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

Cynthia A. Challener

Technology transfer of bioprocesses, while common in the biopharmaceutical industry, can be complex and present numerous challenges. Projects with accelerated development timelines that also involve multiple contract service providers have the potential to magnify the difficulties. Both contract manufacturing organizations (CMOs)/contract development and manufacturing organizations (CDMOs) and sponsor companies can facilitate the process using pragmatic approaches that mitigate risks and ensure cooperation between all parties involved.

	Material, specification, and change-management issues

	When transferring a bioprocess to a CDMO, manufacturers often face multiple challenges that can include meeting the material demands of their clinical or commercial strategy and achieving aggressive timelines. These constraints must be met while accommodating the facility fit and scale-up needs determined by both the established process and the CDMO’s platform, equipment, and capabilities, according to Frank V. Ritacco, director of scientific and technical affairs for pharma services at Patheon, part of Thermo Fisher Scientific.

	Abel Hastings, director of process sciences at Fujifilm Diosynth Biotechnologies, adds there are some themes that often slow the progression of sponsor projects, including materials challenges, specification ambiguity, and challenges with historical change management. “The implications of an ill-selected material can linger and hinder manufacturability. Once selected, materials dogma can be difficult to unpick because of the fear of the unknown,” he notes.

	With respect to specifications, Fujifilm splits them into two general categories: safety/efficacy and manufacturability. It is important, according to Hastings, to convey the known safety/efficacy limits as early as possible and communicate what events might cause specifications to change. “As a CDMO, our primary goal is often to adjust the process design to reliably meet these specifications, and knowing the status of specifications up-front helps us guide our clients,” he explains.

	Issues can arise, however, if sponsors establish specifications that are rooted in manufacturability too early, and then the process performance changes in the development stage or when moving a program from one site to another. Establishing expectations for process performance with limited data can, Hastings says, often over-constrain the development team, leading them to necessarily forego improvements in order to achieve a manufacturability specification. 

	Change management during process development, meanwhile, can challenge both sponsors and CDMOs as they work to expedite processes. “In this day and age of accelerated processes and ever-changing team members, capturing rationale for change becomes increasingly important to guard against knowledge loss as team members leave a company and to help guide development in an unemotional manner,” Hastings asserts. 

	While commercial processes typically have robust quality and change-control systems, earlier-phase projects can often change quickly and with limited traceability. “We recommend taking a balanced approach in order to capture pertinent information while not hindering development,” comments Hastings. Some sponsors use iterative risk assessments or failure mode and effects analysis tools to quickly capture changes and build catalogs of development and lifecycle changes. “This approach allows the user to both convey historical details and to project forward-looking risks in order to steer development in a planned way,” Hastings observes.

	The overall challenge in tech transfer is to ensure that the sponsor’s process will be reproduced in a similar, robust, and compliant way. Manufacturing product in the quality and quantity in the defined timeframe are indicators of a successful transfer of the manufacturing process to the CMO/CDMO, according to Andrew Bulpin, head of process solutions at MilliporeSigma. “This overall challenge,” he says, “is mainly linked to the process itself, but it also relates to the capacity to transfer the process knowledge built for several years to the CMO/CDMO that will be integrated to ensure a successful tech transfer.”

	It often also varies depending on the development phase of the bioprocess being transferred. Sponsor companies’ early-phase programs are typically challenged by transferring processes that do not fit into their external partners’ platform operations, according to Emily Schirmer, senior director of process development at Catalent Biologics. “Those partners that can offer a high level of flexibility and unit operation expertise are more successful in accommodating unique or non-traditional processes,” she remarks. 

	In addition, as programs progress through clinical stages, process transfer becomes more difficult because there is less inherent flexibility allowed and process changes or adaptations become more challenging to justify, Schirmer adds. Bulpin agrees that the process parameters in Phase I or II can be slightly adapted or adjusted to ensure a successful tech transfer, while in Phase III the process is more locked with defined critical process parameters, critical raw materials, and designated critical quality attributes (CQAs). Thus, any changes in Phase III should be assessed, justified and, if necessary, validated.

	Scale-up, equipment, and parameter adjustments

	Adding in a scale-up element when transferring a process increases the overall risk for project success and comparability. “It is difficult to discern the differences observed from facility to facility and any disparities that can be observed on scale up independently,” Schirmer says. “These risks,” she notes, “can be minimized by having a good depth of knowledge of the facility’s specific equipment and well-established scaling models.”

	Variations in equipment and material handling at facilities can complicate the tech transfer process, agrees Bulpin. “If the target facility uses different equipment, the raw materials must be compatible with that equipment,” he explains. In addition, to ensure a successful scale up, it is critical that raw materials are available at large scale and equipment capacity is evaluated. “The scale-up strategy of the CMO/CDMO, as well as its expertise in various process types, molecules, and innovative process methods-including perfusion, precipitation, and single-pass tangential flow filtration-is also key,” asserts Bulpin.

	For cell-culture processes in particular, scale up can be challenging because scaling to larger volume is not linear, and multiple engineering parameters must be optimized to match process performance developed at the bench scale and confirmed at pilot to manufacturing scales of 2000 L and beyond, according to Ritacco. Harvest and downstream purification processes also need to be scaled up to match product quality and impurity profiles, and sometimes adapted to address differences in product titer and impurity profiles observed at larger scale.

	Even if projects don’t involve scale-up, generally they still require a thorough investigation of which parameters need adjustment to fit best within the CMO/CDMO facility and equipment constraints without impacting specifications, Hastings observes. “In our view, scale changes and facility-fit adjustments are not complications but rather just part of what we do,” he says.

	Many new biologic drug candidates are awarded some form of accelerated approval designation. While accelerated approval designations may allow a faster path to the clinic or to commercial approval for breakthrough therapies, the time it takes to develop a bioprocess that will be robust, scalable, and reproducibly deliver target product quality remains significant, according to Ritacco. “Fast-tracking the timeline and schedule without compromising product quality and patient safety is an additional challenge,” Bulpin says.

	While some product development steps can be reduced, Bulpin insists that risk analysis and decision justifications should not be underestimated. “Sufficient understanding of the process is necessary to ensure control of operating parameters to consistently deliver safe and efficacious product to patients, and achieving this on an accelerated timeline requires a skilled team leveraging well-established processes and methods, as well as past experience to streamline development and avoid pitfalls,” adds Ritacco.

	It is also extremely important for sponsor companies to work with a partner who has extensive experience with tech transfer and scale up into commercial launch, according to Schirmer. “A typical program with an external partner is designed to have a process-acquisition phase, which includes a paper transfer followed by establishing the process at a small scale. Then the scale up occurs within the facility infrastructure. These scale-up activities can, however, be minimized by performing the process acquisition at the manufacturing scale to meet accelerated timelines,” she says.

	Fujifilm often observes three particular challenges with accelerated programs: prioritization, collaboration and communication, and planning. Most sponsors with accelerated designations greatly reduce timelines, Hastings says, by focusing on refining their processes to reliably achieve CQAs, often at a cost to the yield. “The most successful projects have a cross-functional team that is clear on their priorities and what success looks like. Ensuring all members of the team work together to settle on the right balance of yield and CQA reliability will ensure teams aren’t derailed by conflicting priorities,” observes Hastings.

	One problem Hastings has observed, however, is that as teams turn attention to accelerating development timelines, they have a tendency to unintentionally reduce the circle of communication. “The most successful teams, however, enlarge their circle to engage all functional areas, allowing everyone to be part of the process of building the best balance of speed, reliability, and risk,” he asserts.

	Planning for an accelerated designation project, meanwhile, requires a balance of creativity, dedication, and pragmatism, according to Hastings. “Teams need to be able to challenge their platform expectations to strike a balance to improve timelines. This planning cannot be done once,  but rather needs to evolve as the scientific understanding of the process grows and teams need to be aware that any new data might require an adjustment to the project plan,” he adds.

	Engaging with multiple outsourcing partners

	For many projects, it is necessary to transfer a bioprocess from one CMO/CDMO to another. Regardless of the reason, it is essential that everyone involved does not overlook the complexities associated with leveraging previous data and maintaining technical continuity, according to Hastings. 

