Archived Content. This content was archived on June 24, 2013.

Transcription

1 This content was archived on June 24, Archived Content Information identified as archived on the Web is for reference, research or recordkeeping purposes. It has not been altered or updated after the date of archiving. Web pages that are archived on the Web are not subject to the Government of Canada Web Standards. As per the Communications Policy of the Government of Canada, you can request alternate formats on the "Contact Us" page.

2 Health Products and Food Branch Inspectorate Graham Spry Building, 2 nd Floor 250 Lanark Avenue Address Locator # 2002B Ottawa, Ontario K1A 0K9 February 15, To: Associations The final version of the Positron Emitting Radiopharmaceuticals (PER) Annex to the Good Manufacturing Practices (GMP) Guidelines is now available on the Health Products and Food Branch Inspectorate website of Health Canada: These guidelines were developed in consultation with a working group of external experts, with the objective of enhancing Health Canada s ability to ensure the high quality, safety, and efficacy of PERs used in Canada, and to provide further clarification to manufacturers on the regulatory requirements for the production of these drugs. The draft version of this document was posted on Health Canada s website for comment in January 2005, and comments and suggestions received during the public consultation period were considered in the finalization of this document. Inquiries about this document can be addressed to the Drug GMP Inspection Unit by telephone at (613) , by fax at (613) , or by at GMP_Questions_BPF@hc-sc.gc.ca. Original signed by Diana Dowthwaite Director, Compliance & Enforcement Coordination Division

3 Health Canada Health Products and Food Branch OUR MANDATE: To promote good nutrition and informed use of drugs, food, medical devices and natural health products, and to maximize the safety and efficacy of drugs, food, natural health products, medical devices, biologics and related biotechnology products in the Canadian marketplace and health system. Health Products and Food Branch Inspectorate ANNEX TO THE GOOD MANUFACTURING PRACTICES GUIDELINES GOOD MANUFACTURING PRACTICES (GMP) FOR POSITRON EMITTING RADIOPHARMACEUTICALS (PERs) Guide-0071 Supersedes: New document Date issued: February 15, 2006 Date of implementation: March 30, 2006 Ce document est aussi disponible en français.

4 TABLE OF CONTENTS INTRODUCTION... Page 4 SCOPE... Page 4 GLOSSARY OF TERMS... Page 5 DEFINITIONS... Page 6 PREMISES... Page 9 C Page 9 EQUIPMENT... Page 10 C Page 10 PERSONNEL... Page 11 C Page 11 SANITATION... Page 12 C and C Page 12 RAW MATERIAL TESTING... Page 12 C and C Page 12 MANUFACTURING CONTROL... Page 13 C and C Page 13 QUALITY CONTROL DEPARTMENT... Page 14 C to C Page 14 PACKAGING MATERIAL TESTING... Page 15 C and C Page 15 FINISHED PRODUCT TESTING... Page 15 C and C Page 15 RECORDS... Page 16 C to C Page 16 SAMPLES... Page 17 C Page 17 Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 2

5 STABILITY... Page 17 C and C Page 17 STERILE PRODUCTS... Page 18 C Page 18 REFERENCES... Page 19 Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 3

