The Manufacturing Of DNA Vaccines

The Manufacturing Of DNA Vaccines A detailed design and layout of the facility for the manufacturing of DNA vaccines was developed. The factors foremost in the design and layout of the DNA vaccines facility were compliance to current good manufacturing practices (cGMP), regulatory guidelines, health, safety and environment, effective production, optimum material and personnel flow, effective cleanliness, minimisation of contamination and enhance maintenance. The total site area is 108m X 91m (9828m2) and plant/production area is 32m X 20m (640m2) with space for future expansion. To reduce the impact of airborne particles, relative humidity, pressure and temperature on the purity, efficacy, and safety DNA vaccines product, a containment/cleanrooms of class 100 was design with controlled-air environment with access via airlock, HVAC and high efficiency particulate air (HEPA) filters. In order to conform and comply to current good manufacturing practices (cGMP) and regulations, the following key component of cGMP were i ncorporated into the design, validation master plan (VMP), standard operating procedures (SOPs), appropriate quality control (QC), cleaning-in-place (CIP), sterilisation-in-place (SIP), trained personnel, documentation, health, safety and environment, utilities required and waste treatment process. The entire project timeline was estimated with the aid of Gantt chart project management technique to be a year and 4.5 months with reference to literatures on similar projects. 1.1 Introduction The demand for DNA vaccines for gene therapy, vaccination and for the treatment of diseases such as cancer, malaria, swine flu, HIV, melanoma, etc. is on the increase (Prather et al., 2003; Williams et al., 2009). This is because DNA vaccines triggers cellular and humoral immune responses, safe and stable (Prather et al., 2003). Therefore, there is need to design manufacturing facility for DNA vaccines production to meet the rising demand. However, the design, operations and layout of the manufacturing facility must conform and comply to standards, specifications and guidelines stipulated by regulatory authorities such as the U.S. Food and Drug Administration (FDA), Medicines and Healthcare products Regulatory Agency (MHRA), European Medicines Evaluation Agency (EMEA), World Health Organisation (WHO) and the regulation of the country in which the facility is to be constructed. In addition to meeting this regulations and guidelines the DNA vaccines production process, design and premi ses of its manufacture must conform to good design practices (GDP) and current good manufacturing practices (cGMP) (Shamlou, 2003; Przybylowski et al., 2007). The commercial scale production of DNA vaccines is justified by economics/cost, health, safety and environment, compliance to legal standards and production under Good Manufacturing Practices (GMP) (Shamlou, 2003). This is to ensure that manufacturing processes are controlled and performed according to design specifications and operational procedures in order to ensure that quality is built into the product (DNA vaccines) to assure safety, efficacy, purity and identity consistently (Przybylowski et al., 2007). In addition, GMP requirements are open ended, however the International Society of Pharmaceutical Engineers (ISPE) has enumerated the principal steps to current GMP which include standard operational procedures (SOPs), qualification and validation of process performance, design, quality control testing, adequate process control, sterilization in place (SIP), cleaning in place (CIP), layout design, quality management, documentation and audit of facility as necessary to ensuring specification and maintenance of product identity and compliance to regulations (WHO, FDA, MHRA, etc.) and current good manufacturing practices (cGMP) (Day, 2004). The issue of location for the manufacturing facility is crucial to its profitability as it is influenced by raw material supply, transportation, utilities, environmental impact, waste disposal, local community considerations, personnel, climate, plant size and availability of land (Sinnott, 2005). Moreover, before the design and installation of a new facility for pharmaceutical and biopharmaceutical product manufacture, an environmental impact assessment (EIA) is perform and approved (Davda, 2004). Hitherto, the design of any manufacturing facility must integrate the design of a treatment process and safe disposal of the waste generated to specified legal standards by regulatory authorities and eliminate/minimise harm to health and safety of personnel, environment and product contamination. The manufacturing facility layout must be designed to aid good raw material flow, waste flow and personnel flow around the factory to reduce risk, cross contamination and ensure that production ac tivities and factory operations are performed smoothly and follow a defined procedure. The pharmaceutical manufacturing process must be conducted in clean environment and clean rooms in which the temperature, pressure, air borne particles and relative humidity are controlled to specified conditions by regulators (U.S. FDA, WHO, ISO, MHRA, etc). All these are the component of current Good Manufacturing Practices (cGMP) to build quality assurance, consistency and safety of therapeutic product (DNA vaccines) to human life (Signore and Terry, 2008). The entire operations and activity should be performed by trained and competent personnel and quality management for a satisfactory quality assurance (QA/QC). 1.2 Aims and objectives 1. The defined goal of this project is to develop a detailed design and layout of a manufacturing facility for the production of DNA vaccines for commercial scale, applying current Good Manufacturing Practices (cGMP) and in compliance to regulatory guideline (FDA, FDA, MHRA, WHO, etc.). 