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GUIDELINES

Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals

Philip Elsinga&Sergio Todde&Ivan Penuelas&

Geerd Meyer&Brit Farstad&Alain Faivre-Chauvet&

Renata Mikolajczak&Gerrit Westera&

Tanja Gmeiner-Stopar&Clemens Decristoforo&

The Radiopharmacy Committee of the EANM

#The Author(s) 2010. This article is published with open access at Springerlink.comAbstractThis guidance is meant as a guidance to Part B of

the EANM"Guidelines on Good Radiopharmacy Practice (GRPP)"issued by the Radiopharmacy Committee of the EANM (seewww.eanm.org), covering the small-scale"in house"preparation of radiopharmaceuticals which are not kit procedures. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of, for example, PET, therapeutic or other radiopharmaceuticals which are not intended for commercial purposes or distribution. This guideline summarizes the views of the Radiopharmacy Committee beheldresponsible.The recommendationsshould be taken in the context of good practice of nuclear medicine and do not substitute for national reviewed by the EANM Dosimetry Committee and the Drug Development Committee . The guidelines have been brought to the attention of the National Societies of Nuclear Medicine.P. Elsinga

Nuclear Medicine and Molecular Imaging,

University Medical Center Groningen,

Groningen, The Netherlands

S. Todde

Centro di Bioimmagini Molecolari,

University of Milano-Bicocca,

Monza, Italy

I. Penuelas

Radiopharmacy Unit, Nuclear Medicine Department,

Clinica Universitaria de Navara,

Pamplona, Spain

G. Meyer

Medizinische Hochschule Hannover, Klinik für Nuclear Medizin,

Hannover, Germany

B. Farstad

Isotope Laboratories, Institute for Energy Technology,

Kjeller, Norway

A. Faivre-Chauvet

Departement de Recherche en Cancerologie, INSERM,

Universitè de Nantes,

Nantes, France

R. Mikolajczak

Research and Development, Radioisotope Centre Polatom,

Otwock, PolandG. Westera

Nuclear Medicine Department, University Hospital Zurich,

Zurich, Switzerland

T. Gmeiner-Stopar

Department of Nuclear Medicine Radiopharmacy and Clinical Biochemistry, University Medical Centre Ljubljana,

Ljubliana, Slovenjia

C. Decristoforo (*)

Clinical Department of Nuclear Medicine,

Medical University Innsbruck,

Anichstrasse 35,

6020 Innsbruck, Austria

e-mail: Clemens.Decristoforo@uki.at

Eur J Nucl Med Mol Imaging

DOI 10.1007/s00259-010-1407-3

KeywordsRadiopharmaceuticals.Quality assurance.

PET .cGRPP

Abbreviations

API Active pharmaceutical ingredient

BET Bacterial endotoxin test

cGRPP Current good radiopharmacy practice

EANM European Association of Nuclear Medicine

HEPA filterHigh-efficiency particulate air filter

HPLC High-performance liquid chromatography

LAFW Laminar air flow workbench

QA Quality assurance

QC Quality control

RPR Responsible person for the small-scale

preparation of radiopharmaceuticals

SOP Standard operating procedure

SSRP Small-scale"in-house"radiopharmaceutical

Definitions

Guidelines Guidelines are not mandatory but

recommendations for the effective implementation of EU Directives by the Member States.

Guidances Guidances are not mandatory but

recommendations in a more specific and detailed form for the effective implementation of Directives by the

Member States.

European

RegulationsEuropean Regulations are manda-

tory in all countries, being directly applied without translation into the national legislation.

European Directives European Directives are rules

addressed by the EU Commission to the Member States to be trans- lated into the respective national legislation and effectively imple- mented. Directives are mandatory. Radiopharmaceutical A radiopharmaceutical is any me- dicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose.

Small-scale

radiopharmaceuticalA small-scale radiopharmaceutical is any in-house radiopharmaceutical prepared on a small scale (for PET,

SPECTor therapeutic applications),

excluding preparations based on la- belling licensed kits and generators, and excluding preparation of kits. Finished product A finished product is a medicinal product which has undergone allstages of production, including packaging in its final container.

Preparation Preparation includes all operations

involve in the purchase of materials and products, production, QC, re- lease and storage of a medicinal product and the related controls. Starting material Starting material is any substance usedinthepreparationofamedicinal product, but excluding packaging materials.

Precursor A precursor is an API used as a

starting material for the preparation of a (radio)pharmaceutical.

