**6. Scientific guidelines**

As is stated in the EMA website [8] "*The European Medicines Agency's Committee for Medicinal Products for Human Use prepares scientific guidelines in consultation with regulatory authorities in the European Union (EU) Member States, to help applicants prepare marketing authorisation applications for human medicines. Guidelines reflect a harmonised approach of the EU Member States and the Agency on how to interpret and apply the requirements for the demonstration of quality, safety and efficacy set out in the Community directives".*

These guidelines are complementary to European Pharmacopoeia monographs and chapters, since as detailed in the directive 2001/83 EC (annex I) [6] with respect to the quality part (chemical, pharmaceutical and biological) of the dossier, all monographs including general monographs and general chapters of the European Pharmacopoeia are applicable.

The catalogue of guidelines is categorised according to the Common Technical Document (CTD) [15] when they concern general issues and include the guidelines that are globally harmonised through the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

The Guideline on Radiopharmaceuticals [16] issued by EMA Committee for human medicinal products provides information about specific requirements for radiopharmaceuticals in applications for both marketing and clinical trial authorisations.

Altogether, regulatory authorities and industry prepared ICH scientific guidelines as shown in **Table 2**.

However, CHMP scientific guidelines are just issued by the European Medicines Agency's Committee for Medicinal Products for Human Use.

In addition to the application of the mentioned guidelines, the manufacturing process shall comply with the requirements of Commission Directive 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively laying down the principles and guidelines of Good Manufacturing Practice (GMP) for medicinal products for human use and with the principles and guidelines on GMP, published by the commission in the rules governing medicinal products in the European Community, Volume 4 [17]. In particular, the EU GMP annex 3 [11] specifically addresses some of the practices, which may be specific for radiopharmaceuticals.

Furthermore, there are also other guidelines published whose main objective is to harmonise inspection procedures worldwide by developing common standards in the field of GMPs and by providing training opportunities to Inspectors. They are issued by The Pharmaceutical Inspection Co-operation Scheme (PIC/S) who is a non-binding, informal co-operative arrangement between Regulatory Authorities in the field of Good Manufacturing Practice (GMP) of medicinal products for human or veterinary use. Particularly, the annex 3 of PIC/S Guide to good practices for the preparation of medicinal products in healthcare establishments is devoted to Radiopharmaceuticals [10].

Similarly, EDQM has published in the European Pharmacopoeia, the monograph 5.19 Extemporaneous preparation of Radiopharmaceuticals [12]. Although this monograph is only for information, it covers guidance for preparing "kit-based preparations (from licensed and unlicensed kits) and unlicensed preparations containing radionuclides for positron emission tomography (PET), single photon emission computed tomography (SPECT) or for therapeutic applications".

In the USP several monographs can also be found regarding radiopharmaceuticals preparation, such as USP (825) [18] radiopharmaceuticals preparation, compounding, dispensing and repackaging or USP (823) [19] Positron emission tomography drugs for compounding, investigational, and research uses.

Besides, other "for information" guidelines can be mentioned. For instance, a guideline to achieve a good radiopharmacy practice for small-scale preparation was issued by The European Association of Nuclear Medicine (EANM) [20]. This is a professional non-profit medical association that facilitates communication worldwide among individuals pursuing clinical and research excellence in nuclear medicine.

In conclusion, many guidelines and guidance documents have been issued to foster good radiopharmacy practices for licensed or not licensed radiopharmaceuticals in both large and small-scale preparation.


**Table 2.**

*Summary of the parties involved in the ICH guidelines development.*

## **7. Radiopharmaceuticals preparation outside the marketing track in the European Union**

In the European Union (UE), the community code relating to medicinal products for human use is regulated by the Directive 2001/83/EC [6] as amended. This Directive has to be adopted by Member States. The rate and extent of adoption and interpretation of the Directive varies among countries. Each Member State may introduce changes, provided the general scope and limits of the directive is maintained.

In this way, several European Member States have set up a regulatory framework in which radiopharmaceuticals for routine use can be prepared on site without the requirements of a marketing authorization. These exemptions flow from the definitions in Article 3 of Directive 2001/83/EC [6], the so-called magistral and officinal formulae, and from Article 5(1) of Directive 2001/83/EC aimed to fulfil special needs.

The European Court of Justice. Document 62013CJ0544 and Judgement of the Court (Third Chamber) of 16 July 2015 has clarified both situations of Articles 3 and 5 [21].

Considering article 3, 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 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". It was also stated 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.

Similarly, by virtue of Article 5(1) of Directive 2001/83 [6], to fulfil special needs, exclude from the provisions of that directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised healthcare professional and for use by an individual patient under his direct personal responsibility. In that regard, the court has held that it is apparent from the conditions as a whole set out in that provision, read in the light of the fundamental objectives of that directive, and in particular the objective of seeking to safeguard public health, 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 (see, to that effect, judgement in Commission v Poland, C-185/10, EU:C:2012:181, paragraphs 29 and 36).

