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

Cynthia A. Challener

Increasing emphasis on patient centricity is driving the development of different oral dosage forms of APIs used in adult products for specialty patient populations. Poor patient compliance is a significant issue in the pharmaceutical industry that can be addressed to a significant degree through the formulation of dosage forms designed for convenience and ease of use.

	Modification of adult medications for children by dividing tablets or capsules into smaller segments to achieve lower doses or aid in swallowing, however, can lead to incorrect and/or nonuniform doses and compromise the performance of any sustained-release coating in the product. In some cases, excipients suitable for adult formulations can pose safety issues for children.

	Age-appropriate medications are now required by regulatory agencies for children. Elderly patients and patients suffering from dementia and disorders that lead to problems with swallowing also benefit from specialty dosage forms. In all of these cases, the emphasis is placed on patient acceptability, which can be impacted by physiological, physical, and psychological factors.

	“Overall, the practicality of administering an existing drug to a different patient population will determine its acceptability,” says Rob Harris, director, science and technology at Catalent.

	Specifically, there are several factors to consider. The first, according to Jim Jingjun Huang, founder and CEO of Ascendia Pharmaceuticals, is efficacy and safety, which is determined by extrapolating the pharmacokinetics and pharmacodynamics for the existing formulation to the targeted population. The acceptability of the excipients in the existing formulation in the target population-taking their use levels into consideration-must also be established. For many specialty populations, the swallowability and taste of the existing formulation may need to be modified. Finally, dose accuracy, and if appropriate flexibility, must also be assured for the target population.

	“Taste-masking, swallowability, dose flexibility, and excipient acceptability are all important for pediatric formulations, whereas dosing accuracy, swallowability, and the capability for multi-drug administration are important for geriatric formulations,” Huang notes.

	For instance, Harris points to tablets, which are suitable for teenagers, but not patients two years old or younger. The pediatric patient group is unique, adds Anthony Qu, vice-president of scientific affairs for Cambrex. “The pediatric patient population includes infants, children, and adolescents. You cannot simply cut an adult dosage down. Pediatric formulations should vary from adult formulations depending on the patient age, body size, swallowing capability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles,” he asserts.

	It is also important to note, according to Qu, that pediatric formulations can benefit other patient groups that have swallowing issues, such as the elderly, patients who have had a stroke, or patients with long-term diseases such as Parkinson’s or Alzheimer’s.

	There are many sources of information to assess patient acceptability. “The fastest and least costly method of evaluation is to review relevant publications, the content of which include results of patient focus groups or patient and caregiver surveys,” Harris says.

	There are numerous challenges to reformulating existing adult products for specialty patient populations. For all of these types of projects, accurate extrapolation of the PK/PD can present real difficulties, according to Huang.

	For most specialty populations, swallowability and palatability are key elements in the design of suitable dosage forms. “Most drugs have an unpleasant taste, and therefore due consideration needs to be given to making medicines acceptable from this perspective,” observes Harris. For children and the elderly, the actual dose can also be problematic; while an adult may be able to take a large tablet containing 500 mg of drug, administering a similar-sized tablet to a five-year-old child is much more challenging, he notes.

	The physical differences of age, body weight, swallowing capability, and tolerance within the pediatric population are also challenging and create the need for dose flexibility, according to Qu. He adds that stability, shelf-life, and bioavailability issues can further complicate formulation development. Ensuring excipient acceptability for pediatric formulations adds another layer of complexity, according to Huang.

	The first step in a reformulation project for a specialty population is to consider the age range of the patients and the dose range of the drug to be given. It is then important, observes Harris, to consider the drivers for achieving dose acceptability and compliance for that patient population, and what might the complications be in administering the drug to these patients.

	Questions that should be answered when looking to overcome reformulation challenges, according to Qu, are:

		What measurable dose form is required based on mg/kg body weight?

		Does the API formulation have a bad taste, and if so, can this taste be suppressed or masked?

		Is the formulation stable or not stable?

	“The goal is to determine the formulation strategy that will ensure similar exposure of the API in the new dosage form for new patient population as is achieved with the adult product and address the specific needs of the target population,” Huang explains. The solubility of the API must be considered to determine if a solubilization technology will be needed to achieve this goal. The stability of the API will determine whether a liquid (i.e., solution, syrup, suspension) product is possible, or if a solid dosage form will be necessary, Qu adds.

	Once the various factors have been considered and the relevant questions answered, it is possible to determine the optimum formulation and oral dosage approach. The main options include traditional liquid and solid (i.e., tablets, capsules) formulations, as well as newer dosage forms, such as chewable and fast dissolving tablets, rapidly dissolving and mucoadhesive oral thin films and multi-particulate formulations such as mini-tablets.

	“The traditional approach has been to use solution or suspension formulations because they are easy to swallow and provide dose flexibility. However, the use of sugars, flavors, and preservatives in these formulations can have detrimental effects on children and are consequently becoming less popular,” says Harris. These formulations also typically need to be refrigerated in-between use, have a shorter shelf-life, and can have overall stability issues compared to other forms, according to Qu. Furthermore, accurate dosing can be an issue due to varying spoon sizes.

	Traditional solid-dosage forms are well-established technologies that have stable, long-term shelf-lives, are pre-measured for dosing, and can be coated to mask taste or added to food, according to Qu. “Conversely,” he says, “they can be difficult to swallow for some patients, and certain types of formulations are hydroscopic and require special packaging and storage in a dry place.”

	Chewable tablets are another option often suitable for pediatric patients. “These formulations typically benefit from enhanced bioavailability and are convenient because water is not required for consumption and absorption is typically fast,” Qu says. On the other hand, these formulations typically contain sorbitol, which could have potential side effects in children. Other factors to consider, according to Qu, are the material flow, types of lubricants used, disintegration acceptance, taste, compressibility, and stability.

	Orally dispersible tablets in which the tablet rapidly disintegrates in the mouth have become popular and certainly allow for easy swallowing of the dose, according to Harris. Qu notes, however, that they present their own hurdles as well, such as lower strength levels and half-lives.

	Mini-tablets are the most common type of multi-particulate formulation. These small (typically 2–3 mm in diameter) versions of normal tablets can be readily swallowed by very young children. They also offer great dose flexibility, because the number of minitabs can be varied to achieve the required dose, according to Harris. In addition, unpleasant tastes can be masked using barrier coatings.

	A further benefit of mini-tablets is the ability to combine different types of tablets in one dosage form (within a capsule or compressed into a tablet), according to Qu. “It is relatively easy to combine immediate and sustained release mini-tablets in one product. Similarly, mini-tablets facilitate the formulation of fixed-dose combination products containing two or three different APIs,” he observes.

	One potential solution to the potential solubility, stability, and taste-masking issues is to utilize nanotechnologies, such as nanoparticles or nanoemulsions, which can encapsulate the molecules into a nano-formulation that can mask the taste and protect the compound from degradation, according to Huang. Another approach, he says, could be a change in the route of administration to injectables; a long-acting injectable for chronic disease would address the taste, dose accuracy, safety, and compliance issues associated with oral dosage forms.