Radionuclide

precursorA radionuclide precursor is any radionuclide produced for the radiolabelling of another substance prior to administration.

Substance for

pharmaceutical useA substances for pharmaceutical use are any organic or inorganic substance that is used as an active substance or excipient for the pro- duction of medicinal products for human or veterinary use. It may be used as such or as a starting material for subsequent formulation to prepare medicinal products. Qualified Person A Qualified Person typically is a licensed pharmacist, biologist or chemist (or a person with another permitted academic qualification) who has several years experience working in pharmaceutical manufac- turing operations, and has passed examinations attesting to his or her knowledge (EU Directive 2001/83).

The requirement for responsibility by

a Qualified Person has been extended to material for use in clinical trials since the introduction of EU Direc- tive 2001/20/EC. In countries that are part of the Pharmaceutical Inspection

Convention and Pharmaceutical In-

spection Co-operation Scheme, the samerolemaybetermedResponsible

Person or Authorized Person.

Responsible Person A Responsible Person for the small- scale preparation of radiopharma- ceuticals (RPR) is a person with an equivalent academic background to a QP with at least 2 years of practical experience in radiophar- maceutical preparation, having

Eur J Nucl Med Mol Imaging

shown sufficient scientific and technical education and experience in radiopharmacy practice and re- lated fields. The EANM syllabus on radiopharmacy covers the main aspects of the knowledge required.

RPRs are ultimately responsible for

all aspects of the preparation of radiopharmaceuticals at small-scale radiopharmacies including the re- lease of these items unless local or national regulations require different qualifications.

Small-scale

radiopharmacyA small-scale radiopharmacy is a facility where the small-scale prepa- ration of radiopharmaceuticals is carried out under a license that is in accordancewithnationalregulations.

The termsmall-scaleradiopharmacy

is not related to the size of the facility, that may vary in a broad range, but only to the kind of radiopharmaceutical preparation performed.

Good radiopharmacy

practiceGood radiopharmacy practice is described in the"Guidelines on

Good Radiopharmacy Practice

(GRPP)"issued by the Radiophar- macy Committee of the EANM (see www.eanm.org).

Introduction

In Europe, radiopharmaceuticals are considered as a special group of medicines. Therefore, their preparation and use are regulated by a number of EU directives, regulations and rules that have been adopted by member states. The rate of adoption of directives varies between countries and each member state may introduce changes, provided the general scope and limits of each directive are maintained. Specific articles have been put in place concerning radiopharma- ceuticals that are to receive marketing authorization or are prepared starting from licensed products (radionuclide generators, labelling kits and precursor radionuclides). However, radiopharmaceuticals may also be prepared outside the marketing authorization track or used outside the indications they have been registered for. Small-scale preparations at nonindustrial sites (hospital pharmacies, nuclear medicine departments, PET centres) indeed repre- sent an increasingly important segment of application. The "Guidelines on Good Radiopharmacy Practice (GRPP)"

issued by the Radiopharmacy Committee of the EANM(seewww.eanm.org) is a useful reference for QA into the

small-scale preparation of radiopharmaceuticals and their nonradioactive precursors. This guidance is intended to help small-scale radiophar- macies to implement cGRPP, and represents the views of the EANM Radiopharmacy Committee. The basis of this guid- ance is published in the cGRPP guidelines mentioned above and it covers topics comparable to those covered in the [1]. It addresses resources, procedures, and documentation for small-scale preparations. The guidance provides practical examples of methods or procedures that small-scale radio- pharmacies could use to comply with the proposed cGRPP requirements. It describes the thinking on a topic, has no binding value and should be viewed only as a recommen- dation. The use of the wordshouldin this guidance indicates that something is suggested or recommended, but not mandatory. Readers should consult their competent authority to verify specific national requirements and regulations. The present document also provides guidance on the EU requirements concerning quality of starting materials and finished radiopharmaceutical products. This guidance is of great importance because most of the existing rules are intended for medicinal products in general and are not specific for radiopharmaceuticals. Moreover, some of the current regulations do not take into account the special characteristics of radiopharmaceuticals, such as their short shelf life, which is due to the short physical half-life of the radionuclide, the small scale of the preparation and the low or absent toxicity of the final product, which is due to the peculiar no-carrier-added nature of radiopharmaceuticals.