United Kingdom (UK) is the clear example of applying the exception of art 5(1) of the Directive 2001/83/EC [6], despite after Brexit is no longer part of the European Union (UE). The regulation 167 of the Human Medicines Regulations 2012 sets out the exemption from the requirement for a medicinal product, placed on the market in the UK to hold a marketing authorisation. Additionally, the Medicines and Healthcare Products Regulatory Agency (MHRA) issued the MHRA Guidance Note 14 called "The supply of unlicensed medicinal products ("specials") [22].

In some Member States (Austria, Belgium etc..) the preparation of PET radiopharmaceuticals could be considered, in many situations, as magistral formulas since they are prepared in accordance with a medical prescription for an individual *Quality in Non-Licensed Radiopharmaceutical Products: Are We Achieving the Goal? DOI: http://dx.doi.org/10.5772/intechopen.99388*

patient. The preparation of radiopharmaceuticals as magistral formulae is not covered under the Directive 2001/83/EC [6], therefore its legislation falls under the responsibility of each Member State.

In Germany, PET radiopharmaceuticals can be manufactured according to the requirements set in article 13(2b) of the Medicinal Products Act (Arzneimittelgesetz, AMG) where it is stated that "*a person who is a doctor or dentist or who is otherwise authorised to practise medicine on humans does not require a licence according to paragraph 1, insofar as the medicinal products are manufactured under his direct professional responsibility for the purpose of personal use on a specific patient*". However, it is important to note that the compliance with the Medicinal Products Act is controlled by the Federal States, coming along with the acceptance of varying practices by different state authorities. Hence, there is currently a lively discussion in the nuclear medicine community about minimum standards for this production, though the use of radiopharmaceuticals with marketing authorisation is preferential.

By contrast, in Spain, the preparation of radiopharmaceuticals cannot be considered as magistral formulae since they must be prepared with legally recognised action and indication substances as stated in Royal Legislative Decree RDL 1/2015. Therefore, the only way to prepare PET radiopharmaceuticals outside the marketing authorisation track would be under the regulatory framework of article 47.1c in Real Decree (RD) 1345/2007 on the marketing authorization procedure in medicines for human use [23]. This Decree completes the RDL 1/2015 [24], which is the transposition of Directive 2001/83/EC [6]. The article 47.1.c in the RD 1345/2007 [23] establishes the following criteria:

The marketing authorisation for PET radiopharmaceuticals will not be required, whenever they are prepared in an approved radiopharmaceutical unit under the supervision and control of a radiopharmaceutical specialist, provided that they meet the following requirements:


Beyond the lack of alignment regarding the definition of radiopharmaceuticals preparations analysed above, differences can also be found with respect to the requirements that manufacturers have to comply with in their preparation. The following examples depict this situation:


• In the rest of the Member States there are different degrees of compliance with Good Manufacturing Practices (GMPs). In some countries as Germany full adherence to GMPs is required, while in other countries such as Italy special or adapted GMPs are enforced. Finally, there are other countries where this compliance is not clearly specified.

Summarising, there are different ways to carry out the radiopharmaceuticals small scale preparation outside the marketing authorisation track, depending on the national legislation in each Member State. Hence, a cornerstone of the radiopharmaceutical's preparation might currently be the lack of harmonisation at European level, especially regarding the quality standards applicable to these preparations.

Nevertheless, leaving aside the lack of harmonisation among countries, special attention shall be drawn to the achievement of the highest standard quality radiopharmaceutical preparations. It is a fact that, as a rule, this goal is accomplished in the manufacturing processes for medicinal products by applying GMPs. For sure, these practices should consider the special nature of radiopharmaceuticals balancing aseptic handling with radiation protection. Besides, authorities should ensure that manufacturers in their territory are subject to routine GMP inspections.

In the field of clinical trial this goal is on its way thanks to the new Regulation 536/2014 [25] repealing the Directive 2001/20/EC. This regulation will achieve the harmonisation between Member States, through the creation of a uniform regulatory framework for the authorization of clinical trials. It is to be noted that European Regulations are not transposed by the European Members but directly applied. Therefore, European Member States shall be compliant with this regulation.

