Guidelines for Good Manufacturing Practice of Radiopharmaceuticals
Version 1.2
1 September 2010 Page 1 of 71
Scope of These Guidelines
These guidelines for manufacturing radiopharmaceuticals are intended to complement those already available (by SFDA) for pharmaceutical products as well as those for sterile pharmaceutical products.
The regulatory procedures necessary to control radiopharmaceutical products are in large part determined by the source of these products and methods of manufacture. Manufacturing procedures within the scope of these guidelines include: ¾ The manufacturing of radiopharmaceuticals in centralized radiopharmacies. ¾ The manufacturing of radiopharmaceuticals in nuclear institutes industrial manufacturers. ¾ The manufacturing of radiopharmaceuticals in positron emission tomography (PET) centers.
Radiopharmaceuticals can be classified into four categories: 1- Ready-for-use radioactive products. 2- Radionuclide generators. 3- Non-radioactive components (kits) for the preparation of compounds with a radioactive component (usually the elute from a radionuclide generator). 4- Precursors used for radiolabeling other substances before administration.
Radiopharmaceutical products include inorganic compounds, organic compounds, peptides, proteins, monoclonal antibodies and fragments and oligonucleotides labeled with radionuclide with half-lives varying from a few minutes to several days.
1 September 2010 Page 2 of 71 Glossary
Accelerator (Cyclotron): A machine to accelerate charged particles linearly or in circular paths by means of an electromagnetic field. The accelerated particles such as alpha (α) particles, protons (p), deuterons (d), and heavy ions possess high energies and can cause nuclear reactions in target atoms by irradiation.
Aerobic: A term used to indicate the growth of microorganisms in the presence of oxygen.
Anaerobic: A term used to indicate the growth of microorganisms in the absence of oxygen.
Annihilation Radiation: Gamma radiations of 511 keV energy emitted at 180˚ after a positron particle (β+) particle is annihilated by combining with an electron in matter.
Antibody (Ab): A substance that is produced in response to an antigen and forms a specific complex with it.
Aseptic Technique Aseptic technique refers to carrying out a procedure under controlled conditions in a manner that will minimize the chance of contamination.
Authorized Person: Person recognized by the authority as having the necessary basic scientific and technical background and experience.
Becquerel (Bq): A unit of radioactivity. One becquerel is equal to 1 disintegration per second.
Batch A defined quantity of final product produced in one production run often expressed either in mass (mg or gram) or volume (mL or L) or total radioactivity (Ci or GBq), total number of vials or doses.
1 September 2010 Page 3 of 71 Carrier-Free: A term used to indicate the absence of any stable isotopic atoms in a radionuclide sample.
Calibration 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.
Chelating Agent: A compound that binds to a metal ion by more than one coordinate covalent bond.
Clean Room A room in which the air is highly filtered in order to keep out impurities.
Colloid: A dispersion of a substance in a liquid. The size of the dispersed particles (colloid) ranges from 10 nm to 1 μm.
Critical Organ: The organ that is functionally essential for the body and receives the highest radiation dose after administration of radioactivity.
Cross-Contamination 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 multi-product facilities, potential cross-contamination can occur throughout the manufacturing process.
Curie (Ci): A unit of radioactivity. A curie is defined as 3.7 x 1010 disintegrations per second.
Dosage: A general term for the amount of a radiopharmaceutical administered in millicuries or millibecquerel.
1 September 2010 Page 4 of 71 Elution: A method of "washing off" an adsorbed substance from a solid adsorbing matter (such as ion- exchange resin) with a liquid.
Free Radical: A highly reactive chemical species that has one or more unpaired electrons.
Freeze Drying Freeze drying (lyophilization) is a process in which water is removed from a product after it is frozen and placed under a vacuum allowing the ice to change directly from solid to vapor without passing through a liquid phase.
Generator, Radionuclide: A device in which a short-lived daughter is separated chemically and periodically from a long-lived parent adsorbed on adsorbent material. For example, 99mTc is separated from 99Mo from the molybdenum generator by eluting with saline.
Half-Life (tl/2): A unique characteristic of a radionuclide, defined by the time during which an initial activity of a radionuclide is reduced to one half. It is related to the decay constant (λ) by tl/2 = 0.693/λ.
Hot Cell A lead shielded total containment cabinets providing an environment of different classes.
Ionization Chamber: A gas-fi1led instrument used to measure radioactivity or exposure in terms of ion pairs produced in gas by radiations.
Isotopes: Nuclides having the same atomic number, that is, the same number of protons in the nucleus,
14 12 but different number of neutrons. Examples are 6 C and 6 C .
Labeled Compound: A compound containing radionuclide as integral component of the molecule.
1 September 2010 Page 5 of 71 Marketing Authorization It is a legal governmental permission process given to radiopharmaceuticals manufacturer to control their marketing.
Manufacturing Authorization It is a legal governmental permission process given to radiopharmaceuticals manufacturer to control their production.
Metastable State (m): An excited state of a nuclide that decays to the ground state by the emission of radiation with a measurable half-life (e.g. 99mTc).
No Carrier Added (NCA): Indicates the status of a radionuclide sample where no stable atom of the same element has been added purposely.
Parenteral: A term indicating the route of drug administration other than oral. Examples are intrathecal, intravenous, interstitial, and intramuscular.
Radiation Safety Officer: A physicist who oversees of radiation safety in work place as well as the general public in the vicinity.
Radiochemical Purity: The fraction of the total radioactivity in the desired chemical form. If 99mTc-MAA is 90% pure, then 90% of the radioactivity is in the 99mTc-MAA form.
Radiolysis: A process by which radiolabeled compounds are broken up by radiations from the radionuclide in labeled molecules.
Radionuclidic Purity: The fraction of the total radioactivity in the form of the stated radionuclide. Any extraneous radioactivity such as 99Mo in 99mTc-radiopharmaceuticals is an impurity. Radiopharmaceutical:
1 September 2010 Page 6 of 71 A radioactive drug that can be administered safely to humans for diagnostic and therapeutic purposes.
Radiosynthesizer Unit (RSU) A closed-system device for the automated synthesis of radioactive drug substances. The system may be controlled by graphical computer software programs.
Sievert (Sv): The unit of absorbed dose equivalent and equal to 100 rem.
Standard Operating Procedure (SOP): An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.
Target Material A chemical substance which is bombarded with nuclear particles to produce a desired radionuclide.
Tracer: A radionuclide or a compound labeled with a radionuclide that may be used to follow its distribution or course through a chemical, physical, or metabolic process.
1 September 2010 Page 7 of 71
Chapter 1 Radiation Protection and Safety
Introduction Radiation protection and safety at any radiopharmaceutical production facility is concerned with the protection of individuals and mankind as a whole. The main type of radiation of interest in nuclear medicine practice is classed as ionizing radiation, including X-rays (x), gamma rays (γ), beta particles (β), alpha particles (α), positrons (β+), neutrons (n) and protons (p). The major objective of radiation safety is to reduce public and occupational exposure to a minimum, keeping in mind the "ALARA" principle (As Low As Reasonably Achievable) and the current national or/and international guidelines.
Principle 1.1 Following careful attention to the four fundamental factors together with the use of well-planned techniques and procedures should lead to the safest working conditions and lowest exposures: a- Time of exposure: The time spent near radioactive material should be minimized. b- Distance from the source: The distance from the source should be kept as far as practicable. c- Amount of shielding present: The amount of shielding required depends on the radiation type, quantity and energy. d- Radioactivity of the source: The quantity of radioactivity used should be the minimum necessary to produce a satisfactory result. 1.2 The following rules are the minimum requirement for good radiation practice and should be observed in radiopharmaceutical manufacturing facilities when working with radioactive materials: a- laboratory coats and disposable gloves should be worn at all times. Safety glasses should be used if the work is of a hazardous nature. Gloves should be changed at regular intervals in order to minimize the spread of contamination. b- personal film badges or thermoluminescent dosimeters (TLDs) must be worn at all times when handling radioactive materials or working in areas where they are handled or stored. c- all working surfaces should be covered with absorbent paper that has an impermeable plastic coating on the reverse side.
1 September 2010 Page 8 of 71 d- radioactive materials should be kept in closed, sealed vials within shielding containers at all times. e- all shielding containers and vials should bear a label identifying the radiopharmaceutical, the total radioactivity, the volume and/or the radioactive concentration and the time and date of calibration. f- small spills that present no radiological hazard to persons should be cleaned up immediately. More serious spills may require evacuation of the area before cleanup is undertaken and should be reported to the local radiation safety officer. g- eating, drinking, smoking, the administration of medication or the application of cosmetics should be prohibited in areas where radioactive materials are handled or stored. h- foodstuffs, drinks or medication should not be stored in the same area as radioactive materials. i- in order to demonstrate confinement of radioactivity, a suitable electronic radiation detector should always be available when radioactive materials are manipulated. j- appropriate radioactive waste management (storage and disposal) should be in place in accordance with national and/or international radiation control legislation. k- current occupational exposure limits should be in accordance with national and/or international radiation control legislation.
Management and Training 1.3 Management: a- management should ensure safe and efficient facility operations at all times by establishing an organization, keeping in view the workload and support from other groups. b- the operation and maintenance of the facility should be entrusted to the facility operation group. c- the radiation protection services should be provided by the health physics personnel. d- the supporting facilities/services that comprise water, electricity, heating, air-conditioning, ventilation, compressed air, workshop, housekeeping, telephone, security, etc. should be the responsibility of the independent general service department. However, other supporting services (such as fire fighting, transport) should be provided after arrangement with the local radiation safety office. e- the movement of all radioactive materials from the facility should be strictly controlled through administration measures. Access to the facility should be controlled by security and head of facility.
1 September 2010 Page 9 of 71 f- the radiation work should be reviewed by the local radiation safety office or committee. It should review abnormal and normal operations, unusual occurrences, proposals for experiments, changes and modifications in the facility equipment and radioactive laboratories, working procedures, emergency planning and preparedness, etc. This radiation safety office or committee should report to the Head of the facility and give its comments and recommendations for further guidance by submission to the National Nuclear Regulatory Body.
