Unique Challenges of Radioligand Therapy Manufacturing

Although regulatory guidance addresses radiation-related patient safety risks associated with therapeutic radiopharmaceutical drug product development, very little industry guidance addresses the commercial manufacturing and validation of those processes.

Background

Most radiopharmaceuticals, specifically RLTs, use isotopes with short half-lives of days or even hours. A single hiccup in the complex flow of on-demand manufacturing, release, and distribution could render the therapy ineffective by the time it reaches its patient. Given how time-sensitive and logistically complex this process is, certain aspects of validation become extremely important to ensure effective and safe delivery. Validation protocols must challenge and demonstrate a right-first-time approach, because quick turnaround of batch records and subsequent batch release is critical.

Unique safety aspects such as shield effectiveness and contamination control must be validated. Finally, the appropriate level of risk needs to be well-understood and adopted in validation to support a robust validation effort and at the same time allow for the flexibility to manufacture and deliver complex therapies at high speed. This presents unique challenges in the validation of RLT facilities and processes, but given unique challenges, there are unique solutions. Aspects of the RLT validation methodology could and should be applied to other drug manufacturing modalities to shorten the supply chain and to reduce production and release time, products time to market, and validation time and costs.

Novel Modalities With Minimal Guidance

Radiopharmaceutical manufacturing’s first challenge is the limited industry and regulatory guidance for what is a relatively novel drug modality, particularly with respect to RLT drug products. Most of the published regulatory guidance focuses on patient safety, given the novel risk associated with radio-pharmaceuticals. With conventional drug products, patient safety is an inherent aspect of product quality: most drug products do not, by their very nature, pose a risk to patient safety. Unlike conventional drug products, the same radiation that works as therapeutically against targeted tissues, such as cancer, can cause considerable harm when exposed to normal, healthy tissue.

Thus, most regulatory guidance has focused on the development and clinical study of therapeutic radiopharmaceuticals to ensure radiation-related patient safety. Similar patient safety risks exist for diagnostic radiopharmaceuticals; however, radioactivity and radiation doses are typically much lower, and pose much less risk to patient safety. The US Food and Drug Administration (FDA) has published draft guidance documents that address some aspects of radiopharmaceutical drug products, including the following:

• Guidance for Industry: Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic Radiopharmaceuticals (2011) addresses the design of nonclinical late radiation toxicity studies to help minimize the risk of late-occurring radiation toxicities in clinical trials of therapeutic radiopharmaceuticals.
• Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry: Draft Guidance (2018) provides information to help sponsors design an appropriate nonclinical program to develop oncological therapeutical radiopharmaceuticals and provide recommendations for certain aspects of product labeling. This guidance primarily addresses ligand and radiation toxicity evaluation and labeling information requirements for evaluated toxicity, particularly to support first-in-human studies. This guidance supplements International Council for Harmonization (ICH) Safety Guideline S9, Nonclinical Evaluation for Anticancer Pharmaceuticals (2009).
• Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development: Draft Guidance (2025) is intended to help sponsors identify optimized dosages (administered activity and schedule) for radiopharmaceutical therapies (RPTs) for oncology indications during clinical development and before submitting a marketing application for a new indication and usage. This guidance covers participant population considerations, trial design, safety monitoring, and dosimetry for dosage optimization trials. Much of this guidance addresses radiation toxicity determination and calculation of acute and cumulative exposure limits.

But developing a therapeutic radiopharmaceutical drug product that is inherently safe for patients is only one part of providing a commercially viable therapy for patients. That drug product must be manufactured, released, shipped, and distributed to patients. Each part of this process, from drug development to effective patient dose, presents unique challenges.

Manufacture: Hands-off Aseptic Fill-Finish

RLT and general radiopharmaceutical manufacturing pose a unique and particular health and safety risk to operators and personnel involved because of the exposure and contamination risks posed by the radioisotopes used in the drug products. The drug products—typically administered intravenously and therefore primarily produced using aseptic fill-finish processes—must be protected from the operators to ensure sterility; but the operators must also be protected from the drug product.

Manufacturers must use as low as reasonably achievable (ALARA) strategies to minimize radioisotope exposure to process-and-support personnel. Time, distance, and shielding are the mitigation techniques used to lower operator exposure to radiation. These ALARA strategies involve reducing exposure time, increasing distance between personnel and radioisotopes, and increasing shielding between personnel and radioisotopes. Shielding requirements vary by emission type. A sheet of paper is sufficient for alpha particles. A sheet of metal is sufficient for beta particles. Thick blocks of lead or similarly dense metals are required for gamma emissions.

Following ALARA, operator intervention in fill-finish isolators must be minimized. Direct process intervention increases exposure time and minimizes exposure distance. Further, typical isolator glove materials of construction—such as ethylene propylene diene rubber (EDPM), neoprene, and rubber—do not provide sufficient shielding for beta particles or gamma emissions. One technology used for radioligand therapy manufacturing ALARA is robotics, which can eliminate direct operator intervention throughout manufacturing, from introduction of the radioisotope source to removal of shielded finished drug product.

