WHO/IAEA tackle investigational radiopharmaceutical GMP in draft guidance

Regulatory NewsRegulatory News | 08 March 2021 |  By 

The World Health Organization (WHO) and the International Atomic Energy Agency (IAEA) have released a draft guideline on good manufacturing practices for investigational radiopharmaceuticals.
The March 2021 document is the first working draft of a revision to the existing guidelines on good manufacturing practices (GMP) for investigational products. Consultation is open through the end of April 2021, with a revised document expected to be worked up for public consultation by July 2021.
The revisions are coming as the use of radiopharmaceuticals to diagnose and treat cancers and other diseases is expanding rapidly; this growth “is accompanied by a set of challenges due to the complexity and unique nature of these agents,” according to the draft.
"Having inadequate manufacturing controls during early clinical evaluations either carries the risks of unnecessary patient harm or jeopardizes the validity of the collected study results,” noted the authors of the draft guidance. However, they pointed out, overly burdensome or redundant controls may slow innovation in an area where lifesaving technologies are being developed.
Accordingly, the framework adopted in the draft guidance is to set out minimum GMP standards for Phase 1-3 clinical investigations of novel radiopharmaceuticals that are not yet authorized or approved.
The overarching goals of process and analytical method validation steps are to make sure that clinical trial participants are kept safe from risks associated with quality issues; to ensure in-batch and batch-to-batch consistency of radiopharmaceuticals; and that the future commercial product is consistent with the investigational product.
Consideration should also be given to setting an appropriate dosage during the investigational stage. Should the final commercial dosage vary from the investigational dosage, sponsors should provide evidence “that the final dosage form is equivalent, in terms of bioavailability and stability, to that used in the clinical trials,” according to the draft guidance.
As the investigational radiopharmaceutical progresses through the clinical trial process, quality standards may shift. In early-phase trials, just the critical manufacturing controls may apply, while by the time the candidate product reaches phase 3 trials, the developer should be using commercial-equivalent characterization techniques.
The guidance walks developers through details of a recommended quality management system and lays out what should be covered in a quality risk management system. The document also goes into detail regarding which personnel should be involved with which aspects of product development and the clinical trial process.
Documentation, including which components should be included in specifications, is also addressed in the guidance. As with other aspects of the development program, documentation may be “less vigorous” in early phases, but “they would still need to be adequate in order to allow for traceability of the manufacturing process.”
Equipment, materials, and details of production are also addressed, to include when outsourcing production steps might be appropriate. Minimum container labeling is also specified in the guidance document.
Quality control systems should take into account the half-lives of radionuclides. Here, for example, it may not make sense to collect retention samples, since meaningful data may not be drawn from a sample that is several half-lives away from peak levels.
Special considerations for shipping are also addressed. Destruction of radiopharmaceuticals is ordinarily not necessary because of radioactive decay.
Unique problems may also crop up during the validation stage: “The validation of aseptic investigational radiopharmaceutical preparation procedures presents special problems, as the batch size is often very small and the number of units filled may be not adequate for a full validation protocol,” notes the draft guidance. A media fill test should be conducted as a prerequisite for radiopharmaceutical manufacture.
Guidelines for selection and maintenance of the manufacturing premises are specified; considerations unique to the production and handling of potentially radiotoxic materials is addressed. General principles for radiopharmaceutical manufacture and handling are referenced as applicable in the investigational setting as well. For example, the guidance notes that “The recirculation of radioactive contaminated air should not be allowed.”

WHO and IAEA also released a technical guidance document to procurement of radiotherapy equipment, taking into account the need to make sure maintenance and safety infrastructures are in place in the facilities planning to acquire the equipment.
“IAEA data shows that around one-third of countries still do not have radiotherapy available, out of which 28 are in Africa,” said May Abdel-Wahab, Director of IAEA’s Division of Human Health, in a press release announcing the availability of the guidance. “Many of them would benefit from increased access to radiotherapy services. The key is tailoring radiation oncology solutions to the situation on the ground, underpinned by appropriate safety infrastructure.”  


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