Are we "preparing" radiopharmaceuticals?,EJNMMI Radiopharmacy and Chemistry

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Are we "preparing" radiopharmaceuticals?
EJNMMI Radiopharmacy and Chemistry Pub Date : 2016-07-22 , DOI: 10.1186/s41181-016-0011-7
Clemens Decristoforo _{1,

2} , Marianne Patt ₃

Affiliation

Today drugs are almost exclusively manufactured industrially. This has been driven by cost savings, but also by a public mandate of high quality and especially standardization, that is difficult to maintain in a non-industrial setting. On the other hand the same public asks for “personalized”or “precision medicine”(Reza Mirnezami et al. 2012) precisely tailored to each patient’s requirements. The more personalized medicines becomes, the less effective a large industrial production can be. In such a situation, not only drug manufacturers have to adopt their strategies, but also the regulatory framework, in which medicine is embedded and drugs are produced, has to implement these trends. That also holds true for radiopharmaceuticals (Lange et al. 2015).

Stimulated by activities especially of the EANM and its Radiopharmacy Committee, which drafted a number of guidelines and guidance documents (e.g. (Elsinga et al. 2010; Aerts et al. 2014)), recently PIC/S has released specific guidelines for radiopharmaceuticals prepared in healthcare establishments (Pharmaceutical Inspection Co-operation Scheme. Document PE 010–4 and Annex 3: Good practices for the preparation of radiopharmaceuticals in healthcare establishments 2014) and the EDQM has published a chapter on the “Extemporaneous Preparation of Radiopharmaceuticals” (Extemporaneous preparation of radiopharmaceutical preparations. Chapter 5.19). In these documents a clear distinction is made between industrial and small scale extemporaneous preparation of radiopharmaceuticals, providing guidance on “Good Practices” distinct from industrial standards.

The European Parliament and the European Commission now recently have issued a legal act that regulates the requirements for clinical trials within the European Union (EU regulation No 536/2014). The overall purpose of this regulation was to facilitate and harmonise clinical research in the member states and therefore the regulation has very clearly exempted the preparation of radiopharmaceuticals from the requirements of GMP (Decristoforo et al. 2014) if it “is carried out in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member State concerned to carry out such process, and if the investigational medicinal products are intended to be used exclusively in hospitals, health centres or clinics taking part in the same clinical trial in the same Member State”, thereby specifying the framework in which it should be applied, not being intended for radiopharmaceuticals manufactured industrially and being distributed. In a similar way a number of European member states have set up a regulatory framework in which radiopharmaceuticals for routine use (i.e. not for clinical trials) can be prepared on site without the requirements of a marketing authorisation. These exemptions can be derived from the definitions in Article 3 of Directive 2001/83 (The European Parliament and the Council of the European Union 2001), the so called magistral and officinal formulae.

In this context it should be considered that the European Court of justice has recently clarified the situation for “magistral formulae” defined as “any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient” (The European Court of Justice. Document 62013CJ0544 and Judgment of the Court (Third Chamber) of 16 July 2015). The European Court of Justice specified that “[such a preparation] must of necessity be prepared on the basis of a prior prescription issued by a professional person qualified to do so”. This prescription must, in addition “be ‘for an individual patient’” and “that patient must be identified before the medicinal product is produced and it must be produced specifically for that patient”. In a simpler wording such preparations have to be “extemporaneously”. It was also stated that “that the exception provided for in that provision can only concern situations in which the doctor considers that the state of health of his individual patients requires that a medicinal product be administered for which there is no authorised equivalent on the national market or which is unavailable on that market”, clearly excluding competition with licensed medicinal products. Also specifically excluded in this ruling were preparations “on the basis of the needs known in advance, to be used in emergency departments and, in any event, on the basis of orders placed before a specified patient had been identified” and “Preparations prepared and delivered to non-hospital pharmacies, on the basis of a ‘subscription’, even if an ‘initial medical prescription’ was drawn up for each specific patient”. The Court ruled that the aforementioned preparations were not “magistral” but medicinal products “prepared industrially or manufactured by a method involving an industrial process….. Such a process is characterised in general by a succession of operations, which may, in particular, be mechanical or chemical, in order to obtain a significant quantity of a standardised product.”

Translated to the preparation of PET radiopharmaceuticals it could be derived from this ruling, that PET preparations can be considered in many situations as being “magistral”. Typically a type of prescriptions by the physician referring an individual patient to Nuclear Medicine is provided, for whom the PET radiopharmaceutical is prepared, possibly with the exemption of FDG production in large departments where the preparation is made without necessarily always knowing the individual patient, and especially if it is shipped to different sites. However in this context also “officinal preparations” could be considered, in case a monograph for the radiopharmaceutical is available (which today is the case for most routinely used PET radiopharmaceuticals).