1.4 Personnel Training: For the safety of workers and environment against nuclear hazards, management should establish, implement and assess personnel training. a- all radiation workers at the facility should undergo training according to the nature of their jobs and their responsibilities. b- all technical staff members should be obliged to attend a basic nuclear orientation course and then they should be given additional on job training within the facility. c- only qualified and/or certified senior technical staff and supervisors are allowed to run various operations in the facility. d- certificates should be awarded by an independent national regulatory body (if applicable).
Radiation Monitoring 1.5 External Radiation Monitoring: a- Areas and neighboring areas in which radiation sources are used or stored should be monitored at regular intervals. b- radiation surveys should be performed before starting a project or using radiation sources, after any significant modification of set-up and also periodically during operation. c- frequency of radiation surveys should be determined by the area health physicist depending on the nature and scale of operations carried out in the area. d- all radiation surveys should be carried out and a proper record should be maintained by heath physics personnel.
1.6 Surface Contamination Monitoring: a- principal objectives of a program of monitoring for surface contamination can be summarized as follows: i. to detect failure of containment;
1 September 2010 Page 10 of 71 ii. to detect departures from good operating procedures; iii. to limit surface contamination to levels at which the general standards of goods housekeeping are adequate; and iv. to provide information for the planning of programs of individuals monitoring and of air monitoring and for defining operational procedures. b- the presence of contamination on such surfaces as floors, bench tops, clothing, skin and so on should be monitored. c- smear surveys (wipe tests) are an indirect method of measuring surface contamination levels.
1.7 Air Contamination Monitoring: Air monitoring should be carried out in areas where airborne contamination may occur by disturbance of surface contamination on the surface in the active area.
1.8 Personnel Monitoring: a- the radiation exposure due to internally deposited radionuclide (such as inhalations and ingestion, etc.) should be determined periodically by either whole body counting or monitoring of excreta such as urine (Bioassay) or by scanning a particular organ. b- in case of an incident resulting in widespread contamination of laboratory environment, the workers should be asked to provide urine samples for immediate analysis.
Ventilation 1.9 Proper ventilation (shielded fume hood) should be maintained in the radiochemical laboratories where unsealed radioactive materials (gas, liquid, etc.) are handled when activity level between 1 and 10 times the maximum recommended body burden. 1.10 Glove boxes should be used when there is potential hazard of contaminating the working environment and/or exposing the worker more than 10 times recommended maximum body burden and/or whole body dose limit respectively. Airflow through the glove box is usually smaller than that of a fume hood and is in the order of 0.01 to 0.02 m3 /sec (25-50 ft3 /min).
Shielding and Remote Handling 1.11 Shielding should be provided for safe working conditions. The amount of shielding required depends on the radiation type, quantity and energy, the dimensions and
1 September 2010 Page 11 of 71 radioactivity of the sources and the dose rate that is considered acceptable for radiation workers. 1.12 Gamma radiation can be effectively shielded by using lead bricks or lead pots. 1.13 Beta and Alpha radiation are effectively shielded with aluminum or perspex. 1.14 Neutron radiation requires special shielding conditions (such as Boron mixed materials).
Packaging and Transportation of Radiopharmaceuticals 1.15 The packaging and transportation of either radioactive substances and/or radiopharmaceuticals should be designed to confirm to the national and/or international guidelines of radioactive material packaging and transportation. The necessary shielding against ionizing radiation and preventing loss and spillage of radioactive substances during the transport and in case of transport accidents should be provided. 1.16 The radiation levels should never exceed specified maximum levels (as defined by national and/or international regulatory authorities) when measured on the surface of the package and at 1 meter distance from the surface of the package. 1.17 To reduce radiation hazards from radioactive substances during transport and to prevent loss of radioactive substances, the following factors are of importance. a- selecting means of transport. b- design of packaging. c- administrative and physical control of package and transport. d- emergency planning.
Radioactive Waste 1.18 To avoid any serious source of internal and external radiation hazards from radioactive waste, adequate arrangements should be made for the proper collection and safe disposal of all kinds of radioactive wastes generated at the facility.
Decontamination 1.19 Personnel, clothing, equipment and work places may become contaminated with radioactive materials during routine operations in a radioactive area. It is the responsibility of the radiation workers concerned to ensure that decontamination operation is performed to reduce contamination at least to the permissible levels.
1 September 2010 Page 12 of 71 Chapter 2 Quality Management
Principle The main difference between radiopharmaceuticals and conventional medicines lies in the radioactivity and short usable life (in most instances) of the radioactive product. Radiopharmaceuticals are released to Nuclear Medicine Centers and administered to the patients before the completion of all the Quality Control testing. Therefore, the manufacturing authorization holder must ensure that the manufactured radiopharmaceutical products are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, efficacy and quality. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the organization, including organization suppliers and distributors. To achieve quality objective reliability there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating Good Manufacturing Practice and thus Quality Control. Such system should be fully documented and its effectiveness monitored. All parts of the Quality Assurance systems should be adequately resourced with competent personnel, suitable and sufficient premises, equipment and facilities.
The basic concepts of Quality Assurance, Good Manufacturing Practice and Quality Control are inter-related. They are described here in order to emphasize their relationships and their fundamental importance to the production and control of products.
Quality Assurance (Q.A.) 2.1 Quality Assurance is a wide ranging concept that covers all matters which individually or collectively influence quality of a product. It is the sum total of organized arrangements made with the objective of ensuring that products are of the quality required for their intended use. The system of Quality Assurance appropriate for the manufacture of radiopharmaceutical products should ensure that: a- products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice and Good Laboratory Practice; b- manufacturing and control operations are clearly specified and Good Manufacturing Practice applied; c- all staff responsibilities are clearly specified;
1 September 2010 Page 13 of 71 d- arrangements are made for the manufacture, supply and use of the correct raw and packaging materials; e- all necessary controls on intermediate products, and any other in-process controls and validations are carried out; f- the product is correctly processed and checked, according to the defined procedures; g- products are not sold or supplied before an authorized person has certified that each production batch has been produced and controlled in accordance with the requirements of the Saudi Food & Drug Authority (SFDA) and any other regulations relevant to the production, control and release of products; h- satisfactory arrangements exist to ensure that the products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; i- there is a procedure for self-inspection and/or quality audit which regularly appraises the effectiveness and applicability of the quality assurance system.
Good Manufacturing Practice for Radiopharmaceutical Products (GMP) 2.2 Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Saudi Food & Drug Authority (SFDA) or product specification. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are as follow: a- all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing products of the required quality and complying with their specifications; b- all critical processes and significant changes to the process are validated; c- all necessary facilities to ensure GMP are provided including: i- appropriately qualified and trained personnel; ii- adequate premises and space; iii- suitable equipment and services; iv- approved procedures and instructions; v- correct materials, containers and labels; vi- suitable storage and transport. d- procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities;
1 September 2010 Page 14 of 71 e- operators are trained to carry out procedures correctly; f- records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated; g- records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; h- distribution of products minimizes any risk to their quality; i- a system is available to recall any batch of product, from sale or supply; j- complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent reoccurrence.
Quality Control (Q.C.) 2.3 Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications, testing, organization, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are neither released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The basic requirements of Quality Control are as follow: a- adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing raw materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; b- samples of raw materials, packaging materials, intermediate products, bulk products and finished products are taken by trained personnel and by methods approved by Quality Control; c- test methods are validated; d- records are made, manually and/or by recording instruments which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated; e- the finished products contain active ingredients complying with the qualitative and quantitative composition of the marketing authorization, are of the purity required, and are enclosed within their proper container and correctly labeled; f- records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against
1 September 2010 Page 15 of 71 specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures; g- no batch of product is released for sale or supply prior to certification by an authorized person that it is in accordance with the requirements of the marketing authorization; h- sufficient reference samples of raw materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.
1 September 2010 Page 16 of 71 Chapter 3 Personnel and Training
Principle The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of radiopharmaceutical products relies upon people. For this reason there must be sufficient number of qualified personnel to carry out all tasks which are the responsibility of the producer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of GMP and the radiation protection practice that affect them. The producer must have an updated organization chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of GMP. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.
Personnel Qualifications 3.1 The producer should have an adequate number of personnel with the necessary qualifications including appropriate education, training and practical experience in the field of radiochemistry, radiopharmacy, radiation physics, microbiology and other related disciplines and skills.
Key Personnel 3.2 Key Personnel include the head of Production, the head of Q.C., and authorized person(s). Normally key posts should be occupied by full-time personnel. The heads of Production and Q.C. must be independent from each other. In addition an adequate number of technically trained personnel should be available to carry out the production and control operations in accordance with established procedures and specifications.
Key Personnel Responsibilities Production Supervisor 3.3 A person responsible for supervising radiopharmaceutical production section generally has at least the following responsibilities: a- to approve the instructions relating to production operations and to ensure their strict implementation;
1 September 2010 Page 17 of 71 b- to ensure that the production records are evaluated and signed by an authorized person before they are sent to the Q.C. unit; c- to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality; d- to check the maintenance of his section, premises and equipment; e- to ensure that the appropriate validations are done; f- to ensure that the required initial and continuing training of his section personnel is carried out and adapted according to need.
Q.C. Supervisor 3.4 A person responsible for supervising the Q.C. section generally has at least the following responsibilities: a- to approve or reject raw materials, packaging materials, intermediate, bulk and finished products; b- to evaluate batch records; c- to ensure that all necessary testing is carried out; d- to approve specifications, sampling instructions, test methods and other quality control procedures; e- to approve and monitor any contract analysis; f- to check the maintenance of his department, premises and equipment; g- to ensure that the appropriate validations are done; h- to ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.
Operators 3.5 The persons engaging in activities in production and quality control generally have the following responsibilities relating to quality. These may include: a- the authorization of written procedures and other documents, including amendments; b- the monitoring and control of the manufacturing environment; c- facility cleanness; d- calibration and process validation; e- the approval and monitoring of suppliers of materials; f- the approval and monitoring of contract manufacturers; g- the designation and monitoring of storage conditions for materials and products; h- the retention of records;
1 September 2010 Page 18 of 71 i- the monitoring of compliance with the requirements of GMP; j- the inspection and investigation to monitor factors which may affect product quality.
