Pharmaceutical Manufacturing Facilities Research Articles

Study of psychrophilic and psychrotolerant micro-organisms isolated in cold rooms used for pharmaceutical processing

To examine for psychrophilic or psychrotolerant micro-organisms in pharmaceutical cold rooms (in relation to numbers, incidents and species) and to determine, where such micro-organisms are present, whether standard microbiological environmental monitoring regimes require modification. This is presented as a case study. Comparative environmental monitoring within different pharmaceutical facility cold rooms (using standard mesophilic and low temperature incubation). Data were collected over two periods, 5 years apart. The results indicated that psychrophilic micro-organisms were not present and that those micro-organisms deemed psychrotolerant, primarily pseudomonads, could be grown on standard media under mesophilic conditions. Psychrophilic micro-organisms were not detected and those considered to be psychrotolerant were only found in low numbers. Pyschrotolerant organisms were recovered under both low temperature incubation conditions and under standard conditions (between 20 and 35°C). Further evaluation may be required, using alternative agar, and microbiologists should regularly review the species recovered to note differences between different environments. The study came about from requests made by US and UK regulators concerning the risk of any extremophiles present in pharmaceutical manufacturing facilities upon product safety. Regulators expressed concerns about whether standard, and accepted, environmental monitoring regimes were capable of detecting such micro-organisms. The data provide a benchmark to support pharmaceutical manufacturers in relation to their existing monitoring programmes or as a case study with which to undertake a similar study.

경기지역 산업시설 방류수 생태독성 영향 평가

Objectives: Industrial development in Korea results in a rapid increase in the number of chemicals, some of which may be responsible for toxicity to aquatic ecosystems. In addition, the types of hazardous chemicals included in industrial effluents have gradually increased. Therefore, chemical analysis alone is not enough to assess ecological effects of toxic chemicals in wastewater. Methods: In response to new regulations as whole effluent toxicity (WET) tests for effluent discharge of 15 publicly owned treatment works (POTWs) and 25 industrial effluent treatment plants in Gyeonggi-do, which will be effective from 2011, a necessity of studies emerges that investigates toxicity levels. Results: In case of the public treatment plants, none of them had exceeded the criteria for ecotoxicity. As for individual wastewater discharge facilities, on the other hand, two types were found to exceed the criteria: pulp and paper manufacturing facilities and pharmaceutical manufacturing facilities. For the pulp and paper manufacturing facilities, monitoring results could not help determine the exact toxicant identification. However, Daphnia magna inhibition effect or death was found to leave white plums, suggesting that suspended solids treated and the polymer used in coagulant dose. In case of pharmaceutical manufacturing facilities, the general water quality parameters cannot affect Daphia magna. However, conductivity and salinity can have an effect to be 14,000 <TEX>${\mu}s/cm$</TEX>, 8.1‰ by salts, respectively. Toxicity Identification Evaluation (TIE) and Toxicity Reduction Evaluation (TRE) procedures results appeared to be effective for identifying toxic compounds in <TEX>$Cl^{-}$</TEX> and <TEX>$SO_4^{2-}$</TEX>. Conclusions: It is necessary to develop control measures for water treatment chemicals and salts used for processes such as coagulation in individual wastewater discharge facilities in order to achieve the goal to protect aquatic ecosystems in public waters.

INDUSTRY ISSUES: Pharmaceutical Factories as a Source of Drugs in Water

INDUSTRY ISSUES: Pharmaceutical Factories as a Source of Drugs in Water

Integrating Pharmaceutical-Supported Research Evidence in Residency Training

Back to table of contents Previous article Next article Communications and UpdatesFull AccessIntegrating Pharmaceutical-Supported Research Evidence in Residency TrainingMansoor Malik, M.D., Imran Trimzi, M.D., and Gerard Gallucci, M.D., M.H.S.Mansoor MalikWashington, DCSearch for more papers by this author, M.D., Imran TrimziSearch for more papers by this author, M.D., and Gerard GallucciNew Castle, D.E.Search for more papers by this author, M.D., M.H.S.Published Online:1 Sep 2010https://doi.org/10.1176/appi.ajp.2010.10040637AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: As residency program directors, we read with interest the recent article by David B. Merrill, M.D., et al. (1), published in the April 2010 issue of the Journal (1). This article highlighted a number of very important issues in resident education. As pointed out, pharmaceutical-industry-supported research has been playing an increasingly important role in academia, but most residency programs provide little or no training about the controversies and intricacies involved in these relationships (2). Although this area encompasses a number of core competence issues, such issues are not covered in most residency curricula (3). It is encouraging that the psychiatric field as a whole is moving away from this once cozy and awkward relationship with the big pharmaceutical companies, but it is important to introduce ways to educate future residents about the financial, ethical, and clinical implications of collaboration with the pharmaceutical industry on a consistent basis.We recommend that involvement with pharmaceutical-supported research be an integral part of any resident training program. This can certainly be achieved through the participation of residents with an ongoing pharmaceutical-sponsored research project. However, in practice, these opportunities are limited outside of research-oriented training programs. These relationships can also be addressed in the didactics program for residents, preferably by a senior researcher who is knowledgeable about these relationships.At the Delaware Psychiatry Residency Program, we have introduced lectures based on the empirical data of physician interactions with industry. Residents develop a better understanding about their biases and prescribing practices but also develop an appreciation of the ethical framework in which to evaluate physician contact and dealings with industry. In addition to the didactics highlighting these topics, residents have also visited a local pharmaceutical manufacturing facility with three senior faculty members. This opportunity not only provided them with the unique experience of learning about what is involved in medication development but also encouraged discussion about physicians' attitudes toward the drug industry.Although most physicians participate only occasionally in company-sponsored trials, most see detailers and attend company-sponsored CME courses. Appropriate and ethical interaction with the pharmaceutical industry should be an integral part of psychiatry training.Washington, DCNew Castle, D.E.accepted for publication in June 2010.The authors report no financial relationships with commercial interests.

