Quality Assurance and Management Systems in ...

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3 “Sed quis custodier ipso custodes?” – Decimus Iunius. Iuvenalis (Juvenal), lst century AD servicing) since 2000, and according to ISO 9001:2000 since Y2000.
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Quality Assurance and Management Systems in Nuclear Chemistry and Radiopharmacy F. Macášek 1,2 and P. Kováč 1 1

BIONT, a.s., Karloveská 63, SK-84229 Bratislava, 2 Department of Nuclear Chemistry, Comenius University, Bratislava, Slovakia The validity of experimental data obtained in radiochemical and radiopharmaceutical laboratories is of elevated public impact value. Confined conclusions should be done on a high degree of reliability by politicians, the persons responsible for nuclear or radiation safety, or qualified persons responsible for batch release in radiopharmacy, etc. Therefor, good practice of radiochemical laboratory or radioecological measurements should become a normative under umbrella of ISO 17025 standard. The practical issues, such as the sampling plans, external audit of the suppliers, Shewhart diagrams, validation of analytical control methods, and out-of-specification assay are substantiated by case studies.

Background The BIONT facility for the production and application of radionuclides and radiopharmaceuticals in medical positron emission tomography (PET) was established as a state-owned, joint stock company in 2005 by the Slovak Office of Standards, Metrology and Testing. During the design qualification of the enterprise, misleading environmental concerns appeared in the public. An extremely precaution limit of an exceeding of natural radiation background in the closest environment of our facility was stated to be 1% (!), what cannot be measured, just calculated. Also, being a new enterprise in the field of radiopharmaceuticals production in Slovakia – completely unexplored activity in our country after splitting from Czech Republic - it met a conservative appraisal among physicians and drug inspectors. At the same time, numeral new normatives and guides [1-3] on human drugs preparation, the radiopharmaceuticals being no exempted, appeared just during the period of our facilities design and construction. Consequently, thorough compliance with current international safety and quality standards was indispensable at both preparatory and operation stages of our enterprise. It helped to establish the PET radiopharmaceuticals production on a level of current EU legislation [4,5], and the BIONT quality management system of radiopharmaceutical design, development and production [6,7] has been approved by Lloyd’s Register Quality Assurance [8] according to ISO 9001:2000, and again under the ISO 9001:2009 standard [9]. Quality assurance The quality assurance, and even more the quality management, by no means can be reduced to quality control.

requirements” 1. Within the scope of this paper, as the main requirements can be indicated:

- Pharmacopoeial composition of radiopharmaceutical, and its delivery in desired amount and time to medical clinic. - Fullness, representativeness and trustworthiness of data on radioactive contamination of environment, their state-of-the-art radiological interpretation. Between the object under investigation and results of its assay there lays a complex chain of generating, receiving and transferring of information. General questions are ƒ ƒ

how far the quality of assay reflects the real properties of object, and how relevant are the monitored characteristics for object quality assessment.

Quality assurance is designed to prevent any nonconformities in the resulting product which is either of material (e.g. radionuclide or radiopharmaceutical) or information (e.g. result of analysis or drug quality control attest) origin. This approach is much presumed at short-lived radiopharmaceuticals production, having limited possibility of replicant quality control. Though there is general tendency to systems unification, some practical problems arise when various quality assurance systems are applied. It is typical in the field radiopharmaceuticals production and testing when the radiation safety rules, Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) principles are envisaged in their production, quality control and pre-clinical testing. For the ISO 9001 quality assurance management is typical an effort for permanent improvement of processes, GMP and GMP are under

According to ISO 9000, quality is defined as “the degree to which a set of inherent characteristics fulfils 1

It is understood that the customer requirements are scientifically, legislatively and ethically correct.

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very conservative pharmacopoeial control of processes and product quality, not to risk any harm for patients.

servicing) since 2000, and according to ISO 9001:2000 since Y2000. [14]

Quality vs. Quantity in Quality Assurance It is recognised, that the experimental data obtained in radiochemical and radiopharmaceutical laboratories are often of a high public impact value. However, rules of quality assurance of received and published information seem to be still insufficiently elaborated in application guides and normatives. As a result, serious legal consequences may arise.