	For pediatric formulations, it is essential to ensure that all of the selected excipients are safe for consumption by children. “Excipients play a key role in how a drug product is manufactured, stored, consumed, and delivered in the body. Just like with dosage and formulation, not all excipients that are appropriate for adult formulations will work in pediatric formulations. Children may not be able to metabolize or eliminate the excipient in the same way that an adult can, which can cause issues such as stomach upset (indigestion, flatulence, diarrhea), breathing trouble, intoxication, or worse,” Qu explains.

	In some cases, there may be different safety limits for an excipient that is used in an adult formulation versus a pediatric formulation, and guidance exists on this topic. In other cases, an excipient may need to be replaced completely with a different alternative. Formulators must decide what function each excipient is serving in the adult formulation, and then select and assess alternative, child-acceptable excipients that offer similar functionality, according to Harris. He points to the European Paediatric Formulation Initiative Safety and Toxicity of Excipients for Paediatrics database as a good place to start in selecting suitable excipients for use in children-friendly medicines.

	“Selecting suitable excipients for a pediatric formulation is not normally challenging, but there are restrictions. The key point here,” Harris stresses, “is that excipients are not inactive ingredients.”

	Successful reformulation of adult medicines for specialty patient populations can be successfully achieved by starting with a ‘patient-first’ mind set, which requires consideration of the formulation type that will best suit the needs of the patient, not only for getting the drug into the body, but also for ease of use and patient acceptance, according to Harris.

	The development of pediatric and other specialty formulations requires extensive knowledge and expertise in not only a wide variety of dosage forms and technologies, but awareness of the key determinants for patient acceptability. “As a result, many companies rely on experienced [contract development and manufacturing organizations] CDMOs with specialist expertise in this field,” says Qu. “Such CDMOs will be able to provide guidance and develop the right formulations that consider the age and taste preferences of the target population in the context of different dosage forms, in addition to paying attention to regulatory approval early in the development process,” he concludes.

	1. European Paediatric Formulation Initiative, 

Safety and Toxicity of Excipients for Paediatrics


	Vol. 43, No. 11
	November 2019
	Pages: 22–24

	When referring to this article, please cite it as C. Challener, “Adapting APIs for Specialty Dosage Forms," 

Articles

Several factors must be considered when reformulating APIs for pediatric, geriatric, and other specialty patient populations.

Adapting APIs for Specialty Dosage Forms

The stability of clinical trial materials, regardless of the trial phase, must be understood to ensure patient safety. Stability can be affected by the nature of the API, the production process, the choice of excipients, the container and container closure system, and other factors. Stability testing is therefore essential for demonstrating that the formulations administered to patients in any clinical trial will remain unchanged throughout the duration of the trial. The type and length of stability tests typically depend on the phase of development and the nature of the clinical trial (e.g., use of placebo or comparator drug). 

	Various guidance documents from FDA and the European Medicines Agency (EMA) have been published regarding stability testing of clinical trials materials (CTMs). The language regarding duration of testing in these documents tends to be vague, however. For Phase I trials, FDA recommends monitoring of the stability and quality of the drug during the clinical trial (1). Similarly, EMA recommends an ongoing stability program be performed with accelerated and long-term storage studies initiated prior to the study (2).

	For Phase II and III trials, FDA expects submission of a description of the stability performance and also suggests the development of stability-indicating analytical procedures that will detect significant changes in the quality of the drug product (3). The agency also encourages the completion of stress studies at Phase II, while in Phase III studies these stability studies should be extended to provide marketing application stability data.

	While the International Council for Harmonization (ICH) guidelines on stability testing (4) specifically indicate that formal stability protocols do not apply to CTMs and such protocols are not required for clinical stability studies or submission as part of clinical authorization applications, it is highly recommended that companies do conduct stability studies by means of established procedures.

	For CTMs, at a minimum, real-time data must be collected for a sufficient period to demonstrate shelf life for the product in use, as well as cover the duration for any intended clinical trial, according to Alyn McNaughton, technical director at Lonza Pharma & Biotech. The essential purpose of these stability studies, adds Geoff Carr, director of analytical development for Patheon Pharma Services by Thermo Fisher Scientific, is to ensure that CTMs will remain satisfactory over the period that they are intended to be administered to subjects enrolled in the clinical study, which is often dependent on the clinical trial phase.

	The duration of a clinical phase will vary depending upon the number of subjects required to complete the study, the therapeutic indication and the data read out period, according to Teresa Iley, director of pharmaceutical development and manufacture for Intertek Pharmaceutical Services. It also tends to get longer as the project progresses, which impacts the required length of the stability study, adds McNaughton.

	“As stability testing is commonly on the critical path for any product development, due to the need for real-time data, most stability studies are extended beyond the required time period to gain more knowledge about the product’s robustness and potential maximum shelf life. This approach allows an understanding of product supply needs for future clinical evaluation; for example, if additional manufacturing may be required during a clinical study to supplement product supply for batches that will expire during the clinical study, or if the product’s shelf life is not long enough for future trials or even for a viable commercial product,” he says.

	Iley notes that shelf-life justification can be supplemented by data generated from technical batches manufactured in support of clinical trial applications, but it is typically recommended that the actual batches used to supply the trial are also assessed concurrently with the trial.

	Initially a CTM is put on stability at both the long-term or storage temperature and under accelerated conditions. If the material is stable under both, the shelf life can be extrapolated up to twice the period covered by the long-term data (5), according to Judy Carmody, founder and principal consultant of Carmody Quality Solutions. “For Phase I trials, for instance, there may be one pull point at three months, which would allow an extrapolated shelf life of six months,” she explains.

	CTMs for Phase II or III studies are likely to be much closer to the product intended for commercialization, adds Carr. “These trials are usually larger, longer duration, multicenter, and often in multiple countries, so longer-term stability studies (e.g., two years or more) are likely to be more appropriate,” he says. In addition, Carr notes that because the formulations are likely to be closer to the intended commercial products, data from these studies may be used as supportive in new drug applications.

	The use of accelerated data to justify shelf life longer than real-time data can be a source of confusion, according to McNaughton. “Accelerated data collection provides a means of predicting the shelf life beyond the actual age of the product. However, interpreting any changes in the product impurity profile, relative to the toxicology-based safety information, can prove challenging in situations where the product does demonstrate some instability. It is also critical to ensure that real-time data, when it does catch up to the age of the product at the end of the study, remain in specification,” he explains.

	The vague guidance regarding stability testing for CTMs can have a number of impacts, including on study designs. For instance, because many companies base their studies on ICH guidelines, especially Q1A(R2) (6), and then make modifications to make protocols more suitable for CTMs, there is often considerable variation in how different companies conduct their studies, according to Carr.

	In addition, because it is important to ensure that batches in clinical studies always have the data available to demonstrate they remain in specification during the duration of the trial, it is necessary to continuously update the shelf life as soon as data are available and before the previous shelf life expires, McNaughton stresses. That can be challenging during early-phase studies, but simpler for later-phase trials because more time is available for completing stability studies.

	On the other hand, if changes in the chemical or physical stability of a drug product are identified in stability studies, clinical programs may need to be suspended until new batches can be supplied, according to Iley. She notes that data provided from technical batches can be a good indicator of how clinical batches will perform and could save precious time when planning for contingencies.