Exploring antecedents of individual grieving stages during an anticipated worksite closure

A grieving stages framework based on Kubler‐Ross (1969) was successfully operationalized and applied to an anticipated worksite closure for 53 complete data employees across four times in a pharmaceutical manufacturing facility. As predicted, the means for denial, bargaining, and depression significantly decreased, while exploration increased. However, anger and acceptance remained stable over time. Grieving stages were used as individual outcomes at Times 2 (N=89), 3 (N=77), and 4 (N=53) in regression analyses to test additional study hypotheses. Perceived contract violation had the strongest influence on grieving stages. Perceived job alternatives became more important for exploration and acceptance of leaving at Time 4. Being the primary income source, having lower core self‐evaluation, and stronger community ties were generally linked to greater employee depression about leaving the company across times. Additional applications for the suggested grieving stages measure are needed in future job loss research.

Notification vs Approval

©2007 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack G. Notification vs approval. 2007;5(3):255-258. hen a pharmaceutical firm wants to begin evaluating their compound in humans in the US, they are required to file an Investigational New Drug (IND) Application (21 CFR 312.1) with the US Food and Drug Administration (FDA). The IND is technically a request for an exemption from US law prohibiting interstate shipment of investigational drugs and assurance that the FDA will not stop (does not reject as unsafe) the initial clinical trial described in the IND. The sponsoring firm provides information on the preclinical biology of the compound (pharmacodynamics, pharmacokinetics, and toxicology), pharmaceutics and manufacturing, and the planned clinical study. Also included is the name and qualifications of the proposed clinical investigator(s). The application must have sufficient safety information at exaggerated doses to allow estimation of the potential benefit-risk ratio. The application is submitted using FDA Form 1571 (http://www.fda.gov/opacom/morechoices/fdaforms). The content of an IND is detailed in 21 CFR 312.23. An interesting, and I believe unique, aspect of the US IND process is that this is a notification (ie, unless we hear from you in 30 days, we will start our clinical study) rather than an approval (ie, we will start the studies after you authorize it; 21 CFR 312.40). This is the difference between the teenager saying “I’m taking the car, bye” and “May I take the car?” With respect to medical devices, the situation has some parallels and some differences from pharmaceuticals. Sponsoring firms wishing to evaluate an investigational medical device in humans in the U.S. must submit an investigational device exemption (IDE), which includes manufacturing and preclinical information on the device. There is also a 30-day review period from the FDA. However, in this case, the sponsor must wait for written approval from the FDA (21 CFR 812.42). Thus, the device review system is an approval, not a notification. There are other categories where only a notification, rather than a prior approval, is required by the FDA. These apply to changes to the formulation or manufacturing process for an approved drug. For some “moderate changes,” the manufacturer may identify these issues as either “Changes Being Effected in 30 Days” (21 CFR 314.70(c)(3)) or “Changes Being Effected” (21 CFR 314.70(c)(7)). In the first case, the FDA has 30 days to contact the sponsor to disallow the change. In the second case, if the FDA disapproves the supplemental application, it may order the manufacturer to cease distribution of the drug product made with the manufacturing change. For some “minor changes,” the manufacturer may make the change and notify the FDA in its next annual report (21 CRF 314.70). Going back to the IND process, as a resident of California, a geographically large state with pharmaceutical manufacturing facilities and experienced clinical investigators, what if I don’t want to technically ship the investigational drug across state lines? Do I still have to file an IND with the FDA? The answer is yes — the California equivalent of the FDA, the Food and Drug Branch (www.dhs.ca.gov/fdb/) will defer an applicant to the federal process. Also of note is that the firm does not have to show that the compound is effective in animal models (eg, this compound cures keratoconjunctivitis in animals), but rather to provide a rationale for the planned human investigation (eg, this compound releases mucin from the conjunctiva, and release of mucin may improve keratoconjunctivitis sicca). Thus, at least for the US, the FDA does not “approve” INDs — they just don’t reject them. In general, the situation is similar in developed nations around the world with respect to the need for application to the regulatory authorities in order to conduct human studies of investigational pharmaceuticals.