It is well known that e.g. in environmental analysis the request for data uncertainty become reasonable low when a rapid screening is essential. At production of PET radiopharmaceuticals the quality parameters of product should be preserved under GMP, but reliability of justin-time delivery is also within the scope of ISO 9001 quality management system (QMS), and is important both for producer and diagnostic clinic. We have experienced a strong decrease of this quality indicator, normally always much above 90%, in the last period when our production should have been tripled to satisfy the temporary market demands (Fig. 1). Most of these delays were caused due to a critical point, aseptic filling device performance.

In scientific publications sphere, more complex criteria, such as Hirsch’s h-index 2 [10] are under development, offering a better assessing not only of author’s quality, but also the quality of experimental and derived data presented by him/her. Citation index is used to do it, but is not a secret that high score is achievable also (a) in areas of small but highly co-operative groups of scientists which, in positive sense, administer the capacity of validation team, or (b) by papers of high methodological value, which are applied in many laboratories serving in most confident role of interlaboratory comparison. In last case, the h-index can be considered quite suitable also for metrics of publications quality. However, the phase of its realistic application lasts too long. Moreover, it remains questionable in the case (a) where the influence of the domain of research, personal empathy, social links, language and access barriers, multiple authorship, and last not least the aim of citation, may introduce serious and systematic distortion of the basis of assessment. Consequently, the only way to ensure reliability of the data published in sensitive areas of strong impact and back-feed is acceptation of adequate independent audit and inspection, based on such systems like ISO 17025 for testing laboratories [11]. One of the oldest problems, dating back to antique time, „but who supervises supervisors?“ 3 concerns not only the governance. Self-inspection and inspection-open approach is important part of the quality assurance of performance of e.g. control and non-clinical testing laboratories [12]. Obviously, this practice becomes more and more spread in the institution responsible for environmental protection or drug safety data, authorised or not, according to the international quality management systems [13]. The IAEA Safeguard Analytical Laboratory of fissile materials is probably the most prominent one which can be mentioned in this respect. Its quality management system had been certified according to ISO 9002:1994 (Quality systems - Model for quality assurance in production, installation and

2 H-index is the number of publications per year (p) during period of n years is combined with their new citations per year (c) every subsequent year, h = cnp / ( p + c ) . 3 “Sed quis custodier ipso custodes?” – Decimus Iunius Iuvenalis (Juvenal), lst century AD

Fig. 1.

A long-term conformity of radiopharmaceutical production.

biontFDG™

As a rule, delayed deliveries are connected with manufacturer or distributor penalisation. Therefore, a review of new orders for production or services is always beneficially to ensure quality of outputs, i.e. satisfaction of customer in sense of QMS. Records reliability There are many determinants decreasing reliability of data on their way from a source to addressee, such as undetermined quality of used inputs, lack of measurements traceability, primary data incompleteness, and data loss or inadequate treatment. These can be triggered by number of reasons: - low competence of personnel - inadequate custody of samples - faint observation of circumstances - fear of controversy - need in defendable data - decreased budget of performance - self-censorship - priority and patenting race - time schedule pressure - employer interests - cherishing of know-how - unfair competition - merits of publications quantity

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- publisher interests - political motivation. Examples of scrupulous records can be seen in many classical laboratory notebooks like those of Ernest Rutherford [15] or Pierre and Maria Curie [16], though they do not look as glossy as present documentation done electronically. Not mentioning, a century later it would be difficult to find fellows like Hans Geiger and Ernest Marsden, the Rutherford’s assistants, who had been sitting in the dark for two years on end, to visually count some hundred thousands of the variously positioned flashes from the alpha particles on a fluorescent screen. Vice versa, among the claims of 110-118 elements there are sound examples of abundant inadequacy of data validation during the race for priorities [17]. Typical examples of „on-the-request” presentation are data of environmental radioactivity for decision sphere, when often, instead of presentation of large natural variability, an “unfailingly” narrow laboratory uncertainty of measurements is presented and appreciated [18]. It is neglected mostly that the highest contributions to combined uncertainty of the specific radioactivity results originate in sampling and sample heterogeneity [19]. Further, it is not quite legitimate when, without thorough control of samples custody, some (radio)analysts intent to link their measurements to the samples which were not taken under their supervision. Responsibility for such results remains undisclosed unless environmentalists and radiochemists do not closely cooperate [20]. By its nature, the forensic analysis and interpretation ought to be on a high level of truthfulness. Still curious things occur. Four years ago it happened that some three foreigners were arrested in Slovakia for allegedly trying to peddle around one pound of weapons-grade highly enriched uranium! Few days later, a lab technician said “preliminary examinations showed it was low-enriched uranium”. Issue? The previously reported figure “98.6%” was not a degree of uranium enrichment, but the confidence of radiation measurement [20].