Training 3.6 All production and Q.C. personnel should be trained in the principles of GMP, radiation protection and any relevant theory of the tasks assigned to them. Similarly, all other personnel (e.g. maintenance, service, cleaning) whose duties take them into manufacturing areas should receive appropriate training. 3.7 Newly recruited personnel should receive training appropriate to the duties assigned to them. 3.8 Continuing training should be given by qualified individuals, and its practical effectiveness should be periodically assessed and recorded. Training programs should be available, approved by either the person responsible for Production or the person responsible for Q.C. 3.9 Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly radioactive, toxic, infectious or sensitizing materials are handled, should be given specific training by qualified individuals. 3.10 Visitors or untrained personnel should not be taken into the production and Q.C. areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised. 3.11 The concept of Q.A. and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions.
Personal Hygiene 3.12 There should be an adequate number of personnel at all level having knowledge, skill and capabilities relevant to their assigned function, in good mental and physical health, and able to execute their duties professionally and properly. 3.13 All personnel should receive medical examination upon recruitment. It must be the producer's responsibility that there are instructions ensuring that health conditions that can be of relevance to the quality of products come to the producer's knowledge. After the first medical examination, examinations should be carried out periodically when necessary for the work and personal health.
1 September 2010 Page 19 of 71 3.14 Steps should be taken to ensure that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the production of pharmaceutical products. 3.15 Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out. 3.16 Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production, laboratory and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected, should be forbidden. 3.17 Direct contact should be avoided between the operator's hands and the exposed product as well as with any part of the equipment that comes into contact with the products. 3.18 Personnel should be instructed to use the hand-washing facilities. 3.19 All employees should be instructed and encouraged to report to their immediate supervisor any conditions that they consider may adversely affect the products.
1 September 2010 Page 20 of 71 Chapter 4 Premises and Facilities
Principle Premises should be located, designed, constructed, and equipped to suit the operation to be carried out according to GMP and radiation protection. The individual working areas should be adequate so that any risk of errors, cross-contamination or other mix-ups are eliminated or reduced to a minimum.
Premises 4.1 Premises should be sited to provide radiation and contamination protection to personnel and environment. 4.2 Premises should be sited to avoid contamination from external environment or adjacent premises. 4.3 Premises should be carefully maintained, to facilitate and enhance quality of products. facility should be cleaned and where applicable disinfected according to detailed written procedures. 4.4 Premises should be designed and equipped to afford maximum protection against the entry of insects or other animals. 4.5 Steps should be taken in order to prevent the entry of unauthorized people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in these areas. 4.6 Buildings and facilities should have adequate working space for the orderly placement of equipment and materials to prevent mix-ups and contamination. 4.7 The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups or contamination. 4.8 There should be defined areas or other control systems for the following activities: a- receipt, identification, sampling and quarantine of incoming materials, pending testing and approval; b- quarantine before release or rejection of the products; c- sampling of the products; d- holding rejected materials before further disposition (e.g., return, reprocessing or destruction); e- storage of released materials and shielded storage for released radioactive products; f- production and Q.C. operations; g- packaging and labeling operations;
1 September 2010 Page 21 of 71 4.9 Adequate, clean washing, showering, radiodecontamination and toilet facilities should be provided for personnel. These washing facilities should be equipped with hot and cold water as appropriate, soap or detergent, air driers or single service towels. 4.10 A dedicated and self-contained facilities must be available for the production of particular products, such as highly radioactive materials, biological preparations and products derived from human blood or plasma. 4.11 Walls, floors and ceilings of production area should be smooth, free from cracks and open joints. Also it should not shed particulate matter and should permit easy and effective cleaning and if necessary disinfection. 4.12 Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas. 4.13 Premises for the packaging of products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.
Production and Quality Control Areas 4.14 Production and Q.C. laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross- contamination. There should be adequate suitable storage space for samples and records. 4.15 Production and Q.C. laboratories should be separated from each other. 4.16 Q.C. laboratories for radiopharmaceuticals and biologicals should be separated from each other. 4.17 Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity,etc.
Storage Areas 4.18 Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products including: raw and packaging materials, intermediates, finished products, products in quarantine (released, rejected, returned or recalled). 4.19 Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these conditions should be provided, checked and monitored.
1 September 2010 Page 22 of 71 4.20 Receiving and dispatch ways should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage. 4.21 Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine should give equivalent security. 4.22 There should be a separate sampling area for raw materials and it should be conducted in such a way to prevent contamination or cross-contamination. 4.23 Segregated areas should be provided for the storage of rejected, recalled or returned materials or products. 4.24 Highly radioactive materials or products should be labeled and stored in shielded and secure areas. 4.25 Printed packaging materials are considered critical to the conformity of the products and special attention should be paid to the safe and secure storage of these materials.
Utilities 4.26 All utilities that could impact on product quality (e.g. steam, gases, compressed air, heating, ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available. 4.27 Adequate ventilation, air filtration and exhaust systems should be provided, where needed. These systems should be designed and constructed to minimize risks of contamination and cross-contamination and should include equipment for control of air pressure, dust, humidity, temperature and microorganisms, as appropriate to the stage of manufacture. Particular attention should be given to areas where products are exposed to the environment. 4.28 Separate air handling units should be used for radioactive and non-radioactive areas. Air extracted from areas where radioactive products are handled should not be recirculated and should be exhausted through appropriate filters (that are regularly checked for performance) to avoid environmental contamination. 4.29 Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control systems or alternative means. Pipework should be located to avoid risks of contamination. 4.30 Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when needed.
1 September 2010 Page 23 of 71 4.31 Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the products during their manufacture and storage, or the accurate functioning of equipment. 4.32 In general any radioactivity should be handled within maintained negative pressure. In contrast positive pressure areas should be used to process sterile products. Therefore, the production of radiopharmaceuticals should be carried out under negative pressure surrounded by a positive pressure zone in order to protect the internal and external environment.
Ancillary Areas 4.33 Rest and refreshment rooms should be separate from other areas. 4.34 Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas. 4.35 Maintenance workshops should be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. 4.36 Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.
Lighting 4.37 Adequate lighting should be provided in all areas, particularly in productions areas where visual on-line controls are carried out.
Sewage and Refuse 4.38 Specific disposal systems should be mandatory for radioactive substances. These systems should be carefully maintained and documented to prevent radiocontamination and exposure of personnel and others within and outside the facility. 4.39 In other hand, non-radioactive sewage, refuse, and other waste should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.
1 September 2010 Page 24 of 71 Sanitation 4.40 Buildings used in the manufacture of products should be properly maintained and kept in a clean condition and should be free of infestation by rodents, birds, insects and other vermin. 4.41 Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipments and materials to be used in cleaning buildings and facilities. 4.42 Written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labeling materials, or finished products.
Water 4.43 Water used in the manufacture of products should be demonstrated to be suitable for its intended use. 4.44 Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored.
1 September 2010 Page 25 of 71 Chapter 5 Equipment
Principle Equipments must be designed, constructed, located, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and in general, any adverse effect on the quality of products. In addition, it should take in consideration aspects of radiation protection and contamination to personnel and to the environment.
Design and Construction 5.1 Equipment used in the manufacturing of products should be of appropriate design, construction, adequate size and suitably located in order that the quality designed into each product can be assured and reproducible on the batch-to-batch production basis. 5.2 Manufacturing equipment should be designed, located and maintained to suit its intended purpose. 5.3 Equipment should be installed in such a way as to prevent any risk of error or of contamination. 5.4 Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. 5.5 Production equipment that comes in contact with the product should not be reactive, absorptive or additive which could affect the quality of the product. 5.6 Closed or contained equipment should be used whenever appropriate. Where open equipment is used or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination. 5.7 Balances and measuring equipment of an appropriate range and precision should be available for production and control operations. 5.8 Distilled, deionised and where appropriate other water pipes, should be sanitized according to written procedures which detail the action limits for microbiological contamination and the measures to be taken to ensure a reliable production of water of an appropriate quality. 5.9 Autoclaves used in the production areas for radiopharmaceuticals may be placed behind a lead shield to minimize radiation exposure to staff. In such circumstances it is important to allow for the increase in time needed to obtain the temperature required for the shielded vial within the autoclave.
1 September 2010 Page 26 of 71 5.10 Such autoclaves shall be checked for contamination immediately after use to minimize cross contamination of vials of the next autoclave cycle and to avoid distribution of contamination vials. 5.11 When used, conveyor belts should not pass through a partition between a clean area and a processing area of a lower level of air cleanliness unless the belt is situated in a sterilized tunnel or is continually sterilized.
Maintenance and Cleaning 5.12 Equipment should be cleaned and maintained according to the written procedures and without posing any hazard to the quality of the product. 5.13 Preventative maintenance should be carried out according to the written procedure schedule. 5.14 Defective equipment should be removed from production and control areas and la- beled as such until repaired, revalidated and calibrated prior to reuse. 5.15 Equipment should be cleaned, stored, and where appropriate sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the product. 5.16 Cleaning equipment used should not be a source of contamination and should be chosen to suit the operations. 5.17 After all planned or necessary equipment maintenance in clean areas, the area should be cleaned and disinfected appropriately before processing recommences if the standard of cleanliness and/or asepsis has not been maintained during the maintenance. 5.18 All equipment including sterilizers, air filtration systems, water treatment systems including stills should be subject to planned maintenance according to the written procedures and should be validated and approved by quality control after any major maintenance work has been carried out. 5.19 Glove boxes and other enclosures should also frequently cleaned externally and internally to avoid external contaminated vials. 5.20 Tongs and forceps used to increase the distance between the vials and the operator's hands and body shall also be frequently cleaned and checked. Lead shielding such as lead pots, lead castle/bricks used to minimize radiation exposure to staff shall be kept well painted and cleaned. 5.21 Records should be kept for maintenance, cleaning and sanitizing.
1 September 2010 Page 27 of 71 Calibration 5.22 All equipment should carry a labeling stating the last calibration date and next calibration date due and should be signed off by an authorized person. 5.23 Control, weighing, measuring, monitoring and test equipment should be calibrated according to written procedures and established schedules. 5.24 Equipment calibrations should be performed using certified standards. 5.25 Records of these calibrations should be maintained. 5.26 The current calibration status of equipments should be known and verifiable. 5.27 Instruments that do not meet calibration criteria should not be used.
