Therapy Manufacturing - Best Practices

Part
01
of four
Part
01

Cell Therapy Manufacturing: Best Practices, Pt. 1

Best practices related to cell therapy manufacturing (CTM) include the application of strong quality management and automation in manufacturing processes. Experts also suggest the use of dissolvable microcarrier-based cell culture to increase the efficiency in the process of cell therapy manufacturing.

Strong Quality Management

Automation

  • Fabio Fachin, the head of Takeda cell therapy engineering and automation, advises the CTM manufacturers to utilize automated processes instead of manual ones to overcome the processing challenges.
  • Even though that CTM products are specified and personalized for each patient, fully-automated processes will improve the efficiency and efficacy of each manufacturing run. Experts believe that it will allow manufacturers to deliver extensively optimized and individualized drugs for the patient with distinct indications.
  • Fachin also stated that automation should be applied in every part of cell therapy production, including processing, analytics, and data management.
  • The advantages of applying automation in cell therapy production include reducing the risk of microbial contamination due to the zero human contact and the fact that less skilled workers may do and perform the automated processes, thus lowering the cost of labor.

Dissolvable Microcarrier-Based Cell Culture

Research Strategy

To determine the best practices concerning cell therapy manufacturing, our research team first sought information from articles and reports that were written by the experts and other relevant researchers. Our primary focus was on the practices that could improve the efficiency, efficacy, and quality of cell therapy manufacturing products. We also ensured that the articles and reports we referred were updated, as in not older than 24 months of Wonder's standard. Since our sources were written by professionals and experts, we concluded that the practices we compiled in this study are the current best practices related to cell therapy manufacturing.
Part
02
of four
Part
02

Cell Therapy Manufacturing: Best Practices, Pt. 2

Part 1 of the best practices articles related to cell therapy manufacturing (CTM) included the application of strong quality management, introducing automation in manufacturing processes and the use of dissolvable microcarrier-based cell culture to increase the efficiency in the process of cell therapy manufacturing. The second part expands that list to include the issue of scalability, which impact the cost of the products; and that of integration of the entire supply chain, which is essential to ensure the processes necessary are not compromised.

Manufacturing Processes Should be Designed for Scalability

  • Recent cell therapy approvals have resulted in an influx of investment in cell therapy — over $13 billion in 2018. However, this has resulted in the unintended consequences of the manufacturing of products with, among other things, less than Phase II-grade manufacturing readiness.
  • Essentially, companies are rushing into manufacturing using underdeveloped processes, which will result in higher costs of goods due to manual intermediate steps and custom technologies used.
  • Instead, the best practices involve focusing on lean, scalable production, such as the bioreactor platform suitable for allogenic products and can be scaled up.
  • Further, there should be minimal modification to keep manufacturing costs low, thus speeding up slow adoption rates of cell therapy products.

Integrated Manufacturing and Supply Chains

  • Like any other pharmaceutical product, success in cell therapy requires consistency and reproducibility in order to be successful. Using end-to-end integrated manufacturing solutions accomplishes this.
  • Cell therapy manufacturing is unlike a conventional manufacturing operation, which tends to be confined to a manufacturing facility. Instead, it goes through different phases and hand-off points starting with the collection of cells in a clinical facility and ending with the administration of the products, possibly in a different clinical setting and via manufacturing facilities.
  • This is a significantly different issue from the scalability issue as this encompasses the entire process, rather than merely the manufacturing site. Failure to manage the supply chain carefully could result in upstream, and possibly deadly, consequences for patients.

Research Strategy

To determine the best practices concerning cell therapy manufacturing, our research team first sought information from articles and reports that were written by the experts and other relevant researchers. Our primary focus was on the practices that could improve the efficiency, efficacy, and quality of cell therapy manufacturing products. We also ensured that the articles and reports we referred were updated, as in not older than 24 months of Wonder's standard. Since our sources were written by professionals and experts, we conclude that the practices we compiled in this study are the current best practices related to cell therapy manufacturing.



Part
03
of four
Part
03

Cell Therapy Clinical Trials: Best Practices, Pt. 1

Having well-defined endpoints, being overseen by a regulatory authority, and having an ethics review are three best practices in stem cell therapy clinical trials. Additionally, dosage level was found to be a critical challenge in the design of trials.

Types of Clinical Trials

  • Human clinical trials are broken into four phases, with each phase having particular goals. Additionally, each phase is viewed as a separate trial and must receive approval from the FDA before the next phase can begin.
  • Phase 1 trials are focused on safety. They usually involve a relatively small number of healthy volunteers (20-100) and the purpose is to determine the effects the drug/treatment has on humans. This phase does not examine the effectiveness of the potential treatment.
  • Phase 2 trials focus on the efficacy of the treatment. Typically, these trials involve two groups where one receives the treatment being tested and one does not. This allows researchers to determine whether the treatment is potentially effective, and this phase also continues to focus on safety.
  • Phase 3 trials are large scale trials usually involving hundreds or thousands of patients. This phase is an opportunity to determine if the results seen in Phase 2 can be duplicated in a larger group and for a longer period. Treatments that successfully make it through Phase 3 trials can request FDA approval.
  • Phase 4 trials are conducted after a treatment has gone to market. The purpose may be monitoring long-term effects, comparing the treatment to others on the market, or examining the long term impact on quality of life.

