Guidelines for Good Manufacturing Practice of ... · PDF file1 September 2010 Page 1 of 71 Version 1.2 Guidelines for Good Manufacturing Practice of Radiopharmaceuticals

1 September 2010 Page 1 of 71

Version 1.2

Guidelines for Good Manufacturing Practice of Radiopharmaceuticals


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:

The manufacturing of radiopharmaceuticals in centralized radiopharmacies.

The manufacturing of radiopharmaceuticals in nuclear institutes

industrial manufacturers.

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.

Scope of These Guidelines


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.

Glossary


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.


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,

but different number of neutrons. Examples are C146 and C12

6 .

Labeled Compound:

A compound containing radionuclide as integral component of the molecule.


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:


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.


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.

Chapter 1 Radiation Protection and Safety


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.


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;


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


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.


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;

Chapter 2 Quality Management


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;


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


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.


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;

Chapter 3 Personnel and Training


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;


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.


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.


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;

Chapter 4 Premises and Facilities


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.


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.


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.


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.


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.

Chapter 5 Equipment


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.


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.


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.

Chapter 6 Documentation and Records


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.


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


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;


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:


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


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;


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:


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.


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.


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.


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.


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.

Chapter 7 Materials Management


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.


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.


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.


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.

Chapter 8 Production of Radiopharmaceuticals


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


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.


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.


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.


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.


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


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.


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.


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.

Chapter 9 Quality Controls


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.


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.


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.


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.


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.

Chapter 10 Complaints and Product Recall


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.


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.


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

Chapter 11 Contract Manufacture and Analysis


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


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.


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.

Chapter 12 Self Inspection


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.


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.

Chapter 13 Product Regulation and Manufacturer Licensing


ANNEXES


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.


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

ANNEX 1 Manufacture of Sterile Products


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

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”

Grade

Maximum Number of Particles Permitted

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


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

Grade

Recommended Limits for Microbial Contamination

air sample

cfu*/m3

settle plates

(diam. 9 0

mm),

cfu/4 hours

contact plates

(diam. 55

mm),

cfu/plate

Glove print

5 fingers

cfu/glove US ISO EU

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.


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.


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)

ANNEX 2 Comparison Between Manufacturing and Compounding


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

National Authorities


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.

References