federation was issued in November 2017. Earlier in the year, the group also published updated guidelines on both excipient good manufacturing practice (GMP) (5) and good distribution practice (GDP) (6), as well as excipient risk assessments (7), according to DiPaola.

	Regulatory proliferation driving communication

	The proliferation of regulations in many different countries and regions around the world has resulted in different excipient requirements that are often not fully aligned with one another. Global excipient suppliers must work with customers to find ways to meet these challenges across multiple regions, sometimes for one particular type of application, according to Zawislak.

	 “More diligence is required when excipients fall under drug or API regulations,” she says. For example, she notes that Brazil and India have requirements for a specific amount of remaining shelf life for imported drug products, which includes excipients, APIs, and finished drug products. Defining a shelf life in this case is different than for APIs and drug products imported into other countries. “Open communication between raw material suppliers and formulators is particularly important here, because without knowledge of the end use, suppliers cannot help ensure that formulations are in compliance,” Zawislak states.

	With the proliferation of more regulations for excipients in the BRICK countries and in emerging countries, Dow Pharma Solutions is also initiating dialogue with regulatory agencies as well as customers to address some of these differences. “We see this situation providing a good opportunity, because it opens lines of communication and leads to greater awareness of the key role excipients have in pharmaceutical products,” asserts Zawislak.

	In addition to focusing on excipient quality in recent years, regulatory agencies have strengthened their positions on preventing drug adulteration of both APIs and excipients by enacting a number of new regulations, ultimately requiring tighter control of the manufacturing processes and testing, according to DiPaola.

	 “A major area of concern in excipient quality is contamination from a number of potential sources, including viruses; microbial and endotoxin/pyrogen contaminants; transmissible spongiform encephalopathy; and impurities resulting from raw materials, byproducts generated during processing, and product degradants. Lack of sterility for excipients deemed sterile is also a potential issue,” DiPaola says.

	These problems can occur for a number of reasons ranging from the lack of dedicated equipment and/or facilities for the manufacturing of excipients; poor environmental control during manufacturing; and/or inappropriate storage and shipping conditions, among others.

	Given this sizeable list of concerns, regulatory bodies have begun to expect excipient users (e.g., drug manufacturers) to perform extensive risk analyses and implement mitigation plans for situations deemed to be high-risk. “Such mitigation strategies may require more testing of excipients for the presence of contaminants or require more control of the manufacturing process and distribution,” notes DiPaola.

	One example is the EU guideline that became effective in 2016. It requires more formalized risk assessments to be conducted on a regular basis. This approach is not limited to the EU, however, according to Zawislak. “We have seen risk assessments become more of a standard globally as a tool in managing raw material and supplier qualification,” she says.

IPEC-PQG Good Manufacturing Practices (GMP) for Pharmaceutical Excipients 2017

 (5), which was published in May 2017, was updated partly in response to the increased requirements for drug manufacturers to perform risk assessments for excipients to determine the appropriate level of GMP that should be used to produce them. It also takes into account third-party standards (EXCiPACT and ANSI) “against which excipient suppliers can be certified to provide assurance that they are operating in conformance with excipient GMP,” according to an IPEC news release (8).

	With increasing regulatory and business demands, the relationships between excipient suppliers and medicinal product manufacturers have never been so important, according to Dominik Odenbach, director, global regulatory and external affairs, Pharma & Human Nutrition, BASF. “A mutual understanding of what is appropriate to ensure the safe and reliable supply of high quality excipients is essential, and it is in the quality agreement that these expectations can be defined,” he explains.

 (4) reinforces the fact that the business of ensuring excipient safety is a shared responsibility between excipient users and suppliers, according to DiPaola. “The quality agreement enables the drug manufacturer and the excipient supplier to establish a partnership through which all quality requirements and responsibilities are clearly delineated. This legally binding agreement provides a process by which costly product quality issues can be minimized and ensures that the drug manufacturer can meet its regulatory expectations and requirements,” he explains.

	“We have found that use of the IPEC QA templates published in 2009 significantly facilitate and accelerate the negotiations between excipient suppliers and customers and, hence, reduce the workload related to the review and discussion of quality agreements for all parties involved,” adds Odenbach. “BASF strongly promotes the use and further optimization of standard templates.”

	The major change incorporated in this latest version of the 

 is the addition of the Manufacturer’s Statement. The original version of the guide addressed the need to have a quality agreement between the excipient manufacturer and its direct customer (e.g., the drug product manufacturer or distributor) and between the distributor and its customer.