Computerized Systems 5.28 Radiopharmaceuticals production related computerized systems should be validated. 5.29 Appropriate operational qualification should demonstrate the suitability of computer hardware and software to perform assigned tasks. 5.30 Computerized systems should have sufficient controls to prevent unauthorized access. In addition, the identity of operators entering and/or confirming data should be recorded. 5.31 Written procedures should be available for the operation and maintenance of computerized systems. 5.32 Incidents related to computerized systems that could affect the quality of products or the reliability of records or test results should be recorded and investigated. 5.33 Changes to the computerized system should be made according to a change procedure and should be formally authorized, documented and validated. Records should be kept of all changes, including modifications and enhancements made to the hardware, software and any other critical component of the system. 5.34 If system breakdowns or failures would result in the permanent loss of records, a back- up system should be provided. A means of ensuring data protection should be established for all computerized systems. 5.35 The procedures to be followed if the system fails or breaks down should be defined and validated. Any failures and remedial action taken should be recorded.
1 September 2010 Page 28 of 71 Chapter 6 Documentation and Records
Principle Documentation is an essential part of an effective quality assurance system. The main purposes are to define the system, to reduce the risk of misinterpretation and error inherent in oral communication, to ensure that detailed instructions are available to personnel and that established procedures are carried out in accordance with instructions. The documentation system should make it possible to trace an individual product back through the whole process including the use and disposal of each material and to discover the reason for defective radiopharmaceuticals. The documentation system should be designed to include both pharmaceutical and radiation protection aspects. It should be prepared and distributed with control. All documentation material should be dated and authorized by the relevant competent persons. Documents should be regularly reviewed and kept up-to-date.
General Requirements 6.1 All documents related to the manufacture of products should be prepared, reviewed, approved, dated and distributed according to written procedures. Such documents can be in paper or electronic form. 6.2 Documents of standard operating procedures (SOP) should be available for major items of manufacturing and test equipment. 6.3 Documents should have unambiguous title and contents; nature and purpose should be clearly stated. Reproduced documents should be clear, legible and reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 6.4 Documents should be regularly reviewed and kept up-to-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents. 6.5 Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible and indelible handwriting. Sufficient space should be provided for such entries. 6.6 The records should be authentic, unambiguous and completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of radiopharmaceutical products are traceable. They should be retained for at least one year after the expiry date of the finished product.
1 September 2010 Page 29 of 71 6.7 Any alteration made to the entry on a document and record should be recorded, signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. 6.8 A record of radioactive material activity received, used, and disposed should be kept as per requirements. Accurate values of radioactivity must be given on the secondary container, as it is difficult to give this information on primary container. 6.9 Data may be recorded by electronic data processing systems, photographic or other reliable means. But detailed procedures relating to the system in use should be available and the accuracy of the records should be checked.
Documents Required Specifications 6.10 There should be appropriately authorized and dated specifications for raw and packaging materials, bulk products and finished products, in terms of its chemical, physical and biological characteristics.
Specifications for Raw and Packaging Materials, Bulk Products and Finished Products 6.11 A set of specifications should be established for each raw and packaging materials, bulk products and finished products The list of specifications for raw materials, packaging materials and finished products is given below (appropriate items are applicable): a- name and code number; b- description of physical form and appearance; c- supplier(s) approved; d- tests and limits for identity, purity and assay; e- radioactivity contents should be recorded with time; f- sampling (including reference sample) and analytical methods to be used; g- storage conditions; h- safety precautions to be observed; i- expiry.
1 September 2010 Page 30 of 71 Manufacturing Document (Master Document) and Processing Instructions Formally authorized Manufacturing Document and Processing Instructions should exist for each product and batch size to be manufactured. 6.12 The Manufacturing Document should include: a- name of the product, with a product reference code unique to the batch produced; b- description of the radiopharmaceutical form, strength of the product and batch size; c- list of all raw materials to be used, the amount of each, described the designated name and a reference which is unique to that material. d- statement of the final yield with the acceptable limits and relevant intermediate yields, where applicable. 6.13 The Processing Instructions should include: a- statement of the processing location and the principal equipment to be used; b- methods to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating and sterilizing); c- detailed stepwise processing instructions (e.g. checks on materials, pretreatment, sequence for adding materials, mixing times, temperatures and pressure.); d- instructions for any in-process controls with their limits; e- where necessary, the requirements for bulk storage of the products including the container, labeling and special storage conditions where applicable; f- any special precautions to be observed.
Packaging Instructions 6.14 There should be formally authorized Packaging Instructions for each product, pack size and type. These should normally include, or have a reference to, the following: a- name of the product; b- description of radiopharmaceuticals, strength and shielding required; c- the pack size expressed in terms of number, activity or volume of the product in the final container; d- complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material; e- where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf life of the product; f- special precautions to be observed. g- description of the packaging operation, including any significant subsidiary
1 September 2010 Page 31 of 71 operations, and equipment to be used; h- details of in-process controls with instructions for sampling and acceptance limits.
Records Required 6.15 Records provide a history of each radioactive and non-radioactive raw material and batch of radiopharmaceuticals, including their preparation, packaging, quality control, storage and distribution and also of all other relevant parameters that can affect the quality of the final product.
Raw Material Records Receipt 6.16 There should be written procedures and records for the receipt of each delivery of each raw and packaging material. 6.17 The records of the receipts should include: a- the name of the material on the delivery note and container; b- the "in-house" name and/or code of material (if different from supplier); c- date of receipt; d- supplier’s name and manufacturer’s name; e- manufacturer’s batch or reference number; f- total quantity and number of containers received; g- the specific identification number assigned after receipt; h- any relevant comment (such as incorrect labeling, container damage, broken seals and evidence of contamination). 6.18 There should be written procedures for the internal labeling, quarantine and storage of raw materials, packaging materials and other materials.
Sampling 6.19 There should be written procedures for sampling, which include: a- the person(s) authorized to withdraw samples; b- method of sampling, the sampling plan and standard used in the sampling plan; c- precautionary measures taken during sampling including use of special equipment and sample container(s) by authorized person(s) to withdraw samples; d- location of sampling; e- quantity of sample(s) to be withdrawn;
1 September 2010 Page 32 of 71 f- name of the product and code number; g- date of sampling.
Testing 6.20 There should be written procedures for testing materials and products at different stages of manufacture. The record of testing should include at least the following data: a- the name of the material or product and, where applicable, dosage form; b- the batch number and the manufacturer and/or supplier; c- reference to the relevant specifications, testing procedures and equipment to be used; d- test results, including observations and calculations, and reference to specifications (limits); e- date of inspection and testing; f- the initials of the person(s) who performed the testing and verified the testing and calculations ; g- a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person; h- a cross reference to any relevant certificate of analysis.
Batch Manufacturing Records 6.21 The batch manufacturing record is one of the most important documents for following and recording the production process. It may contain details of complete method and must carry a batch number. Batch manufacturing record must contain: a- name of the product; b- space for recording checks of equipment and workstations. c- batch numbers for each raw material. d- initials of person(s) who weighed or measured each material and initials of person who checked each of these operations. This check also includes identity and batch number of material. e- results of yield measurements at intermediate stages and of process controls signed by the person carrying them out along with the initials of the person responsible for each critical stage of manufacture. f- the final yield and the number of containers. g- a signature from the process supervisor confirming that everything has proceeded
1 September 2010 Page 33 of 71 in accordance with the master formula and that any variation is adequately explained. h- if the final dispensing and packaging is not included in the manufacturing process, a separate batch dispensing record may be kept containing all details about dispensing, packaging etc. including specimens of labels and instructions for use etc. i- quality control test results of reference to special reports. j- date and signature of the person authorizing the release of the product.
Quality Control Records 6.22 Quality control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows: a- a description of samples received for testing, including the material name, source, quantity, batch number or other distinctive code and the date of sampling and testing; b- a statement of, or reference to each test method used; c- a statement of the weight or measure of sample used for each test as described by the method; data on, or reference to the preparation and testing of reference standards, reagents and standard solutions; d- a complete record of all raw data generated during each test, in addition to graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested; e- a record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors; f- a statement of the test results and how they compare with established acceptance criteria; g- the signature of the person who performed each test and the date(s) tests were performed; h- the date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards. 6.23 Complete records should also be maintained for: a- any modifications to an established analytical method; b- periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;
1 September 2010 Page 34 of 71 c- all stability testing performed on finished products; d- out-of-specification (OOS) investigations and corrective action taken.
Release and Rejection Records 6.24 There should be written procedures for the release and rejection of materials and products, and in particular for the release for sale of the finished product by an authorized person.
Batch Packaging Records 6.25 A Batch Packaging Record should be kept for each batch or part of a batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity to be packed. 6.26 Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. Batch Packaging Records must contain: a- name of the product; b- dates, and times of the packaging operations; c- name of the responsible person carrying out the packaging operation; d- initials of the operators of the different significant steps; e- records of checks for identity and conformity with the packaging instructions; f- details of the packaging operations carried out, including references to equipment and the packaging lines used (if applicable); g- notes on any special problems or unusual events including details with signed authorization for any deviation from the manufacturing formula and processing instructions; h- quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of product obtained, in order to provide for an adequate reconciliation.
When radioactivity is involved in the packaging an additional operation namely shielding is required.
1 September 2010 Page 35 of 71 Distribution Records 6.27 There should be written procedures for the distribution of each batch of a product to facilitate recall of the batch, if necessary. The distribution record should include at least the following data: a- name, address and number of the customer that the product is shipped to; b- delivery order date and number; c- name, dosage form, strength, quantity delivered, batch number and expiry date of the product; d- special storage requirements or precautionary measures to handle the product; e- radiation protection measures in addition to the approval of radiation safety officer.
Records of Product Complaints and Adverse Reactions Report 6.28 There should be written procedures for the handling of product complaints. The record of product complaints and adverse reactions report should include at least the following data: a- product name and batch number; b- type of complaint or adverse reactions report; c- source of complaint or adverse reactions report; d- summary of complaint or adverse reactions report; e- method of handling of complaint or adverse reactions report; f- result of investigation; g- evaluation of complaint or adverse reactions report; h- response and follow up action to the complaint or adverse reactions report.
Returned, Recalled and Destruction Records 6.29 There should be written procedures for the handling of returned, recalled or destructed products. The record should include at least the following data: a- product name, batch number and batch size of returned, recalled or destructed product; b- date of receiving of the product returned or recalled; c- reason of return or recall; d- quantity of product returned, recalled or destructed; e- source of product returned, recalled or destructed; f- the handling and disposition of returned product.