	To proactively address this issue, Fujifilm identifies new, unique, or difficult (NUD) elements, such as process-specific factors that depend on equipment idiosyncrasies that may not be fully evident to a sponsor while the process is running at a CDMO. “When a process is moved from one CDMO to another, the receiving site rarely has access to complete equipment-specific details, which can make interpretation of previously generated data challenging and incur risk,” Hastings says. 

	“At Fujifilm, we work hard to identify NUDs as early as possible and then categorize them as equipment-specific versus equipment-agnostic. This approach allows us to suggest studies that may improve facility fit,” he adds.

	Differences in equipment throughout the process, as well as differences in scale, require optimization of multiple engineering parameters to match process performance in cell culture, harvest, and downstream purification processes between facilities, Ritacco agrees. He also points out that analytical methods have to be transferred, established, qualified, and ultimately validated to assure consistency in analytical results between manufacturers.

	Hastings also notes that some processes include historical elements that are difficult to translate into and out of batch records. “In some cases, sponsors deal with this issue by maintaining some of the same staff throughout transfers to minimize the chances that so-called tribal knowledge is lost,” he observes.

	Transparency between all team members, adds Schirmer, can actually be the catalyst to a successful development, scale up, and tech transfer of a drug with an accelerated approval designation. “Whether the process technology transfer occurs between the sponsor company and the external partner, or between two external partners, the importance of transparency is the same. Communication is also critical. If all parties are aligned and understand the path forward, it is much more likely that the transfer will be a success,” she comments.

	The general constraints are the same for any tech transfer process, including those between outsourcing providers, although the confidentiality becomes more marked and the training process can be slightly different. “The aim remains the same,” Bulpin says. “In addition, any process, analytical, equipment, raw material, and/or regulatory gaps should be listed and mitigated to meet specifications and ensure a successful tech transfer.”

	Technology transfer introduces additional risk to the development and commercialization of biopharmaceuticals, so minimizing risk is fundamental to successful technology transfer of bioprocesses. 

	A clear project plan with milestones that are mutually agreed upon sets the stage for a successful program, Schirmer observes. “Risks should be identified at the onset of the project and continuously re-evaluated to determine effectiveness of mitigations and any additional risks,” she says. In addition, risk assessments should be backed by scientific reasoning and process data.

	The main strategy, according to Bulpin, is to consider tech transfer-with or without scale up-as an entire project with dedicated subject matter experts, communication flow, clear responsibilities, and planning. Dedicating one individual to the management of one CMO/CDMO group helps with this approach, except for quality assurance and regulatory topics, which Bulpin says should be managed globally to ensure process compliance.

	The preparation and review of thorough process descriptions, facility fit, and tech transfer documentation, with appropriate quality review and oversight, go a long way toward achieving a successful tech transfer, adds Ritacco. The experience and expertise of the teams involved is also critical. “A highly skilled and experienced team will anticipate potential challenges and leverage their deep understanding of bioprocess development, tech transfer, and manufacturing to achieve the desired process performance and product quality in a new facility, even when the timeline may be challenging,” he asserts.

	It is also important, according to Hastings, for everyone involved in a tech transfer project to recognize up-front that priorities may change during the development cycle for biologics with accelerated approval designations. Risk-based tools can be used to segment process characterization into two or more phases and to design the process to prioritize CQAs over yield. “Using this approach, it is possible for sponsors to start their process performance qualification (PPQ) in parallel with some process characterization work, thereby shortening the timeline from clinical manufacturing to PPQ,” Hastings observes.

	On the other hand, it can result in post-approval yield fluctuation, which makes business-planning difficult. Fujifilm see this issue as an opportunity to move through a natural transition point. “Purposefully pivoting from biologic license application-enabling activities to business-enabling process improvements at the optimum time will allow programs to benefit from both accelerated PPQ and long-term commercial pay-back,” he concludes. 

	Cynthia A. Challener, PhD, is a contributing editor to 


	Vol. 44, No. 5
	May 2020
	Pages: 56–58

	When referring to this article, please cite it as C. Challener, “Ensuring Smooth Tech Transfer of Bioprocesses to Outsourcing Partners,” 

Articles

Experience, communication, collaboration, transparency, planning, and prioritization contribute to success.

Ensuring Smooth Tech Transfer of Bioprocesses to Outsourcing Partners

Human coronaviruses (HCoVs) in the past were considered to cause nothing more than the common cold in healthy people. That changed with the advent of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in the past decade. The latest coronavirusâ2019-nCoV, since renamed by the World Health Organization as COVID-19âemerged in December 2019 in Wuhan, China. As of late February 2020, it had sickened tens of thousands and killed nearly 3000 people.

	Four of these large, enveloped, positive-strand RNA viruses are endemic globally and thought to cause 10–30% of upper respiratory tract infections in adults (1). They possess a surface spike (S) glycoprotein that binds to host cell receptors, and the nature of this protein is believed to determine the main properties of each coronavirus. SARS-CoV was the first coronavirus to jump from animals to humans; MERS-CoV and COVID-19 have as well.

	The genetic sequence for COVID-19 was released to public databases on Jan. 10, 2020 by the Shanghai Public Health Clinical Center & School of Public Health (1). The three-dimensional (3-D) structure of the spike protein suggests that it binds more tightly to human cell surface receptors than SARS-CoV, a possible reason that this coronavirus exhibits greater infectivity (2).

	Platform diagnostic methods have been rapidly adapted to include COVID-19 for early identification of cases. Several academic and industrial researchers have also focused on applying novel vaccine development and manufacturing platforms to the accelerated development of a COVID-19 vaccine.

	In terms of vaccine development and protection against dangerous viral pathogens, there is nothing particularly unique about coronaviruses, according to Eric von Hofe, chief scientific officer of NuGenerex Immuno-Oncology. “All of the recent potentially pandemic viruses, including SARS and MERS and two flu viruses (avian and swine flu), have the common feature that they simply had never been seen before by the human immune system. That said, we now know a lot about how the human immune system protects against viral infections and can rapidly identify the critical parts of a new virus to target for vaccine development,” he says.

	Traditional vaccines, like the seasonal flu vaccine, are made by growing up large quantities of the virus and in some way killing or inactivating it so that it can be used safely as a vaccine. This approach is an old technology from the middle of the past century, according to von Hofe. “The main problem here is the time it takes to produce the vaccine, which is at least a year and can be several. Ideally, we’d have a platform technology that could be used to produce a vaccine in a few months,” he observes.

	Such technology platforms should be flexible enough to respond to any new viral threat. “We would like to have a simple ‘plug-and-play’ setup where the critical components of a new virus required to make the vaccine can be determined by rapid computer analysis and plugged into the platform to generate a vaccine,” von Hofe notes. “Getting all of the critical components produced and structured in a way that perfectly models the vaccine is the big challenge,” he adds.

	The best way, von Hofe says, is to follow a reductionist strategy to identify key viral components that alone produce complete protection in a safe vaccine that can be manufactured rapidly and in a cost-effective manner. “Clearly this is a tall order, but we’re making good progress in that direction,” he asserts.

	As an example, he points to the development of subunit vaccines that rely on recombinant DNA to encode a critical subunit of the vaccine that generates a response. There are additional challenges to this approach, however. “While responses can be produced, the protection may be short-lived, as there is no guarantee that immunological memory will be generated as is possible with a whole virus vaccine,” von Hofe comments.

	San Diego-based Inovio Pharmaceuticals is one company developing a DNA-based vaccine against COVID-19. The biotech was the first to advance a vaccine (INO-4700) against MERS-CoV into human testing and is currently preparing to initiate a Phase II trial for INO-4700 in the Middle East. This vaccine, however, cannot be used against COVID-19 because the two coronaviruses are too different.

	To develop a new vaccine, Inovio first converts the virus’ RNA into DNA and identifies short sections that will, according to computer simulations, generate the greatest immune response. The plasmids are then produced in large quantities using bacteria. The overall development and approval timeline is thereby significantly reduced.