The Regulation 536/2014 [25], in the case of radiopharmaceuticals used in clinical trials stablishes differences between therapeutic and diagnostic radiopharmaceuticals. While therapeutic radiopharmaceuticals are considered as any other medicinal product used in a Clinical Trial, regarding diagnostic radiopharmaceuticals substantial changes are introduced by the following article (Art. 61.5.b of Regulation 536/2014):

*"preparation of radiopharmaceuticals used as diagnostic investigational medicinal products where this process is carried out in hospitals, health centers or clinics, by pharmacists or other persons legally authorized 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 centers or clinics taking part in the same clinical trial in the same Member State".*

Based on the analysis of this article in conjunction with other relevant ones of this regulation it is observed that:


*Quality in Non-Licensed Radiopharmaceutical Products: Are We Achieving the Goal? DOI: http://dx.doi.org/10.5772/intechopen.99388*

*"Member States shall make the processes set out in paragraph 5 subject to appropriate and proportionate requirements to ensure subject safety and reliability and robustness of the data generated in the clinical trial. They shall subject the processes to regular inspections."*

3.Simplified labelling of diagnostic radiopharmaceuticals used as investigational medicinal products (IMPs) and auxiliary medicinal products (AMPs)

It should be noted that this exception for diagnostic radiopharmaceutical is only in the context of a clinical trial where the number of patients and the length of study is limited. Moreover, art 61.6 of Regulation 536/2014 leaves open the possibility for each Member State of having regular inspections with their specific requirements.

This situation shall be seen as totally different from the small-scale radiopharmaceutical preparation on a routine basis, where bypassing the compliance with good manufacturing practices affecting the quality of the radiopharmaceuticals could have an impact on a much larger number of patients in the day-to-day usage.

## **8. Starting materials for the PET radiopharmaceuticals preparations**

The definition of a starting material is depicted in part II of Good Manicuring Practices (GMPs) [28] as shown in the extract below:

*"An Active Substance Starting Material is a raw material, intermediate, or an active substance that is used in the production of an active substance and that is incorporated as a significant structural fragment into the structure of the active substance. An Active Substance Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement or produced in-house. Active Substance Starting Materials normally have defined chemical properties and structure".*

In case of the PET Radiopharmaceutical preparations, the main starting material is the chemical precursor whose definition is stated in the European Pharmacopoeia monograph 2902 named Chemical Precursors for Radiopharmaceuticals Preparations [29] as follows:

*"Chemical precursors are non-radioactive substances obtained by chemical synthesis for combination with a radionuclide".*

In this monograph a risk assessment is requested whenever the radiopharmaceutical preparation is required for special needs of individual patients, provided that non individual monograph for the precursor is available. Likewise, differences between diagnostic use versus therapeutic use as well as the frequency of use shall be taken into account for the risk assessment. These indications are fully described in the paragraph below extracted from monograph 2902:

*"Where a chemical precursor not described in an individual monograph of the European Pharmacopoeia is used in a radiopharmaceutical preparation prepared for the special needs of individual patients, the need for compliance with this general monograph is decided in the light of a risk assessment.*

*This risk assessment takes account of:*


The quality of the chemical precursors is critical to ensure the final quality of the radiopharmaceutical product. These precursors are used in radiolabelling reactions for the preparation of the radioactive pharmaceutical ingredients (APIs) that are not isolated and/or fully analysed before incorporation in the final radiopharmaceutical preparation. For this reason, according to the Guideline on Radiopharmaceuticals [16] they should satisfy the Note for Guidance on Summary of Requirements for Active Substances in Part II of the Dossier [30].

It is relevant to remark that during the radiopharmaceutical quality dossier preparation to be submitted to the relevant authorities, the information on chemical precursors including those for synthesis of PET radiopharmaceuticals may be presented in a separate Section 3.2.S following the requirements of the Common Technical Document (CTD). This is stated in the European Commission Document Volume 2B Notice to Applicants Medicinal products for human use [15]. This approach must be followed for both marketing authorisation (MAA) and clinical trial authorization (CTA) applications.

In particular, the module 3 of the CTD covers chemical and pharmaceutical data including data for biological/ biotechnological products. This module has two parts: drug substance and drug product part. In the case of the chemical precursor of the radiopharmaceutical preparation, it should comply with the drug substance requirements section.

The Guideline on Radiopharmaceuticals [16] describes the specific additional information that needs to be submitted in relation to radiopharmaceuticals, when preparing the radiopharmaceutical quality dossier. The following sections included in **Table 3** should be completed:

The information depicted in **Table 3** can be submitted by the applicant to the regulatory authorities following two different procedures:


*"Where the active substance and/or a raw and starting material or excipient(s) are the subject of a monograph of the European Pharmacopoeia, the applicant can apply for a certificate of suitability that, where granted by the European Directorate for the Quality of Medicines, shall be presented in the relevant section of this Module. Those certificates of suitability of the monograph of the European Pharmacopoeia are deemed to replace the relevant data of the corresponding sections described in this Module. The manufacturer shall give the assurance in writing to the applicant that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of Medicines."*

On the contrary, if the applicant did not want to use either of the two previous procedures, all sections could be submitted directly to the regulatory authorities.