2. Provide detail methods for qualification and validation of the design and layout, performance, quality control and enumerate the personnel/staff involved in the project. 3. Estimate the timeline of the project. 2.1 Process overview DNA vaccines production mainly starts on a bench scale through pilot scale to large scale production (Ferreira et al., 2000; Bequette et al., 2004). The design of a large scale facility for the manufacturing of DNA vaccines involves the selection of suitable plasmid DNA constructs/vectors (ColE1-type vectors, pUC vectors, pBR322 plasmid vector, etc.) that will replicate at high copy numbers, the production microorganism cell bank (Escherichia Coli), subsequently followed by fermentation process in the bioreactor under optimum conditions and control media (temperature, pH, pressure, etc.) to maximise cell growth, cell lysis to break the cells to release the DNA, isolation by precipitation of genomic DNA, cell debris, proteins and RNA, purification by anion exchange chromatographic technique because DNA is negatively charged, formulation and blending, sterile filling, packaging and storage in the fridge (Ferreira et al., 2000; Prather et al., 2003; Przybylowski et al., 2007).   2.2 Design of flowsheet The conceptual design of the process flowsheet for DNA vaccines production under cGMP was based on the knowledge of the process block diagram in Fig.1 above and the performance of the associated unit operations. The process flowsheet shown in Fig.2 is interconnection of the various unit operations, fermentation, the downstream processing (cell lysis, precipitation, clarification and concentration, primary purification (anion-exchange chromatography) and secondary purification (size exclusion chromatography)) and blending and formulation of the bulk product into usable form (Prazeres and Ferreira, 2004). Each pieces of equipment in the process flow sheet are designed to conform and comply with standard and code of practice of either International Organisation for Standardization (ISO), British Standard Institution (BSI), American Petroleum Institute (API), American Society for Testing Materials (ASTM), American National Standard Institution (ANSI), etc. to ensure safety, selection of suitable material of construction, and also equipment manufacturers work to produce facilities according to standardized design and size (Sinnott, 2005). Also each pieces of equipment are hygienically designed with good polished surfaces and piping for easy CIP and SIP, elimination of dead zones and sharp edges to avoid microbial growth and contamination and constructed with stainless steel material to eliminate contamination. The final product DNA vaccines are sterilely filled into vials and stored at -20oC in the freezer (Przybylowski et al., 2007). 3.1 Site layout design The site layout was designed to prevent product contamination, environmental pollution and to safeguard the health and safety of personnel. The various unit operations shown on the process flowsheet in Fig.2 and the ancillary buildings required to support the manufacturing facility for DNA vaccine production are laid out to give an economical flow of raw materials to final product storage, flow of personnel and waste around the production site to conform to good manufacturing practice (GMP), reduce risk and product contamination (Sinnott, 2005; Signore and Terry, 2008). The site layout design in Fig.3 was done with consideration to future expansion of the DNA production. Clean rooms, waste treatment area, hazardous process and raw materials were isolated and arranged for safety of product, personnel and environment. The size of the site is 108m X 91m (9828m2) as shown in Fig.3 and the ancillary buildings and support services required for the manufacturing facility are: Storages for raw materials and DNA vaccines. Quality control laboratory. Maintenance workshops and warehouse. Utilities: steam, compressed air, power generation, refrigeration, water (WFI), CO2, N2 etc. Cleaning-in-place (CIP) and Sterilisation-in-place (SIP). Effluent treatment and disposal plant. Process control room Administrative offices Fire stations and other emergency services Amenities required include: roads and car parks, first aid centre, canteen, security, rest room, changing room, training room and visitors centre. 3.2 Facility layout design The detailed design and layout of the DNA vaccines production rooms and equipment is designed to minimise risk, reduce cross contamination, permit effective cleaning and sterilisation of external and internal surfaces of process equipment by the use of clean in place (CIP) and sterilisation in place (SIP), enhance maintenance and control of clean rooms temperature, pressure and relative humidity (RH) under standard operating procedures (SOPs) (Przybylowski et al., 2007). The facility layout design also considered the cleanrooms, equipment and the flow of materials and personnel as key factors that impact on manufacturing cost, operational procedures and productivity (Drira et al., 2007). The DNA vaccines manufacturing facility layout design is 32m X 20m (640m2) in size as shown in Fig.4 to ensure efficiency and safety of the production environment and manufacturing process which are dependent on the layout of the facility (Jacobson et al., 2002). 