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Health Products and Food Branch InspectorateGraham Spry Building, 2nd Floor250 Lanark AvenueAddress Locator # 2002BOttawa, OntarioK1A 0K9

February 15, 2006

06-101671-686

To: Associations

The final version of the Positron Emitting Radiopharmaceuticals (PER) Annex to theGood Manufacturing Practices (GMP) Guidelines is now available on the Health Products andFood Branch Inspectorate website of Health Canada:

http://web.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/index_e .html

These guidelines were developed in consultation with a working group of externalexperts, 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 manufacturerson the regulatory requirements for the production of these drugs. The draft version of thisdocument was posted on Health Canada’s website for comment in January 2005, and commentsand suggestions received during the public consultation period were considered in thefinalization of this document.

Inquiries about this document can be addressed to the Drug GMP Inspection Unit bytelephone at (613) 952-9319, by fax at (613) 957-6709, or by e-mail [email protected].

Original signed by

Diana DowthwaiteDirector, Compliance & EnforcementCoordination Division

mailto:[email protected].

Health CanadaHealth 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 EMITTINGRADIOPHARMACEUTICALS (PERs)

Guide-0071

Supersedes:New document

Date issued:February 15, 2006

Date of implementation:March 30, 2006

Ce document est aussi disponible en français.

Health Canada / Health Products and Food Branch Inspectorate

Annex to GMP for Positron Emitting Radiopharmaceuticals (GUI-0071) / January 2006 Page 2

TABLE OF CONTENTS

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SCOPE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 4

GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 5

DEFINITIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 6

PREMISES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 9C.02.004 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 9

EQUIPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 10C.02.005 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 10

PERSONNEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 11C.02.006 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 11

SANITATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 12C.02.007 and C.02.008 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 12

RAW MATERIAL TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 12C.02.009 and C.02.010 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 12

MANUFACTURING CONTROL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 13C.02.011 and C.02.012 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 13

QUALITY CONTROL DEPARTMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 14C.02.013 to C.02.015 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 14

PACKAGING MATERIAL TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 15C.02.016 and C.02.017 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 15

FINISHED PRODUCT TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 15C.02.018 and C.02.019 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 15

RECORDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 16C.02.020 to C.02.024 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 16

SAMPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 17C.02.025 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 17



STABILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 17C.02.027 and C.02.028 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 17

STERILE PRODUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 18C.02.029 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 18

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 19


1. Good Manufacturing Practices (GMP) Guidelines 2002 Edition


INTRODUCTION

Positron Emitting Radiopharmaceuticals (PERs) used in Positron Emission Tomography (PET) are ScheduleC drugs to the Food and Drugs Act and are regulated under the Food and Drug Regulations. The Regulationsaddressing 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 drugis manufactured, the process, conditions and controls of manufacture therein are suitable to ensure that thedrug 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 ManufacturingPractices (GMP) for Schedule C drugs may be different from its application to PERs due to the uniqueproduction, quality control and handling characteristics of the latter. Hence this Annex is dedicated to all theaspects 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 ofchemical source, the finished product (PER drugs) may contain other impurities of radioactive origin such asradionuclidic 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 shortshelf-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 tomaintain the appropriate radioactive dose regimen. For these reasons, the continuous assessment of theeffectiveness of the quality assurance program is essential.

The guidance in this Annex, when placed in context with the general Guidelines for GMP, should facilitatecompliance 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. AustralianTherapeutic 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 forPositron Emitting Radiopharmaceuticals (PERs)”. The guidelines covered herein are applicable for all PERs.In addition, all sections of the main GMP Guidelines1 are applicable unless otherwise stated in this Annex.Interpretations in this Annex take precedence and/or supersede those in the main GMP Guidelines.Interpretations in the main GMP Guidelines that are not applicable are indicated in this Annex.



Like the GMP Annex for Schedule C drugs, radiation safety requirements are not covered in this Annex. TheCanadian Nuclear Safety Commission (CNSC) provides Regulations and guidance documents which areapplicable to this type of activity. More specifically, the CNSC Design Guide for Basic and IntermediateLevel Radioisotope Laboratories is applicable to the following sections of the Annex to the GMP:PREMISES, EQUIPMENT, SANITATION (handling and storage of radioactive wastes and personnelbehaviour) and MANUFACTURING CONTROL (procedure writing related to management of rejectedradioactive materials).