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complex on-line monitoring of the enterprise processes are desirable. However, additional risk appears in systematic reproduction and propagation of errors in electronic data. ISO 9001:2008 plays more attention to the used hardware / software as compared with its Y2001 version. Particularly, Good Automated Manufacturing Practice (GAMP) needs comprehensive validation before being allowed in pharmaceutical process, and since 2008 its fifth version [22] has been implemented. Documents are safely handled and audited in the ALFRESCO system [23]. In our company such principles were anchored in a most complex corporal production information and control system. Monitoring of quality Shewhart diagrams [24] are efficient tool of nuclear analytical measurements [25] but also of long-term control of complex manufacturing and diagnostics systems. We apply them to monitor e.g. the yields of synthesis of radiopharmaceuticals [6,7]. A crucial specification of radiopharmaceuticals is volume activity which determines individual dose applied to a patient. According to pharmacopoeia, the declared activity should not differ from prescribed value more than for 10%. Shewhart plot of the ratio of activity signal measured by ionisation chambers in production site and that in quality control laboratory (which is traceable to national standard) provides quick information on conformance, and a single deviation behind 2σ (Fig. 2) is disposition for laboratory investigation and preventive measures, if necessary.

The determinants which can be used to increase reliability of published data are: ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ ƒ

inputs of demonstrated quality 4 open and well controlled documentation automated data collection presence of separate quality assurance units individual responsibility and self-control inter-laboratory comparison independent inspection and audition adequate statistical treatment qualified interpretation.

Most of the factors leading to data mishandling are of subject’s nature. High degree of automation and a 4

in this case, quality is not ensured by a trademark, price or material / equipment supplier, but by their performance qualification in a process

Fig. 2. Shewhart diagram of ratio of radiopharmaceutical activity assay by ionising chambers of the production (AP) and quality control unit (QC) respectively. Earlier we mentioned the traditional radiological approach to complicated and heterogeneous assay of environmental objects. In radiopharmacy, quite different sort of problem with representativeness of sampling occurs. The problems are in limited possibilities of time and expenditures to perform classical assay. Nevertheless, qualified conclusions should be done on a high degree of reliability, as it will be demonstrated below by outliers declaration.

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Traditionally, the most trivial way of getting compliance with quality criteria is to make several measurements, calculate a mean value (as the most probable expectation of true value), and standard deviation (as a measure of variability of results). Such procedure is not always feasible in the cases such as the just-in-time production, expensive input materials, analysis of (ultra)short-lived radiopharmaceuticals, or particle monitoring in the clean rooms, when the small number and/or size of samples is a must. Recent synthesis of FGD or another radiopharmaceutical is performed in pre-prepared cartridges for modules of automatic synthesis unit and their price is not negligible contribution to total running costs of synthesis. An example of rational and not traditional (“take two or better three samples”) input materials control follows. Usually, due to expiration time, the synthesis cassettes are purchased for a several weeks work. Let us consider purchase of batch of N=50 units. Standard request of input quality control is to ensure compliance of 98% (i.e. not more than one unit, 0 ≤ r ≤1) of purchased modules at a reliability 95% (Q=0.98N at P=0.95). The question is, how many (n) conforming samples should be identified to ensure such compliance? Applying Bayesian statistics [26, 27],

⎛Q⎞ ⎜ ⎟ n Q !( N − n)! P ( r > 0 | N , Q, n) = 1 − ⎝ ⎠ = 1 − N !(Q − n)! ⎛N⎞ ⎜ ⎟ ⎝n⎠

(1)

the answer is illustrated in Fig. 3.