	The need to re-supply batches may also arise due to factors such as subject recruitment delays or dropouts, changes to dosing regimens, the introduction of new active, excipient, or packaging materials or revision to manufacturing processes. “Using a risk-based approach, it may be possible to undertake bridging studies to justify these changes, but it may also require performance of new or extended analytical studies. Any of these factors can impact the trial design and supporting stability program,” Iley says.

	The design of bridging studies will depend on the changes that created the need to perform them, according to Carmody. They typically involve the use of the established analytical methods, with comparison of results to previous data to confirm agreement.

	Any issues identified related to the chemical or physical stability of the drug product could cause a delay to the entire clinical development program. “A well-designed stability study, initiated early in the program, will facilitate detection of these issues and lessen any impact they may otherwise cause if not understood and resolved quickly,” asserts Iley.

	The key challenge is the fact that as candidates progress through the development cycle, typically changes are made to the formulation, manufacturing process, analytical methodology, container closure system, or other aspects. Any such change requires generation of new stability data, according to Carmody. “The new material must also be demonstrated to be stable for the duration of the clinical trial. Any additional time for manufacturing the new CTM further adds to the potential for delays due to the need for additional stability studies,” she says.

	A development program would, however, take decades if each of these studies were run sequentially to completion, according to McNaughton. “It is necessary to take risks based on limited data from partial studies, which must be done while ensuring that product used in trials remains covered by a stability study that demonstrates it remains within specification,” he says.

	This necessary approach results in a balancing act of timing and risk with respect to determination of the best time to conduct these studies, and sometimes, when shelf life is limited or not yet known, ensuring a contingency to remanufacture to keep a clinical trial supplied is required. “Careful extrapolation of data obtained from samples stored at accelerated conditions can help predict when additional batches may be required to support clinical studies and therefore allow planning with some level of confidence when manufacturing slots will be required,” Iley adds.

	There are also often increasing types of stability tests that need to be conducted as candidates move through later clinical trials. For instance, Carmody notes that diluents added to a powder to create a solution for infusion must be subjected to stability studies if the diluent manufacturer cannot provide relevant data. The in-use stability of the solution formed with the diluent must also be demonstrated. This information will impact the product handling protocol for the trial. “In-use studies should therefore be executed during early stages because the results directly impact and inform formulation and process development activities,” Carmody says.

	API availability is an important factor as well because synthetic route and process development typically proceed in parallel with clinical programs, according to Carr. “Supplies are often limited around Phase I as synthetic route and scale-up activities have not yet progressed. Limiting stability study duration is important for avoiding wastage of valuable API,” he observes. API availability generally increases as candidates move to Phases II and III, so longer-term stability studies can be more readily supported. In addition, Carr comments that long-term data are more useful at this point because the nature of the API and dosage form is likely to be more representative of future commercial batches.

	Complications can also arise in early-phase studies if the product is not tested promptly. In some cases, artificial failures can occur due to product being older than it should when tested, according to McNaughton. “As a result, an incorrect short shelf life can be assigned or the product can even fail specifications during the clinical trial, when in reality it is in specification at the shelf life when it should have been tested. Such situations add expense and uncertainty in a project, and in some cases the risk of withdrawal from the trial and program termination,” McNaughton says.

	Method development/validation challenges

	Often during early-phase studies, knowledge of both products and methods are limited, according to McNaughton. “When unknown degradation occurs, or a method does not behave as anticipated due to an unforeseen change, this can lead to pressure on the project. There exists a need to explain the change and justify it as safe for ongoing work or understand quickly that it is a change that does have an impact on product safety,” he notes.

	Establishing methods at the start of the process and how the method lifecycle progresses (e.g., identification of new impurities, formulation changes) can require careful assessment and may identify gaps in planned studies or potentially initiate new studies, Iley says.

	What is important, adds Carr, is the strategy for method development/validation. Because CTMs are considered GMP at Phase I, at least some validation of analytical procedures is required. Many companies adopt an approach of “phase-appropriate validation” or “qualification” using methods that have only been partially validated. “The objective is to be economic with the resources applied to validation without compromising patient safety,” he states.

	Quality-by-design approaches to analytical method development/validation conflict with this strategy, however. Even so, Carr remarks that analytical development can only proceed to a certain extent until the full details of product strength and formulation are known. He suggests that, given the likelihood of limited knowledge regarding potential degradation products and how to set limits for them, the best approach is to use “alert limits” rather than pass/fail limits or “report results” with no defined limits. “Alert limits may be set applying ICH Q3B(R2) principles (5); an advantage of this approach is that if an alert limit is exceeded, an investigation can be conducted but confirmation of the result does not necessarily require a batch to be rejected, as would be the case with an out-of-specification result,” Carr explains. Alert limits are also useful for pharmaceutical performance testing, such as dissolution for solid oral-dosage forms and viscosity for semi solids.

	The issue of validation is perhaps one of the most confusing aspects of conducting stability studies, according to Carmody. It is a Catch-22; stability studies and stability-indicating studies (forced degradation of the CTM) should be validated, but validation is typically not completed until Phase III.

	“What should be done,” Carmody says, “is to understand the target product profile, mechanism of action, and other important characteristics (e.g., solubility, chromophoric, etc.) to identify the most appropriate analytical methods to choose from.” The best methods can then be chosen for identification, potency, purity, and impurity analyses and the relevant parameters validated according to regulatory authority expectations. For any deviations, good scientific rational must be documented.

	“Even for Phase I CTMs, analytical methods can be developed with the intended use and validation parameters in mind. As important, stability-indicating studies and appropriate methods must be developed to ensure that the possible degradation products for the CTM can be detected,” Carmody states.

	Carmody also notes it is important that stability programs be run by qualified personnel with the relevant knowledge. “There are different expectations for stability testing compared to traditional quality control testing. If analytical groups are going to be responsible for stability testing, then the people involved should be trained on the regulations and requirements,” she asserts.

	While for the most part the focus of stability testing is on the API and formulated drug product, stability testing of placebos and blinded clinical comparators is also important. Stability testing on placebos is not particularly challenging because, in general, it essentially involves appearance testing and tests for other properties that could impact a blinded study.

	The same is not true for blinded comparators, according to Carr. These products typically come from other companies. They often have been repackaged in new containers and may even have been manipulated in some way to ensure appropriate blinding for the study. As a result, there is little information available. “Stability testing is likely to be based on comparisons between the unchanged product in the original packaging versus the repackaged blinded product, and it can be very challenging to establish and validate suitable analytical procedures for this type of study,” Carr observes.

	Comprehensive approach and logical strategy beneficial

	A carefully designed study that stratifies the storage conditions, specific tests, and material batches is required to avoid the often-nebulous growth of a stability program while still generating pivotal development data, according to Iley. “Ensuring strong, validated methods are in place and planning for potential trial extensions in the stability program design with the inclusion of optional time points and sufficient spare samples to support them is essential,” she adds.

	The more knowledge of the product and methods that is generated in advance, the more a study can be de-risked, agrees McNaughton. “It is important to ensure sufficient windows for testing are left, before the data are critically required, to allow for investigational work to take place at every time point in the early stages of a product. For this investigational work, there also needs to be sufficient product added to the study to facilitate investigations to examine what may or may not be a critical change,” he adds.

