Quality management systems in radiochemistry and ...

DOI: 10.1007/s10967-009-0533-5

Journal of Radioanalytical and Nuclear Chemistry, Vol. 280, No.2 (2009) 389–400

Quality management systems in radiochemistry and radiopharmacy – applications in academy and industry F. Macášek,a,b* P. Kováč,a P. Rajec,a,b R. Lepeja a BIONT,

b Faculty

a.s., Karloveská 63, SK-84229 Bratislava, Slovakia of Natural Sciences, Comenius University, Bratislava, Slovakia (Received February 17, 2009)

Except the nuclear fuel reprocessing and nuclear materials safeguards, at present there are two areas of an increased responsibility of nuclear scientists for their results: radioecology and human medicaments. At both of them, quality and trustfulness of results is of great importance for their end-users and may have serious economical and legal consequences. The trends of implementation of good laboratory and manufacturing practices under umbrella of international quality management standards like ISO 17025:2005 and ISO 9001:2000 in radiochemical and radiopharmaceutical laboratories are discussed as expanding to “good scientific practice”. The case studies of the Comenius University laboratory LARCHA authorized for radiochemical analysis, and the company BIONT producing medical radionuclides and PET radiopharmaceuticals are used as the examples.

Role of quality management systems in nuclear chemistry Recent trends of introducing good laboratory practice in each area of experimental scientific work are evident. The quality assurance challenge is connected with a tremendous increase of the laboratory data productivity, together with confidence in the quality of used modern technological and measurement equipment. At the same time, usually tight schedules of new results output and limited feasibility of results verification, a risk of inflate and invalidated information must be eliminated by the increased self-control: nobody can weigh all circumstances influencing the results origin and exactness better than their authors themselves. Thus, the quality assurance systems represent an economic and legitimate form of scientific and industrial ethics. Role of chemistry in nuclear fuel preparation and reprocessing is properly recognized. The radiochemical methods developed for safeguard purposes that involve procedures for nuclear material accountancy, control, containment and surveillance, including verification of data and onsite inspections are well established.1 Most likely, except the safeguards there are two areas of an increased responsibility of nuclear scientists for their results: 1) Radioecology,2,3 and 2) Human medicaments.4 Quality management in radioecology Results of the radiochemical analysis of the environment often help decision sphere to make important judgment on public information, sanctioning and area planning. Data should be well planned, properly statistically handled and evaluated, and

integrity of their databases must be ensured and documented. The role of a nuclear scientist appears not only in performing laboratory analysis but also in tight collaboration with a client requesting the data for a specific aim and also in close co-operation with the institutions planning and performing external sampling. Implementation of the ISO 17025:2005 standard5 in sampling procedures, radiochemical separation techniques, radiometric and statistics assay seems to be a necessity. Research and university laboratories accreditation according to this standard is appreciated by the NPP and other nuclear facilities and governmental authorities. Analytical scenarios must be designed from the very beginning by co-operation of environmentalists and (radio)analytical chemists or other nuclear specialists. The way of radionuclides determination in environmental objects strongly depends upon the mode of application of the data received. Data quality objectives (DQOs) are “qualitative and quantitative statements derived from the process that clarify study technical and quality objectives, define the appropriate type of data, and specify tolerable levels of potential decision errors that will be used as the basis for establishing the quality and quantity of data needed to support decisions”.6,7 Data validation descriptors include data sources, analytical method and detection limit, data review, and data quality indicators. The last ones define8 precision, bias, representativeness, comparability, and completeness. The process for determining the utility of obtained data is based on scientific and statistical evaluation if they are of right type, quality, and quantity to support their intended use.9 As an example, IAEA as a user requests (1988) different precision of data for food and environmental radioactivity when going from rough screening to a fast (less than 24 hours) data collection (Table 1).