	Inovio began animal testing of INO-4800, its COVID-19 vaccine candidate, in February 2020 and is aiming to begin human safety testing in early summer 2020. The company will conduct tests in both the United States and China, the latter in collaboration with Beijing Advaccine Biotechnology Co. (3). Work in the US is supported by a $9-million grant from the Coalition for Epidemic Preparedness Innovations (CEPI). The collaboration with Beijing Advaccine is anticipated to accelerate developed on INO-4800 in China by providing access to not only its vaccine expertise, but also its relationship and experience with Chinese regulatory authorities and clinical trial management in the country.

	Two companies, both also supported by grants from CEPI, have developed platform technologies based on messenger RNA (mRNA). Cambridge, MA-based Moderna-which has developed numerous prophylactic mRNA vaccines with positive Phase I clinical readouts and also has a fully integrated clinical-material manufacturing site-is progressing its COVID-19 vaccine candidate (mRNA-1273) into the clinic (4,5). The Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), collaborated with Moderna to design the vaccine. NIAID will conduct investigational new drug-enabling studies and a Phase I clinical study in the US.

	Moderna’s mRNA vaccines can contain multiple mRNAs coding for different proteins and mimic natural infection, thus stimulating a more potent response, according to the company. Only the coding region of the mRNA must be changed for each new vaccine. The rapid discovery approach and the manufacturing agility of mRNA vaccine design and production also make it an effective platform technology.

	Just 42 days after sequence selection, Moderna shipped the first batch of mRNA-1273 to NIAID for use in a planned Phase I clinical study in the US. The mRNA vaccine encodes for a prefusion stabilized form of the COVID-19 S protein.
	
	German biotech CureVac also has an mRNA platform technology for vaccine development and manufacturing suited for rapid response to viral outbreaks, it says (6). Using an extensive in-house nucleotide sequence library, CureVac is able to identify optimum sequences for any given vaccine target and eliminate the need for chemical modification, shrinking the development timeline.

	The company has also developed specific carrier molecules for its mRNA products, including lipid nanoparticles (LNPs), developed in partnership with Acuitas Therapeutics and Arcturus Therapeutics). It is developing 

, a mobile, automated production unit for rapid supply of LNP-formulated mRNA vaccine candidates.

	A fourth group receiving funding from CEPI for application of a vaccine platform technology to accelerated development and manufacture of a COVID-19 vaccine is located at Australia’s University of Queensland (UQ) School of Chemistry and Molecular Biosciences (7). Its rapid response technology relies on molecular clamp technology, an approach developed by UQ researchers and patented by UniQuest.

	The molecular clamp technology is used to create subunit vaccines against class I and III enveloped viruses by stabilizing the pre-fusion form of viral fusion proteins, thus mimicking the protein conformation found on live virus and generating a strong immune response. A polypeptide is used to maintain the pre-fusion structure and prevent the protein from folding after entry into the cell.

	The platform technology, which does not require prior knowledge of a protein’s quaternary structure, therefore facilitates the expression of recombinant viral glycoproteins without loss of native antigenicity (8). It has previously been used to produce chimeric polypeptides that mimic the pre-fusion conformations of several enveloped viruses. The goal is to complete preclinical development within 16 weeks and then progress directly to Phase I clinical trials, with completion of that step in 10 weeks, followed by large-scale production of more than 200,000 doses in eight weeks.

	For its COVID-19 vaccine, the UQ researchers created a first candidate in the laboratory in just three weeks (9). This work confirmed that the engineered vaccine candidate is readily recognized by the immune system and triggers a protective immune response. Plans for preclinical testing were underway as of late February, and the researchers hope to begin clinical testing by mid-2020.

	NuGenerex Immuno-Oncology is focusing on what von Hofe refers to as the smallest and simplest fragments of the virus needed to produce an immune response. These short fragments of proteins are identified by a computer algorithm and can be made rapidly by entirely synthetic means. They are modified to ensure that they activate immune cells that are key in producing immunological memory. “While these virus fragments may not produce as complete a response as whole inactivated viruses, they basically produce a ‘memory’, so when a person treated with our vaccine does encounter the virus, he or she is more prepared to mount an effective response,” von Hofe explains. The technology is also a platform approach because it can be applied to virtually any virus that may emerge as a threat.

	While these smaller biotechs have generated attention for their accelerated development platforms, Big Pharma companies have also been actively working on COVID-19 vaccine candidates. Both Johnson & Johnson and Sanofi are collaborating with the US Department of Health & Human Services (HHS).

	Johnson & Johnson’s Janssen Pharmaceutical Companies unit is collaborating with the HHS’ Biomedical Advanced Research and Development Authority (BARDA) to rapidly advance the initial stages of Janssen’s COVID-19 vaccine development program, which is based on its AdVac and PER.C6 platform technologies (10). BARDA is funding accelerated development of a candidate into Phase I clinical trials, while Janssen is upscaling its manufacturing capacities.

	Sanofi Pasteur, the vaccines global business unit of Sanofi, is also collaborating with BARDA, using its established recombinant DNA technology platform to accelerate the development of a potential COVID-19 vaccine (11). This technology produces an exact genetic match to proteins found on the surface of the virus, which are then expressed using Sanofi’s insect (baculovirus) expression platform. The technology is used for Sanofi’s licensed recombinant influenza vaccine and a SARS vaccine that has been shown in non-clinical studies to be immunogenic and afford partial protection in animal challenge models.

	1. C. I. Paules, H. D. Marston, and A. S. Fauci, 

, online, doi:10.1001/jama.2020.0757 (Jan. 23, 2020).
	2. T. Hesman Saev, “To Tackle the New Coronavirus, Scientists Are Accelerating the Vaccine Process,” 

, Feb. 21, 2020.
	3. Inovio, “Inovio Collaborating with Beijing Advaccine To Advance INO-4800 Vaccine Against New Coronavirus in China,” Press Release, Jan. 30, 2020.
	4. Moderna, “Moderna Announces Funding Award from CEPI to Accelerate Development of Messenger RNA (mRNA) Vaccine Against Novel Coronavirus,” Press Release, January 23, 2020.
	5. Moderna, “Moderna Ships mRNA Vaccine Against Novel Coronavirus (mRNA-1273) for Phase 1 Study,” Press Release, Feb. 24, 2020.
	6. CureVac, “CureVac and CEPI extend their Cooperation to Develop a Vaccine against Coronavirus nCoV-2019,” Press Release, Jan. 31, 2020.
	7. University of Queensland, “Race to Develop Coronavirus Vaccine,” Press Release, Jan. 24, 2020.
	8. K. Chappell, D. Watterson, and P. Young, “Rapid Response Pipeline for Stabilized Subunit Vaccines,” Presentation at the Vaccine Technology VIII Conference (June 2018).
	9. University of Queensland, “Significant Step in COVID-19 Vaccine Quest,” Press Release, February 21, 2020.
	10. Johnson & Johnson, “Johnson & Johnson Announces Collaboration with US Department of Health & Human Services to Accelerate Development of a Potential Novel Coronavirus Vaccine,” Press Release, Feb. 11, 2020.
	11. Sanofi, “Sanofi Joins Forces with US Department of Health and Human Services to Advance a Novel Coronavirus Vaccine,” Press Release, Feb. 18, 2020.

Vol. 44, No. 4â¨
	April 2020
	Pages: 22–26

	When referring to this article, please cite it as C. Challener, “Can Vaccine Development Be Safely Accelerated?" 

Biopharma companies responding to the COVID-19 outbreak think accelerating the development of vaccines is safe.

Can Vaccine Development Be Safely Accelerated?

Fixed-dose combination (FDC) drugs offer a number of benefits to drug manufacturers, patients, and caregivers. These medicines contain two or more active ingredients in a defined composition or fixed ratio. The greater focus on patient centricity and improving patient medication adherence has led to a growing interest in FDC formulations.

	In the past five years, approximately 43 fixed-dose combinations were approved in the United States, according to Anil Kane, global head of scientific and technical affairs at Thermo Fisher Scientific. The majority were treatments for cardiovascular, metabolic disorder (including diabetes), and infectious diseases (including HIV). Most are solid, orally delivered drugs.