6 INTRODUCTION Positron Emitting Radiopharmaceuticals (PERs) used in Positron Emission Tomography (PET) are Schedule C drugs to the Food and Drugs Act and are regulated under the Food and Drug Regulations. The Regulations addressing the sale of Schedule C drugs are found within Part C, Divisions 1A, 2, 3, 5 and 8. In addition, Section 12 to the Food and Drugs Act does not permit the sale of drugs unless the premises in which the drug is manufactured, the process, conditions and controls of manufacture therein are suitable to ensure that the drug will meet the required quality and will not be unsafe for use. The application of Division 2 of the Food and Drugs Regulations and the Annex to Good Manufacturing Practices (GMP) for Schedule C drugs may be different from its application to PERs due to the unique production, quality control and handling characteristics of the latter. Hence this Annex is dedicated to all the aspects of GMP that have a bearing on this class of radiopharmaceutical drugs. PERs are used in PET as diagnostic agents as well as tools in research. In addition to the impurities of chemical source, the finished product (PER drugs) may contain other impurities of radioactive origin such as radionuclidic and/or radiochemical. Such impurities may have a detrimental effect on the utility, quality, safety and reliability of the drug as a diagnostic agent, and possibly on the radiation dose to the patient. Due to the relatively short half-life of most positron emitting radionuclides a majority of PERs have a short shelf-life, and they are often administered to patients within a short time after fabrication (production). Release of the product before completion of certain quality control tests might be necessary in order to maintain the appropriate radioactive dose regimen. For these reasons, the continuous assessment of the effectiveness of the quality assurance program is essential. The guidance in this Annex, when placed in context with the general Guidelines for GMP, should facilitate compliance with Division 2 of the Food and Drug Regulations by fabricators, packagers/labellers, distributors and importers of PERs. The principles and concepts adopted internationally for radiopharmaceuticals and PERs (eg. Australian Therapeutic Goods Administration (TGA), World Health Organization (WHO), and United States Food and Drug Administration (FDA)) were taken into account in the development of this Annex. SCOPE This Annex will be known as ANNEX TO THE GMP GUIDELINES: Good Manufacturing Practices for Positron Emitting Radiopharmaceuticals (PERs). The guidelines covered herein are applicable for all PERs. In addition, all sections of the main GMP Guidelines 1 are applicable unless otherwise stated in this Annex. s in this Annex take precedence and/or supersede those in the main GMP Guidelines. s in the main GMP Guidelines that are not applicable are indicated in this Annex. 1. Good Manufacturing Practices (GMP) Guidelines 2002 Edition Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 4

7 Like the GMP Annex for Schedule C drugs, radiation safety requirements are not covered in this Annex. The Canadian Nuclear Safety Commission (CNSC) provides Regulations and guidance documents which are applicable to this type of activity. More specifically, the CNSC Design Guide for Basic and Intermediate Level Radioisotope Laboratories is applicable to the following sections of the Annex to the GMP: PREMISES, EQUIPMENT, SANITATION (handling and storage of radioactive wastes and personnel behaviour) and MANUFACTURING CONTROL (procedure writing related to management of rejected radioactive materials). Standard Operating Procedures (SOPs) concerning conditions of transportation are defined under the RAW MATERIAL TESTING section of the main GMP Guidelines and should follow recommendations from the CNSC. Radioactive contamination of the environment in which a drug is prepared can directly affect its quality. Thus, in addition to CNSC requirements, it is essential to follow the GMP Guidelines given in this Annex for PERs. In this guideline, shall is used to express a requirement, i.e., a provision that the user is obliged to satisfy in order to comply with the regulatory requirements; should is used to express a recommendation or that which is advised but not required; and may is used to express an option or that which is permissible within the limits of the guidance document. The content of this Annex should not be regarded as the only interpretation of the GMP Regulations nor does it intend to cover every conceivable case. Alternative means of complying with these Regulations may be considered with the appropriate scientific justification. Different approaches may be called for as new technologies emerge. The numbering of the s in this Annex is not intended to correspond to that of the GMP Guidelines. GLOSSARY OF TERMS Abbreviations BGTD Bq Ci CNSC FDA GBq GC GMP PET PER QC RSU Biologics and Genetic Therapies Directorate Becquerel Curie Canadian Nuclear Safety Commission Food and Drug Administration GigaBecquerel Gas Chromatography Good Manufacturing Practices Positron Emission Tomography Positron Emitting Radiopharmaceutical Quality Control Radiosynthesizer Unit Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 5

