**3. Radiopharmaceutical's dosage forms. Alternative methods to control sterility in radiopharmaceuticals**

Radiopharmaceuticals are medicinal products on prescription that can be delivered orally (in pill form), intravenously (injected into a patient's vein) or interstitially (inserted into a cavity in the body). The intravenous route of administration is the most used in Radiopharmaceuticals application. According to the European Pharmacopoeia monograph regarding Radiopharmaceutical preparations (01625) [2], these products must be sterile as stated in the following extract.

"*Radiopharmaceutical preparations for parenteral administration comply with the test for sterility. They must be prepared using precautions designed to exclude microbial contamination and to ensure sterility. The test for sterility is carried out as described in the general method (2.6.1)."* [3].

Moreover, the pharmacopoeia also considers the specific nature of radiopharmaceuticals, as specified in this other extract.

*"Special difficulties arise with radiopharmaceutical preparations because of the short half-life of some radionuclides, the small size of batches and the radiation hazards. In the case that the monograph states that the preparation can be released for use before completion of the test for sterility, the sterility test must be started as soon as practically possible in relation to the radiation."*

With the conventional sterility method (2.6.1) [3] the portions of the media should be incubated for 14 days. Though the test must be started as soon as practically possible in relation to the radiation, it will take several days to achieve a safe level of exposure. This means that sterility testing results would be available around three weeks after the radiopharmaceutical preparation. Consequently, the outcomes of the tests when following this method seldom enable proactive corrective actions to be taken in case a lack of sterility is detected.

Alternative methods for control of microbiological quality have been described in European Pharmacopoeia (5.1.6) [4]. They have shown potential for real-time o near real-time results with the possibility of earlier corrective action. Although this pharmacopoeia chapter is published for information, these new methods, if validated and adapted for routine use can also offer significant improvements in the quality of testing.

Similarly, USP has another monograph (1071) [5] where the following extract can be found.

*"Rapid microbial tests for release of sterile short-life products: a risk-based approach".*

In this chapter, positron emission tomographic (PET) products are mentioned as an example where these rapid methods could be applied.

*"It is widely recognized that the current growth-based sterility tests with an incubation period of at least 14 days are not suitable for products with a short shelf-life or for products prepared for immediate use, which are usually infused into patients before the completion of the test (1). These short-life products include compounded sterile preparations (CSPs),* **positron emission tomographic (PET) products***, and cell and gene therapies, which require a new generation of risk-based approaches that include rapid microbial tests".*

The information provided in these pharmacopoeia chapters may be used as a supplement or as an alternative microbiological method and to give guidance on validation of the chosen method. It is neither the intention to recommend one method over another, nor to provide an exclusive list of alternative methods that can be used.

#### **Rapid microbial tests described in USP (1071)**


**Alternative methods for control of microbiological quality described in Ph. Eur 5.16** There are 3 major types of determination specific to microbiological tests:

#### **1. Qualitative tests for the presence or absence of micro-organisms**:


#### **2. Quantitative tests for enumeration of micro-organisms:**


#### **3. Identification tests**

• Biochemical and morphological characterisation

#### **Table 1.**

*List with alternative methods of microbiological quality described in pharmacopoeia European and USP.*

In both chapters, European Pharmacopoeia (5.1.6) [4] and USP monograph (1071) [5], it is stated that risk analysis tools may be used to determine which alternative method is to be implemented as well as to balance user requirement specification including time to result, specificity, limit of detection (LOD), sample size, and product attributes. The microbiological alternative methods proposed in European Pharmacopoeia and USP are described in **Table 1**.

#### **4. Types of radiopharmaceutical marketing authorisations**

Licensed radiopharmaceuticals manufactured under GMP requirements.

In the European Union, radiopharmaceutical compounds are considered a special group of medicines. Their manufacturing/preparing and uses are regulated by directives and regulations that must be adopted by Member States. (Directive 2001/83/EC [6] and Regulation (EC) No 726/2004 [7]).

For a radiopharmaceutical to be available on the market, sold and marketed, it needs to have a marketing authorisation. The marketing authorisation application must provide evidence of the efficacy, safety, and quality of the radiopharmaceutical. When applying for a marketing authorisation for a radiopharmaceutical, the marketing authorisation application is submitted to a regulatory authority, which will assess the medicinal product's pharmaceutical and chemical quality, efficacy, and safety, as well as its risk–benefit ratio.

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

In the EU, there are four types of marketing authorisation application procedures. These procedures can be found in European Medicines Agency (EMA) website [8] in its section devoted to medicine for human use marketing authorisations:

