Microbial Stability of Pharmaceutical and Cosmetic Products

This review gives a brief overview about microbial contamination in pharmaceutical products. We discuss the distribution and potential sources of microorganisms in different areas, ranging from manufacturing sites, pharmacy stores, hospitals, to the post-market phase. We also discuss the factors that affect microbial contamination in popular dosage forms (e.g., tablets, sterile products, cosmetics). When these products are contaminated, the microorganisms can cause changes. The effects range from mild changes (e.g., discoloration, texture alteration) to severe effects (e.g., changes in activities, toxicity). The most common method for countering microbial contamination is the use of preservatives. We review some frequently used preservatives, and we describe the mechanisms by which microorganisms develop resistance to these preservatives. Finally, because preservatives are inherently toxic, we review the efforts of researchers to utilize water activity and other non-preservative approaches to combat microbial contamination.     

On the Shelf Life of Pharmaceutical Products

This article proposes new terminology that distinguishes between different concepts involved in the discussion of the shelf life of pharmaceutical products. Such comprehensive and common language is currently lacking from various guidelines, which confuses implementation and impedes comparisons of different methodologies. The five new terms that are necessary for a coherent discussion of shelf life are: true shelf life, estimated shelf life, supported shelf life, maximum shelf life, and labeled shelf life. These concepts are already in use, but not named as such. The article discusses various levels of "product" on which different stakeholders tend to focus (e.g., a single-dosage unit, a batch, a production process, etc.). The article also highlights a key missing element in the discussion of shelf life-a Quality Statement, which defines the quality standard for all key stakeholders. Arguments are presented that for regulatory and statistical reasons the true product shelf life should be defined in terms of a suitably small quantile (e.g., fifth) of the distribution of batch shelf lives. The choice of quantile translates to an upper bound on the probability that a randomly selected batch will be nonconforming when tested at the storage time defined by the labeled shelf life. For this strategy, a random-batch model is required. This approach, unlike a fixed-batch model, allows estimation of both within- and between-batch variability, and allows inferences to be made about the entire production process. This work was conducted by the Stability Shelf Life Working Group of the Product Quality Research Institute.     

Toxic Element Contamination of Natural Health Products and Pharmaceutical Preparations

Background

Concern has recently emerged regarding the safety of natural health products (NHPs)–therapies that are increasingly recommended by various health providers, including conventional physicians. Recognizing that most individuals in the Western world now consume vitamins and many take herbal agents, this study endeavored to determine levels of toxic element contamination within a range of NHPs.

Methods

Toxic element testing was performed on 121 NHPs (including Ayurvedic, traditional Chinese, and various marine-source products) as well as 49 routinely prescribed pharmaceutical preparations. Testing was also performed on several batches of one prenatal supplement, with multiple samples tested within each batch. Results were compared to existing toxicant regulatory limits.

Results

Toxic element contamination was found in many supplements and pharmaceuticals; levels exceeding established limits were only found in a small percentage of the NHPs tested and none of the drugs tested. Some NHPs demonstrated contamination levels above preferred daily endpoints for mercury, cadmium, lead, arsenic or aluminum. NHPs manufactured in China generally had higher levels of mercury and aluminum.

Conclusions

Exposure to toxic elements is occurring regularly as a result of some contaminated NHPs. Best practices for quality control–developed and implemented by the NHP industry with government oversight–is recommended to guard the safety of unsuspecting consumers.     

Comparison of Fc N-Glycosylation of Pharmaceutical Products of Intravenous Immunoglobulin G

Intravenous immunoglobulin (IVIg) products from different pharmaceutical companies vary in composition, in part because of the selected blood donors and production process. N-glycosylation of the Fc-portion of IgG varies between blood donors and may influence both the side-effects and therapeutic effectiveness of IVIg. At present, the variation in Fc N-glycosylation between IVIg products has not been defined. Utilizing mass spectrometry, we performed relative quantitation of the Fc N-glycosylation of IgG, assessing a total of 154 unique lot numbers of IVIg. Seven products showed comparable Fc N-glycosylation, with only one product differing from the others in all glycosylation features (galactosylation, sialylation, fucosylation and bisecting N-acetylglucosamine). However, the mean difference did not exceed 3%. Within product variation was present to a minor degree, but largely indistinguishable from analytical variation. In conclusion, we expect that the minor variation in Fc N-glycosylation between IVIg products has a small effect, if any, on the biological activity.     