* E-mail: [email protected] 0236–5731/USD 20.00 © 2009 Akadémiai Kiadó, Budapest

Akadémiai Kiadó, Budapest Springer, Dordrecht

F. MACÁŠEK et al.: QUALITY MANAGEMENT SYSTEMS IN RADIOCHEMISTRY AND RADIOPHARMACY Table 1. User request of environmental radioactivity measurements Type of monitoring Screening Very Fast Fast

Tolerable bias 10x 2–3x 20–50%

Assessment time 5–15 min 1–6 hrs 6–24 hrs

Sampling User satisfaction with a low precision of radiochemical analysis comes from the fact, that the objects of environmental origin are rather heterogeneous, i.e., of large variability per se and it gives no sense to request precise laboratory methodology in such situations. Much more important is to analyze large sets of samples to get a picture of real seasonal and regional changeability of environmental objects and reflect it in final results.10 A delicate question is the results reporting, where occur good examples of good practice rules breaking. Traceability of data should be ensured and interpretation of data can not be done in isolation of sampling and laboratory survey. Environmentalist would present radioecological data without a detail reference to sample conserving, treatment and laboratory assay, and misinterpretation of laboratory data may occur without consultancy with radiochemists.11 Vice versa, radiochemists quite often publish the data identified with certain environmental objects without description of the sampling technique and sampling plans. Often is forgotten that it is the sample collector who is responsible for the care and custody of the samples accompanied by a chain-of-custody record to the laboratory. Identification and designation of the sample are critical to being able to relate the analytical result to a site location. Even if the identity of samples is well declared and communications between the field personnel and laboratory is ensured, accredited analytical laboratory should not certify the link of analytical result to a sampled field object, and can only account for uncertainties that occur after sample receipt.12 Good practice of radioanalytical laboratories It is recognized that for improving the quality and reliability of analytical data for the measurement and monitoring of radioactivity in the environment, even in well established radioanalytical laboratories should run under a quality assurance program.13 We recognize that the ISO standard 17025:2005 fully covers the requests for a good practice of radioanalytical control laboratories (the laboratory LARCHA of Comenius University in particular) even when laboratory conforming to 17025 does not necessarily operate to all the requirements of ISO 9001:2000. The situation in radiopharmaceutical control laboratories described below is similar.

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Metrologic conformance Applications of standards and dedicated equipment increase the price of analysis but are the necessity in authorized laboratory, like the LARCHA, which is authorized for radiochemical analysis of alpha, beta and gamma radionuclides in environmental samples. Authorization of laboratory LARCHA according to the ISO/IEC Standard 17025:2005 was issued by the Slovak National Accreditation Service and traceability to national standards of activity should have been ensured when providing radioanalytical results for Slovak nuclear industry establishments. Uncertainties A unique feature of radioactivity measurement is its entirely random character that enables calculation of expected standard deviation even for a single measurement of a single sample.14,15 However, fluctuations of radioactive decay determine just the minimal possible precision, which can be expected in radioactivity assay, and its realistic value is given by the uncertainties propagation, since the sampling till final assay. Importance of correct evaluation of results precision and uncertainty is crucial by intercomparison tests. Interlaboratory tests LARCHA laboratory is regularly participated in the Environmental Radioactivity proficiency tests organized by National Physic Laboratory (NPL) England and the IAEA-CU-2006-03 world-wide proficiency test (PT) on the determination of gamma emitting radionuclides in water grass and soil.16 The exercises are designed to identify analytical problems of an accredited laboratory and to provide a regular forum for discussion and technology transfer in this area. It is interesting to mention that even among accredited laboratories some results were discrepant. In the latest proficiency tests organized by National Physic Laboratory during the year 2007, 76% of the gamma spectrometry results were in agreement. The performance of the participants who participated in NPL Exercises before 2007 was slightly better. The main parameters for laboratory evaluation usually are zeta-score, z-test, relative uncertainty of the laboratory value RL, and u-score value.17 It is clear that laboratory participation on PT exercises is vital for selfevaluation and for checking the traceability to national and international standards. It is also proved for the laboratory and the client that methods used for radionuclides determination in environmental samples are validated according to rules of ISO/IEC 17025:2005.