	FDC medicines, because they contain multiple APIs, provide advantages for patients and opportunities for manufacturers. From a patient perspective, according to Torkel Gren, senior director and science and technology officer at Recipharm AB, FDC products can be consumed quickly and easily because fewer tablets need to be taken. “By altering and controlling API release rates through the combination of multiple drug products into a single carrier, treatment is ultimately more efficient and straight-forward for patients,” he says. “To this end, FDCs have helped to improve patient compliance and by extension the overall treatment of diseases,” Gren adds. FDCs also have the potential to offer patients increased efficacy and synergistic effects that may enable the need for lower doses, according to Kane.

	For manufacturers, Gren notes that formulating FDCs has enabled the introduction of new products with improved properties and with significantly lower development costs. “Reformulating and combining drugs that have been proven to be safe and effective into FDCs represents an essential strategy for drug development companies to realize maximal commercial potential returns in a faster way than developing new molecular entities, which can be a lengthy, expensive, and high-risk endeavour,” agrees Kane.

	Lifecycle management, Kane observes, is in fact one of the major strategies used in the pharmaceutical industry in response to several significant trends, including patent expiry of major blockbuster drugs in the coming 5–10 years, stiffer competition in the market due to the presence of generic players, and a drought in the pharmaceutical R&D pipeline. Combination drugs also offer an opportunity for intellectual property and exclusivity.

	Developing an FDC formulation that offers these benefits and challenges can be difficult, however. Because many active ingredients are incompatible-meaning they are less stable in the presence of each other-selecting excipients and processes that reduce the degradation rate of the active ingredients and afford the optimal composition and process parameters increases in difficulty as the number of active ingredients increases, Gren notes. In fact, the main challenge to fixed-dose combination development usually involves product formulation and manufacturing strategy to address stability, dose differential, and analytical method development issues, according to Kane.

	The APIs in an FDC must be physically and chemically compatible with one another and all of the excipients used in the formulation and not generate any new impurities or raise any new drug-drug interactions. “The physicochemical properties and stability of each of the APIs in an FDC will define the formulation approaches to maintain stability during the shelf life of the combined drug product. As an example, the hygroscopicity of one active drug substance can influence the stability of the other drug in a combination product unless they are completely separated by way of multiple techniques,” explains Kane.

	Dosage size is another challenge experienced during pharmaceutical development, according to Gren. For example, if several high-dosage drugs are combined, the resulting target may be too large to be consumed by the patient. Differentials in individual drug doses are another issue. “The particle size distribution of a low-dose drug and the distribution of a second high-dose drug can impact the content uniformity of the former and the flow and processability of the latter in a single two-layer tablet,” Kane observes.

	From an analytical chemistry standpoint, it may be challenging to develop an analytical method that can quantitate all of the active ingredients and their degradation products, according to Gren. New analytical methodologies are often required to be developed for these innovative formulation strategies to accurately assess the product potency of multiple ingredients, as well as potential degradation products and their quality parameters, Kane agrees. “One alternative,” says Gren, “is to apply several analytical methods. However, the employment of multiple analytical methods will increase quality control costs and subsequently impact the cost of goods,” he notes.

	Finally, Kane observes that the packaging of a fixed-dose combination product may need to be re-considered based on the criticality of the multiple actives and their stability profiles in combination.

	The best way to overcome these challenges, Kane asserts, is for formulators to fully evaluate/understand the individual drugs that need to be combined in FDC products with respect the API characteristics, forced degradation and stability profiles, site of absorption and pharmacokinetics, potential for drug-drug interactions and chemical compatibility, and the individual doses required to have an optimal therapeutic effect. “A thorough pre-formulation assessment of the combination and generation of critical data is the key to a successful formulation development strategy,” he concludes.

	Clarity around the stability of the APIs to be formulated into an FDC product can be gained through retrieved literature data and experimental work, notes Gren. “Gathering information and knowledge around the specific patient population and other market conditions, combined with an understanding of stability issues, will allow for a clear development strategy to be outlined and implemented,” he states.

	Where the APIs in FDCs are known to be incompatible in the presence of each other, formulation in a single pill can be achieved using a number of different options. Kane identifies multilayer tablets, compression-coated tablets, multi-particulates in capsules, and combinations of coated and uncoated beads and pellets of one active placed with a powder of another active as common technologies.

	A suitable way to manage incompatibilities is by separating the different active ingredients with multilayer tablets or by including one of the drug substances in the coating and another at the core of the tablet, Gren notes. Formulation of different actives into separate pellets that can then be mixed into a capsule or tablet can make it easier to vary the doses of each API, he adds. For modified-release formulations, the pellets are typically coated.

	It is important to note, however, that although pellet technology has broad applications in oral FDCs, it is not a universal tool. “While some drug substances can be readily combined in a conventional tablet without any problems occurring, liquid or semi-solid formulations are often required for some indications and administration routes,” Gren comments.

	In general, therefore, the strategy for developing FDCs is entirely dependent on the individual active ingredients in the combination, their dose, stability profile, target release profile, sight of release, and other factors, Kane asserts.

	Looking to the future, 3D printing has recently been introduced as a manufacturing method for pharmaceutical products and may enable contract development and manufacturing organizations to effectively customize combination drugs for individual patients, according to Gren. He notes that it could also potentially facilitate the separation of different drug substances to reduce incompatibility issues.

	The first approval of a product manufactured using 3D printing (Aprecia Pharmaceuticals’ Spritam) was granted by FDA in 2015. “There are, however, several quality assurance and regulatory issues that need to be solved before this technology can be employed across the industry on a larger scale,” Gren says.


	Vol. 44, No. 3â¨
	March 2020
	Pages: 22–24

	When referring to this article, please cite it as C. Challener, “Characterizing APIs is Essential for Combo Drug Formulations," 

Formulating fixed-dose combination drugs proves more complex than simply adding one ingredient to another. 

Characterizing APIs is Essential for Combo Drug Formulations

Although not pharmacologically active, excipients have a direct impact on the performance of formulated drugs, and their quality and purity are equally important to assuring drug product safety. Because excipients are seldom pure compounds, consistent composition is of utmost importance, asserts Irwin Silverstein, president of IBS Consulting in Quality. Conformance to good manufacturing practices (GMP) is also important so that the customer can rely on the excipient manufacturer’s certificate of analysis (CoA). The wide variety of compounds approved for use as excipients in pharmaceutical formulations, however, creates challenges for sourcing.

	Pharmaceutical excipients are typically multifunctional chemistries not exclusively designed and formulized for the pharmaceutical industry. As a result, these molecules often originate from other applications and industries and are later utilized within the pharmaceutical industry, according to Jessica Cansler, a senior quality management specialist with BASF. “The initial manufacturing and quality standards of these molecules were focused more to the requirements of the original application areas and industries, not to the manufacturing and quality requirements of the pharma industry,” she says.

	It is incumbent upon pharmaceutical manufacturers to understand the full excipient supply chain and have in-depth knowledge about selected suppliers. Recognizing that risk cannot be avoided but must be mitigated is equally important.

	The challenges to excipient sourcing vary according to the type of supplier from which the manufacturer is purchasing the material. “Lack of transparency about manufacturing locations and the entire excipient supply chain can provide challenges,” notes Fernanda Onofre, technical service manager for pharma solutions at DuPont Nutrition & Bioscience.

	One of the biggest challenges, perhaps, is that many industrial-scale manufacturers make products in multi-application plants, and the volumes produced for the pharma industry are typically only a fraction of the total production, making it difficult to fulfill pharmaceutical industry expectations (GMP, quality, etc.), according to Cansler.

	It can also be challenging to trace back the source of the original materials and understand the quality level of the ingredients, as many are ‘tested up’ to monograph standards rather than produced under the appropriate guidelines, she notes. In some cases, it can be difficult for drug manufacturers to find an appropriate excipient manufacturer fulfilling pharma quality expectations, particularly for legacy products; sometimes drug manufacturers must make compromises and accept what is available on the market.