Standard Operating Procedures (SOPs) concerning conditions of transportation are defined under the RAWMATERIAL TESTING section of the main GMP Guidelines and should follow recommendations from theCNSC. Radioactive contamination of the environment in which a drug is prepared can directly affect itsquality. Thus, in addition to CNSC requirements, it is essential to follow the GMP Guidelines given in thisAnnex for PERs.

In this guideline, “shall” is used to express a requirement, i.e., a provision that the user is obliged to satisfy inorder to comply with the regulatory requirements; “should” is used to express a recommendation or thatwhich is advised but not required; and “may” is used to express an option or that which is permissible withinthe limits of the guidance document.

The content of this Annex should not be regarded as the only interpretation of the GMP Regulations nor doesit intend to cover every conceivable case. Alternative means of complying with these Regulations may beconsidered with the appropriate scientific justification. Different approaches may be called for as newtechnologies emerge.

The numbering of the Interpretations in this Annex is not intended to correspond to that of the GMPGuidelines.

GLOSSARY OF TERMS

Abbreviations

BGTD Biologics and Genetic Therapies DirectorateBq Becquerel Ci Curie CNSC Canadian Nuclear Safety Commission FDA Food and Drug AdministrationGBq GigaBecquerelGC Gas ChromatographyGMP Good Manufacturing PracticesPET Positron Emission Tomography PER Positron Emitting Radiopharmaceutical QC Quality Control RSU Radiosynthesizer Unit



SOP Standard Operating ProcedureTGA Therapeutic Goods AdministrationWHO World Health Organization

DEFINITIONS

The following definitions which supplement the definitions provided under the Glossary of Terms in thegeneral Guidelines for GMP may be useful to fabricators, packagers/labellers, distributors and importers ofPERs. The definitions given below apply to the terms used in this Annex. They may have different meaningsin other contexts. Excerpts from the sections of the Food and Drugs Act and Regulations are shown inbrackets.

ACCELERATOR (accélérateur) - A device to accelerate energetic charged particles linearly or in circularpaths by means of a radiofrequency field and an electromagnetic field in case of cyclotrons. The acceleratedparticles 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 oftenexpressed either in mass (mg or g) or volume (mL or L) or total radioactivity (Ci or GBq), total number ofvials or doses.

CALIBRATION (étalonnage) - Set of tests that confirms under desired conditions, the relationship betweenvalues indicated by a measuring instrument or measuring system, or values represented by a materialmeasure, and the corresponding values of a reference standard.

CAMPAIGN PRODUCTION (production consécutive) - Sequential processing of material, either differentproducts in a multi-product facility or different lots of the same product in a dedicated facility, over a definedperiod of time. Campaign production could occur at any point in a production process where commonrooms/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 modifiesand 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 rawmaterial 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 productor 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 bulkprocess intermediate, that can be used in the preparation of a drug listed in Schedule C to the Act. [C.03.001]



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 Laminarflow), 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 rawmaterials with their quantities, their radioactivity and the packaging materials, together with adetailed description of the procedures and precautions required to fabricate a specified quantity of a finishedproduct as well as the processing instructions, including in-process controls.

MULTIPLE-DOSE CONTAINER (récipient multi-doses) - Container that permits withdrawal ofsuccessive portions of the contents without changing the concentration, quality or purity of the remainingportion.

NO-CARRIER-ADDED (sans entraîneur ajouté) - Indicates the status of a radionuclide samplewhere no stable atom of the same element has been added purposely.

PARAMETRIC RELEASE (libération en fonction de paramètre) – A validated system of release that givesthe assurance that the product is of the intended quality based on information collected during themanufacturing process and on the compliance with specific GMP requirements related to Parametric Release.

POSITRON EMITTING RADIOPHARMACEUTICALS (PERs) (produits radiopharmaceutiquesémetteurs de positrons) - Drugs labelled with positron emitting radionuclides or containing positron emittingradionuclides that exhibit spontaneous transformation of unstable nuclei through positron decay.

