The Burkholderia cepacia complex (BCC) species are a group of gram-negative, rod-shaped bacteria that have been shown in recent years to be of concern for patients, and thus for manu-facturers of drugs and products that contribute to patient health. Species belonging to the BCC are opportunistic pathogens that have been involved in negative patient outcomes, especially for particularly vulnerable patient populations. As such, regulatory bodies tasked with protec-ting public health, such as the US FDA, have taken notice and issued numerous recalls for products that contain species from the Burkholderia cepacia complex. In turn, manufacturers have begun to revisit microbiological controls and their efficacy in preventing BCC-contaminated products. Aside from the need to detect the presence of B. cepacia complex species in tested samples, another important tool in the repertoire of microbiological controls is the ability to accurately identify microorganisms to the species level. B. cepacia species have proven problematic in this regard, challenging traditional methods and necessitating ad-vances in microbial identification strategies.
Manufacturing activities within the pharmaceutical industry are governed by CGMPs that date back to the mid-1960s and are changed rarely. The reason they remain essentially constant is straightforward: the core principles of CGMP are well known and are broadly applicable in a myriad of situations en-compassing various dosage forms, scale of operation, design of equipment, facility, and more. The content in 21 Code of Federal Regulations (CFR) 211.113 a) provides the following expectation, “Ap-propriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed” (1). By itself, this expectation, which dates to a major revision of 21 CFR 211 in 1978, raises no extraordinary concerns. While it requires proce-dures be in place to prevent microbial contamination by objectionable species, it must be understood that it does not mandate their complete absence from any non-sterile material. The critical phrases state that procedures are required, but those procedures have a nondefinitive outcome. So while the procedures are required, there is no absolute mandate required that the product be free from objection-able microorganisms.
Although marijuana is classified as a Schedule I drug “having no medical use, with a high potential for abuse” by the U.S. Federal Drug Enforcement Administration, Western States including Colorado, Alaska, Oregon and Washington have legalized the sale of powdered cannabis for both recreational and medical use. As powdered cannabis has the potential for microbial contamination, during culti-vation, harvesting, drying, storage and distribution with fecal pathogens, molds, especially Aspergil-lus fumigatus, and aflatoxin, attention must be given to its production and appropriate microbiologi-cal test procedures and specifications established that reflect user risk.
Setting microbiological specifications is complicated by having two broad user groups, namely recre-ational and medical users and that powdered cannabis is most commonly smoked but also may be used as an ingredient in baked goods and further processed to an extract. In medical use, smoking cannabis has been used to control weight loss associated HIV-AIDS, prevent nausea associated with chemotherapy, and alleviate pain associated with a range of illnesses. These patient populations will be more susceptible to microbial infection than recreational users. With respect to mode of admin-istration, the microbiological quality requirement will be different for cannabis that is smoked or eaten. As many medicinal cannabis users have severely compromised immune systems, medical can-nabis distributed by licensed producers in the Netherlands and Canada is irradiated for control of the bioburden.
To evaluate the effect of water activity (a(w) 0.98-0.89, adjusted with glycerol, sorbitol, glucose, or NaCl) and temperature (5-25 degrees C) on the lag phase and radial growth rate (mm day(-1)) of the important citrus spoilage fungi, such as Penicillium italicum and Penicillium digitatum grown in pota-to dextrose agar (PDA) medium. To select, among models based on the use of different solutes, a model fitting accurately the growth of these species in relation to a(w) and temperature.
METHODS AND RESULTS:
Extensive data analyses showed for both Penicillium species a highly significant effect of a(w), tem-perature, solutes and their interactions on radial growth rate (P < 0.0001). Radial growth rate was inhibited and the lag phase (i.e. the time required for growth) lengthened as the a(w) of the medium decreased. NaCl appeared to causes the greatest stress on growth when compared with other nonionic solutes. Penicillium italicum stopped growing at 0.96 a(w) and P. digitatum at 0.93 a(w). Under the dry conditions where growth was observed, P. italicum grew faster than P. digitatum at low temperature and P. digitatum remained more active at ambient temperature. Multiple regres-sion analysis applied to the square roots of the growth rates observed in the presence of each solute showed that both the 'glycerol model' and the 'sorbitol model' yielded a good prediction of P. itali-cum growth and the 'sorbitol model' gave an accurate fit for P. digitatum growth, offering high-quality prediction within the experimental limits described.