1 September 2010 Page 36 of 71 g- the guidelines for making decision either to salvage, reprocess, or destroy the returned or recalled product and the method of destruction; h- follow up action taken.
Others 6.30 Log books should be kept for major or critical equipments. In addition written procedures for validation, calibration, maintenance, environmental monitoring, cleaning, pest control, training and batch numbering should be established and implemented.
1 September 2010 Page 37 of 71 Chapter 7 Materials Management
Principle The manufacturing of radiopharmaceutical products involves the use of materials such as radioactive raw materials, non-radioactive raw materials and packaging materials. Consequently, special precautions must be taken in selecting, handling, testing and storing of these materials.
General Requirements 7.1 There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, approval or rejection of materials and packaging materials prior delivery. 7.2 Manufacturers should have a system for evaluating the suppliers of critical materials. 7.3 Materials should be purchased against an agreed specification approved by the quality unit(s) and should be identified with a distinctive code for each lot in each shipment received. 7.4 Changing the source of supply of raw materials should be approved by the quality unit. 7.5 Working standards can be established as in-house reference standards. These standards including reference standards must be stored in secure area. 7.6 Flint neutral borosilicate glass vials (USP type-1/equivalent) should be used for dispensing. 7.7 Sterile kit formulation and rubber stoppers with split ends should be used for freeze- drying operation. 7.8 Packing materials include thermocol boxes, cardboard boxes, tin containers, absorbent cotton, lead containers, labels etc. should be used. Outdated or obsolete primary packaging material should be destroyed and this disposal should be recorded.
Receipt and Quarantine 7.9 Upon receipt and before acceptance, each container or group of containers of materials should be examined visually for correct labeling, container damage, broken seals and evidence of tampering or contamination. Materials should be held under quarantine until they have been sampled, examined or tested as appropriate, and released by Q.C. for use. 7.10 Any canceled or damaged packaging material must be disposed of promptly. 7.11 Only raw materials that have been released by Q.C. can be used by production, such release should be by written instructions.
1 September 2010 Page 38 of 71 Sampling and Testing of Materials 7.12 Each lot of materials should be withheld from use until the lot has been sampled, tested, or examined and released for use by the quality control unit. 7.13 Representative samples of each shipment of each lot should be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, should be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve samples. 7.14 Samples should be conducted and collected in accordance with the following procedures: a- The containers of components selected should be cleaned where necessary, by appropriate means. b- Sterile equipment and aseptic sampling techniques should be used when necessary. c- Sample containers should be identified so that the following information can be determined: i- name of the material sampled; ii- the lot number; iii- the container from which the sample was taken; iv- the date on which the sample was taken; v- the name of the person who collected the sample. 7.15 Samples should be examined and tested as follows: a- At least one test should be conducted to verify the identity of each component of product. Specific identity tests, if they exist, should be used. b- Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Full analysis should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a full analysis should be performed at appropriate intervals and compared with the Certificates of Analysis. A report of analysis may be accepted from the supplier of a material, provided that at least one specific identity test is conducted by the manufacturer. Reliability of Certificates of Analysis should be checked at regular intervals. c- Each lot of a material that is liable to microbiological contamination should be subjected to microbiological tests before use.
1 September 2010 Page 39 of 71 d- Materials should be re-tested as appropriate to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity). Storage 7.16 Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination. 7.17 Materials stored in bags, or boxes should be stored off the floor and suitably spaced to permit cleaning and inspection. 7.18 Where special storage conditions are required (e.g. temperature, humidity, shielding) these should be provided, monitored and recorded. 7.19 Printed packaging materials should be stored in a designated secure area and the access to this area is limited to authorized person(s). 7.20 Printed packaging materials should be stored in closed containers in such a way as to prevent mix-ups. 7.21 A storage procedure that ensures the oldest stock of raw material, intermediate or ancillary item is utilized before a newer and identical stock item is utilized (i.e. First In / First Out "FIFO" principle concept). 7.22 Printed materials, cut labels and other loose printed materials should be issued by an authorized person following a documented procedure. These printed materials should be stored separately to avoid mix-up.
Waste materials 7.23 Provision should be made for the proper and safe storage of waste materials awaiting disposal. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed cupboards, as required by national legislation. 7.24 Waste material should not be allowed to accumulate. It should be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals. 7.25 To avoid any serious source of internal and external radiation hazards from radioactive waste adequate arrangements should be made for the proper collection and safe disposal of all kinds of radioactive wastes generated at the facility.
Dispensing 7.26 Dispensing of raw material should be done by authorized personnel in accordance with written procedures to ensure that the correct materials are accurately dispensed, labeled and the reference number must be documented for each material upon dispensing.
1 September 2010 Page 40 of 71 7.27 Proper measures must be taken to avoid cross contamination during dispensing. 7.28 Materials dispensed for a production batch must be kept together and labeled accordingly.
1 September 2010 Page 41 of 71 Chapter 8 Production of Radiopharmaceuticals
Principle Radiopharmaceuticals production practice can be categorized into: 1- Ready-for-use radioactive products. 2- Radionuclide generators. 3- Non-radioactive components (kits) for the preparation of compounds with a radioactive component (usually the elute from a radionuclide generator). 4- Precursors used for radiolabeling other substances before administration. Production facility requirements for these four categories are different and discussed in separate sections. The central radiopharmacy that may include positron emission tomography also undertakes the production/formulation of radiopharmaceuticals and hence is discussed in separate section in this chapter. In addition contingency plans for dealing with any foreseeable emergency situation involving radioactivity should be written down, displayed and known by personnel.
Hot Lab Procedure 8.1 Radiopharmaceuticals preparation should be performed in accordance with an approved written procedure which should be safe, straightforward and reliable. Careful attention should be given to prevent cross-contamination between products during production. 8.2 All radiopharmaceuticals should be handled either in fume hoods, glove boxes, hot cells, biohazard safety cabinets or laminar flow hoods (LFH) (based on the nature of radioisotopes). 8.3 Glove boxes should be provided with adequate shielding and remote handling facilities. 8.4 Separate areas should be used for each product to avoid cross contamination and should be provided with equipment and instruments necessary for the operation. 8.5 Introduction of the materials into the glove boxes/hot cells and removal of the products should be done without the spread of the radioactivity. 8.6 The transfer, storage and handling of radioactivity outside the glove boxes/hot cells should be done with adequate shielding and remote handling devices so as to minimize radiation exposure to personnel. 8.7 All of the operation should be carefully designed and standardized to minimize the spread of radioactivity. 8.8 Glove boxes/hot cells/ LFH should meet ventilation requirements for radioactive handling as described under Chapter 2.
1 September 2010 Page 42 of 71 8.9 Glove boxes/hot cells/LFH should comply with air quality requirements as per the codes of GMP for injectable and other preparations (Annex 1). 8.10 The facilities should satisfy the following conditions: a- All processes involving the manufacturing sterile radiopharmaceuticals should be carried out inside laminar flow hood class A placed in class C clean room. All processes involving the manufacturing non-sterile radiopharmaceuticals should be carried out in class C environment. b- hot lab, preparation room and quality control room should be provided with controlled environment to avoid contamination by microorganisms and particles. c- glove box/hot-cells for combining radiation protection and clean room requirements should be well standardized following national or international guidelines. 8.11 All other equipment should be chosen so as to maintain the air quality during operation. 8.12 Other facilities required at the hot lab: a- radioactive waste should be collected separately with lead shielding. b- personnel monitoring must be done as described in Chapter 2. c- radiation monitoring should be done during the processing operation. d- in case of contamination, steps as described under radiation protection procedures must be adopted.
Manufacture of Sterile Cold Kits 8.13 These products are strictly not radiopharmaceuticals, however, since they are the precursors for radiopharmaceuticals, are described as radiopharmaceuticals for practical purposes. 8.14 The manufacture of these kits involves special requirements to avoid the risk of microbial, pyrogen and particulate contamination. 8.15 Sterile kit preparations should be manufactured in accordance with GMP guidelines applicable to sterile injectable products in Class A workstation and Class B environment. Kits which can be terminally sterilized (e.g. S-colloid) may be prepared in Class A workstation and Class C environments. 8.16 Class A Laminar Air Flow (LAF) bench situated in a clean room of Class C should provide such an atmosphere for preparing and dispensing of kit solution. 8.17 A periodic sanitation program for the premises indicating cleaning procedures and cleaning intervals should be established and implemented. The microbial
1 September 2010 Page 43 of 71 contamination level in the room as well as dispensing areas should be monitored at regular intervals. 8.18 All preliminary work, such as cleaning, sterilization of glassware, containers, closures, filters and preparation of bulk solutions for the kits should be performed in the room adjacent to the kit preparation and dispensing room that is interconnected by hatches (pass box installed with interlock) for material transfer. 8.19 All surfaces in the area should be designed to facilitate cleaning and disinfecting.
Manufacturing Process A- Laminar Air Flow (LAF) Bench (vertical or horizontal air flow type or others) 8.20 The particle count in the LAF bench environment should not exceed a total of 3500 particles/m3 of a size of 0.5μm or greater and the greatest particle present in any sample should not exceed 5μm (Annex 1). 8.21 The LAF bench should be disinfected by swabbing with an appropriate disinfectant before using. 8.22 The performance of the LAF bench should be regularly checked by measurement of air velocity and periodical exposure of nutrient agar culture plate in the working area to detect microbial contamination.
B- Freeze Drying 8.23 A shelf type freeze-drying unit with required capacity should be used. 8.24 The unit should have facilities for stoppering the vials under vacuum or nitrogen gas by mechanical means. 8.25 Each time prior to loading of the samples, the freeze-dryer should be operated without load and performance of the machine with respect to the important parameters checked. 8.26 Where an isolator is used for the manufacture of sterile cold kits, this unit should be located inside clean air condition (class D). 8.27 The chemical identity of starting materials should be verified according to methods specified in the BP, USP or other pharmacopoeia. These materials should be tested for chemical purity and the presence of heavy metal contaminants. All materials should be handled as outlined in starting material control, in such a way that identity, potency and purity are guaranteed. 8.28 All water used for cold kit preparation must be at least of the quality of water for Injections BP, USP or other pharmacopoeia.