	It is also crucial to understand what climate zones the product may be exposed to. “There is little point in generating data for a product in the relatively temperate zone if the product also needs to be used in a tropical zone, and vice versa,” says McNaughton. Determining the behavior of the product components is also key, because if they do not behave according to Arrhenius predictions under accelerated conditions, then a false failure could occur that does not reflect the true performance of the product under its real-time storage conditions.

	Using batches of drug product, including any secondary packaging, that have been manufactured to established procedures is also important, according to Iley. “Although requirements may change or vary during the course of product development, the closer to the final processes and procedures, the less influence they may have on the data obtained from the stability program,” she explains. She also says it is best to expect the unexpected and plan for mitigation.

	The most important considerations are, according to Carr, to do what is needed to establish the shelf life for CTMs to ensure patient safety and reliable clinical data. It is then important to determine whether it is sensible to extend the study to collect additional stability data that could support a future new drug application filing.

	“Full stability programs must be implemented to address all of the different aspects of clinical trials, from different doses to diluents, placebos, and comparator drugs. An understanding of other potential impacts on stability must also be considered, from critical raw materials to reference standards. All may need to go on stability,” Carmody asserts.

	Equally important, she says, is consideration of appropriate time points for testing and the trending and statistical analysis of data throughout the testing period. “Shelf life is determined when the stability data crosses specified criteria. That needs to be predicted and not discovered after the fact. It is essential to understand the behavior of the CTM and intervene and make necessary changes if the stability data [are] not trending in the right direction,” she concludes.

Guidance for Industry: cGMP for Phase I Investigational Drugs

Guideline on the Requirements for the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials

Guidance for Industry: INDs for Phase II and Phase III Chemistry, Manufacturing and Controls Information

 (Rockville, MD, May 2003).
	4. ICH, Q1A(R2) 

Stability Testing of New Drug Substances and Products

, Step 4 version (ICH, 2003).
	6. ICH, Q3B(R2) 


	Vol. 43, No. 10
	October 2019
	Pages: 22–26

	When referring to this article, please cite it as C. Challener, “Stability Testing for Small-Molecule Clinical Trial Materials," 

Limited guidance and numerous challenges create confusion about the scope and timing of stability testing for drugs in development.

Stability Testing for Small-Molecule Clinical Trial Materials

The rapid advance of gene and modified cell therapies and growing interest in viral vaccine therapies are creating significant demand for large-scale viral-vector manufacturing capabilities. Biopharma companies and contract manufacturers alike face a host of challenges as they work to meet this crucial market need, from a limited availability of technology to a lack of standardization to complex and evolving regulatory pathways.

	There are numerous challenges to sourcing effective large-scale manufacturing solutions for viral vector production. Based on conversations with customers over the past several years, Univercells has identified the major hurdles in large-scale virus manufacture, which include expensive manufacturing facilities, lack of expertise, limitations in the number of scalable manufacturing technologies available in the market, and the high cost of good manufacturing practice (GMP)-grade reagents including transfection mix, plasmids, and bovine serum, according to Thomas Theelen, business development manager at the company.

	“Equipment and facility setup using the technology that is available, most of which has been adapted from other therapeutic areas, is very expensive and often does not support product manufacture through different maturity stages including process development, clinical trials, and commercialization. In addition, the level of expertise around developing large-scale manufacturing processes for gene therapies is limited, and the use of flatware for cell culture and sub-optimal down-stream processing protocols result in low yields; both factors also influence the overall cost of goods sold (COGS),” Theelen explains.

	“Existing manufacturing processes are often complex with hard-to-control unit operations and unfavorable COGS profiles,” agrees Xin Swanson, head of commercial development for viral vector gene therapy, Lonza Pharma & Biotech. As an example, she points to the widely used transient transfection process for associated adeno virus and lentivirus (AAV and LV, respectively) production, which mainly uses adherent cells and lacks scalability and lot-to-lot consistency due to variability in transfection efficiencies. In addition, she notes that many downstream processes for early-stage clinical production often employ gradient centrifugation steps that lack the ability to be furthered scaled.

	“Overall the volumetric productivity of virus particles per cell from culture systems and complete virus recovery rates through downstream processing are sub-optimal among existing production systems, both of which negatively impacts COGS. As a result, the lack of standardized production platforms that support industrialized scale processes is the leading challenge,” Swanson concludes.

	Further complicating the situation is a lack of standardized and advanced analytical methods for vector characterization and release testing (including in-process samples), which makes it difficult to have well-understood manufacturing processes before incorporating process improvement steps, according to Swanson. Other challenges include a lack of automation in key steps of the manufacturing process; immature supply chains, which creates risk and leads to a lack of standardization/innovation of critical raw materials; and rapidly advancing regulatory pathways that are complex to manage among different jurisdictions.

	Many of these challenges have existed for several years, with some developments occurring along the way. For instance, Theelen observes that novel scalable bioreactor systems, the implementation of continuous bioprocessing, and the introduction of new resins for viral vector purification are having an impact. “Several companies are developing suspension-based processes and implementing stable producer cell lines,” he notes. However, he adds that even though stable cell lines have the potential to significantly reduce COGS, developing robust processes using these stable cell lines is still a challenge. The same is true for suspension-based processes, which currently require significant investments in process development and extend the time to market.

	What has largely changed, according to Swanson, is the timeline for overcoming these challenges. “It is critical to meet the clinical and commercial manufacturing needs for these curative therapies, and the need is becoming more urgent due to the rapid advance of clinical progress. The lack of manufacturing scalability has created a vector shortage, and the collection of sufficient vector chemistry, manufacturing, and controls (CMC) information has become a bottleneck during the product development lifecycle,” she asserts.

	Theelen adds that to ensure that more gene and other next-generation therapies reach patients, reducing COGS is necessary to increase availability, facilitate reimbursement, alleviate the burden on healthcare budgets, and ensure that innovator companies can offer their products at an affordable price while maintaining sustainable gross margins. “Scalable and reliable technologies for cost-effective cell and gene therapy manufacture will reduce the reliance of biopharmaceutical companies on hard-to-acquire expertise and dependence on contract development and manufacturing organizations (CDMOs),” he says.

	Additionally, Theelen notes that developing technologies that facilitate process and product development will shorten the time-to-market and reduce development costs, while increasing the number of technology candidates will intensify competition and finally drive down materials and equipment costs.

	Technology innovation is key to addressing the challenges associated with large-scale GMP viral vector manufacturing, agrees Tania Pereira Chilima, NevoLine product manager at Univercells. “Solutions that are tailored for gene therapy manufacture and combine a low capital investment, scalability, ease-of-operation, and robustness while maintaining product quality are needed,” she comments.

	It is also important that these technologies are able to accommodate the manufacture of gene therapy products with low and high annual demands in order to ease the development and commercialization of personalized gene therapies and viral vector-based vaccines. Lowering the capital investment is also necessary for reducing the entry barriers for gene therapy start-up companies.

	Swanson adds that all of the major challenges must be tackled concurrently in order to address the manufacturing challenges. “The optimal goal is to deliver products that will meet target product profiles with defined quality attributes while realizing the need to increase process productivity and reduce COGS,” she says.