At the bottom line the discussion focusses on the question, are we “preparing” or “manufacturing” radiopharmaceuticals. If they are (extemporaneously, on a small scale, locally) prepared, exemptions as stated above may apply, whereas in they are (industrially) manufactured, the framework of GMP implemented within a manufacturing authorisation should be applied. The European Pharmacopeia (Ph. Eur.) as a legal basis for almost all European countries have tried to clarify what they see as “preparation”, in the monograph on “Pharmaceutical Preparations” (Pharmaceutical preparations. Monograph N° 2619) the following definition can be found: “the ‘manufacture’ of unlicensed pharmaceutical preparations in pharmacies or other healthcare establishments (the term ‘preparation’ is used instead of ‘manufacture’ in order clearly to distinguish it from the industrial manufacture of licensed pharmaceutical preparations)”. Even more specifically the term radiopharmaceutical preparation is used in the General text 5.19 of the Ph. Eur. and explicitly includes kit-based preparations as well as unlicensed preparations for PET and SPECT.

Applying this definition to radiopharmaceuticals underlines the clear distinction between the industrial manufacturing in a framework of “licensing” i.e. marketing authorisation or clinical trials aiming at a marketing authorisation versus the local, extemporaneous preparation of radiopharmaceuticals being it for patient diagnosis or within the framework of a local clinical trial.

Discussions with regulatory bodies should try to stress this point, giving the Nuclear Medicine community the possibility to provide required (novel or established) radiopharmaceuticals for patients needs and to bring the speciality forward towards the times of personalized medicine, tailor-made for patients need that deserve the best medicines, being radioactive or not.

26 November 2018
The metadata in the HTML format of these original articles (Eppard et al., 2017; Decristoforo & Patt, 2017; Domnanich et al., 2017; Chan et al., 2017; Jovalekic et al., 2017; Zhang & Villalobos, 2017; Meckel et al., 2017; Li et al., 2017; Colin et al., 2017; Koziorowski et al., 2017; Ooms et al., 2017; Elsinga, 2017; Seemann et al., 2017; Müller et al., 2017; Luurtsema et al., 2017) were published with an incorrect cover date. The correct cover date is December 2016. This does not alter the text of the original articles.

Aerts J, Ballinger JR, Behe M, Decristoforo C, Elsinga PH, Faivre-Chauvet A, et al. Guidance on current good radiopharmacy practice for the small-scale preparation of radiopharmaceuticals using automated modules: a European perspective. J Labelled Comp Radiopharm. 2014;57(10):615–20. doi:10.1002/jlcr.3227.
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Affiliations

Department of Nuclear Medicine, Medical University Innsbruck, Innsbruck, Austria
Clemens Decristoforo
Klinik und Poliklinik für Nuklearmedizin, University of Leipzig, Leipzig, Germany
Marianne Patt
Universitätsklinik für Nuklearmedizin, Medizinische Universität Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria
Clemens Decristoforo

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Corresponding author

Correspondence to Clemens Decristoforo.

EANM: European Association of Nuclear Medicine
EDQM: European Directorate for the Quality of Medicines & HealthCare
Extemporaneous: individually (prepared) for a specific patient or patient group, supplied after preparation (from European Pharmacopoeia: Pharmaceutical Preparation)
GMP: Good Manufacturing Practice
Kit: Any preparation to be reconstituted or combined with radionuclides in the final radiopharmaceutical, usually prior to its administration.
Magistral: prepared in a pharmacy in accordance with a medical prescription for an individual patient
Manufacture: larger scale commercial/industrial production; all operations of purchase of material and products, Production, Quality Control, release, storage, distribution of medicinal products and the related control (from European Pharmacopoeia: Pharmaceutical Preparations)
Officinal: prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia and intended to be supplied directly to the patients served by the pharmacy in question
Parenteral: sterile preparations intended for administration by injection, infusion or implantation into the human or animal body
PET: Positron Emission Tomography
PIC/S: Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme
Preparation: small scale non-industrial production; the ‘manufacture’ of unlicensed pharmaceutical preparations in pharmacies or other healthcare establishments (from European Pharmacopoeia: Pharmaceutical Preparation)
Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Decristoforo, C., Patt, M. Are we “preparing” radiopharmaceuticals?. EJNMMI radiopharm. chem. 1, 12 (2017). https://doi.org/10.1186/s41181-016-0011-7

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Received: 31 March 2016
Accepted: 31 March 2016
Published: 22 July 2016
DOI: https://doi.org/10.1186/s41181-016-0011-7

中文翻译：

我们是在“准备”放射性药物吗？

如今，毒品几乎都是工业制造的。这是由节省成本，也是由高质量，特别是标准化的公共指令驱动的，这在非工业环境中很难维持。另一方面，同一位公众则要求精确地根据每个患者的需求量身定制的“个性化”或“精密药物”（Reza Mirnezami等，2012）。个性化药物变得越多，大型工业生产的效果就越差。在这种情况下，不仅药品制造商必须采取其策略，而且嵌入药品和生产药品的监管框架也必须实现这些趋势。放射性药物也是如此（Lange等，2015）。

