La moral y los valores vistos por los niños y adolescentes

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99mTc labelled kits include pH measurement, visual inspection and radiochemical purity (using radio-TLC); QC on ^99mTc/⁹⁹Mo generators include early radionuclidic purity test to check for

99Mo breakthrough, elution yield and aluminium ions. QC on PET radiopharmaceuticals, and more generally on extemporaneous preparations, are more complex and, in addition to the previously cited test, also radiochemical purity with HPLC, radionuclidic purity with NaI(Tl) or (preferably) HPGe detectors, residual solvent, as well as endotoxin content and sterility, are assessed.

IV-2. NORTH AMERICA

111 (b) Radiopharmaceuticals to be used in clinical trials

Manufacture of Positron Emission Tomography (PET) radiopharmaceuticals used for FDA approved diagnostic indications are regulated by PET drug class specific regulation called

‘21CFR 212 Current Good Manufacturing Practice for Positron Emission Tomography Drugs’, recognizing the special nature of these agents. These agents require preparation from raw materials – a complex process that involves radionuclide production, incorporation, drug purification, and formulation. This type of radiopharmaceutical preparation falls under the practice of manufacturing and is governed entirely by the FDA. The exact QC testing requirements for these agents are intentionally not defined in detail in order to provide flexibility to the manufacturers of different PET drugs. The regulation currently affects manufacture of PET agents requiring a marketing authorization: [¹⁸F]FDG, [¹⁸F]NaF, [¹⁸F]Fluciclovine, [¹³N]NH3, [¹¹C]choline, [⁶⁸Ga]DOTATATE, [¹⁸F]Florbetapir, [¹⁸F]Florbetaben and [¹⁸F]Flutemetamol. The regulation does specify that QC has to be performed for materials acceptance, in-process if applicable, and on the final drug product. It also requires that the QC methods be validated for accuracy, sensitivity, precision, and specificity.

Similar to manufacture of the kits that are subsequently radiolabelled in nuclear pharmacies, manufacture of FDA approved radiopharmaceuticals with relatively long half-lives (mostly radiotherapy pharmaceuticals such as [²²³Ra]Radium Chloride or[¹³¹I]Sodium Iodide) is governed by the FDA- issued United States Code of Federal Regulations [IV-28]. Usually, a central manufacturing facility makes a large batch of radiopharmaceuticals, and distributes smaller sub-batches to local nuclear pharmacies. Patient unit dose preparation and dispensing are then performed under the practice of nuclear pharmacy compounding.). Usually, a central manufacturing facility makes a large batch of radiopharmaceuticals, and distributes smaller sub-batches to local nuclear pharmacies. Patient unit dose preparation and dispensing are then performed under the practice of nuclear pharmacy compounding.

(c) Radiopharmaceuticals with marketing authorization

The manufacture of radiopharmaceuticals produced for clinical trial investigations is governed by the FDA regulation titled ‘21 CFR 312 Investigational New Drug Application’. The regulation requires investigators to perform studies to gather enough data in order to reasonably estimate the expected agent safety and behaviour in human subjects, as well as to establish agent manufacturing controls that allow the investigators to reliably produce the investigational agent of acceptable quality. The obtained data is then compiled into a document called the Investigational New Drug Application, or IND. The IND application is submitted to the FDA for a 30-day review period. During the 30-day review period, FDA and the investigators communicate in order to address any deficiencies or concerns related to the IND application. If no major deficiencies exist at the end of the 30-day review period, the FDA allows the investigators to proceed with the clinical trial. If deficiencies or concerns from the FDA do exist at the end of the 30-day review period, the FDA may put the application on hold until the concerns are addressed by the investigators.