	CDMOs have a vital role to play when it comes to manufacturing innovation for viral vector production. “Given the fast pace of clinical development timelines and the unconventional demand curve of curative therapies, CDMOs offer competitive advantages not only from a manufacturing technology advancement perspective, but also from a cost perspective with respect to optimizing capital expenditures and better managing operating expenses,” Swanson states.

	Pereira Chilima agrees that CDMOs are a major gateway for the adoption of new technologies. “Many established gene-therapy developers rely on CDMOs throughout all stages of product development and even once they reach the commercialization stage. The expertise of CDMOs in large-scale production helps cell therapy developers evaluate different avenues for cell therapy manufacture and select the technologies to be used once they decide to internalize product production,” she explains.

	CDMOs are also in the unique position of developing and providing manufacturing platform processes that will allow drug developers to focus on product innovation and significantly shorten the gene-to-product development timeline, according to Swanson.

	One of the most important developments highlighted by Swanson has been the transitioning of cell-culture processes from an adherent format to a suspensions format via cell-line adaptation, which is enabling better scalability. Development of stable producer cell lines is also reducing process variability and enabling the adoption of intensified processing solutions. A better understanding of the important qualities of critical raw materials, such as animal serum, plasmids, non-chemically-defined media, and the extractables/leachables associated with single-use technologies has also helped to address some manufacturing challenges.

	Incorporating design-of-experiment study principles and use of improved bioprocess control and data analysis software are allowing process development/optimization to be conducted at the multiparameter level, while new analytical methods, such as more accurate viral vector quantitation techniques, provide a better understanding of impurity profiles and allow for better process monitoring. In downstream processing, density-gradient centrifugation is being replaced with chromatography methods for more consistent and efficient operations.

	Collaboration between the different stakeholders in the industry is necessary to build on preexisting expertise and capitalize on academic innovation to help guide technology developers on the gaps that must be addressed in the industry, according to Pereira Chilima. Adds Swanson, “Collaboration between members of the value chain, ranging from innovators, manufacturers, and reagent and equipment suppliers to regulators, as well as close collaboration between academic and industry partners, is critical in driving solution development.”

	Pereira Chilima also notes that involving the regulatory bodies and payers early on is needed to reduce regulatory barriers and ensure adequate reimbursement.

	These types of collaborative efforts are ongoing, she says. Good examples include the efforts made by the Cell and Gene Therapy Catapult and Cobra Biologics to investigate continuous manufacturing. Univercells is also actively discussing promising collaborations with established gene therapy companies with the aim of combing its expertise to develop manufacturing solutions for end-to-end viral vector production for gene therapy applications.

	Lonza has invested substantial internal research and development efforts in platform development, particularly in the area of AAV and LV production. Specific focus areas include scalable suspension-based transient transfection processes and stable producer cell-line technologies, according to Swanson. Concurrently, the company is investing in the development of novel analytical methods and new media formulations with the aim to provide turn-key solutions.

	Separately, Lonza has invested heavily in a manufacturing capacity expansion with the opening of its dedicated, 300,000-sq.-ft. cell and gene therapy facility in Houston in 2018. The facility uses an extensive modular design concept and employs single-use technologies to allow clients quick access to scaled-up production capacity based on project needs.

	Univercells, meanwhile, has developed the NevoLine platform, a modular and automated manufacturing system delivering affordable viral products such as vaccines and gene therapy vectors. This design of the NevoLine platform relies on a modular approach, allowing for a variety of configurations that provide tailored solutions for a range of products, according to Pereira Chilima. Viral-vector-specific NevoLine platforms can be designed for enabling AAV or LV manufacture for small- and large-scale applications.

	At the core of the NevoLine platform lies the scale-X fixed-bed bioreactor coupled with in-line product concentration to intensify upstream processing and deliver large product quantities within a reduced footprint. “Intensification of each unit steps allows for drastic footprint reduction, enabling the entire process to be placed in self-contained modules such as isolators or biosafety cabinets,” Pereira Chilima explains. “The platform aims to minimize the capital investment for gene therapy manufacturers while delivering the low COGS and flexibility required to support the development and commercialization of gene therapy products, eventually ensuring their availability to patients,” she says.

Vol. 43, No. 9
	September 2019
	Pages: 22–26

	When referring to this article, please cite it as C. Challener, “Seeking Solutions for Large-Scale GMP Viral Vector Manufacturing," 

Innovation in manufacturing technologies must occur to ensure the availability of gene therapies and cell therapies.

Seeking Solutions for Large-Scale GMP Viral Vector Manufacturing

Editor’s Note: This article was published in the September 2019 issue of Pharmaceutical Technology Europe.

Modeling and simulation are recognized to provide assistance in predicting bioreactor performance, both for initial laboratory runs and when scaling to the pilot plant and commercial manufacturing. “Bioreactor performance has consistently improved in biomanufacturing due to a greater understanding of the engineering and biology of cellular systems. To continue to drive efficiency and reduce cost of manufacturing while maintaining or improving quality, reducing bioreactor variation will be required, and predictive models can enable these variation reductions,” asserts Tom Mistretta, director of data sciences at Amgen.

	The continual development of higher-producing cell lines, the switch to chemically defined media, and other advances in cell-culture technology are, however, challenging developers of modeling and simulation software.

	Typically, bench-top bioreactors are operated in the performance design space of larger bioreactors to model scale-up performance, according to Parrish M. Galliher, chief technical officer for upstream and founder of Xcellerex, a GE Healthcare Life Sciences business. “Successful modeling of bioreactors can reduce costs associated with engineering testing and engineering runs, accelerating pathways through preclinical and early clinical phases,” adds Mark T. Smith, staff engineer for single-use technologies in the BioProduction Division of Thermo Fisher Scientific.

	In particular, the inexpensive computing power and excellent computational talent entering the biopharma industry, combined with improvements in computational fluid dynamics (CFD) and metabolic modeling software, are promising to open new doors for more complete cell culture models, according to Smith. “I predict that as modeling becomes more robust, it may be possible to entirely eliminate traditionally performed engineering runs, which in fact is already being done to some extent because in many cases companies and engineers simply ‘get to know’ their bioreactor networks empirically and heuristically, without the need for complex physical modeling in silico,” he asserts.

	The key to successful modeling for the prediction of bioreactor performance, stresses Galliher, is to first calculate the performance design space of the bioreactor at all relevant scales. “Once these design spaces are understood, the scientist can operate any scale bioreactor within the design space of any other bioreactor scale and model any bioreactor of any scale using a bioreactor of any other scale,” Galliher says. He adds that this approach has been used effectively for decades.

	The process of modeling has, in fact, advanced due to the increased capability to aggregate various sources of data (sensor measurements, batch record entries, product quality measurements, maintenance records, etc.) needed to model bioreactor performance, according to Mistretta. “The industry has become more efficient due to the significant improvements in technology for centralized access to various data sources via data lakes,” he observes. In addition, the information systems technology used has been validated and demonstrated to be cost effective, secure, compliant, and scalable with the volume of data generated from manufacturing processes.

	In the past, continuous processing in perfusion mode was generally limited to cell-culture processes involving sensitive products that degrade under conventional batch conditions. Today, there is increasing use of perfusion cell culture to realize other cost, efficiency, and productivity advantages.