Fig. 3. Probability of getting evidence of a noncompliant cassette in a batch of N=50, containing in fact R non-compliant units, by taking n samples. It becomes clear that multiple sampling in such small population of sampled objects is purposeless, unless a serious non-conformance in their batch identity is to be checked by single sample (because one non-compliant sample indicate Q=45 non-compliant units in set of N=50, with probability P=0.9!). The only serious issue, still and all, is the reliable output control at the site of

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producer and checked by consumer’s external audit [7, 28]. Such external audits are accepted privilege of the enterprises working under ISO 9001 QMS. Monitoring of dispensing units should be performed during those periods when open vials are exposed to the ambient environment, and records should show that a level of control was present during these periods. The quality of inner air grade ”A” is defined as to have less than 20 particles sized above 5 μm per cubic meter. Reliable assay is achieved [29] by the continuous air sampling which not necessarily reaches C=20 particles count (Fig. 4).

Fig. 4. Air sampling which provides reliable evidence of large particles concentration in grade “A” clean zone below 20 m-3. Indicators of process capability The metrics of total quality is an uneasy task. Only relatively simple processes, like radiochemical or radiopharmaceuticals synthesis can be easily monitored and quantified by physical parameters. First of all, however, one should recognise that the relation between an information impulse originated in process and its response, i.e. the measured signal, is determined by a transfer function [30]. Resulting uncertainty is a combined uncertainty of the process inherent parameter, and that of detecting device signal. Quality of monitoring is of the same importance as the quality of monitored process. Normally distributed process parameter x can be monitored by process capability index Cpmk [31]. It evaluates deviation of an off-centre process mean μ, obtained with standard deviation σ, from a target value T which lies between the upper and lower limits, USL and LSL correspondingly (Fig.5): ⎧⎪ μ − LSL USL − μ ; C pmk = min ⎨ 2 2 2 2 ⎪⎩ 3 σ + ( μ − T ) 3 σ + ( μ − T )

⎫⎪ ⎬ ⎪⎭

(2)

It may serve as quality indicator of such processes in a state of statistical control, like ﹣ cyclotron target activation efficiency,

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﹣ ﹣ ﹣ ﹣

achievements and fresh ideas. From other hand, only few of authors risk to criticise the superiors in the field. 5

yield of synthesis, radioactive purity of radionuclide, radiochemical purity of product, on time delivery of radiopharmaceutical.

The target value T, and its USL and LSL tolerance fences can be formulated in a technical standard, like Pharmacopoeia, or obtained from statistics of available best practice. For specifications that consist just of a lower limit of quality parameter (for example, purity), one-sided capability index is

C p ,lower =

μ − LSL 3σ

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(3)

Fig. 5. Illustration of process capability index, parameters in Eq.(2): T=78, μ=75, σ=3, LSL=68, USL=88, Cpmk=7/3√(32+32) = 0.47. In current practice of highly qualified operations, the value of long-term process capability index is required as high as Cpmk ≥ 1.33-1.50 for “well-centred” processes, or Cp,lower ≥ 1.25-1.45 for one-side criteria. Both ranges are achievable only for very stabilised and reproducible processes. Results Review and Attesting Generally, for published results (reports, papers, attests) the affirmation and further interpretation of results is a matter of reviewer. Normally the experimental part of publications contains just a list (sometimes not full) of used techniques. There is no room for primary measurements and demonstration of their validation. Quality of results can hardly be reflected, and it is surveyed mostly on the base of author’s publications, patents, reputation in scientific community and so on, it means on a prioritority base. Therefore, and it is immanent to the “peer” review style, the proof of reliability of results rests on the shoulders of reviewer, and it often happens to be false positive or false negative – and both a-priori not objective. Unfortunately, scientific guru’s opinions are often fatal for freshmen