	When the excipient is shipped directly from the excipient manufacturer to the drug manufacturer, there should be no misunderstanding as to the source, according to Silverstein. “However,” he observes, “purchasing through a distributer, broker, or trader may raise a challenge, especially where the excipient has been packaged from bulk or repackaged from discrete packages. Tracing the excipient back to the source relies on having confidence in the packager or repackager and receiving the excipient manufacturer’s certificate of analysis.”

	Issues in the past, according to Chris Moreton, principal with FinnBrit Consulting, have related to the sourcing by a distributor of excipients from multiple manufacturers without notifying the customer, which had only validated one source of supply, as well as the switching of plant species from which excipient starting materials have been derived, impacting excipient performance in the manufacture of the finished drug product. Distributors, Moreton says, must inform their customers of the manufacturing sites for every delivery of an excipient. The pharmaceutical customer must also confirm that the manufacturing site is on their approved list, adds Silverstein.

	The excipient manufacturing process can also provide challenges. “This information is often proprietary, yet drug manufacturers need to understand the raw materials and processes that can impart variability in excipients,” Onofre notes. Regardless of the source, therefore, pharma manufacturers must be willing to invest the time and effort in establishing monitoring systems based on the use of advanced spectroscopic methods, notably for plant-derived excipients, in order to detect unexpected changes in impurity profiles from a single supplier or variations in profiles from different suppliers of the same excipient, according to Moreton. “The difference in levels of concomitant components may impact the performance (manufacture, in-use and/or stability) of the finished pharmaceutical product,” he explains.

	Pharma companies should also be sure to conduct supplier qualifications to ascertain the necessary details about excipient suppliers, a process that can provide challenges as well, according to Onofre. “Thorough qualification requires an on-site audit of the excipient supplier, either by the pharma company themselves or by a trusted third party,” she says.

	The first step, Onofre adds, is for pharma companies to fully engage with their excipient suppliers, asking for clarity on the excipient’s entire lifecycle. “Even in the instances where information may be proprietary, much can be clarified after a discussion with the supplier,” she comments. Detailed discussions under a confidential disclosure agreement (CDA) can also help in understanding excipient variability and how that can affect the formulation and process. “Such discussions aid in excipient risk management and the formulation of robust drug products,” Onofre states.

	Drug makers should also insist that the manufacturing site of the excipient be identified on each lot of the excipient received at the product manufacturing site, Moreton asserts. The International Pharmaceutical Excipients Council (IPEC) CoA guide (1) establishes that the site of manufacture should be disclosed on this document, according to Silverstein. “Ideally, the batch numbering system of the excipient should be site specific, such that a change in the format of the batch number would act as a check for the site of origin,” Moreton adds. Any change in sourcing of the excipient starting material sourcing should also be included as part of the change notification requirements in the quality agreement or in a commercial agreement, with change notification completed per the IPEC significant change guide (2).

	On-site audits conducted by the pharma company itself or via a third party, such as EXCiPACT- an international consortium of excipient, chemical, and quality organizations-should be conducted to gather as much information as possible about the supplier and the excipient, Onofre says. If a third-party has been used for the audit, Silverstein adds that it is important to obtain a copy of the audit report to help assure the validity of the audit conclusions concerning production of an excipient in conformance to GMP.

	To verify the source of the delivered excipient, whether in the original manufacturer’s container, packaged from bulk, or repackaged, Silverstein comments that the user should verify the authenticity of the excipient label, package, and tamper-evident seal.
	Overall, the best approach is to source excipients from excipient manufacturers that clearly commit themselves to the pharmaceutical market and the expectations of the pharmaceutical industry, Cansler asserts. “Usually these excipient manufacturers are appropriately certified to pharmaceutical industry quality standards (e.g., NSF/IPEC/ANSI 363 and/or EXCiPACT),” she says.

	When considering different excipient suppliers, there are some warning signs that could indicate potential issues for pharmaceutical manufacturers. For Moreton, a top red flag is not naming the site of manufacture because that precludes physical audits. “Reliance on the distributer’s paper audits or third-party audits for and on behalf of the distributer-and in which the excipient user has no control and is not consulted ahead of time-should not be acceptable,” he says.

	The claim that an excipient will meet the United States Pharmacopeia (USP) monograph when tested is a key warning sign for Silverstein. “This language may indicate that the excipient was not produced under ‘appropriate’ GMP as required by USP. Refusal to share non-compendial test methods is another red flag; a good supplier wants to facilitate the proper testing of their excipient, he says.
	Pharma manufacturers should also be wary of excipient suppliers that are not aware of current issues, concerns, and trends in the industry they serve, or have to custom-make standard documents, according to Cansler.

	Suppliers that are not known in the pharma industry or only have a small presence, as well as those that are unable to provide the required qualification documentation, historical manufacturing trend data under CDA, and support manufacturing location audits raise concerns as well, adds Onofre. Finally, Moreton points to suppliers that are unwilling to enter into quality/change notification agreements as raising red flags.

	Be on the lookout for positive attributes

	On the flip side, reliable excipient suppliers exhibit a number of recognizable attributes that should be sought. Most importantly, reliable excipient suppliers are open, albeit under confidential disclosure agreements, according to Moreton. They will allow either customer audits or certification to excipient GMP by a recognized accreditation body or certification scheme, adds Silverstein.

	These excipient suppliers recognize the importance of the pharma market to their business profitability and participate in appropriate trade associations and meetings. They also have deep knowledge of their products and can provide technical support for their use in drug formulations and provide products with reliable excipient quality, consistent composition, documentation in order, and an established quality management system at the excipient manufacturing site that complies with pharma excipient GMP requirements and expectations, according to Cansler.

	“Highly reputable companies in the pharma market, with consistently good performance and proven experience over the years tend to strive for customer satisfaction and fulfillment through the reliability of their own services and products provided,” Onofre concludes.

	In addition to an initial onsite audit, pharma manufacturers should closely evaluate several aspects of excipient supplier performance during the selection process. Identification of the GMPs to which the supplier intends to conform is paramount, according to Silverstein. Standard quality, regulatory, and technical documentation for the excipient should be readily available and complete, coupled with a point of contact to ask questions, Cansler observes. Evidence of the supply chain, quality, and services being offered by the supplier should also be provided, along with in-depth information on the manufacturing locations, notes Onofre.

	Access to multiple excipient samples from different campaigns and different raw material lots for qualification is also important, adds Cansler. Excipient suppliers should also sign quality/change notification agreements as part of the overall supply or quality agreement, says Moreton.
	Finally, once a supply agreement is in place, Moreton and Silverstein both note that an effective monitoring program at the excipient user site should be implemented to assess the quality and technical characteristics of the excipient.

	Excipient grades are typically differentiated based on a certain physical characteristic (e.g., particle size, molecular weight, degree of substitution, or viscosity). A change in grade means a change in that physical characteristic. For some formulations, a change in grade may not impact product performance, but for others it could be detrimental to the finished product, according to Moreton.

	“Different grades allow for flexibility in formulation and process design to address various technical challenges in other raw materials or processes used to manufacture the final dosage form,” Onofre explains. She adds that different grades are also critical for optimizing the right process, which can help in cost-saving efforts in areas from wet granulation to direct compression.

	If a specified excipient grade is important to the quality attributes of the drug product, then the formulator should demonstrate in what manner the grade is important, adds Silverstein. “In this case, the homogeneity of the excipient lot for that attribute becomes critical to drug product quality, and the excipient manufacturer should be asked about homogeneity within each lot,” he says. In addition, a change in grade most likely would necessitate a revalidation and a notification under the scale-up and post-approval change (SUPAC) rules, Moreton comments.
	Choosing the right excipient grade used to be at the personal preference of the formulator, but with quality by design widely implemented today, properly designed and executed design of experiments studies give support to the choice of excipient grade, according to Moreton.