	Some of the challenges with perfusion processes include sensor instability and fouling over the course of the culture, which impacts the ability to effectively monitor and control these processes, according to Galliher. Perfusion mode can also create additional risks of contamination due to the continuous removal of depleted media and introduction of fresh media, and these processes involve a significant increase in the media volumes required, which has logistical and cost implications for a manufacturing facility, adds Mistretta.

	Overall, perfusion mode generally places higher performance demands on the reactor, according to Smith. He points to the higher cell densities in perfusion mode, which result in increased oxygen demand in a higher viscosity solution with potentially more cell-free biopolymers and lipids than a fed-batch culture. “Viscosity and solution property changes can fundamentally change mass-transfer mechanisms by impacting bubble size, bubble coalescence, mixing times, shear rates, and other parameters,” he explains.

	As a result, in-silico modeling of systems must be adjusted for such parameters in a meaningful way. There is, however, a limited understanding in how to model such high cell densities due to the relative newness of these operating regimes, according to Smith. Computational models of perfusion processes additionally require consideration of filter effects such as fouling and sieving, Mistretta notes.

	The shift to single-use technologies has also introduced a wider diversity of bioreactor designs, particularly with respect to spargers, baffles, and impeller configurations. “Whereas stainless-steel reactors could be made with relatively similar configurations within and across bioreactor networks, having multiple vendors represented in single-use bioreactor networks increases the level of data and modeling required to successfully predict behavior,” Smith explains.

	In addition, Smith notes there is a need for improved mass transfer performance with reduced shear in single-use bioreactors. “As cultures become more intensified, the need for oxygen transfer increases and is generally accommodated by increasing the oxygen gas passing through the micro-sparger. In many cases, the increased flow through the micro-sparger leads to shear-associated cell damage, likely related to increasing shear at the gas-liquid interface,” he explains.

	To address this problem, oxygen delivery must be achieved through efficient spargers with lower gas-liquid shear rates. “While some vendors already offer such sparger technologies, the industry has been slow to update to these sparger technologies, likely due to the revalidation burden of changes to established bioprocesses,” Smith comments.

	Mistretta agrees that variability of single-use systems does impact cell culture, but Amgen has been able to rapidly detect and determine the root cause for this cell culture variation through the accessibility of process data, material lot data, and process performance models. “These models also support data-driven decision making for impacted lots, and we continue to develop monitoring strategies through predictive models, near-real-time monitoring, and material-control strategies to mitigate unintended variation in performance,” he states.

	More advanced use of hybrid models such as CFD combined with first principles kinetic models are also effective to assess the impact of bioreactor design on performance, according to Mistretta. “Use of CFD models to determine kLa [mass transfer coefficients], mixing time, and shear effect have become pretty standard applications for technology transfer, scale-up, process optimization, and troubleshooting activities at Amgen,” he says.

	In addition, Amgen has demonstrated the utility of finite element models for studying operational risk factors for single-use bioreactor systems. For instance, models were developed to predict how material science aspects of the single-use bioreactors impact pressurization and other operational risks, according to Mistretta. Amgen has also observed more collaboration with single-use bioreactor suppliers with respect to exchanging data and developing models that enable more reliable operations.

	Ultimate Goal: Modeling complete bioreactor performance

	Modeling of the performance of the whole bioreactor including predicting full cell-culture performance seems to be the holy grail, but according to Smith, broad application of complete models has yet to be achieved due to to the complexities of the variables required for accuracy, including the oxygen transfer rate, oxygen uptake rate, carbon dioxide evolution, carbon dioxide stripping, metabolism, cell-line traits, etc.

	In addition, Smith notes that improvements in understanding of cell biology have led to dramatic changes in what a “typical” cell line is capable of producing, with improvements coming from cell-line traits such as gene promoter strength, gene integration site, integration stability, modified metabolic pathways, etc. Furthermore, aspects of bioprocess engineering have shifted, for example from natural to chemically defined media and from batch to fed-batch (and toward continuous) modes.

	“In short,” Smith concludes, “modeling the ‘complete’ bioreactor cell-culture performance for universal application may be not yet be in sight.” He does comment that there appears to be a push among large biopharma toward the use of complete models for the prediction of bioreactor performance in their given networks. However, in any published literature regarding these efforts, there is rarely sufficient detail provided to enable easy reproduction of the models used, and almost never is source code made public for direct application. “In this sense, trade secrecy and intellectual property concerns may be stymying the potential rapid industry-wide advances in performance prediction,” Smith observes.

	 “Even simpler aspects of bioreactor performance are generally still poorly modeled.” He points to the modeling of mass transfer coefficients, which dictate whether a reactor can provide sufficient oxygen to maintain viable cell mass, as an example. “In the past three years, there have been several hundred publications on CFD-based prediction of kLa in bioreactors. While this quantity suggests great interest in the area, they frequently describe the resulting models as ‘adequate,’ ‘sufficient,’ or similarly hesitant verbiage, suggesting in fact there is still space to improve in our performance prediction as an industry,” Smith explains.

	Potentially because of this remaining gap in the predictive power of CFD, many of the product development/pilot-scale models used today, according to Smith, are driven primarily by empirical data leveraging fairly traditional correlations. “This approach seems to be able to provide a similar predictive power to that of CFD without the additional computational effort and resources,” he comments.

	Useful models must be robustly validated with real data. The greater the amount of good data incorporated into a model, the more insight the model can provide. Traditional off-line sampling once or twice daily of key parameters (e.g., viable cell density, glucose, key amino acids, titer, etc.) will not provide the robust data set needed to robustly predict performance on a moment-by-moment basis, according to Smith.

	That is where process analytical technology (PAT) comes in. “Relatively recent application of PAT, such as Raman spectroscopy and biomass probes for inline sensing, are now providing more complete data on cell-culture performance and enabling better, more timely control of reactor automation,” he observes. Advances in sensor technologies have also contributed to enhanced real-time performance predictions of bioreactor performance and enable approaches such as model predictive control-based models, according to Mistretta. It is, in fact, improvement of automation control strategies within the existing capabilities of the bioreactor-not sampling and sensing alone-that is essential to improving bioreactor performance, stresses Smith.

	Further advances in PAT are still needed, however, to enable them to really contribute to model development, according to Galliher. As an example, he notes that while infrared sensors have been touted as being able to measure relevant bioreactor parameters and generate predictive models, they require large computing power and algorithms to cancel out interference from cells, gas bubbles, and media components, all of which change over the course of the run.

	The availability of data (particularly genomic and proteomic data on cellular systems) and the capability to efficiently capture, store, and contextualize the process data needed for modeling have been the most notable advances in predictive bioreactor performance, according to Mistretta. The decreasing cost of the infrastructure needed to run computational models has, he adds, also made it faster to prototype and deploy predictive models for bioreactors.

	One area of rapid development involves the potential application of artificial intelligence (AI) and machine learning (ML) to bioreactor performance modeling. Bioengineers are beginning to discuss how to apply machine learning and digital-twin algorithms to the modeling of bioreactor performance, coupled with CFD modeling of multiphase (liquid and gas) solutions, according to Galliher. He does note, though, that these approaches are in conceptual stage.