F. MACÁŠEK et al.: QUALITY MANAGEMENT SYSTEMS IN RADIOCHEMISTRY AND RADIOPHARMACY

Quality management system in radiopharmacy Production of radiopharmaceuticals (RP) is another area, which needs a most serious quality assurance and control. Many specific features of this production produce several problems. As a typical one, the radiopharmacist dilemma of operator radiation safety and drug aseptic preparation may be mentioned: they represent both technical and normative issues, which had to be solved in rapidly changing world legislative environment.18 The experience of company BIONT concerns the intertwined of construction, launching and certification of radiopharmaceutical production in such state of affairs.19 The harmonization of nuclear and medical science does not lack problems, what was tolerated maybe few years ago is not true at the moment and radiochemists met new challenges. A hope for recognizing the radiopharmaceuticals just as the in vivo radioactive indicators applied in sub-pharmacological doses of active pharmaceutical ingredient has been liquefied. Though there appear new monographs on the radiopharmaceutical preparations and compounding within pharmacopoeias and cGMP guides, still more effort and erudite interdisciplinary approach is needed to clarify several positions in the field. The production of radiopharmaceuticals for positron emission tomography (PET) at present company BIONT facilities have been planned and built as a Slovak priority project during the years 1999-2004 under the support of IAEA. Specificity of a local production establishment consisted in the lack of nuclear research infrastructure and of deeper experience in this field, extended reconstruction of the building dedicated for completely unlike purposes, unexpected opposing of public, serious enhancement of principal regulation acts during the planning and establishment period. The rigorous requests for implementation of quality management systems came not only from the side of supervising authorities but also of the enterprise investor – the Slovak Office of Standards, Metrology and Testing (SOSMT). This all together predetermined the facility design and production launching. The total quality management system of the radionuclides and radiopharmaceuticals production under ISO 9001:2000 standard was proved as a reasonable extension of the good manufacturing of radiopharmaceuticals. It extends the GMP proficiency towards reliability of the just-intime production, environmental concerns and customer satisfaction – the parameters important for public perception, and good economical issues and market competitiveness. In case of radiopharmaceuticals the quality control mentioned above needs even more qualified radiometric, radiochemical and statistics assay of product. High responsibility of QC laboratory and qualified person is

dictated by a short time of decision making and direct responsibility for confirmation of in-specification product and patient safety. No doubt, the existing management systems converge in many elements.20–31 One can consider the good manufacturing practice (GMP), drug production, and radiation safety as the subsystems of total quality management (TQM) system. Our experience was to build our quality management system from the very beginning on the base of ISO 9000:1987 and later under the ISO 9001:2000 quality management system. The improvements introduced by ISO 9001 enhanced such design as an umbrella for all good practice activities, the GMP and GAMP in particular, and as a safeguard for the patients investigated by PET/CT tomography at our nuclear medicine department31 and the environmental issues. Since the pharmaceuticals production is a strongly regulated industry, some additional merit of further quality systems is usually not envisaged.32 Still the implementation of ISO 9000 introduces higher assurance for quality production performance. It stresses such issues like the management responsibility, customer needs and satisfaction, contractual arrangement, subcontractors’ selection and audit, test/inspection methodologies, statistical methodologies, internal audits, job training, personnel competence control, corrective and preventive actions, and also costs evaluation in the area of failures. These features add value and creditability of the enterprises, which are of sophisticated many-sided character and often beginners in the field, like the new radiopharmaceuticals distribution centers in developing countries. Production of PET radiopharmaceutical is specific not only in respect of radioactive and trace concentrations of API, what is typical for immense majority of radiopharmaceuticals, but due to very limited possibilities of corrective measures in case of non-compliance, and individual responsibility of the production and QC operators. It means the preliminary stages of order acceptance, radiopharmaceutical preparation and compounding, and also the quality assurance need exceptional attention which is not included in cGMP rules.33–35 Still, one principal difference remains: from one hand, a philosophy of perpetual improvement in everything typical for ISO 9001 quality management systems, and on another hand a high degree of conservatism and petrifaction in pharmaceutical procedures. For ISO quality management system an inventiveness of performing subjects is encouraged, with GMP and pharmacopoeia any changes are cautious and the subject not only of thorough validation but also of lengthy registration process.36 Tendency to applications of biospecific RP imposes the increasing demands to synthesis and dispensing 391