8 SOP TGA WHO Standard Operating Procedure Therapeutic Goods Administration World Health Organization DEFINITIONS The following definitions which supplement the definitions provided under the Glossary of Terms in the general Guidelines for GMP may be useful to fabricators, packagers/labellers, distributors and importers of PERs. The definitions given below apply to the terms used in this Annex. They may have different meanings in other contexts. Excerpts from the sections of the Food and Drugs Act and Regulations are shown in brackets. ACCELERATOR (accélérateur) - A device to accelerate energetic charged particles linearly or in circular paths by means of a radiofrequency field and an electromagnetic field in case of cyclotrons. The accelerated particles cause nuclear reactions in the atoms of targets placed in their path. BATCH (lot de fabrication) - A defined quantity of final product produced in one production run often expressed either in mass (mg or g) or volume (ml or L) or total radioactivity (Ci or GBq), total number of vials or doses. CALIBRATION (étalonnage) - Set of tests that confirms under desired conditions, the relationship between values indicated by a measuring instrument or measuring system, or values represented by a material measure, and the corresponding values of a reference standard. CAMPAIGN PRODUCTION (production consécutive) - Sequential processing of material, either different products in a multi-product facility or different lots of the same product in a dedicated facility, over a defined period of time. Campaign production could occur at any point in a production process where common rooms/suites and/or equipment are reused for multiple products/lots. CARRIER (entraîneur) - A stable element present with a radionuclide of the same element. CATALYST (catalyseur) - A substance usually used in small amounts relative to the reactants that modifies and increases the rate of a reaction without being consumed in the process. CROSS-CONTAMINATION (contamination croisée) - Contamination of a drug or a radionuclide or a raw material or in-process intermediate with another drug, radionuclide, raw material or in-process intermediate. In multiproduct facilities, potential cross-contamination can occur throughout the manufacturing process. DEDICATED (réservé) - Facility or piece of equipment used only in the fabrication of a particular product or a closely related group of products. DRUG (drogue) - A drug listed in Schedule C to the Act that is in dosage form, or a drug that is a bulk process intermediate, that can be used in the preparation of a drug listed in Schedule C to the Act. [C ] Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 6

9 HALF-LIFE (demie-vie) - Time during which an initial radioactivity of a radionuclide decays to one half. HOT CELL (cellule chaude) - An aseptic total containment cabinet providing a Class A (with Laminar flow), or Class B (with Turbulent flow) environment, and is shielded with lead of various thickness. MANIFOLD (manifold) A unit for connecting a cylindrical pipe fitting, having a number of lateral outlets, for connecting one pipe with several others used in the Radiosynthesizer Unit. MANUFACTURE (fabrication) - all operations including purchase of materials and products, production, quality control, release, storage, distribution and related controls. MASTER FORMULA (formule-type) - A document or set of documents specifying the raw materials with their quantities, their radioactivity and the packaging materials, together with a detailed description of the procedures and precautions required to fabricate a specified quantity of a finished product as well as the processing instructions, including in-process controls. MULTIPLE-DOSE CONTAINER (récipient multi-doses) - Container that permits withdrawal of successive portions of the contents without changing the concentration, quality or purity of the remaining portion. NO-CARRIER-ADDED (sans entraîneur ajouté) - Indicates the status of a radionuclide sample where no stable atom of the same element has been added purposely. PARAMETRIC RELEASE (libération en fonction de paramètre) A validated system of release that gives the assurance that the product is of the intended quality based on information collected during the manufacturing process and on the compliance with specific GMP requirements related to Parametric Release. POSITRON EMITTING RADIOPHARMACEUTICALS (PERs) (produits radiopharmaceutiques émetteurs de positrons) - Drugs labelled with positron emitting radionuclides or containing positron emitting radionuclides that exhibit spontaneous transformation of unstable nuclei through positron decay. PRECURSOR (précurseur) - A chemical substance or molecule which exists as an ingredient, reactant, or intermediate that is used for the chemical or radiochemical synthesis of a particular desired end product. RADIOACTIVE CONCENTRATION (concentration radioactive) - Amount of radioactivity per unit volume such as mci/ml or MBq/mL. RADIOACTIVITY (radioactivité) Spontaneous decay of unstable nuclei and is quantified as the number of disintegrations per unit of time as given in Becquerel (Bq) or Curie (Ci) units. RADIOCHEMICAL PURITY (pureté radiochimique) - The extent to which a drug is free from undesirable or adulterating radiochemicals as defined by specifications. RADIONUCLIDE (radionucléide) An unstable atom that undergoes spontaneous transformation with emissions of subatomic particles and/or photons of energy. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 7