3.2.1 Cleanrooms/containment design One of the principles of GMP is cleanliness and aseptic operations to prevent product contamination by microorganisms, particulate generated during plant operations and changes in room conditions (temperature, relative humidity, etc.). Therefore, DNA vaccines which are biological drugs are manufactured in clean rooms, that is, a room in which the air quality (airborne particles), the temperature, the pressure and relative humidity are controlled to prevent contamination by impurities, dust and microorganisms in the atmosphere and in the ambient air, in order to protect its purity, efficacy and safety (Sutherland, 2008). The layout and design of the production rooms was according to the International Standards Organisation (ISO) 14644-1 cleanrooms classification shown in Table 2 below. The raw materials, fermentation, purification, blending and formulation and product storage clean rooms are designed for class 100 biosafety cabinet fitted with high efficiency particulate air (HEPA) fi lters and HVAC systems to ensure the entry of clean air into the cleanrooms and exit of dirty air inside the rooms (Sutherland, 2008). The flow of air in and out of the cleanrooms is laminar. Other components of the cleanrooms include: Separate airlocks for entry and exit doors for personnel, raw materials and waste products. An inlet port for fresh purified air. An exit vents fitted with activated carbon filter to purify contaminated air before discharge to ensure environmental safety (Sutherland, 2008). Cleanrooms air pressure is maintained below atmospheric to prevent outward leakage. Nonslip floors, electricity, light appropriate and aseptic processing hood. Humidifiers to maintain and control cleanrooms relative humidity and temperatures 4.1 Raw materials Variations in raw materials composition is known to impact on the quality of DNA vaccines produced and also the operations of the plant. Therefore, raw materials require quality control check before used. The raw materials, reagents and utilities required for the DNA vaccines manufacturing facility are: plasmid DNA vectors, nutrients, glucose, water for injection (WFI), sterile air, salt, buffer capacity (to stabilise pH of fermentation), liquid nitrogen N2, and antibiotic, alkaline, master cell bank (MCB) and working cell banks (WCB). These are placed in the quarantine storage room and undergo quality control testing to ensure that specification are met before used for DNA vaccines production for quality assurance (QA/QC). The flow of materials from the raw materials to the final product (DNA vaccines) is shown in FIG. above and the final DNA vaccines products are stored in a sterile room in a freezer at -20oC (Przybylowski et al., 2007). 4.2 Personnel The compliance to current good manufacturing practices (cGMP) and regulatory guideline depends on people and good management structure. It is essential when developing new facility to integrate all relevant personnel from production, logistics, quality control and engineering in the inception phase of the design and layout. Therefore, for a satisfactory quality assurance of the DNA vaccines production, facility design and layout, the interactions and inputs from various disciplines such as chemists, chemical engineers, biochemical engineers, biologists, microbiologist, pharmacists, civil engineers, project managers, mechanical engineers, electrical engineers, architect, cost engineer and many others are required to carry out defined tasks and responsibilities. The flow of personnel around the designed facility layout during operations is shown in FIG. 4.3 Qualification and validation The qualification and validation of pharmaceutical manufacturing facilities at regular intervals is an integral part of good manufacturing practices (GMP). This is documentary evidence that assures that the DNA vaccines production facility is performing satisfactorily and consistently to specification for the intended purpose (Day, 2004). To do this, a validation master plan (VMP) is drawn up which include: design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) to confirm that all was done according to specifications (Day, 2004; Chaloner-larsson et al., 1997). However, an internal audit of the facility and instruments is also conducted to ensure compliance and implementation of cGMP and regulatory guidelines. 4.3.1 Design qualification (DQ) Design qualification is carried on the following production pieces of equipment of the manufacturing facility such as bioreactor, centrifuge, anion-exchange chromatography, size exclusion chromatography, microfiltration system, ultra-filtration system, HVAC systems and lyophilizer, for verification and documentation as a prove to show that the equipment designs conforms to regulatory standards such as ISO 9000, BSI, etc. 4.3.2 Installation qualification (IQ) The IQ is a documented verification that confirms that the manufacturing facility layout, HVAC systems, supporting utilities (steam, CIP, SIP, etc.) and process equipment are built and installed in compliance to the designed specification and manufacturers recommendations (Chaloner-Larsson et al., 1997). The IQ document for each equipment/system contains name of equipment/system, description, model and identification number, the location, utility requirements, any safety feature, date, personnel and approver. 4.3.3 Operational qualification (OQ) The OQ is the documentary verification of the manufacturing facility to confirm that each pieces of equipment operates in accordance to designed specifications and operation conditions and will consistently (Day, 2004). This is accomplished by testing control systems, alarms, switches, and providing standard operations procedures (SOPs) for the operations of the manufacturing facility. 4.3.4 Performance qualification (PQ) Performance qualification (PQ) is a documented verification that confirms that the manufacturing facility and the supporting utilities will consistently perform to required specification under the designed operating ranges to production the DNA vaccines. The following systems and pieces of equipment are validated for performance check: purification processes, bioreactor, HVAC systems, autoclave, CIP, SIP, oven, pure steam generation system, purified water and water for injection systems, centrifuge and lyophilizer. 