Determination of cefmetazole residue at pharmaceutical manufacturing facilities by chemiluminescence flow injection analysis

Application of a sensitive and rapid flow injection analysis (FIA) method with luminol chemiluminescence detection for determination of trace amounts of cefmetazole (CMZ) in cephamycin antibiotic residue in pharmaceutical manufacturing facilities and on pharmaceutical manufacturing equipment has been investigated. The method was shown to be sensitive at a level of limit of detection of 0.06 ng/ml and for linear concentrations in the range of 0.3–1.5 ng/ml. Average recoveries of CMZ from stainless steel plates and glass plates were 62.1% and 60.1%, respectively, by adding 15 ng/100 cm 2, and that of air sampling filters was 91.9% by adding 3 ng/filter. The proposed method has been successfully applied to the determination of CMZ residue in samples collected from an actual manufacturing facility and equipment. According to the results, no detectable CMZ residue was observed, therefore it was verified that no contamination had occurred to other pharmaceutical products manufactured in the facility.

Design, Construction, and Start-up of a Biological Pretreatment Plant for a Large Pharmaceutical Manufacturing Facility

Design, Construction, and Start-up of a Biological Pretreatment Plant for a Large Pharmaceutical Manufacturing Facility

Implications of industrial loads for ammonia pollution in an urban lake.

The recent history of loading of total ammonia (T-NH3) and organic nitrogen (N) from a pharmaceutical manufacturing facility to a municipal treatment plant (Metro) in Syracuse, New York, and the discharge of these constituents from Metro to N-polluted Onondaga Lake is documented. Further, the benefit of the implementation of pretreatment at the pharmaceutical plant, and the effect of an upset event at this treatment facility on loading to Metro and the lake and inlake concentrations are also documented. Models are used as analytical tools to couple loading and in-lake concentrations, to delineate the role that this pharmaceutical facility has played in the lake's ammonia pollution problem, and to evaluate the potential implications of future pretreatment upset events for the success of a rehabilitation program that is underway for the lake. The responsiveness of the lake to reductions in external loading is established by the lower T-NH3 concentration observed in the upper waters of the lake in the spring of 1999. Model analysis demonstrates this reduction was primarily (approximately 75%) because of the decrease in loading from the pharmaceutical facility achieved by pretreatment. An abrupt increase in loading in May 1999 associated with an upset event at the pretreatment facility caused a corresponding increase in the T-NH3 concentration of the lake of approximately 0.5 mg N/L. Model projections demonstrate that the load from the pharmaceutical plant before construction of the pretreatment facility exacerbated the lake's ammonia problems by increasing the occurrence and margin of violations of the toxicity standard. Continued upset events at the pretreatment plant could compromise the lake rehabilitation program.

Control system validation in multipurpose biopharmaceutical facilities

In the biopharmaceutical industry, validation requirements have significant implications in almost every engineering aspect of the production process. Strict demands from the US Food and Drug Administration (FDA) and from the European Commission regulatory authorities for validated systems in bulk pharmaceutical manufacturing facilities have raised both the profile and the importance of this aspect of the design and production process. Successive rulings, particularly by the US FDA, have served to focus an increased amount of time and energy on the development of validation strategies in most manufacturing sites. In some areas, such as the validation of the manufacturing process itself and of the associated production equipment, the requirements have tended to concentrate on the formal documentation of many aspects of the commissioning and production processes which previously were typically checked but not necessarily recorded in detail. The validation of vessel cleaning has, on the other hand, generated a large amount of work (and documentation) which was, in many cases, not previously required such as for example, swab testing or the cleaning of vessels between campaigns of the same product. The validation of computer systems has tended to set a requirement for documentation and verification somewhere in between. In many areas of the validation process there is simply a formal recording of work which would also be completed for an unvalidated computer system. In other areas, new and extensive verification is required above that which would be completed otherwise. In this paper, the details of the validation requirements for computer control systems are reviewed. Particular emphasis is placed on the implications for a multipurpose biopharmaceutical facility. Each step is discussed, from the development of a validation plan, through the definition and design of the software and hardware, to the installation and qualification of the complete system.

Does a Manufacturing Execution System reduce the cost of production for bulk pharmaceuticals?

The Manufacturing Execution System (MES) has reduced the cost of production in several discrete manufacturing industries. One pharmaceutical bulk manufacturing facility has evaluated the installation of a full function MES system and the necessary reengineering of its business processes. The potential lifecycle cost and benefits were evaluated.

Applications of SLAM

Abstract SLAM, a Simulation Language for Alternative Modeling, has been used to model and analyze diverse industrial operations. In this paper, a brief introduction to SLAM will be given which will be followed by a description of three applications. In each application, the objectives, modeling concepts, results, and benefits are presented. The three applications are: Evaluation of a proposed facility for producing a rocket launch system Design and analysis of a pharmaceutical manufacturing facility Analysis of methods for distributing oil products.

Hazard and Operability Studies and their initial applications in R&amp;D

AbstractIncreasing technological complexity together with contemporary social and legal pressures have made it necessary to develop more effective approaches to safety. The need is particularly strong in the design and operation of chemical and pharmaceutical manufacturing facilities. An approach has been developed by one company operating in these fields and applied to its production facilities for a number of years. This paper describes the approach together with the recent extension of the method into the R &amp; D area.