The exact QC requirements for new investigational agents are intentionally not clearly defined in the regulations. Instead, the QC testing commitments, as well as the drug acceptance criteria,

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are described in the section of the IND application called ‘Chemistry, Manufacturing, and Controls’, or CMC. The QC control testing proposed by the subject-matter experts in the CMC is based on the preclinical and agent manufacturing development data. The FDA reviews the proposal during the review period. The final QC testing is based on the consensus between the investigators and the regulatory agency. This mechanism offers many advantages, main one being the flexibility that allows QC testing to be made specific to a specific agent.

Investigational radiopharmaceuticals come in many different forms: different radionuclides, different carrier molecules, different formulation, different stability profiles, and different routes of administration. Due to this variability, each investigational agent may require a different set of QC tests. Ability to establish agent specific QC testing requirements addresses this challenge. Furthermore, QC specifications and the analytical methods that are initially set during first-in-human investigations may change as additional drug manufacturing data is obtained and the agent is better characterized. Relying on the CMC mechanism, these changes can be easily implemented via submission of a CMC amendment to the FDA.

IV-2.1.3. Quality control frequency, tests and the qualified person

Every batch of radiopharmaceutical manufactured for human use must undergo radiopharmaceutical QC testing specific to the drug. Even though QC testing varies depending on the radiopharmaceutical being tested, in general, tests such as radiochemical purity and identity, chemical impurities (i.e. residual solvents and K-222), radionuclidic identity, endotoxin content, visual inspection, pH, bubble point, and radioactivity measurement should be performed. Sterility testing is preformed post release, and must be performed on every batch.

Periodically additional QC testing in the form of radionuclidic purity determination (i.e. trace radionuclide analysis gamma spectroscopy) and osmolality determination may be performed.

Specific activity determination (applicable mostly to agents used for neurology applications) may also need to be determined, but only if the agent localization kinetics may be affected by the specific activity. Lastly, radiolabelled antibody immunoreactivity determination is performed to make sure that the antibody has not lost its ability to bind to the antigen due to modification process (i.e. conjugation and subsequent radionuclide incorporation).

The role of the person responsible for quality (also known as a qualified person in the EU) varies depending on the type of the radiopharmaceutical being produced and the manufacturing facility setting. Also, unlike some European countries where professional training such as being a pharmacist is a requirement to become a QP, there are no defined professional training requirements that exist in the US. Rather, the focus is made on responsible person’s training and expertise in the area. In nuclear pharmacies, pharmacists are normally responsible for the quality assurance of the radiopharmaceuticals being produced. In PET drug producing facilities, trained radiopharmacists are also normally responsible for manufacturing quality assurance. In non-PET radiopharmaceutical manufacturing facilities, a radiochemist, a medical physicist, or a radiopharmacist usually functions as a QA responsible person.

A special consideration should be made with regards to training qualified persons involved in quality assurance of agents used in clinical trials, especially in the first-in-human trials. Agents manufactured for routine clinical normally used have established standards which are based on a large amount of collected manufacturing data. The role of the qualified person in this case is to assure adherence to these established standards. Investigational agents, on the other hand,

113 may not have these standards due to lack of sufficient supporting data as well as the unique nature of these new agents. The responsibilities of qualified persons, in this case, are expanded to include analytical method development and to establish new agent acceptance specifications.

The amount and the type of QC testing should be sufficient to reasonably demonstrate that the quality of the manufactured agent will not cause unnecessary harm to the patient and will allow for accurate evaluation of the investigational agent. Deciding on how much QC testing is sufficient is a critical function for a qualified person involved in investigational agent manufacture. On one hand, insufficient QC may increase the risk of patient harm or negatively affect the accuracy of estimating agent’s efficacy. On the other hand, performing redundant QC testing that is not supported by sound scientific evidence available at the time will require unnecessary additional time and resources, which may make the entire investigation cost prohibitive. The resources may not be available due to limited funding as well as the unwillingness of the investigators to financially invest into agents that statistically have low chance of progressing from clinical trials to marketing authorization. Therefore, qualified persons must be a subject matter expert and must work very closely with the clinicians, researchers, and the regulatory agency experts in order to make an appropriate decision.