Endotoxins quality requirements

To fulhll the monograph requirements with respect to the maximum allowed pyrogen content of about 0.25 endotoxin units per ml, the water used for distillation must be of very high microbial quality. 

Plasmid purification methods vary in the time, expense, and equipment required and in the purity of the plasmid produced. Purity is important to generate high levels of transfection in a reproducible manner. Potential contaminants include bacterial genomic DNA, RNA, protein, endotoxin, chemical residues, trace metals, and undesirable counterions (159). Depending on the user s endpoint, concern regarding any of these contaminants will vary. For example, if the plasmid product is intended for human clinical trials, strict quality control over of all these factors, among others, must be addressed. Lesser concern is warranted for... 

Step Hold Times. Documentation of bioburden and endotoxin control at the manufacturing scale over the entire hold time is accomplished via monitoring of intermediates using in-process samples [33]. In addition, small-scale studies can provide relevant worst-case data. The cumulative worst-case hold times are obtainable from the summation of the maximum individual unit operation hold times. However, this worst case is not required to be validated because such a series of unexpected events is likely to cause adverse drug quality as well as high endotoxin or bioburden. Instead, hold time studies are conducted for process solutions over the maximum durations that they will be held in tanks used for manufacturing [33]. 

The United States Phannacopoeia (USP) has three general specifications for water quality that are apphcable to medical and pharmaceutical uses, namely, USP Water for Injection (WFI), USP Purified Water and Drinking Water [81]. The primary difference between WFI and PW is the tolerance of microorganismas and endotoxins. Sterile WFI is the most demanding and expensive to produce. It is used for the final purification steps of parenteral products or where water is expected to have direct contact with human blood. Standard USP water specifications for pharmaceuticals manufacturing are conductivity =0.2—1.0 pS/cm at 25°C pH 5.0—7.0 TOC level <500 ppb and bacteria count <100 cfu/100 ml. WFI also requires bacteria count <10 cfu/100 ml and endotoxin level <0.25 EU/ml [74]. The types of water recommended for pharmaceutical applications and operations are given in Table 3.9 [82]. 

Because irrigations are used in or on body areas that are usually sterile or have a low degree of contaminatiOTi, there are strict requirements for their production and quality control. In this chapter the use, the design of formulation and preparation method as well as the on site preparation of irrigations will be discussed. With regard to solutions for various types of dialysis, the use of concentrates, the water quality and the requirements for bacterial endotoxins are fully discussed. 

However, the limit should be even lower a patient receives 60 L of water per dialysis treatment. A treatment lasts for 3 h. That means an intravenous administration of 20 L in 1 h. According to the Ph. Eur. the allowed maximum amount of bacterial endotoxins for parenteral use is 5 lU per kg bodyweight in 1 h. This means for a 60 kg patient that 300 lU bacterial endotoxins are allowed to be present in 20 L resulting in a requirement of <0.015 lU/mL. At this moment the assay technique allows an endotoxin limit of 0.025 lU/ mL to be detected and present water treatment units are able to produce water of this quality. This topic and other requirements are under discussion within the Ph. Eur. committee on dialysis solutions. 

Most raw material suppliers indicate the source of the quality specifications on the label. However, it may occur, that despite there being an entry in the Ph. Eur., suppliers, perhaps due to market conditions, will sell substances that meet the requirements of a foreign pharmacopoeia or other standard. Some suppliers may allow the download of a certificate fi om their website or supply a certificate with each delivery. In other cases it may be necessary to contact the supplier to request the certificate to be sent. Such a certificate should refer to which pharmacopoeia or standard the raw material complies. It should also list the pharmacopoeia analytical data of the raw materials including relevant quantifiable impurities such as bacterial endotoxins. A certificate of analysis is signed, or refers to the authorisation by the quaUty officer of the supplier. 

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