Best Practice — Having Well-Defined Endpoints

  • According to the book, "The Management of Clinical Trials," published in June 2018, one important design aspect of phase 1 and 2 stem cell clinical trials is having well-defined and established endpoints. This should be a combination of efficacy markers and surrogate markers, such as biomarkers or imaging studies.
  • This practice is supported by the International Society of Stem Cell Research (ISSCR) who published a list of fundamental questions that should be asked to determine if a clinical trial is well-designed. The specific questions related to endpoints are "Are the trial endpoints well-established for this disease? Are there clinical outcomes, or are surrogate endpoints such as biomarkers or imaging studies used?"
  • A trial on the effectiveness of stem cell therapy in treating multiple sclerosis had the following defined endpoints: disease progression, relapses, ambulation index, Scripps Neurological Rating Scale (NRS), survival, and more.
  • In order for phase 2 trials to be approved to move on to phase 3, they must have a primary endpoint, not only surrogate endpoints. Some examples of endpoints used in stem cell trials for treating chronic heart failure are improved LVEF, improved 6-minute walk distance, and decreased levels of NTproBNP.

Best Practice — Regulatory and Ethics Review

  • Ensuring that the clinical trial has an ethics review is a best practice. This should be conducted by an institutional review board, ethics review board, independent ethics committee or some other group tasked with overseeing that the trial is conducted in an ethical manner.
  • Trials that go through a formal review process with the FDA (in the U.S.) receive the FDA seal of approval. This review process is extensive and ensures that the trial has met certain safety and efficacy requirements.
  • This practice is also confirmed by the ISSCR as one of the fundamental questions to be answered regarding a stem cell trial is, "Has the trial been reviewed and approved by an appropriate regulatory agency and/or undergone review by an ethics/institutional review board?"
  • The ISSCR also lists a trial not being overseen by a regulatory body as problematic.
  • City of Hope, UCSF, UC San Diego, UCLA, UC Davis, and UC Irvine are all examples of places that run clinical trials that have received regulatory approval.

Challenge — Dosing

  • Although challenges of stem cell clinical trials is not the topic of this report, the issue of dosing came up repeatedly in the research and therefore is being addressed.
  • Currently, there are no standardized guidelines for the dosing of stem cells in clinical trials. Many trials do not report how many stem cells are used (because there is no standard for determining this), which means comparisons between patients, across studies, and between phases of trials can not accurately be made.
  • Determining dosing can be particularly challenging because the effectiveness of the cells can vary based on the source, delivery method, cell type and other factors.
  • A study published in 2017 that aimed to test the importance of dosing in stem cell trials, found that the results were different for different doses and highlighted the importance of dosing as a critical component of study design.

Research Strategy

To determine some best practices regarding stem cell therapy clinical trials, we searched for practices that were recommended by multiple experts, and that were utilized by reputable trials.
Part
04
of four
Part
04

Cell Therapy Clinical Trials: Best Practices, Pt. 2

To expand on what has already been said about Best Practices for Cell Therapy Clinical Trials, two more elements have been added to the list. While it's important to have well-defined endpoints and to comply with the current regulations, having informed consent from the patient, supportive evidence and identifying risks are a must.

Informed Consent

  • Agreeing to participate in a clinical trying after coming to an understanding of all the potentials risks and benefits involved in the trial, as well as alternative therapies, is known as "informed consent."
  • Before deciding to partake in a clinical trial or any of the procedures, a prospective should understand its purpose, duration and relevant medical facts of the trial, which will be explained to the participant.
  • Prior to agreeing to participate, every volunteer has the right to know and understand what will happen during a clinical trial. The research staff is obligated to discuss all the pertinent information about the trial with the test subject.
  • Upon request, research centers should provide documents to explain every aspect of the study and the study personnel should also be able to explain the information in the costumer's mother language, in case the test subject's native language is not English.
  • It is the staff's responsibility to help the subject understand the information they provide them and give them enough time to ask any additional questions, which is not possible to accomplish in a single visit.

Supportive Evidence

Identify, Acknowledge and Minimize Risks

Research Strategy

To have an idea of where, what to look-up and what has already been found, the research team reviewed "Cell Therapy Clinical Trials: Best Practices, Pt. 1". We also made sure not to have similar sources nor topics regarding cell therapy clinical trials. Our team found several articles that provide key points to the investigation.

Since test subjects for any clinical trial have the right to know what the study will entail, informed consent was added to the list. To find more information on the matter, the research team explored specialized websites. It goes without saying that anyone who wishes to perform a clinical trial shall inform the subject about any complication or changes the study could cause in their health.

To have more information on what were the standards for best practices by the ISSCR, we used their Guidelines for Stem Cell Research and Clinical Translation. The research team was able to find that clinical trials should be supported by evidence and risks shall be identified and reduced. The most recent documentation that we could find was published in 2016.