4.4 Quality assurance and Quality control (QA/QC) The consistent production of DNA vaccines to meet therapeutic specification of safety, purity, efficacy and potency depends on good quality assurance and quality control (QA/QC) performed by qualified persons (QP). Quality control of the DNA vaccines is one of the key component of current good manufacturing practices (cGMP) and regulatory guideline of U.S. FDA, WHO, MHRA, ISO 9000 etc. It involves testing procedures employed to check that the DNA vaccines product are uniform from batch-to-batch and raw materials used for its production meet the specification, quality and standard. The quality control testing laboratory consists of the following assays for determining quality of raw materials and product purity, efficacy and safety: High performance liquid chromatography (HPLC) to determine the percentage of RNA, supercoiled and nicked. pH meter test for residual buffer salts and alkaline. Agarose gel electrophoresis (AGE) test for plasmid DNA vaccine purity, determine RNA and genomic DNA presence in the product. Gas chromatography test for the presence of ethanol, determine plasmid size Flame ionization detector (FID) test for the presence of isopropanol in the product. Transfection/Immunofluorescent staining test for potency of plasmid DNA vaccines. Kinetic chromogenic limulus amoebacyte lysate (LAL) test to quantify the presence of endotoxin in the product Sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) test for the quantity of proteins in the product (DNA vaccines). GeneQuant spectrophotometer test to quantify the purity of the DNA vaccines product. Bicinchoninic acid (BCA) assay quantify the amount of proteins present in the bulk product. Mass spectrometer, measuring, weighing, recording and control instruments calibrated regularly. The analytical instruments are validated to ensure performance. The DNA vaccines must meet at least minimum specification, purity, efficacy, safety and quality set by regulatory authority after sterile filling before released (Przybylowski et al., 2007; Prather et al., 2003). 4.4.1 Product testing Prior to the release of the DNA vaccines after blending and formulation, the quality control department must test each batch for purity, identity, efficacy, safety and potency using the analytical assays mentioned above, and if the result does not meet regulatory specifications the batch will not be released (Prazeres and Ferreira, 2004). Table 1 below shows an example of DNA vaccines purity and quality specification. 4.5 Documentation Documentation of all the activities and operations is a key requirement for GMP, regulatory bodies, and helpful for management structure, traceability of every batch history, planning, elimination of errors, effective communication, records keeping and design and layout of the DNA vaccines facility. Regulatory authorities such as FDA, EMEA and WHO require documentary evidence as prove that the DNA vaccines facility will perform consistently in compliance to cGMP. The DNA vaccines project documentation include: standard operational procedures (SOPs), design qualification, installation qualification, facility layout design, specification sheets for each pieces of equipment, performance qualification, quality control records, process flow sheet, site plan, personnel records, licence, commissioning, validation master plan (VMP), packaging, labelling, etc. both on paper and electronically (Signore and Terry, 2008; Sinnott, 2005). 4.6 Utilities Utilities are the support services required for effective design, layout and manufacturing process of DNA vaccines, they include: Potable water, USP purified water used for cleaning in place (CIP) to clean process equipment. Water for injection (WFI) used for media preparation, fermentation media and rinsing of equipment after CIP. Clean steam for sterilisation in place (SIP) to sterilise the process equipment after each batch. Electricity for lightening, instrumentation, analytical instrument, etc. Sterile gases such as filtered sterile air for fermentation process, nitrogen N2 for working cell bank storage, heating, ventilation and air-conditioning (HVAC) system. Refrigeration for the storage of the DNA vaccines product at -20oC. 4.6.1 Heating, Ventilation and Air-Conditioning (HVAC) System Heating, ventilation and air-conditioning (HVAC) system is a component of the production clean rooms design and layout, it plays a vital role in ensuring that the manufactured DNA vaccines product quality, efficacy, safety and purity is not impacted by room temperature, relative humidity (RH), air borne particles, pressure and cross contamination in accordance to standards and classifications of rooms by ISO 14644-1, US Fed. Std. 209, BSS5295, EEC, etc. (Zyl, 2005). The HVAC systems for this manufacturing facility include: High efficiency particulate air (HEPA) filters to control air borne particles, dust and microorganisms of the clean rooms. Desiccant dehumidifiers/refrigerated dehumidifiers are used to monitor and control the temperature and relative humidity (RH) of the rooms in order to comply with raw materials and DNA vaccines product requirement. Airlocks and air handling unit (AHU) are put in place for pressure monitoring, control and maintenance of pressure cascade with the production rooms. 