10 RADIONUCLIDE DOSE CALIBRATOR (étalonneur de doses) - Device measuring the radioactivity in Becquerels (Bq) or Curies (Ci), of a radioactive sample. RADIONUCLIDE GENERATOR (générateur de radionucléides) - a radioactive parent and daughter contained in an ion exchange column or dissolved in a suitable solvent in a liquid-liquid extraction system where the radioactive daughter is separated from its parent by elution from the ion exchange column, or a solvent extraction procedure. [C ] RADIONUCLIDIC PURITY (pureté radionucléidique) - The extent to which a drug is free from undesirable or adulterating radionuclides as defined by a specification expressed as a percentage of the radioactivity of the specified radionuclide to the total radioactivity of the source. RADIOSYNTHESIZER UNIT (RSU) (unité de radiosynthèse) - A closed-system device for the synthesis of radioactive drug substances used in the manufacturing of PERs. The system may be controlled by graphical computer software programs. RADIOPHARMACEUTICAL (produit radiopharmaceutique) - a drug that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons. [C ] SPECIFIC ACTIVITY (activité spécifique) - Amount of radioactivity per unit mass or per mole such as mci/mg, MBq/mg or mci/mole, MBq/mole. STARTING MATERIAL (produit de depart) - Any substance entering a production facility for use in the production of a drug product. TARGET MATERIAL (cible) - A chemical substance which is bombarded with nuclear particles to produce a desired radionuclide. TOTAL CONTAINMENT GLOVE BOX (boîte à gants de confinement total) - A totally enclosed environment at negative pressure, whose primary purpose is radioactivity workspace localization. TOTAL RADIOACTIVITY (radioactivité totale) - Amount of radioactivity present in the total volume of a reconstituted preparation or total volume of an eluate or solution, expressed as mci or MBq. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 8

11 PREMISES Regulation C Note: #10 of Regulation C in the main GMP Guidelines is not applicable. 1. PERs and positron emitting radionuclide generators shall be fabricated, packaged/labelled, stored and quality tested in a manner which prevents cross-contamination and mix-up of drugs and/or radioactivity with unwanted sources of radioactivity and/or drugs such as chemical, radionuclidic, radiochemical or radiopharmaceutical contamination. 2. Facilities used for the handling of radioactivity shall be clearly identified and access should be restricted to people involved in the process taking place. Although the same room or area may be designated for various purposes such as radiochemical synthesis, quality control, packaging and storage, whenever possible each area should be separated by a physical barrier. 3. Airflow patterns and ventilation should not present a contamination risk for the products while providing the necessary protection from radioactive airborne exposure to the personnel during critical operations. 4. Aseptic work areas shall be ensured and maintained for the processing of sterile PER drug product by: 4.1 using positive pressure areas to process sterile products which are not radiolabeled; 4.2 using negative pressure in specifically designed areas for containment of radioactivity. 4.3 carrying out the production in negative pressure areas or safety cabinets (e.g. Hot cell, total containment glove box, etc.) surrounded by a positive pressure zone ensuring appropriate air quality requirements. 4.4 dedicating air handling filtration units to specific processing areas such as radioactive or nonradioactive. Air from the operations containing radioactivity shall be exhausted through appropriate filters and the filters routinely checked for efficiency. It shall be ensured that the air is not re-circulated and air outlets are designed to avoid environmental contamination of radioactive particles or gases. It shall also be ensured that a system is in place in order to prevent air from entering aseptic areas in the event the air exhaust is not functioning; alarms and systems need to be in place to alert of changes in air flow patterns in the event of exhaust failure. 4.5 cleaning transfer lines such that no contaminant is introduced into the final radiopharmaceutical product. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 9