受到EANM及其放射性药物委员会的活动的刺激，该委员会起草了许多指南和指南文件（例如（Elsinga等，2010； Aerts等，2014）），最近PIC / S发布了针对在医疗机构（《药品检验合作计划》。文件PE 010-4和附件3：《医疗机构中放射性药物制备的良好做法2014》）和EDQM发表了“放射性药物的临时制备”一章（药物的临时制备）。放射性药物制剂，第5.19章）。在这些文件中，对放射性药物的工业临时制备和小规模临时制备之间有明显的区别，提供了与工业标准不同的“良好实践”指南。

欧洲议会和欧洲委员会最近已发布了一项法律法案，规范了欧盟内部临床试验的要求（EU法规536/2014）。该法规的总体目的是促进和协调成员国的临床研究，因此该法规非常明确地将放射性药物的制备从GMP的要求中排除了（Decristoforo等，2014）。）（如果“是在医院，保健中心或诊所进行的，则是由有关会员国的合法授权的药剂师或其他人进行的，并且如果研究用药品专门用于医院，保健中心，或在同一成员国参加同一临床试验的诊所”，从而规定了应将其应用的框架，而不是打算用于工业化生产和分销的放射性药物。以类似的方式，许多欧洲成员国已经建立了监管框架，可以在不经市场许可的情况下现场准备常规使用（即非临床试验）的放射性药物。2001年），所谓的裁判法院和官方公式。

在这种情况下，应该考虑到欧洲法院最近澄清了“裁判官配方”的定义，“裁判官配方”定义为“在药房中根据个别患者的医疗处方制备的任何药品”（欧洲法院。62013CJ0544号文件和2015年7月16日的法院判决（第三庭））。欧洲法院规定：“ [这种准备]必须根据有资格的专业人员的事先处方来准备”。此外，该处方还必须“针对'个体患者'”和“必须在生产药品之前识别该患者，并且必须专门为该患者生产”。用一种简单的措词，这种准备必须是“即兴的”。还指出，“该规定中的例外情况仅适用于以下情况，即医生认为其个别患者的健康状况要求服用一种在国家市场上没有经过授权的等效产品的药物或在该市场上不可用”，显然不包括与许可药品竞争。该规定中还特别排除了“根据事先已知的需求，准备在急诊室使用的制剂，无论如何，根据在确定特定患者之前下达的命令”和“准备和准备的制剂”。即使为每位特定患者制定了“初始医疗处方”，也要根据“订阅”将其交付给非医院药房。” 法院裁定，上述制剂不是“治安官”，而是“以工业方式制备或通过涉及工业过程的方法制造的药品……。”这种过程的特征通常是一系列连续的操作，特别是可能需要机械的或化学的

从这项裁定可以得出，将PET制剂在很多情况下都视为“重要”，这可以推论为PET放射性药物的制剂。通常，会提供由医师指导个人患者进行核医学的某种处方，为其准备PET放射性药物，并且可能在大型部门中免除FDG的生产，而该部门在进行制备时不一定总是了解个人患者，并且特别是如果将其运送到其他地点。但是，在这种情况下，如果有放射性药物专论的话（今天大多数常规使用的PET放射性药物就是这种情况），也可以考虑“药用制剂”。

最重要的是，讨论集中在这个问题上，我们是“准备”还是“制造”放射性药物。如果它们是（临时地，在本地，小规模地）准备的，则上述豁免可能适用，而在（工业）制造时，则应采用制造许可内实施的GMP框架。欧洲药典（Ph。Eur。）是几乎所有欧洲国家的法律依据，试图在“药物制剂”专着（药物制剂，专着，编号2619）中澄清他们所认为的“制剂”。），可以找到以下定义：药房或其他医疗机构中无牌药物制剂的“制造”（用术语“制剂”代替“制造”，以便将其与许可药品的工业生产区分开来）”。甚至更具体地，在Eur的通用文献5.19中使用术语放射性药物制剂。并且明确包括基于试剂盒的制剂以及PET和SPECT的无证制剂。

将这一定义应用于放射性药物强调了“许可”框架下工业制造的明显区别，即“销售许可”或针对销售许可的临床试验与用于患者诊断或在患者诊断框架内的放射性药物的本地临时制备之间的明显区别。本地临床试验。

与监管机构的讨论应设法强调这一点，使核医学界有可能提供满足患者需求的（新的或成熟的）放射性药物，并使该专业朝着个性化医学的时代发展，为患者量身定制最好的药物，无论是否具有放射性。

2018年11月26日
这些原始文章的HTML格式的元数据（Eppard等人，2017; Decristoforo和Patt，2017; Domnanich等人，2017; Chan等人，2017; Jovalekic等人，2017; Zhang和Villalobos，2017 ; Meckel等人，2017; Li等人，2017; Colin等人，2017; Koziorowski等人，2017; Ooms等人，2017; Elsinga，2017; Seemann等人，2017;Müller等人（2017年； Luurtsema等人，2017年）的发布日期有误。正确的封面日期是2016年12月。这不会更改原始文章的文字。

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