*Quality in Non-Licensed Radiopharmaceutical Products: Are We Achieving the Goal? DOI: http://dx.doi.org/10.5772/intechopen.99388*


#### **Table 3.**

*Module 3 of common technical document (CTD) drug substance part.*

These requirements are mandatory for both clinical trial and marketing authorisation applications, however they should also be compulsory for radiopharmaceuticals prepared outside the marketing authorisation track, regardless of the category to which they belong (magistral formula, special product, etc...). A clear example where this information is required is Spain. Hence, to prepare PET radiopharmaceutical outside the marketing authorisation track under the regulatory framework of article 47.1c in RD 1345/2007 [23], it is always necessary to submit the previously mentioned module 3 of CTD to the regulatory authority (AEMPS). In this way, the quality of the preparation in both chemical precursor and final radiopharmaceutical would be ensured.

It is noteworthy that, as a general rule, the information provided by the chemical precursor manufacturers is very limited. It is usually only submitted the chemical precursor structure, the specification, and some batch results. Obviously, this information should not be considered as sufficient to guaranty the quality of the final product.

Regarding the stability studies, stress testing of the chemical precursor must be performed to identify the likely degradation products, as well as to complete

stability studies to cover storage, shipment, and subsequent use, according to ICH Q 1 A (R2) Stability Testing of new Drug Substances and Products [33]. However, the chemical precursor manufacturer is not obliged to stablish a retest period, but in case no retest period is defined, a statement should be included that the precursor is tested immediately before the drug product manufacture. In case retest period had not been proposed, the radiopharmacy unit would test the chemical precursor before its use. The details on the retest period information should be considered by the drug product manufacturer, in the case under analyse, the radiopharmacy unit.

A relevant problem is that, in most cases, radiopharmacy units are not aware of this fact and even when they knew it, they would not be equipped for performing such tests.

Regarding compliance of GMPs, according to Good Manufacturing Practices Part II: Basic Requirements for Active Substances used as Starting Material [28] the following requirements should be complied:


Considering that radiopharmacy units are not usually equipped to fulfil these requirements, the requested tests could be outsourced following the requirements of GMP Chapter 7 Outsourced Activities [34].

Hence, there should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials. Additionally, for all starting materials and critical components, only qualified vendors should be used. Vendor qualification can be established by an audit, by responses to a Quality Assurance questionnaire, or simply based on experience with this supplier (e.g., the hospital pharmacy). In any case, vendor qualification should always be documented.

As we can see, special attention should be devoted to the purity and control methods for all starting materials, reactants, chemicals, reagents, and solvents used in synthesis and purification regardless they are licensed or unlicensed radiopharmaceuticals. Furthermore, it should be stressed that radiopharmaceuticals containing radionuclides of short physical half-life (e.g., PET radiopharmaceuticals), can be released before all results on finished product testing are available, therefore the consistency of all the steps in the production process has a crucial importance.

#### **9. Conclusion**

This text aimed to provide an overview on the radiopharmaceutical preparations in the European Union, focusing on the main differences between national laws regarding the non-licensed small-scale preparations, while analysing whether the quality expectations on them are really achieved or not. It went through a recap of the alternative methods to control sterility in radiopharmaceuticals, types of radiopharmaceutical marketing authorisations, differences between preparation and manufacturing of radiopharmaceuticals, available guidelines related to the

#### *Quality in Non-Licensed Radiopharmaceutical Products: Are We Achieving the Goal? DOI: http://dx.doi.org/10.5772/intechopen.99388*

quality in radiopharmaceuticals field, radiopharmaceuticals preparation outside the marketing track in the European Union and starting materials quality requirements for PET Radiopharmaceuticals preparations.

The intention was to raise some of the hot topics in the scientific community around the radiopharmaceutical compounds, considered a special group of medicines, that can be prepared outside the marketing authorisation track. In particular, small-scale preparations at non-commercial sites which represent an important segment, despite a lack of harmonisation in the regulation leads to extreme differences in the application and availability of radiopharmaceuticals across Europe.

It is noteworthy, that most radiopharmaceutical preparations are sterile injectable products. As developed along the text, the existing regulation on the manufacture of sterile medicines, shall imply the need of a harmonisation in the European Union regarding the requirements applicable in the small-scale preparation of radiopharmaceuticals, which are currently considered not clear enough. A possible way forward might be the compliance with Good Manufacturing Practices (GMPs) properly adapted to the special nature of small-scale preparation of radiopharmaceuticals.

Moreover, special attention should be put on the quality assurance process for non-licensed starting materials, given that the final radiopharmaceuticals quality chiefly depends on it.

To sum up, the radiopharmacists community should try to achieve a proven quality, efficacy, and safety for our radiopharmaceuticals, regardless if they are licensed or unlicensed products, both in large or small-scale preparations.