Personnel and resources

It is recommended that the number of personnel corre- sponds to the size and complexity of the operation of the small-scale radiopharmacy so as to enable the appropriate completion of all tasks before administration of a finished SSRP to humans. It is recommended that the responsibil- ities and assigned duties of all staff be clearly identified in written policies. An organizational chart that describes the cGRPP-relevant relationships between involved personnel would fulfil this purpose.

General

All operations should be carried out under the control of the RPR. Personnel involved in release of the prepared radio- pharmaceuticals should be appropriately trained in quality systems, cGRPP and the regulatory requirements specific to this type of product. Release of the finished product may be delegated by the RPR to another person, albeit the responsi-

Eur J Nucl Med Mol Imaging

bility for the release of the radiopharmaceutical cannot be delegated. All personnel (including those concerned with cleaning and maintenance) employed in areas where radioactive products are handled should receive additional training specific to this class of product. In particular, they should be given detailed information and appropriate training on radiation protection. The radiation exposure of personnel is monitored with approved personnel dosimeters, which are regularly checked and their readings recorded. This monitoring may be supplemented with electronic dosime- ters, finger dosimeters, etc. After completion of the radiopharmaceutical preparation, both personnel and work places must be checked for radioactive contamination with suitable monitors. Any contamination must be removed immediately or must be contained, and access to the contaminated area must be denied until the radioactivity has decayed to an appropriate dose level. It is recommended that small-scale radiopharmacies have adequate ongoing programmes or plans in place for training staff in new procedures and operations and in the areas where deficiencies have occurred. Small-scale radiopharmacies must maintain an up to date certificates, certificatesoftraining)for eachstaff member.The personnel should include at least two persons, one of whom is be at least very well trained in the upkeep of cGRPP procedures. When only one person is involved in the preparation at some point in time in a small-scale radiopharmacy, all procedures (preparation, QC and release of the product) may have to be done by the same person (the RPR). Therefore rigorous SOPs have to be in place. If preparation by one person is necessary, an additional independent professional should be involved to double check the results and confirm their compliance (four eyes principle). This individual could their meaning and confirm their correctness. All equipment should be remotely controlled or auto- mated so as to produce reports which unequivocally show that the quality of the product meets specifications.

At a facility that produces multiple SSRPs, it is

recommended that the number of personnel be sufficient to perform all tasks, i.e. the production, QC and QA functions, and to prevent mix-ups and cross contamination.

Responsibilities

The RPR should have the following responsibilities: &To establish procedures for the examination and

evaluation of incoming materials and ensure that eachlot of incoming material is examined and evaluated

against specifications before use. &To review the preparation batch records and laboratory control records for accuracy, completeness, and confor- mance to established specifications before authorizing the final release or rejection of a batch or lot of SSRP. &To approve procedures, specifications, process, and methods including related SOPs. &To ensure the personnel are appropriately trained and qualified. &To investigate errors and ensure that appropriate corrective action is taken to prevent their recurrence. &To ensure that the SSRP have adequately defined identity, strength, quality and purity.

The person responsible for QA should have the

following responsibilities: &To manage the general QA system. &To verify that the documentation is correctly written and administrated. &To conduct periodic audits to monitor compliance with established procedures and practices. &To monitor, in cooperation with the other responsible persons, the general management of the activities performed in the small-scale radiopharmacy (e.g. out of specifications, personnel training, radioactive waste management, etc.) At small facilities, for more efficient management, a QA entity located outside the in-house radiopharmacy may be chosen tohelpthe RPR to oversee the areas mentioned above. The person responsible for production should have the following responsibilities: &To write the SOP related to radiopharmaceutical production operations, and to verify that the above instruction are adequately implemented. &To approve the production operations. &To evaluate, sign and store the production records. &To ensure that the products are produced and stored according to the appropriate documentation in order to obtain the required quality. &To verify that premises and production equipment are correctly maintained according to a established mainte- nance programme. &To cooperate with the other responsible persons in the organization and training of the operating personnel.

The person responsible for QC should have the

following responsibilities: To write the SOP related to QC operations, and verify that the above instruction are adequately implemented. &To define specifications, test methods and other QC procedures.

Eur J Nucl Med Mol Imaging

&To approve or reject starting materials and packaging materials. &To evaluate, sign and store the QC reports and records. &To evaluate the batch records. &To verify that premises and QC equipment are correctly maintained according to a established maintenance programme. &To cooperate with the other responsible persons in the organization and training of the operating personnel. Even though responsibility of production and QC shouldquotesdbs_dbs45.pdfusesText_45

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