PRECURSOR (précurseur) - A chemical substance or molecule which exists as an ingredient, reactant, orintermediate that is used for the chemical or radiochemical synthesis of a particular desired end product.

RADIOACTIVE CONCENTRATION (concentration radioactive) - Amount of radioactivity per unitvolume such as mCi/mL or MBq/mL.

RADIOACTIVITY (radioactivité) – Spontaneous decay of unstable nuclei and is quantified as the numberof 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 undesirableor adulterating radiochemicals as defined by specifications.

RADIONUCLIDE (radionucléide) – An unstable atom that undergoes spontaneous transformation withemissions of subatomic particles and/or photons of energy.



RADIONUCLIDE DOSE CALIBRATOR (étalonneur de doses) - Device measuring theradioactivity in Becquerels (Bq) or Curies (Ci), of a radioactive sample.

RADIONUCLIDE GENERATOR (générateur de radionucléides) - a radioactive parent anddaughter contained in an ion exchange column or dissolved in a suitable solvent in a liquid-liquidextraction system where the radioactive daughter is separated from its parent by elution from the ionexchange column, or a solvent extraction procedure. [C.03.001]

RADIONUCLIDIC PURITY (pureté radionucléidique) - The extent to which a drug is free fromundesirable or adulterating radionuclides as defined by a specification expressed as a percentage of theradioactivity of the specified radionuclide to the total radioactivity of the source.

RADIOSYNTHESIZER UNIT (RSU) (unité de radiosynthèse) - A closed-system device for the synthesisof radioactive drug substances used in the manufacturing of PERs. The system may be controlled bygraphical computer software programs.RADIOPHARMACEUTICAL (produit radiopharmaceutique) - a drug that exhibits spontaneousdisintegration of unstable nuclei with the emission of nuclear particles or photons.[C.03.201]

SPECIFIC ACTIVITY (activité spécifique) - Amount of radioactivity per unit mass or per mole such asmCi/mg, MBq/mg or mCi/mole, MBq/mole.

STARTING MATERIAL (produit de depart) - Any substance entering a production facility for use in theproduction of a drug product.

TARGET MATERIAL (cible) - A chemical substance which is bombarded with nuclear particles toproduce a desired radionuclide.

TOTAL CONTAINMENT GLOVE BOX (boîte à gants de confinement total) - A totally enclosedenvironment at negative pressure, whose primary purpose is radioactivity workspace localization.

TOTAL RADIOACTIVITY (radioactivité totale) - Amount of radioactivity present in the totalvolume of a reconstituted preparation or total volume of an eluate or solution, expressed as mCi or MBq.



PREMISES

Regulation

C.02.004

Interpretation

Note: Interpretation #10 of Regulation C.02.004 in the main GMP Guidelines is not applicable.

1. PERs and positron emitting radionuclide generators shall be fabricated, packaged/labelled, stored andquality tested in a manner which prevents cross-contamination and mix-up of drugs and/orradioactivity 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 berestricted to people involved in the process taking place. Although the same room or area may bedesignated for various purposes such as radiochemical synthesis, quality control, packaging andstorage, 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 whileproviding the necessary protection from radioactive airborne exposure to the personnel during criticaloperations.

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, totalcontainment glove box, etc.) surrounded by a positive pressure zone ensuring appropriate airquality requirements.

4.4 dedicating air handling filtration units to specific processing areas such as radioactive or non-radioactive. Air from the operations containing radioactivity shall be exhausted throughappropriate filters and the filters routinely checked for efficiency. It shall be ensured that theair is not re-circulated and air outlets are designed to avoid environmental contamination ofradioactive particles or gases. It shall also be ensured that a system is in place in order toprevent air from entering aseptic areas in the event the air exhaust is not functioning; alarmsand systems need to be in place to alert of changes in air flow patterns in the event of exhaustfailure.

4.5 cleaning transfer lines such that no contaminant is introduced into the finalradiopharmaceutical product.