Mathematical models describing and predicting, as a function of a(w) and temperature, the square root of the radial growth rate of the agents responsible for blue and green decays are important tools for understanding the behaviour of these fungi under natural conditions and for predicting cit-rus fruit spoilage.
SIGNIFICANCE AND IMPACT OF THE STUDY:
Implementation of these results should contribute towards a more rational control strategy against citrus spoilage fungi.
The US Pharmacopeia (USP) and the European Pharmacopoeia (Pharm Eur) "Microbial Limits Tests" are in the final stages of harmonization. They were signed off to Stage 6A at the November 2005 meeting of the Pharmacopeial Discussion Group held in Chicago, Illinois (1), and the harmonized ver-sions have been published (see USP 2006, supplement 2). The harmonized chapters (Stage 6B, see sidebar, "Stages of the Pharmacopeial Discussion Group process") do not differ significantly from the drafts published in 2003 (2–4).
The format of the USP chapters changes dramatically with this harmonization. Whereas the Microbial Limits Tests were two chapters in the USP 29 (5, 6), they are now modified in the harmonized version to mirror the European format (see Table I).
This review of the various elements of the packaging of a pharmaceutical product is aimed at ensur-ing that medicines arrive safely in the hands of the patients for whom they are prescribed.
In the manufacture of pharmaceutical products, quality assurance is defined as “the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality re-quired fortheir intended use”. In addition, the system of quality assurance for the manufacture of pharmaceutical products should ensure that “arrangements are made for the manufacture, supply and use of the correct starting and packagingmaterials”.
Public opinion sometimes considers packaging to be superfluous. However, it must be emphasized that packaging preserves the stability and quality of medicinal products and protects them against all forms of spoilage and tampering. All medicinal products need to be protected and “consequently need to be packaged in containers that conform to prescribed standards, particularly with respect to the exclusion of moisture and light and the prevention of leaching of extractable substances into the contents and of chemical interaction with the contents. . . . However, the limits of acceptability in these various respects depend, at least in part, on climatic variables. Recommendations in The inter-national pharmacopoeia can only be advisory; precise quantitative standards will have to be locally determined”.
The complexity of packaging materials and the highly technological nature of medicinal products is such that manufacturers are confronted with significant problems. Interaction between packaging and such products is possible due to the combination of a multiplicity of container components and active pharmaceutical ingredients, excipients and solvents used in a variety of dosage forms.
The quality of the packaging of pharmaceutical products plays a very important role in the quality of such products. It must:
— protect against all adverse external influences that can alter the properties of the product, e.g. moisture, light, oxygen and temperature variations;
— protect against biological contamination;
— protect against physical damage;
— carry the correct information and identification of the product. The kind of packaging and the ma-terials used must be chosen in such a way that:
— the packaging itself does not have an adverse effect on the product (e.g. through chemical reac-tions, leaching of packaging materials or absorption);
— the product does not have an adverse effect on the packaging, changing its properties or affecting its protective function. The resulting requirements must be met throughout the whole of the intend-ed shelf-life of the product. Given the link between the quality of a pharmaceutical product and the quality of its packaging, pharmaceutical packaging materials and systems must be subject, in princi-ple, to the same quality assurance requirements as pharmaceutical products.
In early 2016, the International Organization for Standardization (ISO) plans to publish the EN ISO 6579-1 standard, which specifies a horizontal method for the detection of Salmonella spp. in the food production chain. Like the preceding version, EN ISO 6579:2002/Amd 1:2007, it will cover products intended for human consumption, animal feeding and environmental samples in food production and handling as well as milk and milk products (previously described in ISO 6785 I IDF 93) and sam-ples from the primary food production stage. It will give greater flexibility for testing labs e.g. for the choice of some culture media and for the range of incubation temperature.