	In fact, the capability to design, develop, and implement machine learning algorithms more efficiently has also allowed modeling to be done in a more systematic way, according to Mistretta. “Machine learning models based on the ability to leverage larger datasets have enabled automated data-driven models of bioreactor performance and offer the potential to help determine fitted parameters in first principles models of bioreactor performance,” he remarks.

	One possible challenge to leveraging AI/ML could be the need for massive data sets in order to avoid overfitting issues. “Considering that biopharma companies are generally trying to minimize the number of culture runs for any given product and that even processes for blockbuster products may only be run 12–20 times per year, there is a relative dearth of information for most cell-line cultures with respect to typical ML data sets,” Smith explains. While each run produces thousands of data points (e.g., second-by-second pH, dissolved oxygen, viable cell density, etc.), these variables are inextricably linked to the chronology of the culture and could lead to further bias, he adds.

	Smith stresses, though, that although AI and ML pose unique challenges to bioengineers, it is possible that experts well-versed in how and when to apply AI may develop creative solutions for deconvoluting and dealing with these types of challenges in the near future, to successfully enable the utilization of these technologies within the bioprocess industry.

	Today, most of the measures of bioreactor performance are at a macro level in commercial facilities, according to Mistretta. To get to highly accurate predictions of bioreactor outputs, additional measurements and a framework for extensible modeling that describes the physiology, chemistry, and mechanics of a bioprocess must be developed, he says. “Genomics and metabolomics-level understanding of bioreactor performance supplemented by real-time advanced sensors to measure post-translational modifications are necessary, and we predict to see these types of advances in the next three to five years,” Mistretta asserts.

Vol. 31, No. 9
	September 2019
	Pages:42–44

	When referring to this article, please cite it as C. Challener, “Cell-Culture Advances Test Bioreactor Performance Models,"

The evolution of cell-culture technology is driving the need for improvements in modeling solutions.

Cell-Culture Advances Test Bioreactor Performance Models

Fixed-dose combination drugs formulated with two or more APIs in a single product to improve compliance through simplification of medication needs has been a popular and beneficial lifecycle management strategy. Controlled-release formulations are also a subject of continued interest in the pharmaceutical industry.

	“There is a particular focus on creating smarter dosage forms that primarily meet the therapeutic index by maintaining the desired plasma concentrations for extended time periods,” states Deep Patel, a senior formulation scientist with Cambrex. “Reducing the frequency of administration to prolong the duration of effective blood levels increases patient compliance, particularly when API combinations are involved,” he adds. Combining multiple APIs in a single product can create a complex situation, if the actives have varying and/or conflicting properties. Selection of the right excipients can be crucial to the successful development of controlled-release products containing multiple APIs.

	Achieving the desired drug-release profile

	There are many different types of controlled-release formulations, and one of the first steps must be to establish whether the drug should be formulated as delayed-release, sustained-release, controlled-release, etc., according to Ronak Savla, global scientific affairs manager at Catalent. The next step is to determine the optimal release kinetics (zero order, first order, or pseudo-zero order), after which point the formulator must design a formulation that meets the dissolution (release) profile. Catalent uses physiologically-based pharmacokinetic modeling (PBPK) to determine the optimal desired dissolution rate via construction of a plasma concentration profile.

o correlation is still one of the biggest challenges, according to Patel, along with risk management of dose dumping under different gastrointestinal (GI) tract conditions. Designing controlled-release delivery systems for biologic APIs that deliver abuse resistance and meet specific requirements for pediatric dosage forms are also key areas of focus.

	Each modified-release dosage form faces both common and unique challenges and requires prototyping to fine-tune the drug release rate and achieve the target pharmacokinetics. “Because modified-release dosage forms contain higher drug loads than immediate-release dosage forms, the potential for dose dumping is a greater concern and must be addressed. API compatibility and stability with excipients must also be assured,” Savla notes. Manufacturing challenges unique to each dosage form include the coating level and drying requirements for coated tablets and multi-layered drug-containing beads and ensuring a homogeneous viscosity and uniform filling of semi-sold fill material incorporated into soft capsules.

	Different target patient populations also present different challenges. “Controlled-release formulations are typically solid dosage forms that can be rather large. Patient populations prone to swallowability issues, such as geriatric and pediatric patients, may not be able to swallow the intact dosage forms,” says Savla. For these patient populations, coated beads (or ‘sprinkles’) filled in two-piece capsules are a popular option. The capsule can be opened, and the contents can be mixed with food or certain liquids. Mini-tablets are another attractive option for toddlers and older children. Another consideration for pediatric patients is whether the excipients are acceptable for use in the population.

	In addition, because controlled-release formulations typically aim to provide once-daily dosing, the drug must have some colonic absorption, which can be an issue for poorly-soluble APIs. With the increasing prevalence of poorly-soluble drug candidates, the use of solubility-enhancing technologies such as amorphous solid dispersions and lipid-based drug delivery systems are necessary. “Coupling solubility enhancement and modified-release requires the use of a significant quantity of excipients and presents great difficulty to achieve target drug load while retaining a patient-friendly dosage form size,” Savla observes.

	Added challenges with multi-API formulations

	The critical properties of controlled-release drugs containing two or more APIs include the potential dose differential and varying release profiles for the different drug substances, the stability and compatibility of the APIs with one another and other ingredients in the formulation, and content uniformity, according to Anil Kane, executive director and global head of technology and scientific affairs at Thermo Fisher Scientific. “If the APIs reside within a monolithic tablet or capsule, additional steps may be required to ensure dose uniformity and compatibility and to maintain the target release rate,” agrees Savla.

	One of the critical considerations during design of controlled-release formulations containing multiple APIs is the half-lives of each API, which may be different and generally require careful selection of excipients to control each drug release, according to Kane. The dose differential is also important. “Combining a very low dose API (e.g., 1–5 mg) with an API with a high dose (450–550 mg) could be another challenge to controlling the release of each in a specific target site in the GI tract,” he states. The site of absorption of each API may also be different, making it difficult to design a controlled-release strategy for the best clinical efficacy.

	The size of fixed-dose combinations (FDCs) formulated as controlled-release products must be considered where swallowability may be an issue, because these dosage forms cannot be split or crushed due to the modified-release functionality. It is prudent, according to Savla, to not create FDCs of two or more APIs with doses in the hundreds of milligrams.

	“A promising approach to creating modified-release FDCs in tablet form would be to borrow and learn from formulations containing both immediate-release and modified-release functionalities,” Savla says. He points to multi-layered drugs containing beads, which allow the creation of multiple-release profiles within a single dosage form.

	Designing a strategy for development of a controlled-release target product profile is important for many reasons. To achieve this goal, according Kane, a thorough understanding of the pharmacokinetic and pharmacodynamic profile of the small molecule related to its clinical efficacy is needed.

	A proper design strategy can have many benefits, including reduction of the frequency of dosing (once-a-day or twice-a-day preparation) and increased safety through avoidance of the possibility of dose dumping. The target patient population may better comply to the medication regimen when consideration is given to the size of the pill to swallow and the time of administration. Another potential benefit is the ability to formulate small-molecule APIs into controlled-release oral solid dosage formats (e.g., tablets, capsules, etc.) or as long-acting sterile injectables.