process. Radiation safety and good manufacturing practice (GMP) of radiopharmaceutical production may have controversial demands for protection of subject (personnel) and object (RP) of the production. Neither the thermal terminal sterilization nor the biohazard laminar boxes principal is feasible. Hence, the dispensing of sterile product in isolator type unit on final stage of preparation is the only possible answer (see further). Radiation safety in clean rooms By application of the ALARA37 and ALARP38 principles in radiopharmacy practice, which lay great emphasis on risk management, the adoption of an effective program of quality assurance is vital in minimizing risk and maximizing benefit in whole process of radiopharmaceutical production and application.39,40 At a normal drug production the safety of patient, given by specified and sterile product comes first. However, it can not be produced at the conditions that can cause harm to operators, his co-workers and surroundings. At the BIONT facility design qualifications process the following safety measures have been evaluated and implemented when reasonable (Table 2). Meantime it is necessary to remark that the more sophisticated technology solution was not always found more appropriate and was considered in bonds to other aspects. For instance, use of a robotic arm for dispensing of radiopharmaceutical is from the point of view of ALARA less substantiated than a proper lead shielding, but in connection with operations in aseptic environment

its use becomes arguable. Another example of inefficient safety measures in PET RP laboratories is the use of 2 mm lead plates in clean room panels, or baryte board which provide good radiation attenuation for X-rays but its effect on 0.5 MeV annihilation radiation is very unconvincing. About 25% attenuation of a radiation field at their application can be achieved much less lavishly by increasing distance operating factor in laboratories by 1.15 times, if necessary. Because in the area next to our PET radiopharmaceutical production, a 72 MeV cyclotron operation is to be launched next building since 2009–2010, environmental impact assessment (EIA) study proposed to distribute the limit 100 µSv/year for radiation doses for members of the public between these facilities in ratio 1:9. Except the radiation safety of operators and environment, further issues came from existing dislocation of the metrological laboratories for ionization radiation in the same building as cyclotron and radiopharmaceutical production, and minimal increase of natural background should have been ensured. The air radioactivity in surroundings is continuously monitored and displayed for the public what made the critically discussed data widely understandable and comparable with natural background. A front panel displaying hour dose rate is very instructive and learns people understand natural background variations. Now everybody may imagine that our contribution to environment can not be directly measured, it can be just assessed at the stage of most conservative design qualification (and what put requirements for additional investments to building construction, air exhaust and waste monitoring systems).

Table 2. Measures undertaken for radiation safety Protected Object Operators of cyclotron

Operators in radiopharmaceuticals production

Analysts in quality control

Medical staff

Patient and accompanying persons

Facility environment

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Optimization measures • Distance operation • Lowly activated targets • Multiple targets • Synthesis boxes shielding • Automatic modules for synthesis • Automatic dispensing station • Exhaust and air conditioning • Protocol training • Microanalysis • Autosampling • Rapid methods • Personnel training • Tailored radiopharmaceutical doses • Catheter applications • Written protocols • Radiodiagnostics justification • Shielding and distance from other patients • Residence time minimization • Exhaust gas trapping • Exhaust filtering


Quality control in the radiopharmaceuticals production The most essential changes in ISO 1702:2005 standard compared with 1999 version consist in replacement of “quality system” by “management system” unless specified otherwise, and in evaluation of the effectiveness of the personnel training actions. In the sphere of radiopharmaceutical quality assurance it makes universal application of ISO 9001:2000 even more reasonable. Input materials control in radiopharmaceutical production differs in character from bulk materials used in a large-scale industry. Pre-prepared set of modules, tubings and chemicals are used in small-sized lots. “Traditional“ sampling of the used lots consisting from 50 kits of chemicals, i.e., one-two or “better” three compliant samples from 50 gives according to Bayesian statistical evaluation41,42 just respectively 10–20–30% confidence of compliance of the rest of lot. In such a way one gets just very vague information on the quality of the whole lot (Table 3). Such sampling is dubious and may serve just for avoiding rough non-compliance of the lot (e.g., packing error, unconditioned store, set after expiration etc.). It appears that output control on the site of producer is much more efficient. To get a high confidence (e.g., 95%) of good quality batch for the 1000 items used for production input, a number of 28 compliant control samples (i.e., 2.8%) should be found by their producer quality control what can increase their cost only for about 3%. However, if such reliability has to be obtained by end-user, e.g., for a purchased lot of 50 kits, as much as 22 samples (i.e., 44%) should be spent by a quality control unit and the actual price of input chemicals for end-user increases for unbearable 79%! Therefore, external audit of the output control at the input material producer site appears to be a solely reasonable mean of their prior quality assurance. A posterior quality control is statistically possible using Shewhart control charts demonstrated later. Radiopharmaceutical specification conformance At output control of radiopharmaceutical parameters, which should validate pharmacopoeias’ specification, similar problem arises as at the input materials control. At the short-lived radiopharmaceuticals (namely the PET ones) a radiochemist at a duty needs to perform analysis in a short time at a minimal possibility to collect statistically significant number of data for evaluation of measurements. Then, its uncertainty is crucial to prove its specification43 within an interval of specification .44 The only possibility in this case is to develop, validate, proof the robustness, and perform analytical methods in such a way that