4.6.2 Water and clean steam systems Purified water, water for injection (WFI) and clean steam are essential utilities generated on site and distributed for use in DNA vaccines production, clean-in-place (CIP), sterilisation-in-place (SIP), and media preparation (Robbins, 2010). In order to ensure safety, purity and efficacy of the DNA vaccines the water used for its production is sterile water for injection (WFI). The WFI is produced from purified water by distillation/reverse osmosis to meet the required standard of purity specified by the United State Pharmacopeia (USP) (pH 5.0-7.0, nonpyrogenic and antimicrobial agent). The WFI is stored at elevated temperature (80-95oC) to eliminated microbial growth, and the system constructed with stainless steel to eliminate contamination (Robbins, 2010). The WFI system design is shown in FIG. 4.7 Waste treatment and management The system for treating the waste generate from the DNA vaccines manufacturing facility is an integral part of the design of the facility, layout and good manufacturing practices (GMP). The major waste generate from the production process are genomic DNA of the host cells, RNA, proteins, cell debris, salts, endotoxins and plasmid isoforms (Ferreira et al., 2000). The waste is treated to regulatory standards (BS, ISO, etc.) to avoid harm to health and safety of personnel and environment (HSE), pollution and eliminate cross contamination of the product. The system for treating the waste is illustrated in FIG. below WWWW Incineration Autoclaved Waste Discharge Autoclave 4.7.1 Health, Safety and Environment (HSE) The DNA vaccines production microorganism poses some hazard. The environmental impact assessment (EIA) of the DNA vaccines production system therefore becomes a key part of the design and layout of the manufacturing facility (Prazeres and Ferreira, 2004). However, the environmental impact assessment (EIA) study and the design will require approval from environmental protection agency before the facility is built (Davda, 2004). To ensure that health, safety and environmental regulations are met, the process design and layout is geared towards minimisation of waste generation, safety of product, safety and health of personnel and incorporation of waste treatment process before discharge to the environment. In addition, the personnel will also be provided with personal protective equipment (PPE) such as hand gloves, gowns, goggles, etc. to work with. 4.8 Legislation and regulation The manufacture of DNA vaccines is highly regulated to ensure that it is safe, efficacious and pure for humans, and also its production carried out in accordance to current GMP (Plumb, 2005). Therefore, before the DNA vaccines can be marketed they must be licence from the relevant regulatory bodies such as the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, the Food and Drug Administration (FDA) in the United States, the EMEA, WHO and so on (Smith and Dennis, 2001). The manufacturing facility used for the production of the DNA vaccines must be licence too (Plumb, 2005). These licences are obtained if and only if the manufacturing facility design, layout and premises of its manufacture conform and comply to current good manufacturing practices (cGMP) and with regulatory standards, guidelines and specifications stipulated by MHRA, FDA, WHO, EMEA, ISO, etc. Hitherto, the company must also provide detailed documentary evidence about the safety, purity an d efficacy of the DNA vaccines and the consistency of its manufacturing process. Signor and Terry reported that the incorporation of current good manufacturing practices (cGMP) into good design practices (GDP) at the inception of the manufacturing facility will ensure that regulatory conditions are met (Signor and Terry, 2008). The regulatory guidelines specify the requirements for the pharmaceutical manufacturing facility, not the methods to achieving it. The regulatory bodies functions include: safeguard public health, licensing, monitoring DNA vaccines post-marketing, regulating clinical trials and publish quality standards. 5.1 Project timeline This project has a definite start, middle and end, which consist of several activities ranging from the environmental impact assessment and design approval, construction to commissioning executed in a defined order to bring the project to completion. It is the function of the project manager to plan, schedule and control these tasks/activities in a specified sequence and allocate materials, manpower, machinery and money to ensure that the project is completed on time (Gray and Erik, 2008). There are several project management techniques available in the literature, but to estimate the timeline of this project the Gantt chart technique was employed, which a plot of each task against time. Each bar represents a task/activity, length of the bar corresponds to the duration of the task and the position indicate the start and finish times. The timeline for key activities of the project are shown in FIG!!!!!!!!!!!!!! below, the Gantt chart was prepared with reference to (Davda, 2004). The e ntire project is expected to take a year and 4.5 months from the Gantt chart. 6.1 Recommendations 1. Legislations and regulations are subject to changes with emergent of robust technology, therefore the design of the manufacturing facility should be above the current specifications and standards. 2. A well defined and detail engineering drawings and specifications that does not require much interpretation. 3. A good relationship between project design team with relevant regulatory authorities and encouragement of their input will fortify the design of the facility and compliance to cGMP. 4. Ensure that all designs, installations and utilities are validated according to validation master plan (VMP) and are working according to design and specification of regulatory bodies. 5. Compliance with current good manufacturing practices (cGMP) at the inception of the design phase of the facility. 6. The DNA vaccines production facility should be designed and layout to harmonized the various regulations by different bodies such the US FDA, UK MHRA, EU, Japan, ISO, WHO, etc. to boost market for the product. 7. The process parameters such as temperature, pH and pressure must be carefully controlled to assure batch-to-batch identity in final product. 7.1 Conclusion Incorporating current good manufacturing practices (cGMP) from the beginning of the design and layout phase of the DNA vaccines facility, the production processes and to the manufacturing premises will ensure that all regulatory specifications are met.