Comparison of Two Procedures for Detection of Salmonella in Food, Feed, and Pharmaceutical Products

A survey of food, feed, and pharmaceutical products was undertaken to compare an accelerated Salmonella detection procedure by enrichment serology (ES) to the traditional procedure outlined in the Bacteriological Analytical Manual (BAM). Excellent agreement between the two methods was obtained in the results of 689 test samples involving 35 different products. In addition to being more rapid and simpler to perform, the ES procedure was just as accurate and sensitive as the BAM procedure.     

Proteomics as a Quality Control Tool of Pharmaceutical Probiotic Bacterial Lysate Products

Probiotic bacteria have a wide range of applications in veterinary and human therapeutics. Inactivated probiotics are complex samples and quality control (QC) should measure as many molecular features as possible. Capillary electrophoresis coupled to mass spectrometry (CE/MS) has been used as a multidimensional and high throughput method for the identification and validation of biomarkers of disease in complex biological samples such as biofluids. In this study we evaluate the suitability of CE/MS to measure the consistency of different lots of the probiotic formulation Pro-Symbioflor which is a bacterial lysate of heat-inactivated Escherichia coli and Enterococcus faecalis. Over 5000 peptides were detected by CE/MS in 5 different lots of the bacterial lysate and in a sample of culture medium. 71 to 75% of the total peptide content was identical in all lots. This percentage increased to 87–89% when allowing the absence of a peptide in one of the 5 samples. These results, based on over 2000 peptides, suggest high similarity of the 5 different lots. Sequence analysis identified peptides of both E. coli and E. faecalis and peptides originating from the culture medium, thus confirming the presence of the strains in the formulation. Ontology analysis suggested that the majority of the peptides identified for E. coli originated from the cell membrane or the fimbrium, while peptides identified for E. faecalis were enriched for peptides originating from the cytoplasm. The bacterial lysate peptides as a whole are recognised as highly conserved molecular patterns by the innate immune system as microbe associated molecular pattern (MAMP). Sequence analysis also identified the presence of soybean, yeast and casein protein fragments that are part of the formulation of the culture medium. In conclusion CE/MS seems an appropriate QC tool to analyze complex biological products such as inactivated probiotic formulations and allows determining the similarity between lots.     

Stability Studies Needed to Define the Handling and Transport Conditions of Sensitive Pharmaceutical or Biotechnological Products

Many pharmaceutical or biotechnological products require transport using temperature-controlled systems to keep their therapeutic properties. There are presently no official guidelines for testing pharmaceutical products in order to define suitable transport specifications. After reviewing the current guidance documents, this paper proposes a methodology for testing pharmaceutical products and defining appropriate transport conditions.     

The Safety Assessment of Toxic Metals in Commonly Used Pharmaceutical Herbal Products and Traditional Herbs for Infants in Jordanian Market

The objective of this study was to assess the levels of contamination by toxic metals (Pb, Al, Ni, Cd and As) that may be present in 25 infant pharmaceutical herbal products and 15 traditional herbs in Jordan. Both products and medicinal herbs are currently prescribed by paediatricians. They are available as over-the-counter medicines and are sold the in herbal market, ensuring easy accessibility for parents. Inductively coupled plasma-optical emission spectroscopy (ICP-OES), with limit of detections (LODs) of 0.10, 1.00, 0.20, 0.15 and 2.00 mg.kg⁻¹ for Pb, Al, Ni, Cd and As respectively, was employed to measure the levels of toxic metals in the samples. Pb, Al and Ni were detected in 88, 76 and 4% of the analysed samples of pharmaceutical herbal products and in 93, 87 and 13% of the analysed samples of traditional herbs, respectively. Neither Cd or As were detected in all analysed samples. The data obtained were subsequently compared by referral to the acceptable limits of toxic heavy metals according to World Health Organisation (WHO) standards. Largely, the results showed acceptable toxic metal levels in the finished pharmaceutical products and the traditional medicinal herbs for infants. One exception to this was Persian Thyme (Satureja thymbra) with Pb content of 41.18 mg.kg⁻¹. Also, the daily intake of detected metals through pharmaceutical herbal products was found to be lower than the daily tolerable intake limit set by the regulatory bodies, except of 8% of products that exceeded the tolerable daily intake of Pb set by US FDA, as compared to traditional medicinal herbs, where the tolerable daily intake for Pb, Al and Ni were exceeded in 40, 60 and 8% of the analysed herbs, respectively. The results obtained revealed that the excessive use of medicinal plants as alternative medicine should be used with caution keeping in mind the safety factor in infants.