	In addition to information provided by excipient suppliers, pharma companies may also conduct grade-differentiating testing when establishing excipient specifications. Talking to the excipient technical experts and sharing the intended use for the excipient and the issues to be addressed in the designed formulation can also help in grade selection, according to Onofre. “Based on the API, the formulation, and the intended process, the excipient supplier can recommend the right excipient and the right grades,” she says.

	Assuring receipt of the right excipient grade starts at a minimum with identification testing and testing against the CoA/monograph listed tests and parameters, according to Cansler. Services such as infrared scanning flaps/windows in packages, whenever possible, can help reassure the customer about the accuracy of the product and reliability of the supply, adds Onofre.

	It is also important to confirm product labeling and product documentation and compare them with the purchase request, Cansler observes. “The excipient specification at the drug maker should clearly link to the excipient supplier’s specification for the grade, and the purchase order should also clearly delineate the grade as it will appear on the excipient package label and CoA,” Silverstein explains. In some cases, he notes that it may also be necessary to discuss with the excipient manufacturer the recommended test method for the parameter that designates the grade and that the accuracy and precision are sufficient to confirm the grade.

	As with all excipients, conducting due diligence when approving an excipient supplier and ensuring quality and supply agreements are in place should result in the right product being sent, according to Onofre. Auditing the site of manufacture and the supply chain are important, agrees Moreton. “Testing of the excipient upon receipt at the customer site is often necessary as well because the grade is critical for the particular application, and formulators would be well-advised to test each lot,” he states. Having a sampling plan based on lot homogeneity is also recommended by Silverstein.

	The most important concept to grasp when dealing with the excipient supply is “Caveat emptor: let the buyer beware!” asserts Moreton. “There are no certainties, and there is always a risk that something may go wrong. However, the risk can be reduced to an acceptable level, but only by acquiring as much knowledge as possible about the excipient and using a combination of site and supply chain auditing, quality/change notification agreements, and an effective monitoring program for all excipient deliveries to the site of use,” he states.

	In addition to risks associated with manufacturing processes for excipients, there is risk associated with the distribution and supply chain of excipients globally, notes Cansler. She points to risks associated with the intermediate storage and transportation of excipients. “Trending topics including fraud and adulteration within the supply chain are of serious concern. In addition to raw material qualification, appropriately established supply-chain traceability and supply-chain security processes should be in place,” she observes.

	The IPEC excipient qualification guide (3), according to Onofre, provides details on recommendations for building a robust supplier qualification process. “Building customer-supplier relationships that are transparent and provide robust information-sharing opportunities is the foundation for success,” she concludes.

Certificate of Analysis Guide for Pharmaceutical Excipients

Significant Change Guide for Pharmaceutical Excipients

Qualification of Excipients for Use in Pharmaceuticals 

â¨
	Vol. 44, No. 2â¨
	February 2020
	â¨Pages: 22–26

	When referring to this article, please cite it as C. Challener, “The Search for Transparency in Excipient Sourcing," 

Researching excipient grades and sources, as well as screening suppliers and materials, form the basis of programs to mitigate risk.

The Search for Transparency in Excipient Sourcing

Effective analytical methods are essential for the successful development and commercialization of both small- and large-molecule drug substances and drug products. As the complexity of both biologic and chemical drug substances increases, analytical methods must evolve as well.

	“Faster, more efficient techniques will give companies an advantage as their products move through the pipeline,” asserts Robin Spivey, director of analytical research and development, Cambrex High Point. Techniques that are more sensitive and more accurate will, she says, better position a company for regulatory acceptance as long as they are willing to help pioneer the techniques. In addition, such companies will be seen as being at the forefront of the industry.

	Some of the most noteworthy advances in analytical methods involve the application of mass spectrometry (MS) for process development and product release of both biologics and synthetic drugs, the enhancement of chromatographic techniques, particularly liquid chromatography (LC), microcrystal electron diffraction, and techniques designed for use as process analytical technology (PAT).

	For biopharmaceuticals, MS was initially limited to use for protein characterization to provide supplemental information for regulatory filings, according to Amit Katiyar, director of analytical and formulation development for bioprocess sciences at Thermo Fisher Scientific. Process release/stability testing continues to largely depend on conventional analytical methods such as LC, capillary gel electrophoresis (CGE), imaged capillary isoelectric focusing (iCIEF), and enzyme-linked immunosorbent assays (ELISA) due to their simplicity and wide adoption in quality control (QC) labs.

	Inclusion of biosimilars, complex non-monoclonal antibody proteins (e.g., fusion proteins), bispecifics, and combination products in the product pipeline, however, is presenting challenges due to the inability to gain a thorough understanding of these molecules using platform methods. “Most of the time, platform methods may not be able to provide the information required to develop and commercialize complex biomolecules. In these cases, MS-based methods are being used for process development and as identity and release/stability indicating methods,” Katiyar observes.

	In addition to using peptide-mapping principles in multi-attribute methods (MAMs), major biopharmaceutical companies are now using MS-based identity methods to release biologic drug substances and drug products. “This approach will provide the opportunity to gather more information on the performance of MS instruments in QC labs that can then be used for implementing MS technology for process development, release, and stability testing,” says Katiyar. The current approach for regulatory filing, he adds, is to use a combined package of conventional methods and MS methods to gain more confidence from health authorities and be able to present a future case for submissions based only on MS data.

	For Da Ren, process development scientific director at Amgen, MAM is probably the most important emerging analytical technology that has been used in process development and release and stability testing of therapeutic proteins. “MAM is an LC/MS-based peptide mapping assay. Unlike profile-based conventional analytical assays, which focus on whole or partial proteins, MAM can identify and quantify protein changes at the amino acid level and can provide more accurate information on product quality related attributes,” he explains. Notably, MAM is capable of replacing four conventional assays including hydrophilic interaction liquid chromatography for glycan profiling, cation exchange chromatography for charge variant analysis, reduced capillary electrophoresis-sodium dodecyl sulfate for clipped variant analysis, and ELISA for protein identification, according to Ren.

	In the case of small-molecule drug development and commercialization, MS detection systems are no longer considered just research tools and are becoming more widely used for routine QC testing, for example determining extremely low level impurities such as genotoxic impurities/potential genotoxic impurities, according to Geoff Carr, director of analytical development in Canada with Thermo Fisher Scientific.

	“These advances are very likely in response to new regulatory guidelines issued by agencies such as FDA and the European Medicines Agency, but also as a result of specific problems that have occurred in the industry, such as recent concerns regarding observations of N-nitrosamine residues in sartans,” Carr explains.

	Chromatographic-based analytical procedures continue to be the most widely used technologies for small-molecule API and drug product analyses and most advances are likely in this area. For the most part, procedures based on high-performance liquid chromatography (LC)/ultra-high-performance LC (HPLC/UHPLC) coupled with ultraviolet detection are most widely used, according to Carr.

	Notable advances in this area, Carr says, include improvements in HPLC/UHPLC column packing chemistries designed to provide better resolution between sample components and greater robustness, such as resistance to particularly high or low pH conditions for mobile phases.

	Advances in crystallography are also important for small-molecule API analysis. Microcrystal electron diffraction, also known as micro-ED or cryo-EM, for instance, can be used for structure determination by electron diffraction using micron-sized crystals. “Typically, millimeter-sized single crystals are necessary to achieve unambiguous determination of the absolute structure of an API using single-crystal X-ray crystallography,” explains Heewon Lee, director of analytical research and quality systems in chemical development US for Boehringer Ingelheim Pharmaceuticals.

	Micro-ED enables the same level of structure determination using micrometer-sized crystals, eliminating the need to grow larger single crystals, which can be challenging. “This capability is very useful for process development, as understanding impurity formation is a critical step to optimize processes,” Lee says.

	Other advances include applications such as near infrared and Raman spectroscopies in support of process analytical technology to enable monitoring of manufacturing processes and the quality of resulting products on-line. “Developments in these areas are in response to regulatory encouragement for the application of quality-by-design approaches for manufacturing drug products,” Carr notes. He adds that this type of technology is more likely to be applied by companies that manufacture their own products and less likely in a contract manufacturing environment.