4.6 raw materials are stored and sampled in a separate area or containment vessel. If sampling isperformed in the storage area, it is conducted in such a way as to prevent contamination orcross contamination. All materials are clearly marked and a log sheet is maintained for eachmaterial.

EQUIPMENT

Regulation

C.02.005

Interpretation

1. Radionuclide Production Target: when a positron emitting radionuclide is produced in an in-houseaccelerator, the following shall be ensured:

1.1 Reusable targets are operated in a manner to ensure that the product is free of any residualradionuclidic, radiochemical or chemical contaminants.

1.2 SOPs are available which describe the responsibility and frequency of cleaning andmaintenance of the target;

Note: Refer to the Raw Material Testing section for information.

2. Radiosynthesis apparatus (including dedicated Radiosynthesis Units): SOPs shall be required forthe operation, maintenance and cleaning of all radiosynthesis apparatus, including dedicatedRadiosynthesis Units. Prior to their initial use in manufacturing and production, the manufacturingprocess shall be validated against the specifications for the PERs being manufactured. In particular, itshall 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 synthesisparameters 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 thecorrect program or process parameters are used.



3. PERs and positron emitting radionuclide generators shall be fabricated, packaged, stored and testedwith equipment which does not contribute to the cross-contamination of drugs with unwanted sourcesof radioactivity such as radionuclidic and radiochemical contamination.

4. Radioactivity measuring equipment shall be shielded or located so as to avoid any source ofbackground radiation.

5. All equipment shall be regularly calibrated for accuracy, precision and reproducibility andcorresponding records maintained.

6. Critical equipment shall be subject to installation, operational, and performance qualification. Theresults shall be documented.

PERSONNEL

Regulation

C.02.006

Interpretation

1. In a PERs manufacturing establishment, regardless of whether it is a hospital, centralizedradiopharmacy, nuclear centre or institution, industrial manufacturer, or contract manufacturer, thehead of the establishment should be a professionally qualified person with extensive knowledge inPERs and PET in general. It is reasonable to expect that the qualifications of the individual includeexperience in radiopharmaceutical sciences and/or nuclear medicine.

2. For the fabricator, packager/labeller and tester, qualified individuals in respect of the PERsmanufacturing and quality control with additional expertise in radiochemistry and radiopharmacyincluding GMPs, should be in charge of, and retained in, the manufacturing department and the qualitycontrol department, respectively.

3. A minimum of two qualified persons shall be involved in the production (fabrication) and qualitycontrol of PERs. The production of the PERs shall be supervised and authorized only by a person withadequate education in radiochemistry including specialized training in PET chemistry and experiencein the manufacturing of PERs. The quality control and batch release shall be supervised and approvedby a different person with specialized knowledge, education and experience/training in the qualitycontrol of PERs and radiopharmaceuticals.

4. Personnel working in areas where radioactive materials are handled shall be given specific safetytraining in accordance with other applicable Federal jurisdictions. The Canadian Nuclear SafetyCommission (CNSC) regulations and guidelines on radiation safety should be consulted.



SANITATION

RegulationsC.02.007 and C.02.008

Interpretation

1. The sanitation program shall include procedures and practices in accordance with other applicablefederal 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 otherapplicable federal regulations. The CNSC regulations and guidelines on radiation safety should beconsulted.

RAW MATERIAL TESTING

Regulations

C.02.009 and C.02.010

Interpretation

Note: Interpretations #6 and #10 of Regulation C.02.009 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 thestarting 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 thesupplier. However, if these are not available or if the material is produced in-house, the PERmanufacturing facility is responsible for making all the testing and data available to the fullspecifications of the material.

3. Acceptance testing may be necessary for the target material if it has a potential impact on the purity ofthe final PER product.

4. The recycling method of O-18 water shall be documented and acceptance criteria/specifications arewell defined.

5. On arrival, packages containing radioactive materials such as importation of off-site PERradionuclides (e.g., F-18, Sr-82), shall be initially processed in accordance with other applicableFederal jurisdictions. The CNSC regulations and guidelines on radiation safety should be consulted.