uncertainty of type B (s = sB)45,46 can be reliably assayed and expected. Only then even a single result may be accepted (declared as “in-specification”) when found within the boarders 44 (Fig. 1). In company BIONT the confidence interval is obtained applying statistics of Student distribution, and reliability of results is requested at the level 95–99%. It is understandable, that high confidence value, which decreases a risk (even if it is again not direct but a stochastic one) for patients. Of course, it leads to larger expenditure on a side of radiopharmaceutical producer but a good quality analytical equipment and high competence of radiochemist/analysts are approved by the high added value and quality assurance. Layout and technology design qualification The commercial shielded cells of air grade “C” (ISO class 7), and especially the devices dedicated to automated dispensing in air grade “A“ (ISO class 5) aseptic environment47–50 passed scrupulous design qualification and operational qualification procedures. The old radiopharmacist dilemma of the operator protection by underpressure in the area of radioactive source and overpressure of clean air around the devices for pharmaceutical processing was solved during the design qualification. Class III/IV tightness shielded cells with closed synthesis modules, were adjusted for class “C” housing. Pressure drop cascades in production area. The manufacturing environment is important for product quality and many parameters are controlled: – Temperature, – Humidity, – Overpressure of production rooms and under pressure in hot cells, – Air movement, – Microbial contamination, and – Particulate contamination the last two ones being critical. Monitoring of these values is important for production documentation. Figure 2 ensured radiation protection against radioaerosols transfer from shielded boxes to operation rooms, and microbiological and particulate contamination from class “D” to class “C”. Table 3. Minimal number (n) of taken and compliant samples necessary for the confirmation of hypothesis of ≥90% conformity of the set of N items Confidence 30% 95% 99%

N = 50 e.g., a lot at its consumer n % 3 6.0 22 44.0 29 58.0

N = 1000 e.g., a lot at its producer n % 28 43

2.8 4.3

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good manufacturing practice. Entire preparatory work is done in class “C” auxiliary rooms in laminar microbiological box with class “A”. Aseptic dispensing of radiopharmaceuticals

Fig. 1. Confirmation of specification: ◊ measured value of specified parameter (prescribed value is 100), s – standard uncertainty of type B (s = sB), …… expected Gaussian occurrence of the result, LLS, ULS – lower and upper limits of specification, ------ acceptation boarders of a single “within specification” result

Unfortunately, none of the dispensing units existing on the European market (year 2003) passed the rigorous external design qualification. The qualifiers included the avoiding of terminal sterilization and aseptic filling of radiopharmaceuticals into open vials (without septum puncture). Further, a continuous particle monitoring and microbial probing, and consequently an in-situ bubble point test of sterilization membrane was requested. In addition it was required to enable identification of vials, measure volume and activity of radiopharmaceutical in standard vials, and communicate with production information system both on stage of programming the dispensing regime and at distributing information for radiopharmaceutical certificate. Under the IAEA technical co-operation project, an isolator type shielded laminar box with double door material transfer system (LaCalhén type) was constructed. Its construction materials should withstand the hydrogen peroxide vapors (HPV) and a laminar flow protects the dispensing unit housing also in an open state (Fig. 3). Continuous monitoring of particle and microbial concentration is performed in the isolator space. Again, reliable prove of concentration of particulates >5 µm fraction, which is allowed below 1 particle per cubic meter, is not possible for the small volume samples taken from working isolator50 – the cumulative statistics of control charts from a long-term series of measurement is used also in this case. Personnel incubator

Fig. 2. Pressure relation applied for radiation safety of operators and aseptic preparation of radiopharmaceuticals