Auditor Independence – 2

Introduction Independence is a fundamental to the reliability of auditors’ reports. It is an attitude of mind characterized by integrity and an objective approach to professional works. A professional auditor should work both independent and seen to be so. Nowadays, but, the trend of providing non-audit services to audit clients seem to be sweeping accounting firms all over the world; impacts of independence impairment caused by this trend should not be ignored. The Meaning of Independence The essential feature of an audit is its independence and, if an accountant performs the accountancy work and then checks it himself, this checking cannot be viewed to be an audit because it lacks independence. From ACCA’s Code of Ethics, the definition of Independence is composed of independence of mind and independence in appearance. In general, independence means an auditor’s opinion must be based on an objective without bias and disinterested assessment of whether the financial statements are presented fairly in conformity with generally accepted accounting principles. The Importance of Independence in relation to the provision of assurance The value of audit derives entirely from its independence. Without independence, auditors’ opinions lack impacts and credibility. The relationship between the auditors and audit clients, however, gives a potential threat to the independence. Influencing Auditors’ Reports on Clients’ Financial Position due to Conflicts of Interests: Possibilities of conflicts of interest between firms and clients, where situations such as, connections of an audit firm with associated firms, family and other personal relationships, financial interests in audit client, employment with audit clients, provision of non-audit service to audit clients, may consequently affect auditors. Without the strength of character to withstand such pressure, auditors may be unable to express independent opinions. Preserving Investors Confidence in the Financial Market Public confidence in the capital market relies heavily on the appearance of auditor independence. Auditor independence helps to ensure quality audits and sustain the circulations of investment with the capital market. Investor confidence is eroded if investors and other users of the financial statement information do not perceive that the auditor was independent in both fact and appearance. Giving Constructive Advice Although there is no formal obligation, a good auditor will be anxious to offer his client assistance on improvements in the financial aspects of the business if he can give an unbiased independent opinion, where added value is brought to clients and to the wider business community. Lowering Litigations Sustaining independence enables the auditors to objectively report on True and Fair Value of any information required to be disclosed in financial accounts, of which the chances of successful negligence lawsuit to a level acceptable will be reduced. The Nature of other services provided by the auditors In the classification from APB, non-audit services is composed of any engagement where an audit firm provides professional services to an audited client other than the audit of financial statements, and pursuant to those other roles which legislation or regulation specify can be performed by the auditor of the entity. There are five different natures of non-audit services categorized by activities arising directly from an audit of a company’s financial statements, services required to be provided by the auditor by laws, services provided by auditors because of their familiarity with the client and, as a consequence, their ability to perform them in a timely and cost effective manner, services provided because of the pool of accounting and related financial skills available to accountancy firms, services provided because of the pool of consulting and general business skills available to accountancy firms Critical Discussion of Ethical Code Requirements Independence is part of the accountant’s code of professional conduct. Under APB Ethical Standards the concept of auditor independence shifted in favor of objectivity and neutrality in the reporting of the financial position and the results of operations, rather than loyalty to a particular party. The Ethical Standards allow audit firms to offer consulting services such as internal auditing and information technology but are subject to certain restrictions, and audit firms are required to disclose fees received from auditing and all non-audit services. However, without providing clear distinctions which makes grey area exists, the rules should err on the side of caution. Auditors and their clients are likely to continually test the limits of what is permissible, including by litigating restrictions they oppose. UK’s Combined Code on Corporate Governance only recommends that audit committees develop policies to govern the future provision of non-audit services, but does not require a pre-approval of non-audit services by audit committees. No specific enforcement mechanism ensures that management does not become involved, directly or indirectly, in selecting auditors or determining audit fees and the scope of audit. Ethical code requirements should focus to a greater extent on the issue of to what extent client management may still be able to influence the audit fee and the scope of audit engagement. Explanation of the Current and Emerging Developments In order to increase revenue, recently, accounting firms not only provides auditing services, other services including bookkeeping, financial information systems design, human resources and management functions, valuation, internal audit, tax, legal, investment banking services and expert services unrelated to audit, also provides. There are several reasons leading to the increasing popularity of providing non-audit service, Price Competition Auditing becomes a low-profit activity that clients increasingly search for the lowest prices and the loosest standards. Competitive bidding in auditing created pressure to reduce audit engagement hours. To maintain overall revenues, high profitability of the numerous new consulting and other non-audit services is being offered. Horizontal Integration The rapid growth of business enterprises on a worldwide basis provided large accounting firms with an opportunity to become the preferred providers of a wide range of business services, the revenues from non-audit services for audit clients quickly outpaced the fees from auditing-only services. Audit Effectiveness Providing non-audit services allows accounting firms to perform better audits because they can obtain a better understanding of the client’s systems, which can achieve the cost-effective goal. Criticism and Analysis of Independence Impaired by Provision of Non-audit Services The relative increase in reliance on revenues from non-audit services may have placed increased pressure on auditor independence. The major accounting firms, seems vigorously opposed reforms to eliminate the growing conflicts of interest arising from auditing and consulting for the same client, because of economic bond which the auditor does not want to lose developed between the client and the accounting firm. In order to be more competitive, accounting firms try to reduce audit fees to attractive customers by reducing engagement hours. But this risk-based auditing approach may not detect fraudulent activities. Some auditors