	Changes in analytical workflows have the potential to impact productivity and efficiency but may also create challenges depending on the nature of the modifications. These changes may also originate as the result of new technology or new processes and approaches.

	As an example of the former, Heewon Lee, director of analytical research and quality systems in chemical development US for Boehringer Ingelheim Pharmaceuticals, points to material identification using Raman spectroscopy as a technique that has impacted analytical workflows associated with small-molecule API manufacturing. “This technique is now mature, and several companies have launched products that are user-friendly and GMP [good manufacturing practice]-compliant. Benefits are gained because this method can be used to identify raw materials, intermediates, and APIs in the process area. QC personnel can then release batches based on the Raman data acquired, streamlining the analytical workflow,” she explains.

	For biologics, using MAM through process development and release and stability testing is a revolutionary analytical workflow, according to Ren. “The continuous monitoring and control of product quality attributes at the amino acid level during product and process characterization as well as release and stability testing enhances the understanding of biotherapeutic products and processes,” he asserts.

	One driver leading to changes in analytical workflows is the desire to achieve greater efficiencies and thereby reduce operating costs, according to Carr. One approach that many pharma companies have taken, he notes, is to implement operational excellence initiatives within laboratory operations.

	Regulatory pressures for improvements in the scientific understanding and quality of drug product is also leading to an evolution in analytical workflows. “We are seeing increasing guidelines focused on analytical development, such as a [Brazilian Health Regulatory Agency] ANVISA guideline on conducting forced degradation studies that is very demanding,” Carr observes.

	There are also initiatives within the International Council for Harmonization (ICH) and the US Pharmacopeial Convention (USP) focused on replacing the traditional development-validation-transfer approach to management of analytical procedures to one based on lifecycle management. “This approach,” asserts Carr, “requires rational development/validation coupled with a process of performance monitoring that leads to continuous improvements.”

	These changes relate to an important development noted by Katiyar; the adoption of phase-appropriate analytical workflows combined with increasing harmonization of workflows across sites and with external partners, such as contract research and development organizations.

	Phase-appropriate development and manufacturing can help pharma companies better handle their expanding product pipelines by enabling the supply of safe clinical materials while maintaining flexibility in manufacturing operations, according to Katiyar. He does note, however, that while ICH guidelines are defined for late-stage development, there is a lack of clarity on the qualification of analytical methods for early phase development.

	“Harmonization using a platform approach to method development and qualification for early and late-stage projects and method validation for late-stage projects, as well as forced-degradation, research comparability, and formal comparability studies and specification setting has provided the opportunity to engage process development, analytical development, operations, quality, and regulatory organizations earlier in the development cycle,” Katiyar says. “The harmonized approach creates a well-defined roadmap for process development and operations teams to execute the program timelines in an efficient manner,” he adds.

	The details of each harmonization approach vary from company to company. In some cases, the harmonized templates may contain specific experiments and acceptance criteria to ensure a successful platform approach, according to Katiyar. In other cases, high-level harmonization guidance provides flexibility during development.

	“Pre-approved generic templates for draft methods, qualification plans, and forced degradation/comparability protocols result in higher productivity due to time savings resulting from a shorter review process for every program,” Katiyar observes. While there may be a need to modify the templates as reflected by the development data, he notes that such changes can be incorporated in the molecule-specific methods/plans, and protocols and subsequent changes can be reviewed by appropriate stakeholders for quality and regulatory compliance.

	Some of the most important advances in sample preparation tools include increasing application of automation and robotics. Quality-by-design (QbD) approaches to analytical testing can often lead to multiple sampling and testing to  achieve a more accurate assessment of the total batch rather than testing one or two samples per batch.

	An example given by Carr is stratified sampling for solid oral dosage forms whereby samples are taken at approximately 20 time points during tablet compression or capsule filling and tested for drug content, and three units from each time point are tested. “In circumstances such as this one, there are huge benefits in having automation available in the lab for the preparation of the analytical samples from the 60 individual tablets that require testing,” he explains.

	Automation of sample preparation for low throughput methods is also critical to improve turn-around times to support process development activities, adds Katiyar. In general, he notes that automation of all in-process methods for biologics-including size-exclusion chromatography, CGE, iCIEF, n-Glycan content and residual host-cell protein, DNA, and Protein A-to support process development activities is crucial for meeting fast-to-first-in-human trials/quick-to-clinic timelines.

	In the field of biologics sample preparation, Process Development Scientific Director Jill Crouse-Zeineddini at Amgen sees acoustic droplet ejection for potency assays as an important advance. Acoustic droplet ejection uses acoustic energy instead of tips to transfer a fixed amount of liquid sample from a source to destination plates freely with excellent accuracy and precision, she explains. “The significance of this technology resides in its superb dispensing performance at a very low sample volume. This technology performs direct dilutions instead of serial dilutions and prepares each dose independently, improving assay precision and throughput,” Crouse-Zeineddini observes.

	Robust aseptic sampling and automated sample preparation for the purification, desalting, and digestion of protein samples, meanwhile, enables many different product quality analyses. “This technology not only significantly improves operational efficiency, but also eliminates potential contamination and mistakes during manual sampling handling,” states Gang Xue, process development scientific director at Amgen.

	Another important point, according to Carr, concerns the reliability of the sample preparation procedure. “This issue is not a new one, but it is becoming more apparent as we apply QbD approaches to our analytical procedures. While the greatest emphasis has been applied to chromatographic parameters, we now realize that the sample preparation stage is at least as important and also needs to be developed using QbD,” he comments.

	For Lee, a specific technology development that has improved sample preparation is once again material identification by Raman spectroscopy for small-molecule drug substances. “Using this technique simplifies sample preparation, because it allows identification of compounds without any physical contact with the sample. Depending on the container material, it is even possible to acquire Raman data through the container without the need to withdraw a sample,” she says.

	Such capability for biologic drug substances has yet to be developed, however, and simplified identity methods to support release and establishing post-shipment identity of bulk drug substance are still required, according to Katiyar. Currently, peptide mapping and binding ELISA are used as identity methods, but they have long turnaround times. Raman spectroscopy has been evaluated for biologics, but it has not yet been adopted by the industry for release of drug substances and drug products. “Simplification using scan-based methods with better specificity and faster turnaround times would be highly beneficial for biopharmaceuticals,” he says.

	When integrated with analytical instruments, aseptic sampling and automated sample preparation has the potential to move in-process and product release testing from offline QC labs to the manufacturing floor, either in-line or online, according to Xue. In addition to enabling real-time monitoring of not only cell growth, but also the critical quality attributes of therapeutic proteins themselves, the technology is beneficial for providing much more granular insights into the conventional batch process and products in-flight, he notes. “More importantly,” Xue states, “it could in the future be crucial for lot definition, process variation detection, and material segregation as required for continuous bioprocessing.”

	For small-molecules, Lee would like to see the widespread adoption of x-ray fluorescence (XRF) for metals testing because it would also reduce turnaround times. “XRF is a powerful method for detecting metals used as catalysts in API manufacturing. Compared to inductively coupled plasma-MS, XRF does not require sample dissolution and digestion, facilitating easier sample preparation and faster turnaround times,” she explains.

	Carr, meanwhile, expects to see increasing us of LC–MS for routine analytical testing. “This technology is widely applied in chemical drug development labs for various purposes and is also used for biopharmaceutical analytical testing, but less for release testing of products and for testing stability samples. The technology has advanced considerably over recent years, and while these instruments were previously only applied in R&D, they have now become highly suitable for use in routine testing labs,” he remarks.

	There are a number of challenges to the adoption of advances in analytical techniques, some of which vary according to the development phase. Adhering to compressed program timelines is the key challenge in getting advances in method adoption for early stage development, according to Katiyar. “Fast-to-first-in-human (FIH)/quick-to-clinic program timelines have been introduced in almost every pharmaceutical organization to provide clinical material for Phase I studies, and these timelines have shrunk from 18 months to less than 12 months during the past five years,” he says.