1 September 2010 Page 44 of 71 8.29 All saline used for cold kit preparation should be of the quality of 0.9 % w/v sodium chloride for Injection BP, USP or other pharmacopoeia. 8.30 Where stannous salts are used in cold kit manufacture, bulk solutions should be maintained under filtered ultra-high-purity nitrogen during preparation. 8.31 Methods of sterilization of all equipment, containers, closures etc. for aseptically processed products should follow the national or/and international standards and procedures. 8.32 The method of choice for the sterilization of bulk solutions used in the preparation of sterile cold kits is by filtration. All filters should undergo a filter integrity test, using a calibrated bubble-point apparatus after the filling cycle is complete. The result should be logged.
C- Gamma Ray Sterilization 8.33 Freeze dried kits may be sterilized by gamma irradiation. But the effects of the irradiation on the kit components should be studied.
Packaging and Labeling Packaging and labeling should be an important aspect of GMP while dispatching radiopharmaceuticals or cold kits. They should be carried out keeping in view the product properties e.g. sensitivity to shock, heat or moisture and also the means of transportation available.
A- Packaging Operation 8.34 When setting up a program for packaging operations, attention should be given to avoid cross-contamination, mix-ups or substitutions. 8.35 Different products should not be packaged in close proximity to each other. 8.36 Name (s) and batch number of the products being dispatched should be displayed on the product. 8.37 Checks should be made to ensure that any electronic code reader, label counters or other similar devices are operating correctly. 8.38 Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. 8.39 Once the packaging of particular product is complete the batch-coded packaging material left should be destroyed.
1 September 2010 Page 45 of 71 B- Labeling 8.40 The label on the container should include: a- the approved name of the product, product identification code and batch number ; b- radioactive concentration with date and time (may be on the secondary container); c- the composition (quantitative); d- instructions for reconstitution or a reference to the location of these instructions (for kits); e- storage conditions; f- the expiry date; g- the name of the manufacturer. 8.41 Additional information may be required to meet regulatory and users requirements.
Central Radiopharmacies 8.42 Operations carried out in hospital and central radiopharmacies vary from simple dispensing to manufacturing of kits and radiopharmaceuticals. So the facilities should commensurate with these functions. The principles of radiopharmacy and pharmaceuticals GMP requirements described in earlier sections should be followed and adopted/modified to the scale of operations. 8.43 Facilities should be designed and constructed as per the radiopharmacy and phar- maceuticals needs. 8.44 On arrival, packages containing radioactive materials should be inspected for signs of damage and monitored with a survey meter for leakage. 8.45 A wipe test should be performed to determine radioactive contamination on the surface of any shipment container and any leakage should be reported to the supplier. 8.46 Serious spills should require evacuation of the area before any cleanup is undertaken and should be first reported to the radiation safety officer. 8.47 Radionuclides, kits and diluents should be checked for identity, expiry time/date and appearance. 8.48 Identifying labels with a dated batch number should be affixed to reagent vials and shielding containers prior to the addition of radioactive material. 8.49 A radiopharmaceutical record sheet should be maintained for each batch of material. The record should include batch-number, manufacturer, date received, expiration time/date, preparation procedure, Q.C. and calibration results. Each dose from this batch should be recorded with the time, activity, dose volume and if applicable patient's name/file number.
1 September 2010 Page 46 of 71 8.50 Appropriate shielding should be selected. Components, labels and equipment should then be rechecked. 8.51 Each preparation should be performed in accordance with an approved written procedure that should be safe and reliable. Where possible, methods should be devised in which all the components required are contained in pre-sterilized vials with the only manipulative procedure being aseptic transfer between vials using syringes. Methods requiring manipulation in open containers should be avoided unless aseptic conditions are adhered. 8.52 The number of cap punctures should be kept to a minimum to prevent coring and shedding of particles. 8.53 Closures should be swabbed with an appropriate bactericide each time an entry is made. 8.54 Careful attention to technique should be given to prevent cross-contamination between products during reconstitution or dispensing procedures. 8.55 The majority of the radiopharmaceuticals in the hospitals are produced by eluting Tc-99m from a closed generator system and adding it to the sterile cold kits in a closed system. This should be done in a place with good hygiene and appropriate shielding. 8.56 When more complex procedures like cell labeling for re-injection is undertaken it is necessary to maintain both cell viability and sterility and to avoid operator exposure to biological and radiation hazards. Therefore, such operation should be performed in Biological Safety Cabinet. 8.57 Radiolabelling of patient cells for re-injection requires, in addition to approved techniques, the use of biological containment devices, which include the following: a- Biological Safety Cabinet Class II (BSC II). b- Biological Containment Device Class III (BCD III), as developed for work with high risk microorganisms. 8.58 Where the manufacturer does not guarantee the sterility of the eluate, the eluate should be sterilized by autoclaving (according to BP or USP specifications or their equivalent) or filtration through a 0.22 micron filter into a sterile vial. The total radioactivity should be measured and volume and calibration time noted. These data should be recorded on a daily worksheet, or similar. Using aseptic technique, the eluate should be used to reconstitute the radiopharmaceutical in accordance with the established protocols or manufacturer's instructions. 8.59 Dosage levels should be determined based on patient history, age, weight, sex and surface area.
1 September 2010 Page 47 of 71 8.60 Each dose should be calculated, aseptically withdrawn and measured prior to administration. 8.61 Care should be taken to ensure even distribution of particulate radiopharmaceuticals prior to withdrawal. 8.62 Unless otherwise indicated, care should be taken to prevent, as far as possible. ingress of air into products containing stannous ion or any other reducing agent. 8.63 Appropriate steps should be taken to ensure that the intended agent, in the intended dose, in the intended dosage form is received by the intended patient at the intended time via the intended route of administration. 8.64 Safe work practices ensuring that there is no possibility of re-use of syringes or needles should be followed. 8.65 Contingency plans for dealing with any foreseeable emergency situation involving radioactivity should be written down, displayed and known by personnel.
Positron Emission Tomography (PET) Radiopharmaceuticals Many radiopharmaceuticals used in positron emission tomography (PET) are prepared using short-lived radionuclides. Because of the very short half-lives involved, the preparation of the radiopharmaceutical should take place either in the medical institution or nearby. In general, the GMP principles applicable to radiopharmaceuticals also apply to PET radiopharmaceuticals. As it is not possible to fully test these preparations prior to patient administration, the preparation process and its control should be thoroughly validated. 8.66 Particular attention should be paid to the irradiation conditions to establish the effect of changes in any parameter on the radionuclidic, radiochemical or chemical purity of the final product. Critical parameters include beam current, threshold energy, particle energy, isotopic composition of target material, target alignment, irradiation time, composition of backing material and chemical purity of target. 8.67 Tests should be established to ensure the satisfactory performance of automated equipment or synthesizers. 8.68 Radiation stability should be established for all components subjected to high radiation exposures and appropriate replacement and maintenance schedules established. 8.69 Because of the short life of the product, release may be based on a limited number of tests. Other tests may be performed subsequent to patient use to confirm the suitability of the product. 8.70 For radiopharmaceuticals labeled with a radionuclide for which the half life is greater than 20 minutes, it is recommended that the tests for pH, appearance, radiochemical
1 September 2010 Page 48 of 71 purity, radionuclidic identity, specific activity and bacterial endotoxin test to be performed on every batch of product. 8.71 For radiopharmaceuticals labeled with a radionuclide for which the half life is less than 20 minutes, it is recommended that the same tests be performed on every Q.C. sub-batch of product. 8.72 Sterility tests for each PET radiopharmaceutical intended for parenteral administration
are performed on each batch (T1/2 ≥ 20.0 minutes) or Q.C. sub-batch (T1/2 < 20.0 minutes). Sterility tests are initiated as soon as possible of sterile filtration. 8.73 Sterility, apyrogenicity, pH, isotonicity, chemical, radionuclidic and radiochemical purity should be determined as part of the final quality control testing during the vali- dation of the preparation procedure and for the initial production batches. Reasons should be sought for any failure to meet specification. In the event of a critical failure (e.g. for sterility) an investigation should be carried out. Where such an investigation leads to amendment of procedures, revalidation should be considered.
Storage of Finished Products
8.74 Written procedures describing the Storage of radiopharmaceutical products should be established and followed. They should include: a- quarantine of radiopharmaceutical products before release by the quality control unit; b- storage of finished radiopharmaceutical products under appropriate conditions of shielding, temperature, humidity, and light so that the identity, strength, quality, and purity of the products are not affected.
Distribution of Finished Products 8.75 Written procedures should be established, and followed, describing the distribution of finished radiopharmaceutical products. They should include: a- a procedure whereby the oldest approved stock of a radiopharmaceutical product is distributed first. Deviation from this requirement is permitted if such deviation is temporary and appropriate. b- a system by which the distribution of each lot of finished radiopharmaceutical product can be readily determined to facilitate its recall if necessary. c- products should be transported in a manner that does not adversely affect their quality. d- special transport or storage conditions for product should be stated on the label.
1 September 2010 Page 49 of 71 Rejection 8.74 Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorized personnel. 8.75 The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorized procedure after evaluation of the risks involved. Record should be kept of the reprocessing.
Recovery 8.76 The recovery of all or part of earlier batches which conform to the required quality by incorporation into a batch of the same product should be carried out in accordance with a defined procedure after the approval of the Q.C. unit.
Returns 8.77 Products returned from the market must be destroyed unless examination, testing and critical assessment by Q.C. prove that the product meets appropriate standards of safety, identity, strength, quality and purity in accordance with a written procedure.
1 September 2010 Page 50 of 71 Chapter 9 Quality Controls
Principle A Q.C. system should be established for each radiopharmaceutical to be prepared. Q.C. should take and test samples of starting materials, relevant intermediate products and finished products for conformity to specifications and to determine their release for use or rejection on the basis of the test results.
It is fully acceptable in a well-established production system to deliver radiopharmaceuticals to the user before some results of the quality control test are available. Some tests may then be finished before the product actually reaches the user; others such as the sterility test can only be used as a measuring control of the processes.
The Q.C. program should also include procedures for verifying the correct operation of equipment used in production and testing, as well as verifying and testing of both the production and storage area environments.
With the well-documented production system, established it is an obvious advantage to direct more effort into continuous surveillance of the method than into actual batch testing.
Sampling 9.1 Samples should be representative of the materials from which they are taken and should be taken in accordance with written instructions giving the method and equipment to be used. The amount to be taken and any special precautions needed. Due to the small number of batch, number of samples should be adequate to permit testing and repeat testing (reference samples).