The air handling systems was designed to protect contamination from environment operators and crosscontamination of the product with adequate, validated cleaning procedures, appropriate levels of protection of product and correct air pressure cascade. Appropriate gowning (type of clothing, proper changing rooms), validated sanitation and adequate transfer procedures for materials and personnel were designed with maximal care. The filtered air entering to the production room is 100% exhausted. Three stage filtration (G4, F9, H14 filters) produce an air suitable for “C” class room. Temperature in production room is kept within 23±2 °C, humidity is 45±15% and overpressure in operator room 20±5 Pa. The data are continually measured and stored in central control system to inspect their adequacy to the

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Because education and training in nuclear chemistry is missing at most current university science majors (medicine, pharmacy),51 generally there is absolutely insufficient pool of competent specialists in fields of radiopharmacy among the qualified staff of physicists, radiochemists and pharmacists. Within a small country like Slovakia with its limited labor market opportunities it is understandable but existing legislative does not advance a realistic solution. In contrast with many European countries, three qualified persons are requested by the Slovak drug production legislation. In our position, personnel were prepared in advance in specialized courses and at external institutions producing and using radiopharmaceuticals. Preparation of directive documents (manuals and standard operation procedures) was important part of personnel training and also a tool of their competence improvement and testing.


Documentation and information technology Traditionally, good practice is connected with a huge amount of paper work originating from the manual recording of data and an addressed personal responsibility. Electronic recording in data-logging systems is a big help to operators and managers of radiopharmaceutical production. However, each system has its own advantages and disadvantages (Table 4). Modern information technologies minimize the disadvantages of electronic recording, which retarded their implementation, but at present they become a standard also in automated pharmaceutical technology.26 In company BIONT a complex corporate information system was established46 (Fig. 4). The information system ensures the control of each important realization step, transfer and data integrity till the radiopharmaceutical attest delivery (Fig. 5): – Raw materials purchase, – Quarantine storage and expiry, – Order for production, – Storage conditions, – Clean room condition (pressure, temperature, humidity), – Cyclotron and targetry performance, – Activated radionuclide delivery, – Route of synthesis, – Dispensing and batch identity, – Quality control LIMS, – Radiopharmaceutical certificate, – Package list, – Radiation monitoring, – Personnel dosimetry, – Personnel control, – The standard operation procedures archive, – Fire monitoring, – Sanitation, – Accounting.

may solve various problems by minimization of microbial, moisture and oxygen influence, contamination by non-added isotope carrier, consumption of analytical samples and time, reaction performance regularity, operation space and shielding size, and also autoradiolysis geometry. For the cyclotron prepared radiotracers, miniaturization of target is a principal problem due to accelerated particles range and optimal thickness of target. Still, advanced lab-on-chip technology may solve lot of the problems mentioned in connection with tough combination of aseptic production of short-lived radioactive drugs.

Challenges Most of the recent problems of rigorous application of pharmaceutical inspection rules towards a flexible radiopharmaceutical production may be solved in future by application of the lab-on-a-chip technology, which rapidly progresses in biotechnological field.53–55 Though, the artifacts of a cumbersome hot-cell reprocessing of reactor materials and targets technology are evident in any PET RP production, the last possesses immanent microchemistry principles and miniaturization

Fig. 3. Design scheme (A) and construction (B) of housing of an automatic dispensing unit DDS-VIALS in an isolator type shielded box DMC with LaCalhén double door system (Tema Sinergie)

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Electronic documentation

Hard copy documentation

Table 4. Choice of documentation technology Advantages • Simplicity of techniques • Limited data monitoring • Low cost • Adjustment flexibility • Authenticity • Simple approach • Basic literacy • Real-time massive and complex processing • Minimization of human vulnerability and errors • Remote control and assay • Prompt decision making • Electronic encrypting

Disadvantages • Uncomforted handling in a radiation and aseptic environment • Operator distraction from further functions • Lengthy data transfer for processing • Subjective errors probability • Fire, water, and atmosphere sensitive • Spacey storage • Dedicated hardware and software • Electronic literacy • Sensors network • Electricity supply dependent • Systematic error proliferation • Increased massive data loss risk