	The shorter timelines are met by relying on platform approaches developed based on knowledge generated over years with multiple molecules. “For new molecules that fit the platform methods, there is no scientific justification to explore new technologies,” Katiyar states. When working in a lab that is operating in a high-efficiency environment, there is often resistance to the introduction of new methods and approaches due to concerns about meeting delivery targets, agrees Carr.

	Once programs move to late-phase development, organizations are hesitant to introduce any change in the control strategy unless it is absolutely needed. This reluctance is particularly strong if a filing has been made to a regulatory agency and/or if significant data have been collected using the older technique, according to Spivey.

	“To be adopted for measuring product quality measurement, the performance of new analytical methods must be equivalent to or better than the methods they replace, and there must be clear evidence that they are reliable and robust across a wide range of operating spaces,” states John Harrahy, director of process development in pivotal attribute sciences with Amgen. The adoption of new technology in the middle of a program, adds Katiyar, requires significant effort to develop the new method, perform bridging studies, requalify the method, perform technology transfer (if outsourced), perform retrospective testing, and define new specifications. Bridging studies cost the sponsor additional money and time, and there is always the risk that a bridging study may show that the methods or techniques are not comparable, adds Spivey.

	There is also often a reluctance on the part of drug companies to be the first to make a submission to FDA with a new technique due to the possibility of the validity of the technique being questioned, Spivey notes. “They don’t want the burden of having to defend the technique to FDA or other regulatory agencies,” she says. There can be some risk with introducing new technologies that have had limited regulatory exposure, adds Harrahy, particularly considering the different regulatory expectations and change control requirements from different regulatory authorities worldwide.

	“With that said,” Harrahy comments, “evaluating innovative technologies is a vital component to ensuring product quality and value to patients, and the ultimate risk of not evaluating new technologies greatly outweighs remaining stagnant.”

	The ideal solution, Katiya argues, is to explore new technologies as part of improvement initiatives without associating them with any programs. This approach provides the flexibility to explore new technologies without putting the program timelines at risk. “Once proof of concept is established and the method is ready to be adopted, a platform approach can be used to implement the new technology,” he comments.

	Senior leadership in large organizations, according to Katiya, must provide guidance to their teams to push innovation without risking program timelines. In addition, it is also important to apply thorough training practices to ensure that scientists really understand the new approaches, says Carr. Continuity of data must also be addressed. “Trend analysis is a widely used tool for monitoring pharmaceutical product quality, and the introduction of new and ‘better’ methods may be perceived to interfere with this trending process,” Carr observes, even though it is more important to apply continuous improvement and accept possible breaks in trends.

	In addition to evaluating new analytical methods separately from specific drug development programs, there are several other strategies that can be used to facilitate the adoption of advances in analytical techniques.

	The best strategy for adopting a new analytical method in a quality setting, according to Harrahy, is to start with the end in mind. Does the proposed method fit the analytical target profile? Is the method sufficiently capable for the product or products that it will measure? Does the methodology require modification to the available GMP/QC environment?

	“The robustness, reliability, and value of introducing any new method must be clearly demonstrated, which is often best accomplished by taking a staged approach: determining the method operable design space in a development laboratory, piloting the method in a development/phase-appropriate setting to monitor ‘real-world’ method capability, performing bridging studies vs. the older method, staging its implementation in QC, and continuously monitoring method performance,” he says. In addition, for regulatory acceptance of novel technologies, early partnered engagement with health authorities is strongly recommended, for example, participating in FDA’s emerging technology platform when the new technology has the potential to improve product quality.

	The most important strategy, agrees Spivey, is to provide ample data demonstrating that new methods are reliable and robust and that there is little or no risk to implementing the technique in a regulated environment. Advances that offer significant advantage over corresponding currently accepted techniques will also have greater likelihood for acceptance. However, Spivey stresses that the advantage would need to be significant enough to be worth the time and money needed for it to be implemented. “Ideally,” she says, “the owner of the technique would perform some preliminary legwork with the regulatory agencies demonstrating the capabilities of the technique. The sponsor would then have some assurance that the agencies would accept their data and make it a less risky approach for them.”

	Another approach, depending on the nature of the old and new/improved methods, is to run both in parallel for a period of time in order to develop an understanding of how their performance and the resulting data compare, Carr suggests.

	For Lee, the key to new analytical method adoption is the sharing of use cases between pharmaceutical companies combined with the publication of white papers and communication with regulatory authorities. Katiyar agrees that sharing knowledge and gaining the feedback of peers and regulatory authorities in timely manner is essential. “Peer-reviewed publications, conference presentations, and Biophorum Operations Group-like forums are the best places to share information and exchange ideas to improve and adopt new technologies on a global scale,” he comments.

	That information sharing should occur between all stakeholders, including contract research, development and manufacturing organization, testing laboratories, biopharmaceutical companies, regulatory authorities, and instrument/equipment vendors.

	“Innovators and service providers need to be open to new ideas and be willing to invest the time and money to implement new techniques. Service providers also, rather than waiting for clients to request a technique before investing in it, should advocate for the use of new methods with their clients,” Spivey asserts. In addition, Katiyar believes innovator companies working with service providers should form an external working group to share new methods and technology to eliminate knowledge gaps caused during technology transfer of methods. “Most of the time,” he remarks, “innovator companies are not willing to share new methods and technologies and thus delay the adoption of new technologies throughout the pharmaceutical industry.”

	Regulators also need to be open to new ideas and willing to work with pharmaceutical companies to ensure that new methods and techniques are acceptable for use in a regulated environment, according to Spivey. It is important for pharma companies and regulatory authorities to remember they have a common goal in identifying new methods and technologies for monitoring and quantifying critical quality attributes that may impact the safety and efficacy of the molecule throughout the lifecycle of the program, adds Katiyar. He points to MAMs as an example where health authorities have accepted data packages consisting of results obtained using conventional approaches supplemented by those obtained using MS-based approaches.

	Instrument/equipment vendors, meanwhile, should be prepared to demonstrate that a new technique is sufficiently better than the currently accepted technique to be worth investing in and worth any potential regulatory risks, asserts Spivey. The dilemma here, according to Carr, is how stakeholders all link together.

	“If a new analytical technology comes up, it will not be accepted by industry/regulators unless the equipment that is required to use it becomes widely available. Maintenance, qualification, and repair services must also be widely available and reliable. Typically, however, a vendor will not set establish this level of availability unless there is a level of confidence that sales targets will be achieved. I think that this is the area where conferences, exhibitions, and publications provide a really valuable platform to get the information from innovators and suppliers circulated to end users,” he says.


	Vol. 44, No. 2
	February 2020
	Pages: 16–21

	When referring to this article, please cite it as C. Challener, “Biopharma Analysis Benefits from New Technology and Methods," 

Analytical solutions are improving for raw material testing, drug product release process development, and more.

Biopharma Analysis Benefits from New Technology and Methods

Viral vectors must be free of viral contaminants, both adventitious agents introduced via raw materials and those generated during processing. Because conventional viral clearance treatments would degrade or destroy many viral vectors, assessment of the potential risk for contamination and the implementation of prevention and control strategies are essential. Detection can be an issue, too. Multiple analytical methods must be used, many of which have performance limitations, adding to the challenge.

	Regulatory authorities require testing to be performed at every stage of the manufacturing process. Cell substrate banks, viral seed banks, raw materials of animal origin, bulk harvests, and the batches of the final manufactured clinical product all have to be tested, according to Francesca Vitelli, head of process development, for viral vectors at Lonza. Both adventitious viral agents and replication-competent viruses are a concern, adds Tony Hitchcock, technical director with Cobra Biologics.

	While there are no regulations solely dedicated to the viral safety of viral vector products, several guidance documents from various agencies provide relevant information on ensuring the viral safety of biological products. There are also guidance documents specifically for cell and gene therapies, according to Karen Tiano, spokesperson for MilliporeSigma, and some do mention that testing for adventitious viruses is expected. Select guidelines for viral contamination testing are listed in 

			Table I. Select international guidelines for viral contamination testing. ICH is International Council for Harmonization.			

There is intense focus on the prevention and control of viral contaminants during viral vector manufacturing, which is driving the need for more accurate and powerful analytical methods for detection.