Flagrant example follows. For reliable detection of superheavy elements 116 and 118, expected at LBNL in gas-filled ion separator of reaction products of 86Kr with 208 Pb [32], a software developed by world-class expert V. Ninov was used. Interpretation of enormous amount of detected events, the sequential alpha emissions, was necessary. The calculations were crucial, reviewed by researcher group and found to be conforming. However, the used software was one-man product, not independently validated, and, what is important, outer interference in records was not barred; when experiments were not confirmed in other laboratories, experts from outside the research team found intentional intervention in the original raw data [33]. In this connection, American Physical Society issued new ethical guide for professional conduct [34]. The reports on cold nuclear synthesis in 1989 [35] received enormous publicity 6 and belonged to the most exciting and cited items not only at the end of 80’s, but discussed even during entire 90’s [36]. In our university laboratory, a small team reproduced as close as possible the Fleischmann-Pons’ experiments [35] and obtained that some result really confirmed their published data. However, the team leader, late professor V. Mikulaj, being not ambitious about priorities but enough selfcritical, did not publish the results as not satisfactorily validated. He meticulously confronted and interpreted collected data not only by electric generation of false signals, but also by variation of cosmic neutron fluxes and periods of solar activity, but the interpretation remained in his shelves. On the whole, the golden rule of good practice: “what is not written it does not exist” possibly will be completed by “but what is written may not exist either”. There are many examples of emotional reviewing of environmental data associated with Chernobyl disaster. Managing them, it is possible to convict not only masses but scholars as well, that “in 1986, the level of irradiation in plants and animals in Western Europe, North America, the Arctic, and eastern Asia were sometimes hundreds and even thousands of times above acceptable norms”, and “some 985,000 people died, mainly of cancer, as a result of the Chernobyl accident” [37]. Is it only а question of tricky stylisation of half-truths? But written by “leading authorities from Eastern Europe” (?), who couldn’t believe them. Practical consequences of such “critical” studies are on the hand. “Billions of dollars for the imaginary protection of humans from radiation are actually spent year after year, while much smaller 5

May we remind that until the early 19th century, most scientists investigating «thunder-stones» shared the Newton's authority view that there is no room for stones falling from the sky.

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Symptomatically, the scientists’ results were published for the first time at a press conference.

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resources for the real savings of lives in poor countries are scandalously lacking”[38]. A customary procedure of measurements treatment is calculation of medium and standard deviation of normal distribution [39], ejecting the outliers which deviates more than 2-3 sigmas as “questionable”, and recalculate the data from the attuned set. Sometimes, a whole set of measurements is discarded as the false or true erroneous one, and measurements are repeated until variation exhibits an „acceptable” result. Such flow-sheet is acceptable only if review of previous results confirmed errors and their probable source. We warned before such procedure in connection with environmental samples when normal distribution of data can not be expected and non-parametric statistics is preferable [18]. In pharmaceuticals quality control such procedure is also not applicable as a standard, because the number of measurements must be strictly pre-defined and all received data, including those “out-of-specification“ (OOS) must be used for calculation of certified result – Fig.5.

Fig. 5a. Evident false positive assay when just an average of results is considered: medium is close to “safe“ ULS-1.64σ limit, but the grey zone of statistically probable values (shaded parallelepiped) is much broader, and result should be declared as OOS.

Specific situation is in control of PET radiopharmaceuticals when, due to shortage of time a small set and even a single measurement is obtainable in a reasonable period of time. Obviously, robust analytical technique used for this purpose should be regularly validated for its reproducibility, and uncertainties of type B are to be received and applied even for a single result 7. Because of occasional voluntarily adjustment of analytical data, in 1993, Barr Laboratories was sued by the US Food and Drug Administration regarding the treatment of OOS results. In the Barr Decision [40], the judge offered the opinion that seven passing results were needed to overcome one previous OOS result. This caused a number of companies to adopt a "seven replicate rule" what was not substantiated by a genuine statistical approach [41]. The OOS problem is now formalised in a guidance document of FDA [42] according to which an average can be used for conformity test together with its variation of full data set, and an unexpected variation in replicate determinations should trigger investigation and documentation requirements.

Fig. 5b. Most formally, individual measurements ♦ and their medium are below upper limit (ULS), but their variation zone indicates insufficient level of confidence. Result is “out of specification” (OOS).

To avoid misinterpretation of analytical results, our batch test certificate contains affirmation of uncertainties as „expanded uncertainty, calculated using a coverage factor of 2, which gives a level of confidence of approximately 95%”. Thus, a single batch of short-lived radiopharmaceutical has very limited possibilities of broader statistical treatment of quality control data. In this respect, GMP rules enable a parametric release of batch, when 7

Of course, uncertainty of radioactive decay rate is the lowest achievable uncertainty here and in no case can replace the combined uncertainty value.