6. The PER manufacturing facility establishes the reliability of the supplier by performing full testingagainst supplier specifications for the first three lots of radionuclides received and at appropriateintervals 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. Notwithstandingsubsection C.02.009 (1), each lot or batch of raw materials containing a radionuclide where thephysical half-life does not permit the completion of its tests under that subsection, validation must beprovided.

MANUFACTURING CONTROL

Regulations

C.02.011 and C.02.012

Interpretation

Note: Interpretations #23, 24, and 25.1 of Regulation C.02.011 in the main GMP Guidelines are notapplicable

Manufacturing Control for PERs is required to ensure proper labelling in order to prevent mix-ups and toensure cleaning and sterility since most of the critical testing is done retrospectively; and to design theproduction methodology in order to prevent cross-contamination. The following are guidelines for ensuringthe above criteria:

1. At all times during processing, shielded containers shall be identified with the name of the contentsand 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 ofradionuclide and shielding.

3. If data are available, it may be used retrospectively for process validation. The data should indicatethat the process is capable of consistently producing batches which meet predetermined specificationsspecifically for radionuclidic purity, radiochemical purity, sterility and endotoxins. The retrospectivevalidation should consider all failures and changes to the process.

4. Although concurrent testing for sterility and endotoxins are not appropriate for PERs, the membranefilter used for the sterile filtration of the final product shall be tested for filter integrity. Refiltrationcan be considered if filter integrity does not meet specifications.



5. Computer systems used in the production of PERs should be validated with a production run todemonstrate that they function as intended. Changes to the computer system including softwareupgrades shall be re-validated.

6. Where the final product is created in situ, validation for cleaning and sterility is required to ensure nocross-contamination of any nature such as radionuclidic, radiochemical or chemical for the target orthe 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 arereleased 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 systemshould 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 theevent a sample is returned the federal guidelines for transportation (refer to CNSC guidelines) shall befollowed.

QUALITY CONTROL DEPARTMENT

Regulations

C.02.013 to C.02.015

Interpretation

Note: Interpretations #4, 6, 7, 8, and 9 of Regulation C.02.014 in the main GMP Guidelines are notapplicable.

Interpretations #1 and 2 of Regulation C.02.015 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 personresponsible 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 aparticular 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 bythe quality control department. Where sterility and/or endotoxin testing is conducted on specific lotsof PERs, such lots may be released prior to completion of sterility and/or endotoxin testing, providedsuch testing is validated a priori and is completed as soon as possible.



4. PERs are stored, transported and handled in strict compliance with the market authorization andCNSC regulations.

PACKAGING MATERIAL TESTING

Regulations

C.02.016 and C.02.017

Interpretation

1. 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 inthe pre-market authorization.

2. Compatibility studies should be conducted on all materials in direct contact with the PER drug productsuch as vials and stoppers, as well as sterile filters, tubing, etc. for PER generators.

FINISHED PRODUCT TESTING

Regulations

C.02.018 and C.02.019

Interpretation

Note: Interpretations #1 and 7 of Regulation C.01.019 in the main GMP Guidelines are not applicable.

The production method for various PER products may vary in different centres, and hence, the testingfor 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, butis not limited to: total radioactivity, specific activity or radioactive concentration, radiochemicalpurity, pH, osmolality, radionuclidic purity, catalyst, residual solvents, etc., together with tolerancesand a description of all test methods or analyses used to determine those properties and attributes, insufficient detail to permit performance by qualified personnel. Such analyses include the monitoringof 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, productrelease tests are based (in real time) on a limited number of tests. The remaining tests are performedon a retrospective basis. However, in order to determine which tests are done on a retrospective basis,a rationale should be prepared and documented.



3. Sterility and endotoxin tests should be conducted on all batches of PERs according to finished productspecifications. 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 aspossible.

RECORDS

Regulations

C.02.020 to C.02.024

Interpretation

Note: Interpretation #7.1 of Regulation C.02.024 in the main GMP Guidelines is not applicable.

1. Maintenance of batch records at the PER manufacturing facility is important for all PER products asmost of them are released with retrospective testing. The batch record information shall include thefollowing:

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 currentfabrication, packaging, labelling and testing procedures shall be maintained by the legal agent inCanada.