12 4.6 raw materials are stored and sampled in a separate area or containment vessel. If sampling is performed in the storage area, it is conducted in such a way as to prevent contamination or cross contamination. All materials are clearly marked and a log sheet is maintained for each material. EQUIPMENT Regulation C Radionuclide Production Target: when a positron emitting radionuclide is produced in an in-house accelerator, the following shall be ensured: 1.1 Reusable targets are operated in a manner to ensure that the product is free of any residual radionuclidic, radiochemical or chemical contaminants. 1.2 SOPs are available which describe the responsibility and frequency of cleaning and maintenance of the target; Note: Refer to the Raw Material Testing section for information. 2. Radiosynthesis apparatus (including dedicated Radiosynthesis Units): SOPs shall be required for the operation, maintenance and cleaning of all radiosynthesis apparatus, including dedicated Radiosynthesis Units. Prior to their initial use in manufacturing and production, the manufacturing process shall be validated against the specifications for the PERs being manufactured. In particular, it shall be demonstrated that a sterile and pyrogen free PER can be produced repeatedly. The following shall be ensured with respect to the RSU: 2.1 cleaning/flushing the RSU as per the user s manual; 2.2 connection of all tubing, including replacement (if needed) reaction vessels; manifold/cartridges, purification columns, and final product collection vial, as needed; 2.3 ensuring that monitoring and/or recording devices for various important chemical synthesis parameters such as temperature, pressure, flow rate, time, and date are properly functioning; 2.4 ensuring that controlling computer systems, if applicable, are recording correctly, and that the correct program or process parameters are used. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 10

13 3. PERs and positron emitting radionuclide generators shall be fabricated, packaged, stored and tested with equipment which does not contribute to the cross-contamination of drugs with unwanted sources of radioactivity such as radionuclidic and radiochemical contamination. 4. Radioactivity measuring equipment shall be shielded or located so as to avoid any source of background radiation. 5. All equipment shall be regularly calibrated for accuracy, precision and reproducibility and corresponding records maintained. 6. Critical equipment shall be subject to installation, operational, and performance qualification. The results shall be documented. PERSONNEL Regulation C In a PERs manufacturing establishment, regardless of whether it is a hospital, centralized radiopharmacy, nuclear centre or institution, industrial manufacturer, or contract manufacturer, the head of the establishment should be a professionally qualified person with extensive knowledge in PERs and PET in general. It is reasonable to expect that the qualifications of the individual include experience in radiopharmaceutical sciences and/or nuclear medicine. 2. For the fabricator, packager/labeller and tester, qualified individuals in respect of the PERs manufacturing and quality control with additional expertise in radiochemistry and radiopharmacy including GMPs, should be in charge of, and retained in, the manufacturing department and the quality control department, respectively. 3. A minimum of two qualified persons shall be involved in the production (fabrication) and quality control of PERs. The production of the PERs shall be supervised and authorized only by a person with adequate education in radiochemistry including specialized training in PET chemistry and experience in the manufacturing of PERs. The quality control and batch release shall be supervised and approved by a different person with specialized knowledge, education and experience/training in the quality control of PERs and radiopharmaceuticals. 4. Personnel working in areas where radioactive materials are handled shall be given specific safety training in accordance with other applicable Federal jurisdictions. The Canadian Nuclear Safety Commission (CNSC) regulations and guidelines on radiation safety should be consulted. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 11