Raw Materials 9.2 Raw materials control should include identity, purity and potency. Analytical certificates may limit the actual Q.C. to identification and evaluation of the certificate. 9.3 Special tests may have to be designed and carried out to show the absence of the very small amounts of specific impurities (e.g. in target enriched material). 9.4 Raw material to be used for the preparation or testing of radiopharmaceuticals should be quarantined until approval for use by Q.C. The new materials which are synthesized in house should be characterized and tested before use.
1 September 2010 Page 51 of 71 Finished Products A. Radionuclidic Purity 9.5 Radionuclidic purity testing should be performed on the radioactive raw material before the preparation of individual labeled compounds. 9.6 Beta and gamma-emitting impurities are normally the main concerns but for fission- produced materials alpha-emitting impurities should also be investigated. 9.7 Energy calibration of instruments should be performed frequently by reference sources and verified daily using a long-lived standard.
B. Radiochemical Purity 9.8 Radiochemical purity should be determined by a variety of techniques including chromatographic separation, solvent extraction, HPLC, electrophoresis and pre- cipitation. The selection of the technique will depend upon the complexity of the radiopharmaceutical preparation.
C. Radioactive Concentration 9.9 Independent determination of the actual radioactive concentration should be carried out by Q.C. with a different instrument from that used in the manufacture. 9.10 For any radiopharmaceuticals, radioactivity content, radioactive concentration and the dose/volume administered should be determined.
D. Chemical Purity 9.11 Chemical contamination such as the presence of trace amounts of metals should be determined and addressed to prevent or reduce possible effects on the radiolabelling of the radiopharmaceuticals. 9.12 For cold kits containing stannous salt as a reducing agent, the stannous content should be determined.
E. Particle Size 9.13 The particle number and sizes in suspensions or colloidal solutions should be determined.
F. Physical Test 9.14 The physical appearance of the radiopharmaceuticals such color and clarity should be determined.
1 September 2010 Page 52 of 71 G. pH 9.15 All radiopharmaceuticals should have an appropriate pH for their stability and integrity.
H. Sterility Test 9.16 All radiopharmaceuticals for parenteral administration should be sterile. Although it is not always possible to await the result of the sterility of the product before release for use because of short half life of the radioactive product, the test should constitute a control of the quality of production. The production process should be validated using appropriate test runs at regular intervals as described in the national or international pharmacopoeias . When radiopharmaceuticals or gases are sterilized by final filtration, all filters should undergo a filter integrity test using a calibrated bubble-point apparatus. 9.17 Sterility tests should be performed based on procedures described in the national or international pharmacopoeias.
I. Bacterial Endotoxin Test 9.18 All radiopharmaceuticals for parenteral administration should be tested for pyrogen by using LAL or/and rabbit test. This test should be performed based on procedures described in the national or international pharmacopoeias.
J. Biological Distribution 9.19 For some radiopharmaceuticals (newly manufactured), the biological distribution test should be performed as an indicator of the quality and expected performance of the radiopharmaceuticals. This test which is generally performed only in early stage of product development, should adopt the established procedures in the pharmacopoeia monographs.
K. Stability Testing 9.20 Stability studies should be performed on a minimum of three production batches. If discordant results are obtained between the three batches, further batches should be examined. 9.21 As many products show a sudden onset of instability, data should be obtained at intermediate points up to and beyond the planned shelf life of the product. 9.22 In the testing program, the product should be tested to full specification at preparation. At intermediate points, parameters that are likely to change should be measured.
1 September 2010 Page 53 of 71 Typical parameters include: a- Physical stability (e.g. particulate matters). b- Chemical stability e.g. pH, benzyl alcohol content. c- Radioactive concentration. d- Radiochemical purity. e- Biodistribution. f- Stannous tin content (for 99mTc cold kits). 9.23 In the stability study, particular attention should be paid to storage conditions. It is desirable that storage conditions be carefully controlled for the study. A room temperature study in non-air conditioned premises may give different results in winter and summer. 9.24 If the product is to be stored under refrigeration without the warning "Do not freeze", then stability, particularly physical stability (e.g. no precipitate formation, no denaturation of protein) at about -5°C should be demonstrated. 9.25 If the product is to be transferred to a second container prior to use (e.g. a syringe, vial) then stability for the storage time in that container should be demonstrated. 9.26 In the case of cold kits, the effect of kit age on the stability of the product after reconstitution should be demonstrated. 9.27 Reconstitution should be performed using the extremes of the reconstitution conditions and measurements should be made both at the time of reconstitution and at or after the time at which the reconstituted product expires. 9.28 Additional stability data should be available covering the claimed shelf life of the inactive product when reconstituted with both the highest and lowest activities of 99mTc to be used for preparation of the 99mTc-labelled radiopharmaceuticals in the minimum and maximum reconstitution volumes. 9.29 Stability data should also be available for the shelf life of the product in its final packaging form e.g. a syringe. 9.30 The data should be available for the highest radioactive concentration to be used for reconstitution.
Laboratory Instrumentation 9.31 A Q.C. system should also include testing of the environment such as ventilation system, air filters and LAF equipment. In addition, the instruments for determining radioactivity should also be regularly calibrated.
1 September 2010 Page 54 of 71 Reference Samples 9.32 Reference samples of all materials used and of the finished products should in principle be kept, normally until one year after the expiry date of the product itself or of the product they were used for or as long as national regulations may require. 9.33 The sample size should be so that two full analyses according to the specifications can be made one to be performed by the manufacturer and the other by an official laboratory. 9.34 Since such samples may require production and storage of large amounts of radioactivity, it may be acceptable to cut down on the sample size in individual cases. 9.35 For 99mTc radiopharmaceuticals at hospitals there is no need to keep reference sample of kits as the manufacturer is supposed to keep such samples. 9.36 As the remains of 99mTc radiopharmaceuticals will have to be kept for a few days for decay, they should also be kept to serve as reference samples for testing should any adverse reaction or unexpected distribution occur.
Water for Injection 9.37 A quality control testing procedure should also be established for locally produced distilled and purified water for injection in accordance with established national and/or international pharmacopoeias.
1 September 2010 Page 55 of 71 Chapter 10 Complaints and Product Recall
Principle Every radiopharmaceutical producer should have operating systems for complaint handling and product recall. In order to provide for all contingencies, operating system should be designed to recall, if necessary, promptly and effectively products known or suspected to be defective from the market.
Complaints 10.1 All quality related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure. 10.2 A qualified person should be designated responsible for handling the complaints and deciding the measures to be taken together with sufficient supporting staff to assist him. 10.3 Complaint records should include: a- name and address of complainant; b- name (and, where appropriate, title) and phone number of person submitting the complaint; c- date complaint is received; d- name and batch number of the product; e- type and nature of complaint; f- details of investigation performed. g- results of investigation and action taken. h- response provided to the originator of complaint; i- final decision on product batch or lot. 10.4 If a product defect is discovered or suspected in a batch, consideration should be given to checking other batches in order to determine whether they are also affected. 10.5 Every complaint, its investigation report and measure to be taken for overcoming the defect should be well documented and preserved for one year after the date that the complaint was received. 10.6 SFDA and all competent authorities of all countries to which product may have been identified or suspected to be defective or reported to have adverse reaction should be informed promptly.
1 September 2010 Page 56 of 71 Product Recalls 10.7 Every radiopharmaceutical producer should have a written procedure (regularly checked and updated when necessary) and an operating team for product recall independent of sales and marketing team. 10.8 The team should have the distribution record of the recall product and should be capable of taking action promptly at any time. 10.9 The distribution records should be readily available to the person(s) responsible for recalls and should contain sufficient information on wholesalers and directly supplied customers (with addresses, phone and/or fax numbers inside and outside working hours, batches and amounts delivered) including those for exported products and medical samples. 10.10 All competent authorities of all countries to which product may have been distributed should be informed promptly. 10.11 Recall product should be placed in quarantine until its fate is determined. 10.12 Quantities of the recall product delivered and recovered should be recorded and evaluated. 10.13 The manufacturers or importers of radiopharmaceuticals, or persons obtaining national or international manufacturing approvals must report recalls of radiopharmaceuticals to the authority concerned.
1 September 2010 Page 57 of 71 Chapter 11 Contract Manufacture and Analysis
Principle Contract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings which could result in a product or work of unsatisfactory quality. There must be a written contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party.
General Requirements 11.1 The contract should cover the manufacture and/or analysis and any technical arrangements made in connection with it. 11.2 All arrangements for contract manufacture and analysis including any proposed changes in technical or other arrangements should be in accordance with the marketing authorization for the product concerned. 11.3 The contract must clearly state the way in which the Authorized Person releasing each batch of product for sale exercises his full responsibility.
The Contract Giver 11.4 The Contract Giver is responsible for assessing the competence of the Contract Acceptor to carry out successfully the work required and for ensuring by means of the contract that the principles and guidelines of GMP as interpreted in this guide are followed. 11.5 The Contract Giver should provide the Contract Acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorization and any other legal requirements. 11.6 The Contract Giver should ensure that the Contract Acceptor is fully aware of any problems associated with the product or the work which might pose a hazard (e.g.: radioactivity) to his premises, equipment, personnel, other materials or other products. 11.7 The Contract Giver should ensure that all processed products and materials delivered to him by the Contract Acceptor comply with their specifications or that the products have been released by an Authorized Person.
The Contract Acceptor 11.8 The Contract Acceptor must have adequate premises and equipment, knowledge and experience, and competent personnel to carry out satisfactorily the work ordered by
1 September 2010 Page 58 of 71 the Contract Giver. Contract manufacture should be undertaken by a manufacturer who is the holder of a manufacturing authorization. 11.9 The Contract Acceptor should ensure that all products or materials delivered to him are suitable for their intended purpose. 11.10 The Contract Acceptor should not pass to a third party any of the work entrusted to him under the contract without the Contract Giver’s prior evaluation and approval of the arrangements. Arrangements made between the Contract Acceptor and any third party should ensure that the manufacturing and analytical information is made available in the same way as between the original Contract Giver and Contract Acceptor. 11.11 The Contract Acceptor should refrain from any activity which may adversely affect the quality of the product manufactured and/or analyzed for the Contract Giver.