Fig. 4. Information system in radiopharmaceuticals production

Benefits of quality management system Personnel competence. The cGMP and EudraLex accent the role of qualified person in the process of quality assurance and radiopharmaceutical certification and release procedure. ISO 9001 adds attention to all personnel competence and training. We tested influence of operator’s preparation and skill to the performance of synthesis. No statistically significant difference in achieved FDG synthesis yield was obtained. That should have been expected due to a high degree of automation of the process; however, some differences could have occurred in preparatory operation steps, which need

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manual skill (material transfer, tubing connections and adjustments etc.). Vice versa, the quality of inputs varying in different periods and increasing elaboration of standard operation procedures may cause the apparent difference in operators’ performance (see below). Dependability. From the target activation to the quality control, about seven-eight critical stages can be distinguished in a raw, which may create non-compliant production steps and even non-reparable failures. If, e.g., 95% total compliance is expected, each of these critical stages should have the geometric average reliability of the order 99.5%.


a)

b) Fig. 5. Examples of BIONT information system outputs: a) pressure monitoring in class “C” area, b) Analytical certificate of FDG radiopharmaceutical

Not mentioning customers’ credit to producer, any non-compliance causes thoughtful financial losses – in case of our company 1 mL of product costs about € 200, and 10 minutes of whole batch sell delay is worth about € 130. Totally, the financial loss from non-conforming

production, penalization at a cancelled delivery in individual cases reaches € 2000 per radiopharmaceutical batch! Each equipment failure was analyzed and preventive countermeasures were undertaken. On account of 397


frequent failures of dispensing unit, which was actually a prototype, its upgrade was proposed and followed by an advanced operation qualification. Further, for all crucial operations spare equipment was ready to hand. For a long-term control the Shewhart control charts were applied e.g. for monitoring of FDG chemical synthesis yield. From 460 synthesis runs, the corrected (chemical) yield was 68±11% However, the areas belonging to different synthesis kits visualize the differences in input materials quality which can not be

obtained by a standard quality control of input materials (Fig. 6). Customer satisfaction. After analysis of dependability, following measures were taken: performance analysis and improvements of dispensing unit and standard operations, reserve operations were ensured for the most dependent steps and as a result higher then 97% average compliance of FDG deliveries was reached in the next six months period (Fig. 7).56

Fig. 6. Control chart of FDG yield (corrected for radioactive decay) in a raw of 460 synthesis – anomalous are areas IV and IX of using different synthesis module kits

Fig. 7. Increased compliance of FDG deliveries to customers after analysis of dependability and corrective measures taken in November 2006 (06-XI)

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Conclusions

References

Nuclear chemists are carrying responsibility not only in the areas of nuclear weapons proliferation and sustainable nuclear fuel cycle technology but also providing reliable source of knowledge in ecology. The radiopharmaceuticals production illustrates a reasonable extension of the good manufacturing practice towards reliability of the just-in-time production, environmental concerns and customer satisfaction. The total quality management according to the ISO 9001 standard expands the quality criteria from a product to the process of its receiving and to contentment of its final user. The end-users of environmental data are not only the scientists and environmental protection agencies but also whole communities of taxpayers. Similarly, the end-users of a radiopharmaceutical diagnosis are not the final cost covering health insurance companies but the existing and potential patients, which jointly pay for this service. However, we wanted to illustrate on the examples of environmental analysis and radiopharmaceuticals production that the quality of results can be reliably documented only by the quality of the process of its receiving. It also concerns the issues from unique scientific equipment. This introduces a serious change in general philosophy of quality of scientific and technical results. Naturally, the quality criteria of ethical character: author honesty and responsibility, and open, well and completely documented sources are behind the published results. Peer review is feeble without approach to these sources and may discover just formal faults, bias, and in rare cases a plagiarism. Character of nuclear science is a good reason for implementation of a “good scientific practice”. It should be considered not only in the sense of the papers and reports which brings new reliable knowledge, but also taking a care about users of the results, fighting the misunderstanding and misuse, censorship and falsification of the last. Realistically, there is little hope in transformation of specialized paper reviewers into universal laboratory records auditors. Nevertheless, such approach is accepted by the facilities which are certified under ISO 9001 or ISO 17025 quality management system standards and which voluntarily make their practice available for inspection by the auditors of certification bodies and/or participate in laboratory intercomparison studies.

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