14 SANITATION Regulations C and C The sanitation program shall include procedures and practices in accordance with other applicable federal regulations. The CNSC regulations and guidelines on radiation safety should be consulted. 2. Specialized disposal systems shall be adopted for radioactive effluents in accordance with other applicable federal regulations. The CNSC regulations and guidelines on radiation safety should be consulted. RAW MATERIAL TESTING Regulations C and C Note: s #6 and #10 of Regulation C in the main GMP Guidelines are not applicable. 1. Detailed specifications including the source, origin and (where applicable) method of manufacture, test data, suitable storage conditions and expiry dates for all materials and components including the starting materials and/or precursor used in the production and testing of PERs shall be maintained. This is to ensure their suitability for use in the production or testing. 2. As appropriate, certificates of analysis, and/or quality testing data should be obtained from the supplier. However, if these are not available or if the material is produced in-house, the PER manufacturing facility is responsible for making all the testing and data available to the full specifications of the material. 3. Acceptance testing may be necessary for the target material if it has a potential impact on the purity of the final PER product. 4. The recycling method of O-18 water shall be documented and acceptance criteria/specifications are well defined. 5. On arrival, packages containing radioactive materials such as importation of off-site PER radionuclides (e.g., F-18, Sr-82), shall be initially processed in accordance with other applicable Federal jurisdictions. The CNSC regulations and guidelines on radiation safety should be consulted. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 12

15 6. The PER manufacturing facility establishes the reliability of the supplier by performing full testing against supplier specifications for the first three lots of radionuclides received and at appropriate intervals thereafter, but at a minimum, quarterly. 7. Confirming the identity of the raw materials prior to their use is the primary objective of this section. This requirement is usually a part of the pre-approval authorization review. Notwithstanding subsection C (1), each lot or batch of raw materials containing a radionuclide where the physical half-life does not permit the completion of its tests under that subsection, validation must be provided. MANUFACTURING CONTROL Regulations C and C Note: s #23, 24, and 25.1 of Regulation C in the main GMP Guidelines are not applicable Manufacturing Control for PERs is required to ensure proper labelling in order to prevent mix-ups and to ensure cleaning and sterility since most of the critical testing is done retrospectively; and to design the production methodology in order to prevent cross-contamination. The following are guidelines for ensuring the above criteria: 1. At all times during processing, shielded containers shall be identified with the name of the contents and the batch or lot number. 2. In the case of a packaged drug, the master formula also includes for each product, (where applicable), package size and type, the range of radioactivity, concentration in the final container, and the type of radionuclide and shielding. 3. If data are available, it may be used retrospectively for process validation. The data should indicate that the process is capable of consistently producing batches which meet predetermined specifications specifically for radionuclidic purity, radiochemical purity, sterility and endotoxins. The retrospective validation should consider all failures and changes to the process. 4. Although concurrent testing for sterility and endotoxins are not appropriate for PERs, the membrane filter used for the sterile filtration of the final product shall be tested for filter integrity. Refiltration can be considered if filter integrity does not meet specifications. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 13

16 5. Computer systems used in the production of PERs should be validated with a production run to demonstrate that they function as intended. Changes to the computer system including software upgrades shall be re-validated. 6. Where the final product is created in situ, validation for cleaning and sterility is required to ensure no cross-contamination of any nature such as radionuclidic, radiochemical or chemical for the target or the transferring line. 7. Validation for sterility and cleaning is required for the RSU with reusable manifolds. 8. In general, due to the short physical half-life of most PER radionuclides, most of the products are released without completing certain tests. As noted earlier, initial validation tests should be performed, followed by periodic testing. In such situations, the effectiveness of the quality assurance system should be periodically assessed and an effective recall system shall be in place. 9. The purpose of a recall system is to prevent the use of a deviant PER product rather than its retrieval, since the return of PERs is not practical due to the radioactive nature of the product. However, in the event a sample is returned the federal guidelines for transportation (refer to CNSC guidelines) shall be followed. QUALITY CONTROL DEPARTMENT Regulations C to C Note: s #4, 6, 7, 8, and 9 of Regulation C in the main GMP Guidelines are not applicable. s #1 and 2 of Regulation C in the main GMP Guidelines are not applicable. 1. The quality control unit is the final decision-making authority for release of a product; the person responsible for the release of the product is a distinct person from the person (s) who fabricate, package/label or sell the same lot. 2. The area of responsibility of the unit includes authorized decision-making concerning the release of a particular lot of raw material, packaging material or finished PERs. 3. All finished products are held in quarantine (on-site or in transit) and are so identified until released by the quality control department. Where sterility and/or endotoxin testing is conducted on specific lots of PERs, such lots may be released prior to completion of sterility and/or endotoxin testing, provided such testing is validated a priori and is completed as soon as possible. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 14