shifted their concept of independence to becoming trusted advisors to the client’s management. Although acting independence in certain situations is acceptable, too often an auditor’s efforts to help management resulted in concealing true economic performance. It appeared that some auditors ignored their most immediate responsibility to act on behalf of third-party investors or, at a minimum, to be an objective and neutral interpreter of accounting standards. Many non-audit services evolved from requests by audit clients for additional services that their auditors seemed best suited, as well as from the special skills needed to audit new and complex business transactions. Expanding the scope of the specialists’ activities helped firms attract and retain people with skills that were increasing important to effective auditing. Audit firms’ management consulting practices have expended far beyond the skills required for audit support and the traditional areas related to financial planning and controls. Independence questions can arise when these services are marketed to audit clients. However, it is obvious that major accounting firms keep bearing legal risks by providing non-audit services to audit clients. Even ethical standard regarding to provision of non-audit services has been revised; firms could argue that advanced technology and improved education enabled accounting firms to provide many non-audit services to their current client. Conclusion and Recommendations Independence, both historically and philosophically, is the foundation of accounting profession and upon its maintenance depending on the profession’s strength and its stature. From my viewpoint, it is undeniable that Ethical standards put efforts on monitoring auditor independence; but standing at the point of running the business, accounting firms have woven an increasingly complex web of business and financial relationships with their audit clients. The most common case of independence impairment occurs because an auditor becomes so close to the client as to be unable to function objectively. The actual cause of the independence problems, however, generally was not wanton disregard rules. Instead, internal control problems may have caused many of the breach where the weak internal control system is unable to trace employees’ investments. Despite of regulations, area needs to be addressed to improve the auditor independence is the audit firms’ internal control systems, of which all relationships between each auditor and audit clients should be reviewed from time to time. The nature of the non-audit services providing to audit clients maybe different in different era. It appears that there is more mobility of employees and an increase in dual-career families. In the foreseeable future, keeping prohibition on non-audit services would help medium-sized accounting firms secure additional non-audit work with major clients. On the other hand, the increasingly competitive auditing market and the complexity of international business practices may cause some auditors to reduce their focus on objective and neutral interpretation of accounting standards in favor of becoming a trusted advisor for clients. MMUBS Reference Book Graham W. Cosserat and Neil Rodda (2009) Modern Auditing, 3rd ed. , John Wiley & Sons, Ltd Diane Walters and John Dunn (2001) Student‘s Manual of Auditing: The Guide to UK Auditing Practice, 6th ed. , Thomson Learning M. Shere and S. Turley (1991) Current Issues in Auditing, 2nd ed. , Paul Chapman Publishing Ltd Newspaper Article – Internet Copy Editor (2009) ‘Auditor independence important – CMDA’ The Miadhu News. [Online] 4th November. [Accessed on 4th November 2009] http://www. miadhu. com/2009/11/local-news/auditor-independence-important-cmda/ Journal Article – Internet Copy Franklin Strier (2006) ‘Proposals to Improve the Image of the Public Accounting Profession’ CPA Journal, March 2006 Issue http://www. ysscpa. org/cpajournal/2006/306/essentials/p67. htm C. Richard Baker (2005) ‘The Varying Concept of Auditor Independence: Shifting with the Prevailing Environment’ CPA Journal, August 2005 Issue http://www. nysscpa. org/cpajournal/2005/805/infocus/p22. htm Robert H. Colson (2004) ‘CPA Independenc e, Present and Future’ CPA Journal, April 2004 Issue http://www. nysscpa. org/cpajournal/2004/404/essentials/p80. htm Carolyn L. Lousteau and Mark E. Reid (2003) ‘Internal Control Systems for Auditor Independence’ CPA Journal, January 2003 Issue http://www. nysscpa. rg/cpajournal/2003/0103/features/f013603. htm Deborah L. Lindberg and Frank D. Beck (2004) ‘Before and After Enron: CPA’s Views on Auditor Independence’ CPA Journal, November 2004 Issue http://www. nysscpa. org/cpajournal/2004/1104/essentials/p36. htm Mario Christodoulou (2009) ‘Debate rages on over KPMG’s cut-price Rentokil audit deal’ Accountancy Age, 20 August 2009 http://www. accountacyage. com/accountancyage/news/2248103/debate-rages-kpmg-cut-price Internet Source – Organization NASD Notice to Members 02-19. (2002) Auditor Independence: SEC Review of Auditor Independence Rule. Online] [Accessed on March 2002] http://www. finra. org/web/groups/industr y/@ip/@reg/@notice/documents/notices/p003715. pdf Investor Protection (2003) Strengthening the Commission’s Requirements Regarding Auditor Independence. [Online] [Accessed on 20th January 2003] http://www. consumerfed. org/pdfs/011303auditor. pdf Public Oversight Board (2002) Report and Recommendations: Chapter 5: Auditor Independence [Online] [Accessed on March 2002] http://www. pobauditpanel. org/downloads/chapter5. pdf APB (2009) Consultation Paper on audit firms providing non-audit services to

Island Report

Purpose As requested, this report is an assessment of the suitability of Fiji Island for package holidays. The report summarizes the main attractions as well as the accessibility and accommodation. Location and access The Fiji islands are located in the Pacific Ocean off the eastern coast of Australia, therefore the most convenient way of traveling to the island is by plane or by boat. Once on the island, traveling from the airport is possible by using the public transportation such as busses or taxis. Busses run from the airport or the center of the island to any attraction every 15 minutes during the day and every1 hour during the night.Accommodation and restaurants The island aims to provide traditional and authentic Fiji accommodation. This is achieved through the use of bungalows instead of hotels with lined ceilings and thatched roofs. The result is stylish, comfortable and caters for all tastes. There are a lot of restaurants on the island and Fiji’s food is a veritable melting pot of cultural influences from all over the world. However, because of the island’s politics, most of the restaurants close before 10 pm and if tourists want a certain type of restaurant, they have to make a reservation in advance.Tourist attractions Fiji Island offers a wide range of attractions and activities that visitors enjoy such as sailing, scuba-diving, dolphin watching or shopping tours. Also, the island is provided with an open-air fitness where the tourists can relax. However, the prices of this facility are higher in the summer period due to the big number of visitors. Recommendation In conclusion, due to Fiji’s natural beauty as well as the modern facilities, it represents one of the most visited islands and would be able to provide the facilities necessary for a perfect packaged holiday.