Sources
Sources

From Part 02
Quotes
  • "Early approvals also present production opportunities. These opportunities, however, come with potential downsides. For example, early approvals may give manufacturers little time to hone their production processes."
  • "“In recent years, cell therapy approvals have been driven by a tailwind of terrific clinical data,” says Anthony Davies, PhD, founder and CEO of Dark Horse Consulting. “This has thrust commercial licensure on complex products which have spent a relatively short amount of time in pharmaceutical development. Approvals out of, effectively, Phase II trials are becoming likely for products with even less than Phase II–grade chemistry, manufacturing, and control (CMC) readiness.”"
  • "According to Davies, underdeveloped processes increase the cost of goods as a result of the manual steps and the bespoke technologies used. Underdeveloped cell therapy processes also lack scalability, observes Fabio Fachin, PhD, head of cell therapy engineering and automation, Takeda. Designing for scalability is paramount, Fachin insists, because high manufacturing costs slow the adoption of cell therapy products, even when they can boast impressive clinical outcomes."
Quotes
  • "Next, I asked about the key criteria for successful mesenchymal stem cell manufacturing and Dr. Macdonald said that really it is the same as any pharmaceutical product. The product must be safe, effective and it must be able to be manufactured consistently and reproducibly. If any of those elements are absent, then you don’t have a commercial product."
Quotes
  • "END-TO-END INTEGRATED MANUFACTURING SOLUTIONS ENABLE GENE THERAPY COMMERCIALIZATION With clinical success and increased investment from the market, many gene therapy companies are looking toward manufacturing and commercialization of their lead therapies. As gene therapy commercialization is relatively new, there are still several challenges that must be considered when looking at how these products will be manufactured consistently, at appropriate scale, and cost effectively…"
Quotes
  • "In a conventional manufacturing operation, the process is confined to the manufacturing facility. But with cell therapies, this process extends far beyond, creating unique logistical challenges and responsibilities, as well as requiring a paradigm shift in thinking."
  • "Cell therapy manufacturing, in the strictest sense, begins with the collection of cells from the patient, which takes place in a clinical (or apheresis) facility, and ends with the administration of the final drug product to the patient at the bedside. "
  • "“The consequences of not doing that can be essentially fatal to a patient,” continues Dr. Peshwa. Failure to document and control the provenance of the samples could have dire consequences for the patient and no guarantee of consistency, robustness, or quality control for the physicians and manufacturing team."
Quotes
  • "There is a need for robust, flexible cell therapy platforms. For allogeneic products, we describe a bioreactor platform that can be scaled up. For autologous products, we describe a modular platform that can be scaled out."
From Part 03
Quotes
  • "Drug and device testing begins with extensive laboratory research which can involve years of experiments in animals and human cells. If the initial laboratory research is successful, researches send the data to the Food and Drug Administration (FDA) for approval to continue research and testing in humans."
Quotes
  • "Nevertheless, studies are lacking comparing the efficacy and sustainability of the various different cell types, as well as identifying the most effective dose, time of delivery, and route of administration. Other important questions that remain to be investigated are whether concurrent pharmacologic treatments beneficially or adversely interact with the various cell therapies and whether cell therapy increases the risk for opportunistic infections or malignancy development or progression."
Quotes
  • "In this emerging therapeutic area where national and international guidelines and standards are being developed, each stakeholder has a responsibility to rigorously assess these trials to ensure that they are well-designed and based on strong and rational preclinical evidence and that the potential therapy will be safe, effective, and meet patient needs. The risk of poorly designed or ineffective trials or, worse, testing unsafe inter ventions, could put patients at risk of serious harm and undermine the progress of the entire field."
  • "While clinical trials are normally reviewed by national regulator y officials and/or local ethics/institutional review boards, the stakeholders also include physicians who have a vested professional interest in the implementation and outcome of the trial. The physicians running the trial want to help develop therapies for various conditions and are concerned about the health and safety of their patients. Collectively these three groups, each with a unique perspective, can and should provide 360-degree feedback of the trial, the need for which is particularly acute given the complexity of the products and therapeutic approaches."
Quotes
  • "In fact, because stem cell activity often declines with culture, trials employing cultured “expanded stem cell” treatments may not deliver any stem cells at all. It follows from this uncertainty that the interpretation of trial outcomes is correspondingly erroneous at worse or uncertain at best."
From Part 04
Quotes
  • "Before deciding to participate in a clinical trial, a prospective participant should understand the clinical trial process. "
  • "The purpose of the trial, the duration of the trial, the relevant medical facts of the trial, and the potential risks and benefits involved in the trial and alternative therapies will all be explained to the participant."
  • "Before undertaking any of the procedures of the clinical trial, t he participant must sign the informed consent document in order to participate. "
Quotes
  • "Prior to agreeing to participate, every volunteer has the right to know and understand what will happen during a clinical trial. "
  • "To begin, the research staff is obligated to discuss all the pertinent information about the trial—its purpose, the procedures involved, the potential risks and benefits—with you. "
Quotes
  • "Launch of clinical trials should be supported by a systematic appraisal of evidence supporting the intervention."
  • "Risks should be identified and minimized, unknown risks acknowledged, and potential benefits to subjects and society estimated. Studies must anticipate a favorable balance of risks and benefits."