In aseptic fill-finish manufacturing processes, the greatest product quality risk is loss of sterility—and the single greatest contamination source threatening sterility is humans. Therefore, applying robotics technology to conventional pharmaceutical manufacturing aseptic fill-finish processes would similarly eliminate the single greatest risk of product contamination and loss of sterility. Eliminating operator intervention removes the need for isolator glove ports and gloves, a common source of sterile boundary penetration. Fully enclosed isolators eliminate the need for highly classified background environments for the isolators. Aseptic processes in Grade A isolators can safely be conducted using a Grade C or even Grade D background.

Lessons for Conventional Pharmaceutical Manufacturing

Conventional pharmaceutical manufacturing can benefit from completely hands-off isolator technology and robotics to eliminate operator intervention and bolster the contamination control strategy. Downgrading the background environment for aseptic processes can further reduce facility operating and personnel gowning costs.

Release: Right-First-Time Batch Manufacturing

Actinium (Ac 225), a promising isotope in targeted alpha therapy, has a half-life of eight days. Lutetium (Lu 177), the isotope used in the first commercially available RLT product, has a half-life of just more than six and a half days. Fluorine (F 18) has a half-life of a mere 110 minutes. Table 1 shows the half-lives of several isotopes common to diagnostic and therapeutic radiopharmaceuticals.

In conventional pharmaceutical manufacturing, batch release can take, on average, two to three weeks from completion of batch manufacture, and sometimes even longer. Such batch release times simply cannot accommodate drug products with expiration dates based on radioisotope half-lives of days to minutes. RLT drug products must be released in real time, which means they must be manufactured in a right-first-time manner that supports real-time release. Batch release delays generally result from documentation errors, quality deviations, out-of-specification test results, and similar pharmaceutical quality system (PQS) exceptions.

For conventional pharmaceutical manufacturing, right-first-time is an operational efficiency objective intended to minimize overhead and rework costs. It is treated like an ideal to strive for; in radiopharmaceutical manufacturing it is a nonnegotiable expectation. For radiopharmaceutical manufacturing, right-first-time is imperative to delivering diagnostic and therapeutic drug products to patients whose lives may depend on them. For radiopharmaceutical manufacturing, rework is generally not feasible. More importantly, because of radioisotope half-lives, the time required to perform rework and/or to address PQS exceptions will result in expired product. Radiopharmaceutical drug products that are not produced right the first time are essentially rendered useless.

This reality puts extraordinary emphasis on the process validation life cycle: requiring particularly rigorous understanding of product and process science; process risks; and the design, implementation, and demonstration of effectiveness of a holistic process risk control strategy. This rigorous approach to holistic control strategy development and implementation can be applied to conventional pharmaceutical manufacturing processes. This approach includes control of materials, personnel, process variability, data integrity, and other risk sources, rather than just control of critical process parameters. The result would be processes that are more robust and in a better state of control, and would thereby reduce the opportunity for PQS exceptions, documentation errors, and other problems that delay batch acceptance and release.

Lessons for Conventional Pharmaceutical Manufacturing

Conventional pharmaceutical manufacturing can benefit from enhancing quality culture and quality management maturity to lead to real-time, right-first-time batch release, better and more-consistent manufacture of quality drug products, and reduced cost from poor quality.

Shipping Patient Dosing: Supply Chain and Personalized Medicine

With the advent of advanced therapy medicinal products, cell and gene therapies have shifted the pharmaceutical manufacturing paradigm from mass-produced blockbuster drug products to personalized medicine and from batch sizes of tens of thousands to a batch size of one. This paradigm is also true for RLT manufacturing. With this manufacturing, specific drug product doses are manufactured for individual patients based on the required potency (radioactivity) and date/time of administration, even down to specific hours of the day.

Serialization and other means of tracking an individual drug product dose—including through patient-specific filling through labeling, packaging, supply chain, and shipping to the clinic—are required to ensure that the correct patient receives the correct drug product dose. Overall supply chain management is particularly important, from receipt of source isotopes required for drug product synthesis to delivery to the clinic and scheduling on specific days at specified times.

Lessons for Conventional Pharmaceutical Manufacturing

Although this level of specific dose tracking and supply chain management isn’t required for conventional pharmaceutical manufacturing, the controls required to achieve these ends for RLT drug products can be applied to help mitigate supply chain issues experienced with conventional pharmaceutical drug products. Conventional pharmaceutical manufacturing can benefit from supply chain management and strategies to ensure right-time drug delivery and minimize drug shortages.

Conclusion

The conventional pharmaceutical manufacturing industry can learn a lot from radiopharmaceutical manufacturing about manufacturing technologies such as robotics, right-first-time manufacturing, real-time release, supply chain management, and individualized patient dosing. It requires a shift in expectation and culture. Conventional pharmaceutical manufacturing, and the associated validation approaches, view these different mindsets and technologies as nice to have. However, adopting them as standard practice could greatly reduce batch release time, beef up validation efforts, and remove product loss risks. In the radiopharmaceutical world, these ideals are not nice to have; they are required for success.