	The primary role of functional excipients in controlled-release formulations is to modify the release of the drug from the dosage form. There are numerous mechanisms by which these excipients function to release drug, according to Savla: time; pH responsiveness; erosion; osmotic concentration, etc. Controlled-release characteristics can be achieved by the use of polymeric coatings over solid dosage forms such as tablets, capsules, granules, sugar spheres, or ion exchange resins, or alternatively by incorporating polymer matrix systems within solid dosage forms or systems that respond to changes in physical conditions within the formulation, adds Patel.

	Excipients used in controlled-release formulations can, according to Patel, also help to overcome the bitter taste of active ingredients or to protect the gastric mucosa. In some cases, these excipients can be used to deter abuse or to help avoid alcohol-induced dumping. In addition, excipients can be used wisely to target the release of the active drug at a specific site of the gastrointestinal tract, behavior that is triggered by pH of the specific region of the GI tract.

	“The choice of the right excipient in terms of its properties as well as the right quantity and quality, directly impact the release of the drug in the gut for an oral solid dose controlled-release preparation or in the plasma concentration in the systemic circulation for an injectable form,” says Kane. The level of excipients is critical from a safety aspect as well. Patel adds that proper selection of excipients can help drug product manufacturing through improved flowability, enhanced compressibility, improved bioavailability, and particle size distribution specifically when using different combinations of APIs.

	The following categories of excipients and the grade selection are critical in developing an optimal controlled-release formulation, he notes:

		Solubility/permeability enhancers/modifiers

		pH modifiers (to improve stability or release at a targeted region of the gastro intestinal tract)

		Polymers that retard the release the drug based on diffusion, erosion, swelling, etc.

		Excipients/materials that can act as physical barriers.

	Savla provides two examples. pH-responsive polymers are a good choice to protect acid-labile APIs from gastric acid or for those APIs that need to reach the colon. Matrix tablets and semi-solid lipids within soft capsules work via erosion and are options for sustained-release delivery.

	Pulsatile release polymeric excipients, meanwhile, control the selective delivery (when and where) the API is desired, according to Patel. “These excipients provide a unique advantage due to the timely release that is controlled by coating the drug with selective polymers having sustained or enteric modified-release characteristics,” he observes.

	“Overall, the quality and consistency of performance of the excipients, 

, are critical to the success of controlled-release dosage forms,” Kane concludes.

	While the selection of the excipients with the proper functionality at appropriate levels in the drug product formulation are crucial to drug product performance, a deeper understanding of how variability in the excipients can affect drug product performance is also essential. “Maintaining variability of critical material attributes within an acceptable range is important for a given drug product as excipient concentration and characteristics greatly influence drug product performance with respect to stability, bioavailability, and manufacturability,” Patel notes. In addition, says Kane, development of a control strategy is an important component of improved drug product development.

	“A number of drug product recalls identified excipient variability, and therefore a lack of an adequate control strategy, as a contributor to failure of the drug product, further underscoring the need for improved excipient variability understanding,” he observes. To date, however, Kane notes that evaluating the impact of excipient variability on drug product performance has presented a greater challenge than evaluating API and process impacts.

	The overall variability in a particular critical quality attribute is a combination of the variability of the API, the excipients, the manufacturing process, and interactions of any of these individual factors, he notes.

	“At Thermo Fisher Scientific, we have found that identification of the most impactful material properties is critical to evaluating the effects of excipient variability on drug product performance. This excipient variability understanding can then be combined with the knowledge of each of the API properties and the process parameters used to manufacture the drug product to develop an appropriate control strategy that ensures consistent supply of safe and efficacious drug product,” Kane says.

	In the end, says Kane, the experience of the formulation scientists is the key to developing robust optimized controlled-release formulations that perform consistently in a predictable manner. For controlled-release formulations with multiple APIs, a systematic and well-characterized data set for each of the APIs, along with a scientifically designed strategy for the dosage form and the selection of the right quantity and quality of excipients, are key to successful formulation development. The experience and expertise of the formulator will help to avoid any ‘trial and error’ experimentation and can bring speed to these projects, he concludes.

	For Patel, new excipient development is also essential. “The development of excipients that are capable of fulfilling multifunctional roles such as enhancing drug bioavailability and drug stability, as well as controlling the release of the drug according to the therapeutic need, is one of the most important prerequisites for further progress in the design of novel drug delivery systems,” he asserts.

Vol. 43, No. 8
	August 2019
	Pages: 20–22, 45

	When referring to this article, please cite it as C. Challener, “Combo Drugs Require a Complex Design Approach," 

A design strategy can ensure conflicting properties are managed appropriately for multi-API controlled-release formulations.

Combo Drugs Require a Complex Design Approach

Selection of a sterilization strategy for a drug product that requires aseptic manufacturing is generally determined by the stability of the drug substance. For stable products, terminal sterilization, including heat sterilization or exposure to radiation or chemicals such as ethylene oxide or vaporous hydrogen peroxide, is the preferred strategy. These methods are advantageous because the processes can be monitored and validated and they tend to be less prone to error.

	Most biologic drug substances, however, are unstable when exposed to heat, radiation, or chemicals and generally require aseptic manufacturing using sterile filtration. Successful sterile filtration requires a drug product formulation with an appropriate viscosity and compatibility with the contact surfaces and shear stresses involved in pumping the fluid. Single-use technology is widely used in sterile fill/finish operations today, reducing the turnover time and cross-contamination risk.

	The main factors that must be considered from the outset when developing formulations for biologic drug substances that require sterile filtration include, according to Yunsong (Frank) Li, director of process development at Catalent Biologics, the product’s chemical and physical stability under various stress conditions (e.g., thermal, mechanical, photostability) during product manufacturing, storage, shipping, and administration; compatibility with the materials used during sterile fill/finish processing; and compatibility with the final container closure system and administration device.

	Factors related specifically to sterile filtration that can impact the final formulation include the contact surfaces, shear forces involved, and the potential to induce aggregation or particle formation, notes Margaret Faul, vice-president of drug product for Amgen. The method used to sterilize the fill/finish equipment or primary packaging must also be considered because any residual chemicals may interact with the biologic. For instance, antibodies containing methionine residues in the related binding regions of an antibody can become ineffective (lose efficacy) if (accidentally) oxidized (e.g., by vaporous hydrogen peroxide during manufacture), according to Hanns-Christian Mahler, head of drug product services at Lonza Pharma & Biotech.

	In addition, Faul observes that the concentrations of excipients or the biologic drug substance may be reduced by the filter. “The material of construction may affect material loss, while the filter system design may affect the flow properties, and the size may affect the overall process throughput,” she explains.

	To address these issues, certain excipients may be added to minimize process loss to the filter, negative interactions between the biologic and the filter, or residual sterilization chemicals that might lead to particle formation, aggregation, or decreased rates of filtration, according to Faul.

	To ensure that sterile filtration will be effective and that contaminants are excluded, it is therefore necessary to test the process for each batch, adds Andrew Bulpin, head of process solutions at MilliporeSigma. “The adsorption of components of the final formulations and the biologic drug substance to the sterile filter must be analyzed to ensure that the formulation and final concentrations remain within the desired values,” he says.

Sterile filtration is often required for biologics but presents degradation and compatibility challenges.