3. For PER radionuclides, detailed information on the amount received, amount used in fabrication, andthe amount disposed of are maintained by the PET facility that acquires the radionuclide either fromwithin 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.



SAMPLES

Regulation

C.02.025

Interpretation


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 beretained by the fabricator of the drug for a period of three months after the lot or batch is last used inthe 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 ofraw material. These considerations would normally be addressed prior to market authorization specificto 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 isreleased with retrospective testing of those parameters not tested at release due to the short half-life ofthe radionuclide. The sample retention is also useful for investigational purposes when a batch fails tomeet certain specifications, such as sterility.

STABILITY

Regulations

C.02.027 and C.02.028

Interpretation

Note: Interpretation #1 (with the exception of 1.2) of Regulation C.02.027 in the main GMP Guidelines isnot applicable.

1. The aspects of the stability program of the drug are determined prior to marketing and prior toadoption of significant changes in formulation, fabrication procedures, or packaging materials thatmay affect the shelf-life of the drug. Any significant change in the source of radionuclide or anypackaging components in direct contact with the product will necessitate repeat assessment of thestability. 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.



1.2. the stability study should be designed such that data cover at least worst case scenario such asthe highest specific activity, total radioactivity or radioactive concentration to total volume thatis used for the acceptance of the PER drug product as per specification.

1.3. stability testing should include a determination of the stopper and vial compatibility with thePER drug product when in direct contact.

1.4. stability testing addresses the situation of shipping with exposure to extremes of temperatureconditions. The stability during shipping should be validated when no testing for productquality 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 atleast in triplicate samples of the same batch. Appropriate parameters should be analysed to establishthe stability of the PER under the proposed conditions. The test parameters used in the stability studymay 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 isdemonstrated. The stability is determined for the final packaged dosage form.

STERILE PRODUCTS

Regulation

C.02.029

Interpretation


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.

2.2. Aseptic attachment of sterile components and devices such as connecting a sterile syringe or asterile filter device to a sterile needle; inserting a sterile needle through a sanitized stopper intoa vial; and any penetration of, or creation of an open pathway into a sealed container-closuresystem after filling, as might occur with some post-filling sampling techniques.

2.3. Sampling for final product testing and partitioning of bulk PER into separate sterile vials priorto release shall be carried out in a Grade A area. Assembly of closed RSU manifolds andcomponents of “open systems” shall be done in a Grade A environment.



2.4 Sterile filtration requires a minimum filter rating of 0.22 µm. The integrity of the filter shouldbe verified before use and shall be verified after use by an appropriate method such as a bubblepoint, diffusion or pressure hold tests.

3. Air velocity in aseptic areas (e.g. laminar flow hoods) should be sufficient to sweep particulate matteraway from the filling and closing area. Whenever possible, equipment configuration should notdisrupt the laminar flow. Different areas in the fabricating process should be separated by physicalbarriers 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 half-life of the radionuclide involved and/or the thermal instability of the product, additional measuresshould be taken to minimize contamination. Such measures may include, but are not limited to, theuse of closed systems of fabrication and sterile filtration. Such equivalence shall be validated andsubsequent filling operations or any further operations involving the entry or opening of sterile closedcontainers are performed under aseptic conditions.

REFERENCES

1. “Annex 3: Guidelines on Good Manufacturing Practices for Radiopharmaceutical Products” WorldHealth Organization (WHO) Technical Report Series No. 908, 2003

2. “Guidance: PET Drug Products - Current Good Manufacturing Practice (cGMP)” Draft Guidance byFDA, March 2002

3. “Annex to the GMP Guidelines: Good Manufacturing Practices for Schedule C Drugs” GMP Annexfor Schedule C Drugs by Health Canada, June 1999

4. “Guidelines for Good Radiopharmacy Practice” A Guidance document published by Australia NewZealand Society of Nuclear Medicine Radiopharmacy Special Interest Group (ANZSNMRadiopharmacy SIG), September 2001

5. Australian Code of Good Manufacturing Practice for Medicinal Product: Annex 3, Manufacture ofRadiopharmaceuticals, August 2002.

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