The Contract 11.12 A contract should be drawn up between the Contract Giver and the Contract Acceptor which specifies their respective responsibilities relating to the manufacture and control of the product. 11.13 Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in radiopharmaceutical and pharmaceutical technology, analysis and GMP. 11.14 All arrangements for manufacture and analysis must be in accordance with the marketing authorization and agreed by both parties. 11.15 Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the changes. 11.16 The contract should specify the way in which the Authorized Person releasing the batch for sale ensures that each batch has been manufactured and checked for compliance with the requirements of Marketing Authorization. 11.17 The contract should describe clearly who is responsible for purchasing materials, testing and releasing materials, undertaking production and Q.C, including in-process controls and who has responsibility for sampling and analysis. In the case of contract analysis, the contract should state whether or not the Contract Acceptor should take samples at the premises of the manufacturer. 11.18 Manufacturing, analytical and distribution records, and reference samples should be kept by, or be available to, the Contract Giver. Any records relevant to assessing the
1 September 2010 Page 59 of 71 quality of a product in the event of complaints or a suspected defect must be accessible and specified in the defect/recall procedures of the Contract Giver. 11.19 Contract manufacturers (including laboratories) should be evaluated by the contract giver to ensure GMP compliance of the specific operations occurring at the contract sites. Contract Analysis laboratories should comply with the SFDA Guidelines for Good Laboratory Practice (GLP). 11.20 In the case of contract analysis, the Contract Acceptor should understand that he is subject to Inspection by the SFDA.
1 September 2010 Page 60 of 71 Chapter 12 Self Inspection
Principle Self inspections should be conducted in order to monitor the implementation and compliance with GMP principles and to propose necessary corrective measures.
Items for Self Inspection 12.1 Written instructions for self inspection should be established to ensure the compliance with GMP requirements. These may include at least the following items: a- personnel. b- premises and utilities. c- equipment. d- production and in-process control. e- quality control. f- storage of raw materials and finished products. g- documentation. h- printed packaging materials control. i- distribution of the products. j- calibration of instruments or measurement system. k- validation and revalidation. l- maintenance system. m- sanitation and hygiene. n- complaints management. o- recall procedures. p- results of previous self inspection and corrective steps taken.
Self Inspection Team 12.2 Self inspections should be conducted in an independent and detailed way by designated competent person(s) in GMP from the company.
Frequency of Self Inspection 12.3 The frequency at which self inspections are conducted depends on company requirements. Self inspection can be conducted partially (on production line, facility, SOP’s, etc). However, a complete Self inspection should be carried out once a year.
1 September 2010 Page 61 of 71 Self Inspections Records 12.4 All self inspections should be recorded. Reports should contain: a- self inspection results; b- evaluation and conclusions; c- recommended corrective action; d- implementation and assessment of corrective action.
Quality Audits 12.5 Quality audits consist of an examination and assessment of all or part of a quality system with the specific purpose of improving it. It is usually conducted by outside or independent specialists expert in GMP.
1 September 2010 Page 62 of 71 Chapter 13 Product Regulation and Manufacturer Licensing
Principle This section serves as guide to the requirements for regulation of radiopharmaceuticals and of licensing for their manufacture. The use of radiopharmaceuticals should be regulated according to the regulation of the national authorities.
13.1 Supply of unregistered goods or manufacture without a license is illegal. 13.2 A person ("person" here includes a corporation) who intend to obtain a license to import, export, manufacture, supply, distribute, etc. radiopharmaceuticals should have the necessary facilities and permits in accordance to the requirements stipulated by the national authorities in respective countries. 13.3 A licence / registration / permit to manufacture, possess, sell, purchase, dispose of or use radioactive materials must be obtained from the national authorities. In addition, to transport radioactive materials by air, sea, rail or road will require transport permit from the national authorities. 13.4 The person who imports, exports, or makes radiopharmaceuticals for supply must have them included in the register of diagnostic and therapeutic goods unless they are: a- specifically made for a particular person; or b- for clinical trials or for use within the hospital in the absence of a substantially similar registered products; or c- for critical situations; or d- made in a hospital pharmacy for patients within that hospital or its satellite hospitals; or e- cold kits manufactured by a radiopharmacist and/or radiochemist in a public or private hospital for use in the same hospital system. 13.5 The registration number of the product must be included on the product label.
1 September 2010 Page 63 of 71
ANNEXES
1 September 2010 Page 64 of 71 ANNEX 1 Manufacture of Sterile Products
Principle The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.
General Requirements 1- The manufacture of sterile products should be carried out in clean areas. 2- Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. 3- Entry to clean areas for personnel and/or for equipment and materials should be through airlocks. 4- The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. 5- Sterile products must be processed by aseptic means during all stages of processing or terminally sterilized after being sealed in their final container. 6- Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimize the risks of particulate or microbial contamination of the product or materials being handled. 7- Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. There are normally 4 grades of clean areas. Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position. Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. 8- In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air
1 September 2010 Page 65 of 71 system should be provided with appropriate terminal filters such as HEPA for grades A, B and C. Maximum Number of Particles Permitted in Each Grade
Maximum Number of Particles Permitted Grade At Rest In Operation 0.5 - 5 μm 5 μm 0.5 - 5 μm 5 μm US ISO EU per m3 per m3 per m3 per m3 100 5 A 3500 0 3500 0 1000 6 B 3500 0 350000 2000 10000 7 C 350000 2000 3500000 20000 100000 8 D 3500000 20000 not defined not defined
The “at-rest” state is the condition where the installation is operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.
Examples of operations to be carried out in the various grades are given in the table below.
Grade Examples of Operations for Terminally Sterilized Products US ISO EU
100 5 A Filling of products, when unusually at risk 10000 7 C Preparation of solutions, when unusually at risk. Filling of products.
100000 8 D Preparation of solutions and components for subsequent filling
Grade Examples of Operations for Aseptic Preparations US ISO EU
100 5 A Aseptic preparation and filling.
10000 7 C Preparation of solutions to be filtered.
100000 8 D Handling of components after washing.
9- The particulate conditions given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state after completion of operations. The particulate conditions for grade A “in operation”
1 September 2010 Page 66 of 71 given in the table should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. 10- The areas should be monitored during operation, in order to control the particulate cleanliness of the various grades. 11- Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations. 12- Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitization.
Recommended limits for microbiological monitoring of clean areas during operation
Recommended Limits for Microbial Contamination
Grade settle plates contact plates Glove print air sample (diam. 9 0 (diam. 55 5 fingers cfu*/m3 mm), mm), cfu/glove US ISO EU cfu/4 hours cfu/plate
100 5 A < 1 < 1 < 1 < 1 1000 6 B 10 5 5 5 10000 7 C 100 50 25 - 100000 8 D 200 100 50 - * cfu: colony-forming unit.
13- Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action. 14- Changing and washing should follow a written procedure designed to minimize contamination of clean area clothing or carry-through of contaminants to the clean areas. 15- Wristwatches, make-up and jewellery should not be worn in clean areas. 16- The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination.
1 September 2010 Page 67 of 71 The description of clothing required for each grade is given below: Grade D: Hair and beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area. Grade C: Hair, beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes* should be worn. They should shed virtually no fibers or particulate matter. Grade A/B: Headgear should totally enclose hair, beard and moustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilized, non-powdered rubber or plastic gloves and sterilized or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibers or particulate matter and retain particles shed by the body. 22- Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile protective garments should be provided at each work session. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least for every working session.
* For additional information refer to Annex 1 of the Saudi Food & Drug Authority (SFDA) Guidelines for Good Manufacturing Practice (GMP) for Pharmaceutical Product.
1 September 2010 Page 68 of 71
ANNEX 2 Comparison Between Manufacturing and Compounding
Manufacturing Compounding
Producer Manufacturer / Industry Hospital Radiopharmacy
Setting Commercial Mostly Clinical
Standard GMP Code of practice
Regulation National Regulatory Authority (e.g. FDA) Professional body/institution
Distribution Public Distribution Practitioner-patient
Marketing Yes No
Permission Investigational Authority Institutional Review Board (IRB)
1 September 2010 Page 69 of 71
National Authorities
Pharmaceuticals Saudi Food & Drug Authority (SFDA) Tel: +9661 4133102 Fax: +9661 4133528 P.O. Box 84983 Riyadh 11681
Ministry of Health Tel: +9661 4015555 Fax: +9661 4029897
Radioactive Products
General Security (Ministry of Interior) Tel: +9661 4052857 Fax: +9661 4023199
King Abdulaziz City for Science & Technology (KACST) Tel: +9661 4883555 +9661 4883444 Fax: +9661 4883756 P.O. Box 6086 Riyadh 11442
1 September 2010 Page 70 of 71 References
1. The Saudi Food & Drug Authority (SFDA) Guidelines for Good Manufacturing Practice for Pharmaceutical Products, Final Draft November 2005.
2. Guidelines for Good Manufacturing Practices for Radiopharmaceutical, International Atomic Energy Agency, 2001.
3. Guidelines for Good Radiopharmacy Practice, Anzsnm Radiopharmacy SIG, September 2001.
4. Operational Guidance on Hospital Radiopharmacy, A Safe and Effective Approach, EU.
5. Guidelines for Good Manufacturing Practices for Radiopharmaceutical Products, World Health Organization (WHO), Annex 3, 2003.
6. Fundamentals of Nuclear Pharmacy, Gopal Saha, 4th edition, 1997.
7. Good Manufacturing Practices (GMP) for Positron Emitting Radiopharmaceuticals (PERs), Health Canada, January 2005.
8. Guidance for Industry, Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic Radiopharmaceuticals, U.S. Department of Health and Human Services, Food and Drug Administration, June 2005.
9. Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, U.S. Department of Health and Human Services, Food and Drug Administration, September 2004.
10. Guidelines on Current Good Radiopharmacy Practice (cGRPP) In the Production of Radiopharmaceuticals, European Association of Nuclear Medicine (EANM).
11. United States Pharmacopeia: National Formulary 2005, United States Pharmacopeial (November 30, 2004).
12. Guidance, PET Drug Products – Current Good Manufacturing Practice (CGMP), U.S. Department of Health and Human Services, Food and Drug Administration, September 2005.
13. Radioactive Drugs and Radioactive Biological Products, Program 7356.002C, U.S. Department of Health and Human Services, Food and Drug Administration, 10/01/01.
1 September 2010 Page 71 of 71