	In recent years, customers who buy from distributors have been requesting quality agreements with excipient manufacturers as well. However, because there is no direct business relationship between the excipient manufacturer and the distributor’s customer, formalizing a three-way company agreement would be necessary-and complicated, according to Zawislak.

	The Manufacturer’s Statement addresses this gap. It is written by the excipient manufacturer to define its quality responsibilities for manufacturing the excipient through its lifecycle (e.g., maintenance of a quality management system, adherence to GMPs, change notification, etc.). The Manufacturer’s Statement is signed and dated by the manufacturer and can then be attached to agreements between distributors and their customers.

	“It is important to note that the Manufacturer’s Statement is not a full quality agreement between three companies or a stand-alone document. It is, however, a signed statement from the excipient manufacturer regarding its quality responsibilities, which are generally the same regardless of the end-use customer. As a result, the need for a three-way quality agreement is eliminated, yet each party is protected with respect to quality assurance,” Zawislak observes.

	Aside from variations in the regional regulations designed to ensure excipient safety, a key challenge for the pharmaceutical industry is the lack of integrity and transparency within the excipient supply chain and variability in the quality of excipients, according to DiPaola.

	Significant test method variability is another issue for Ann Gulau, a quality assurance scientist at Dow Pharma Solutions. “This variability should be considered when setting monograph and specification limits. Currently, there are many tests that have much higher variability than the monograph specification limits. As a result, significant amounts of material are discarded as unsuitable for pharmaceutical use, despite no real safety or quality concerns,” she explains.

	Further issues for DiPaola are the limited amount of testing currently performed for excipient release and the lack of robust stability data.

	Updated and harmonized monographs needed

	Most current excipient testing is conducted according to pharmacopeia methods, which like excipient regulations, vary on a regional basis.

	“It is not value-added to measure essentially the same properties with different methods to satisfy all regional requirements. There are frequently minor regional test differences in various pharmacopeia that require additional testing or studies to prove equivalency. This additional testing does not improve product quality or patient safety,” asserts Barbara Serr, business analytical leader for Dow Pharma Solutions.

	For instance, despite the global pharmacopoeial harmonization efforts in the US, Europe, and Japan, the 

) develops individual excipient monographs with separate requirements, according to Odenbach. “For an excipient manufacturer, higher analytical efforts and costs to release globally used materials are necessary to introduce products to the Chinese market, if possible at all. These stringent Chinese requirements create new hurdles to trade, restricting choice, and raising costs, also for pharma manufacturers or consumers,” he says.

	Complicating this particular issue is the lack of timely availability of an official-and therewith binding-English translation of the 

 compliance, analytical method set up and validation work must be performed in the release labs of the excipients manufacturers, for non-Chinese speaking lab personnel an impossible task. In addition, from a technical and testing point of view, several excipient monographs require technically non-achievable limits and/or demand the performance of technically non-feasible methods. Furthermore, scientific cooperation with the Chinese Pharmacopoeia experts in advance is difficult and protracted,” Odenbach states.

	Many of these methods also are in need of modernization. “Current methods tend to be highly time consuming, frequently lack appropriate sensitivity, and generally rely on older analytical technologies,” observes DiPaola. Adds Serr: “Continuation of old limit tests to satisfy some regional pharmacopeia is unwarranted and unnecessary testing. Additionally, some test items may simply be historic without any real relationship to patient safety. Monographs should be updated with a focus on items that are real safety concerns instead of simply continuing historical practices without real purpose.

	One recent example of an improvement is the conversion from old wet chemical methods to the use of inductively coupled plasma-mass spectrometry for elemental impurity determinations. “Using this advanced analytical technique has revealed that many excipients do not contain any of the elements of concern,” Serr notes.

	DiPaola would like to see more use of mass spectrometry for the detection and characterization of impurities/contaminants and newer ultra-high-performance liquid chromatography technology with high-resolution columns.

	Ultimately, according to DiPaola, pharmaceutical manufacturers are held accountable for the overall quality and safety of pharmaceutical products. They are thus applying more pressure on excipient suppliers for greater control of the quality and safety of their excipients, as well as tighter control of excipient distribution.

	At the same time, regulation in the pharmaceutical industry is a dynamic situation, according to Zawislak. “Patient safety is the ultimate goal and often requires development of regulations and standards to achieve that goal in an ever-changing world. Regulations also need to keep pace with emerging technologies and innovations in drug development,” she observes.


	Vol. 42, No. 2
	February 2018
	Pages: 36–41, 61

	When referring to this article, please cite it as C. Challener, “Managing Risk in a Complex Excipient Supply Chain," 

Regulations and industry guidelines focus on ensuring excipient safety by specifying risk assessments and shared responsibility.