Fig. 5c. Not only a single value ♦ but also its statistical expectation is well within the safe limits LLS+1.64σ and ULS-1.64σ and result can be trustfully declared as “in specification” (IS). scrutinised preparation of the manufacturing process is envisaged and detailed documentation of its correct performance is always attached for the quality assurance.

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Benefits? Quality assurance and management system establishment and maintenance need a lot of effort from the laboratory and IT staff, and also from enterprise managers and owners. What are the benefits? First, it is the trust of our customers, patients and local public. Second is the reliability of the just-in-time production and minimisation of penalisation. Third is mutual co-operation within the facility. Forth is minimisation of non-compliance during audits and inspections. Fifth is high degree of working and environmental safety. And sixth is good position at the benchmarking on market. Going back to view the nuclear science and technology as a part of public service: important quota of community in our country – which may be not exception - sees the image of nuclear science and technology in dark colours. Radiochemists share this fate twice as much, both as a part of „black” chemistry, and family of "nukes". But let us quote Maria Curie's: "Nothing in life is to be feared. It is only to be understood. Now is the time to understand more, so that we may fear less." [42] The quality of results in nuclear science, as a base of their qualified and open interpretation, should be of good assistance in serving public.

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9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19.

20. References 1. WHO Good Manufacturing Practices for pharmaceutical products, Geneva, World Health Organisation, Geneva (2003). 2. WHO Technical Report Series, No. 908, Annex 3 Guidelines on Good Manufacturing Practices for Radiopharmaceutical Products, World Health Organisation, Geneva (2003). 3. United States Pharmacopoeia . Radiopharmaceuticals for positron emission tomography. In: The United States Pharmacopeia. 27th Ed., United States Pharmacopeial Convention, Rockville (2004) p. 2381. 4. EudraLex Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1. Manufacture of sterile medicinal products, Brussels (2008). 5. EudraLex Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 3 Manufacture of Radiopharmaceuticals, Brussels (2008). 6. F. Macášek; The costs and benefits of the quality management and best practice of [18F]FDG manufacturing, In: Int. Conf. on Clinical PET and Molecular Nuclear Medicine (IPET-2007), Bangkok, Book of Extended Synopses, IAEA, Vienna (2007). pp. 268. 7. F. Macášek, P. Kováč, P. Rajec, and R. Lepej; J.Radioanal.Nucl.Chem. 280, 393 (2009). 8. Certificate of Approval No PRA 6001027, Lloyd’s Register EMEA, Prague Office, 28 August 2010.

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31. D. Montgomery; Introduction to Statistical Quality Control. New York, John Wiley & Sons (2004) p. 776. 32. V. Ninov, K.E. Gregorich, W. Loveland, A. Ghiorso, D.C. Hoffman, D. M. Lee, H. Nitsche, W.J. Swiatecki, U.W. Kirbach, C.A. Laue, J.L. Adams, J.B. Patin, D.A. Shaugnessy, D.A. Strellis, and P.A. Wilk; Phys. Rev. Lett. 83, 1104 (1999). 33. R. Dalton; Nature 420, 728 (2002). 34. http://www.aps.org/policy/statements/02_2.cfm 35. M. Fleischmann and S. Pons; J. Electroanal. Chem. 261(2A), 301 (1989). 36. http://en.wikipedia.org/wiki/Cold_fusion (2010) 37. Chernobyl: Consequences of the Catastrophe for People and the Environment. Eds. A.V. Yablokov, V. B. Nesterenko, A. V. Nesterenko, and J.D. Sherman-Nevinger. Wiley-Blackwell, Chichester (2010). 38. Z. Jaworowski; Physics Today 52(9), 24 (1999). 39. ISO/IEC Guide 98:1995, Guide to the Expression of Uncertainty in Measurement, ISO, Geneva (1995). 40. United States vs. Barr Laboratories, Inc. Civil Action No. 92-1744, US Dist. Lexis 1932; 4 February 1993, as amended 30 March 1993 (1993). 41. H. Köppel, B. Schneider and H. Wätzig; J. Pharm.Biomed. Anal. 44, 718 (2007). 42. Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production. Guidance for Industry. U.S. Department of Health and Human Services, CDER, Silver Spring MD (2006). 43. http://en.wikiquote.org/wiki/Marie_Curie

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