17 4. PERs are stored, transported and handled in strict compliance with the market authorization and CNSC regulations. PACKAGING MATERIAL TESTING Regulations C and C The reuse of lead shielding in generators is permitted only after a full evaluation of the risks involved, including any possible deleterious effects on product integrity. Specific provision is made for such in the pre-market authorization. 2. Compatibility studies should be conducted on all materials in direct contact with the PER drug product such as vials and stoppers, as well as sterile filters, tubing, etc. for PER generators. FINISHED PRODUCT TESTING Regulations C and C Note: s #1 and 7 of Regulation C in the main GMP Guidelines are not applicable. The production method for various PER products may vary in different centres, and hence, the testing for the final product may also vary among centres. In general, the following guidelines should be used: 1. Written specifications should contain a description of the drug in dosage form, which may include, but is not limited to: total radioactivity, specific activity or radioactive concentration, radiochemical purity, ph, osmolality, radionuclidic purity, catalyst, residual solvents, etc., together with tolerances and a description of all test methods or analyses used to determine those properties and attributes, in sufficient detail to permit performance by qualified personnel. Such analyses include the monitoring of generator eluate for purity, radioactivity, radioactive concentration and appearance. 2. Because of the short half-life of most radionuclides and the short shelf-life of most PERs, product release tests are based (in real time) on a limited number of tests. The remaining tests are performed on a retrospective basis. However, in order to determine which tests are done on a retrospective basis, a rationale should be prepared and documented. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 15

18 3. Sterility and endotoxin tests should be conducted on all batches of PERs according to finished product specifications. Such batches may be released prior to completion of sterility and/or endotoxin testing, provided this overall process has been validated in advance and such testing is completed as soon as possible. RECORDS Regulations C to C Note: #7.1 of Regulation C in the main GMP Guidelines is not applicable. 1. Maintenance of batch records at the PER manufacturing facility is important for all PER products as most of them are released with retrospective testing. The batch record information shall include the following: 1.1 list of tests that are performed before release; 1.2 list of tests that are performed retrospectively; 1.3 results of all the test parameters as per product specification; 1.4 record of any deviations and additional testing (if any); 1.5 record of total amount of radioactivity per batch at the end of synthesis and at calibration time; 1.6 total volume per batch; 1.7 specific activity and/or radioactive concentration at calibration time; 2. For PERs imported into Canada, detailed summaries of marketing authorization of the current fabrication, packaging, labelling and testing procedures shall be maintained by the legal agent in Canada. 3. For PER radionuclides, detailed information on the amount received, amount used in fabrication, and the amount disposed of are maintained by the PET facility that acquires the radionuclide either from within Canada or from a country outside of Canada. 4. Distribution records shall be maintained properly. 5. Records shall be available to support an effective recall system. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 16

19 SAMPLES Regulation C Note: #1 of Regulation C in the main GMP Guidelines is not applicable. 1. Samples of radioactive raw material are not required. 2. A sample of each lot or batch of non-radioactive raw material used in the fabrication of a drug shall be retained by the fabricator of the drug for a period of three months after the lot or batch is last used in the fabrication of the drug unless otherwise specified in the fabricator's establishment licence. Acceptable rationale for retaining samples may include short shelf life or extremely small amounts of raw material. These considerations would normally be addressed prior to market authorization specific to a given product upon written request and based on appropriate justification. 3. A sample of the final product shall be retained for a minimum of three months since the product is released with retrospective testing of those parameters not tested at release due to the short half-life of the radionuclide. The sample retention is also useful for investigational purposes when a batch fails to meet certain specifications, such as sterility. STABILITY Regulations C and C Note: #1 (with the exception of 1.2) of Regulation C in the main GMP Guidelines is not applicable. 1. The aspects of the stability program of the drug are determined prior to marketing and prior to adoption of significant changes in formulation, fabrication procedures, or packaging materials that may affect the shelf-life of the drug. Any significant change in the source of radionuclide or any packaging components in direct contact with the product will necessitate repeat assessment of the stability. The following guidelines for stability assessment should be followed: 1.1. the shelf-life should be stated based on time and date of fabrication of the drug. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 17

