By David Loong
Getting clinical data for your experimental medicine is the first big milestone for many start-ups and a condition of many grants for commercializing research. No matter how good your preclinical data from animals are, clinical data from humans is a sure sign that your drug has commercial potential and will attract the attention of investors. High quality clinical data can only be derived from high quality drug product – clinical observations should be due to the active ingredient and not be confounded by impurities, microbial contamination, or unidentified drug variants such as isomers, isoforms, or degradation products of the active ingredient.
This article is the first of a two-part series that aims to give a broad overview of what to look out for when sourcing or manufacturing your experimental medicine for first-in human (FIH), or Phase I clinical trials. It highlights important considerations regarding Good Manufacturing Practices (GMP), quality, and outsourcing. Part 2 of this series delves into specific recommendations for different categories of therapeutics, focusing on the three most common modalities: small molecules, antibodies or biosimilars, and cell and gene therapy products.
What is the objective of FIH trials, and how does therapeutic modality affect trial design?
FIH trials are designed to assess product safety in a small number of humans. Small molecules are considered “toxic until proven safe”. Thus, FIH trials involving small molecules require cautious sub-therapeutic dosing up to a certain “safe and efficacious dose” to assess safety. This data must be evaluated by regulatory authorities for safety concerns prior to commencing Phase II studies at doses deemed to be efficacious. To determine the first dosage for FIH trials, two approaches based on data from relevant animal models can be used. The NOAEL approach, recommended by United States Food and Drug Administration (USFDA), is the dosage where no actual adverse effects were observed in the test subjects. The MABEL approach, recommended by the European Medicines Agency (EMA) for “high-risk medicines”, also considers relevant in vitro data and applies safety factors to estimate a starting dose where any anticipated biological effect may be observed.
On the other hand, monoclonal antibodies (mAbs) and cell and gene therapies (CGTs) are considered “not toxic but possibly immunogenic or tumorigenic”. As the drug-drug interactions and pharmacokinetics can be broadly predicted for these two modalities, many FIH trials commonly incorporate immediate follow-on efficacy studies, also known as a combined Phase I/II design, with only the Institutional Review Board (IRB) reviewing the FIH data. For mAbs, MABEL is increasingly being used to determine starting dosage in FIH studies.
Extensive industry experience exists for the manufacturing of small molecules and mAbs, but less so for cell and gene therapies
The relationship between chemical and mAb active pharmaceutical ingredient (API) manufacturers, and regulatory authorities currently spans over a decade for mAbs, and much longer for chemical APIs. This means manufacturers and regulators have had extensive experience identifying and controlling manufacturing risks for various platforms. For example, the use of organic synthesis for small molecules and CHO cell lines for mAb production are both well extremely well established and there is a clear and detailed regulatory stance for these two modalities.
In contrast, the manufacturing of CGTs (which are also known as Advanced Therapy Medicinal Products in the EMA) is a relatively nascent endeavour. Until now, there has simply not been a need to make large amounts of these materials at such high specification, so manufacturing platforms and analytical methods are still in development. However, processes are starting to shift away from T-flask and benchtop centrifuges into closed-system standalone devices, such as the all-in-one Prodigy by Miltenyi and cell processing modules such as the Sepax by GE. In addition, CGTs also require manufacturing in an aseptic environment as they cannot be terminally sterilized by filtration, unlike small molecules or mAbs.
Considerations for manufacturing material for early stage trials
Is GMP-grade material necessary, or not?
The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S, 1970) is an attempt by 52 regulatory authorities to agree on GMP guidelines. Nonetheless, for Phase I trials authorities acknowledge that the manufacturing process may still be in development, thus processes and analytical methods do not need to be validated at this early stage. As such, “GMP-grade material”, meaning material made in accordance with all PIC/S guidelines for medicinal product manufacturing, is not required for FIH trials. However, implementing GMP-manufacturing is challenging enough to cause a major delay in drug development, which makes it prudent to invest in it as early as possible in practice.
Know what your product is
Your purported active pharmaceutical ingredient should be defined as early as possible. This is self-evident for small molecules because chemical structures are used during discovery. However, since mAbs and CGT are not single physicochemical entities, knowing what your product isn’t is essential to define product-derived impurities. For example, charge or glycoform variants of a desired mAb can have undesirable biological effects, so process control strategies for manufacturing should address how to reduce the amount of such impurities in the final product.
Know your route of administration
Impurities can also arise from the manufacturing process itself. Trace levels of cell culture reagents, carryover from media, or solvents used for purification are examples of process-related impurities, which may also compromise the safety and efficacy of your therapeutic product. Your preclinical studies will have suggested a dosage form for your drug product, which will have an associated specification in the United States Pharmacopeia (USP) or European Pharmacopoeia (Ph. Eur.) for the amount of microbial, endotoxin, and other impurities allowed. Conducting a risk assessment of the manufacturing process will identify undesirable scenarios so that appropriate process controls can be put in place to reduce any ensuing process-related impurities. These critical process parameters are determined by conducting a series of statistical design of experiments (DoE) to examine the effects of process setpoints or ranges, their interactions, and the resulting product purity.
Get to know how your regulatory authority makes decisions
PIC/S guidelines represent the international consensus on GMP in relation to medicinal products and are therefore used by most regulatory authorities to guide decision-making. Although the recommendations are comprehensive, each authority interprets the guidelines slightly differently. Studying the past audit findings of other manufacturers will enable you to understand your authority’s stance on various issues about the supply and quality of your experimental medicine.
Understand the role of the quality department
The quality department in manufacturing serves to prevent out-of-specification material from reaching the patient and potentially causing harm. It implements GMP regulations to ensure pharmaceutical product quality, patient safety, and treatment efficacy. It will also implement other quality standards, such as the ISO 9000, which focuses on organizational development to build quality into everyday operations. PIC/S guidelines recommend having separate production and quality teams to ensure there is no conflict of interest between the people making the product and those checking the resulting specifications.
The quality team is essential because any entity making experimental medicine requires a quality assurance system with change management procedures, written Standard Operating Procedures, and batch records. This is a minimum requirement for making material for human use, regardless of complying with GMP regulations.
In essence, the objective of Phase I trials is to evaluate the safety of your experimental medicine. At such early stages, GMP-grade material is not required, but in practice many of the GMP compliant processes and analytical methods should be instituted as early as possible to avoid major changes in manufacturing pipelines at later stages. Manufacturing processes should be evaluated to reduce sources of product- and process-derived impurities, in accordance with regulatory guidelines based on drug dosage form. At the end of the day, the guidelines are there to ensure that what is administered to the patient is the substance intended, free of contamination, at the correct dose for efficacy, and most importantly, equivalent to the material used for pivotal clinical trials.
 The opinions in this article are meant for general information and should not be taken as professional advice.
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About the Author
David has a PhD in Synthetic Organic Chemistry from the Australian National University. He has over ten years of experience in the pharmaceutical industry including positions at GlaxoSmithKline Manufacturing (Singapore), AMRI Global Discovery Services (Chemistry), Hummingbird Bioscience (preclinical development) and Esco Aster (bioprocessing services). He can be contacted at email@example.com.