Impurity Limits

The Japanese regulatory authority is the Ministry of Health and Welfare (MHW) and the Pharmaceutical and Medical Safety Bureau (PSMB) is responsible for the promulgation of national and international guidelines in the form of Notifications. Guidelines are available on the Internet web-site of the National Institute of Health and Science (http //www.nihs.go.jp). The MHW has not issued specific guidance on the development of chiral drugs, but has nonetheless responded to the enantiomer-versus-racemate scientific debate. The attitude of the MHW and its advisory body, the Central Pharmaceutical Affairs Council (CPAC) is discussed in two articles by Shindo and Caldwell published in 1991 and 1995 [17, 18]. The latter paper analyzes the results of a survey of the Japanese pharmaceutical industry which sought responses on chirality issues. 

Shindo and Caldwell reported that specific reference was made to chiral drugs in only two places in the Japanese Requirements for Drug Manufacturing Approval. 

although there is a lack of formal guidance in Japan, it is apparent that there is a considerable degree of concordance with the regulatory principles established elsewhere. Approval is not proscriptive, is based on the data for individual cases and the applicant is required to justify their reasons for developing a racemate if that is the case. 

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In the AWWA specification standards, technical soHd sodium chlorite should not contain less than 78.0 wt % NaC102. The impurity limits for 80% assay sodium chlorite should not be more than 17.0 wt % sodium chloride, 3.0 wt % sodium carbonate, 3.0 wt % sodium sulfate, and 0.0003 wt % arsenic. The AWWA standards also specify the analysis procedures for all of the chemical components ia the sodium chlorite. 

Besides Type A lead, nine lead alloys are specified in British Standards for various purposes. Their compositions and impurity limits are given in Table 4.13. In addition, alloys for batteries and for anodes are of importance. In due course it is likely that European standards will supersede the current national ones... 

Figure 4.7. Consequences for the case that the proposed regulation is enforced The target level for an impurity is shown for several assumptions in percent of the level found in the official reference sample that was accepted by the authorities. The curves marked A (pessimistic), B, and C (optimistic) indicate how much the detected signal needs to be below the approved limits for assumptions concerning the signal-to-noise relationship, while the curves marked 1-3 give the LOQ in percent of this limit for LOQs of 0.02, 0.01, resp. 0.005. The circle where curves B and 1 intersect points to the lowest concentration of impurity that could just be handled, namely 0.031 %. The square is for an impurity limit of 0.1%, for which the maximal signal (<= 0.087%) would be just a factor of = 4.4 above the highest of these LOQs.

Consequences While this may still appear reasonable, lower accepted impurity limits AIL quickly demand either very high m or then target levels TL below the LOQ, as is demonstrated in Fig. 4.7. If several impurities are involved, each with its own TL and AIL, the risk of at least one exceeding its AIL rapidly increases (joint probabilities, see Section 4.24). For k impurities, the risk is [1 - (1 - 0.05) ], that is for k = 13, every other batch would fail ... 

Part—I has three chapters that exclusively deal with General Aspects of pharmaceutical analysis. Chapter 1 focuses on the pharmaceutical chemicals and their respective purity and management. Critical information with regard to description of the finished product, sampling procedures, bioavailability, identification tests, physical constants and miscellaneous characteristics, such as ash values, loss on drying, clarity and color of solution, specific tests, limit tests of metallic and non-metallic impurities, limits of moisture content, volatile and non-volatile matter and lastly residue on ignition have also been dealt with. Each section provides adequate procedural details supported by ample typical examples from the Official Compendia. Chapter 2 embraces the theory and technique of quantitative analysis with specific emphasis on volumetric analysis, volumetric apparatus, their specifications, standardization and utility. It also includes biomedical analytical chemistry, colorimetric assays, theory and assay of biochemicals, such as urea, bilirubin, cholesterol and enzymatic assays, such as alkaline phosphatase, lactate dehydrogenase, salient features of radioimmunoassay and automated methods of chemical analysis. Chapter 3 provides special emphasis on errors in pharmaceutical analysis and their statistical validation. The first aspect is related to errors in pharmaceutical analysis and embodies classification of errors, accuracy, precision and makes... 

Validation Parameter Identification Impurities (Quantitation) Impurities (Limit) Assay... 

Residual fuel oil is generally more complex than distillate fuels in composition and impurities. Limited data are available, but there are indications that the composition of No. 6 fuel oil includes (volume basis) aromatics (25%), paraffins (15%), naphthenes (45%), and nonhydrocarbon compounds (15%). Polynuclear aromatic hydrocarbons and their alkyl derivatives and metals are important hazardous and persistent components of No. 6 fuel oil. 

This is an equivalent situation to that of the raw material for blood substitutes, and the impurity limits developed for this special application can be used directly. The content of extractable fluorine is a sensitive parameter to characterise the quality of PFCLs. The correlation between the concentration of extractable fluorine in a PFCL and its toxicity was reported by Gervits [19]. Using cell cultures, he was able to correlate the inhibition rate of cell growth to the content of extractable fluorine. Table 2 shows that only very low concentration could be tolerated. 

However, the intra-atomic Coulomb interaction Uf.f affects the dynamics of f spin and f charge in different ways while the spin fluctuation propagator x(q, co) is enhanced by a factor (1 - U fX°(q, co)) which may exhibit a phase transition as Uy is increased, the charge fluctuation propagator C(q, co) is depressed by a factor (1 -H UffC°(q, co)) In the case of light actinide materials no evidence of charge fluctuation has been found. Most of the theoretical effort for the concentrated case (by opposition to the dilute one-impurity limit) has been done within the Fermi hquid theory Main practical results are a T term in electrical resistivity, scaled to order T/T f where T f is the characteristic spin fluctuation temperature (which is of the order - Tp/S where S is the Stoner enhancement factor (S = 1/1 — IN((iF)) and Tp A/ks is the Fermi temperature of the narrow band). 

The Ba(CN)2 used contains metal cation impurities limited to sodium, aluminum, strontium, and 0.05% potassium, plus traces of iron, magnesium and lithium. Each platinum electrode is a 90-100 cm2 heavy sheet with purity > 99%. During the electrolysis, half of each electrode is submerged in the solution. All water used is distilled, and all filters are medium-pore fritted-glass filters. The electrolysis apparatus consists of a variable ac voltage supply with an ac ammeter included in the circuit. 

It remains to calculate l We consider the case when the resistivity is due to impurities. Limiting ourselves to the case of a spherical Fermi surface, we suppose that there are N0 scattering centres per unit volume, and that for each of these the differential cross-section for the scattering of an electron through an angle 0 into the solid angle do is 1(8) do. Then... 

The CPA method has important properties apart from its relative simplicity. It is analytic in z,158 and thus respects the elementary physical constraints causality, Kramers-Kronig relations, sum rules, positive definite spectrum, etc. What is more, it is universal this method describes the virtual-crystal limit A W, the isolated-impurity limit cA - 0 or cA - 1, and the isolated-molecule limit W- 0, with the correct contribution of each molecular level.122 Indeed, the CPA may be derived159 from this last limit, as well as from that in the locator formalism.122... 

Impurities limits for 0,S-TEPP and S,S-TEPP content should be set relative to the active ingredient content. 

The term "significant change" is not defined in the guideline but in the main documents of which it is a subpart. Justification of impurity limits should be based on the ICH Drug Product Impurity Guideline (27). The possible effect of photodegradation on the shelf life should be taken into account to assure that the product will be within specifications for its shelf life. 

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