20 1.2. the stability study should be designed such that data cover at least worst case scenario such as the highest specific activity, total radioactivity or radioactive concentration to total volume that is used for the acceptance of the PER drug product as per specification stability testing should include a determination of the stopper and vial compatibility with the PER drug product when in direct contact stability testing addresses the situation of shipping with exposure to extremes of temperature conditions. The stability during shipping should be validated when no testing for product quality will be performed at the user end (e.g., nuclear medicine facilities). 2. Stability studies should be performed at well defined temperature and humidity, as appropriate, and at least in triplicate samples of the same batch. Appropriate parameters should be analysed to establish the stability of the PER under the proposed conditions. The test parameters used in the stability study may include radiochemical purity, appearance, ph, sterility and endotoxin determination. 3. Where a drug is transferred to a second container, the stability for the storage time in that container is demonstrated. The stability is determined for the final packaged dosage form. STERILE PRODUCTS Regulation C Note: #4 of Regulation C in the main GMP Guidelines is not applicable. 1. The radiochemical synthesis or preparation of the PERs should take place in a hot cell. 2. Activities listed below shall be performed in aseptic systems/areas: 2.1 Aseptic addition of a sterile diluent to a sterile vial using a syringe Aseptic attachment of sterile components and devices such as connecting a sterile syringe or a sterile filter device to a sterile needle; inserting a sterile needle through a sanitized stopper into a vial; and any penetration of, or creation of an open pathway into a sealed container-closure system after filling, as might occur with some post-filling sampling techniques Sampling for final product testing and partitioning of bulk PER into separate sterile vials prior to release shall be carried out in a Grade A area. Assembly of closed RSU manifolds and components of open systems shall be done in a Grade A environment. Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 18

21 2.4 Sterile filtration requires a minimum filter rating of 0.22 µm. The integrity of the filter should be verified before use and shall be verified after use by an appropriate method such as a bubble point, diffusion or pressure hold tests. 3. Air velocity in aseptic areas (e.g. laminar flow hoods) should be sufficient to sweep particulate matter away from the filling and closing area. Whenever possible, equipment configuration should not disrupt the laminar flow. Different areas in the fabricating process should be separated by physical barriers whenever possible and may be supplemented by partial physical barriers (e.g., air curtains) where needed. 4. Since terminal steam sterilization is not possible or practical for PERs, due to the short physical halflife of the radionuclide involved and/or the thermal instability of the product, additional measures should be taken to minimize contamination. Such measures may include, but are not limited to, the use of closed systems of fabrication and sterile filtration. Such equivalence shall be validated and subsequent filling operations or any further operations involving the entry or opening of sterile closed containers are performed under aseptic conditions. REFERENCES 1. Annex 3: Guidelines on Good Manufacturing Practices for Radiopharmaceutical Products World Health Organization (WHO) Technical Report Series No. 908, Guidance: PET Drug Products - Current Good Manufacturing Practice (cgmp) Draft Guidance by FDA, March Annex to the GMP Guidelines: Good Manufacturing Practices for Schedule C Drugs GMP Annex for Schedule C Drugs by Health Canada, June Guidelines for Good Radiopharmacy Practice A Guidance document published by Australia New Zealand Society of Nuclear Medicine Radiopharmacy Special Interest Group (ANZSNM Radiopharmacy SIG), September Australian Code of Good Manufacturing Practice for Medicinal Product: Annex 3, Manufacture of Radiopharmaceuticals, August Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 19