Water Pollution in South America essays

Water Pollution in South America essays In todays world, water pollution is becoming a bigger issue in South America, as well as around the globe. This problem exists all over South America due to the lack of laws and restrictions made and enforced by the governments in these countries. In some places, sewage treatment plants are almost non-existent and the ones that do exist are out-dated and not in working condition. Did you know that in some places in South America sewage runs right out of houses and into nearby rivers and lakes, causing the drinking water to become severely contaminated? This ends up causing harmful side affects on the inhabitants in the area that must survive off this water. South America is inhabited by 3rd World Countries where development is little, poverty and populations are high, and money is hard up. Governments try to raise money and use tax money to fix the severe problem of water pollution but it is not enough to provide working sewage treatment plants that can accommodate the rapidly growing population and the rapidly decreasing amount of water available for use. Many people are uneducated of what can be found in sewage. The sewage in South America contains grease, nutrients (nitrates, phosphates, and food waste), debris, oxygen-demanding chemicals (BOD, COD) acids/alkaloids/salts, toxic chemicals pathogens (disease-causing organisms) suspended solids, human drugs, human wastes, animal wastes, pesticides, and detergents In Mexico City, Mexico, the cause of pollution is the some 30 million inhabitants that contribute to air pollution, smog, and industries that release their wastes into nearby rivers and tributaries. But, in this case, the shortage of water is also a main contribute to the problem. Underground wells become polluted due to the chemicals found in the soils on the land of what used to be covered with several lakes hundreds of years ago. In other places such as Buenos Aires, Argentina, slaughter houses...

3 Cases of Mixed Metaphors

3 Cases of Mixed Metaphors 3 Cases of Mixed Metaphors 3 Cases of Mixed Metaphors By Mark Nichol Efforts to describe something idiomatically with the use of metaphor- a word or phrase that figuratively provides an analogy- more than once in a sentence will likely distractingly interfere with reading comprehension, so avoid using more than one metaphor in a sentence, or at least ensure that they are complementary. Discussions after each example in this post explain the difficulty of using two metaphors, and revisions suggest a solution. 1. What you hear symbolizes something ominous- impending danger lurking just beneath the surface, which has been hanging over our heads in recent years. The metaphors in this sentence come at the reader from both directions, with an allusion to subterranean peril and an indirect reference to the anecdote of the sword of Damocles, in which a king suspends a sword over a courtier’s head by a single hair to teach the man a lesson about the peril of being in a position of power. To avoid this discordance, the metaphors should be consistent in imagery: â€Å"What you hear symbolizes something ominous- impending danger lurking just beneath the surface, which has percolating in recent years.† (Percolating is also a metaphor, but such one-word analogies embedded in our language do not distract as easily as more vivid imagery, and the verb is concordant with the preceding metaphor.) 2. These actions resulted in a significant redirection of market focus and gave the firms a ringside seat when the proverbial music stopped. â€Å"A ringside seat† refers to achieving a privileged position (literally, a front-row seat at a boxing match), and the phrase about music alludes to surviving a round of the game of musical chairs, in which competitors circle a group of chairs that numbers one less than the number of participants and vie to obtain a seat when music that is briefly played suddenly ceases, causing one person to be disqualified in each round. Although both metaphors deal, in a sense, with attainment of privilege, the contexts are different, and one is best abandoned in favor of the other: â€Å"These actions resulted in a significant redirection of market focus and gave the firms a ringside seat when that shift occurred.† 3. The same division within the party that derailed healthcare reform could also rear its head with respect to tax reform.   The reference to figurative derailment is at odds with the clichà ©d metaphor of a threatening creature preparing to strike. Again, sacrifice one metaphor for another (preferably, replacing the clichà © with a straightforward verb): â€Å"The same division within the party that derailed healthcare reform could also occur with respect to tax reform.† (An attempt to match the derailment reference with another train-related metaphor will only call attention to the symmetry at the expense of the point of the sentence.) Want to improve your English in five minutes a day? Get a subscription and start receiving our writing tips and exercises daily! Keep learning! Browse the General category, check our popular posts, or choose a related post below:4 Types of Gerunds and Gerund Phrases75 Idioms and Expressions That Include â€Å"Break†What is an Anagram?

Media Imagery Effects on Adolescent Girls Research Paper - 1

Media Imagery Effects on Adolescent Girls - Research Paper Example In the book Everything’s an Argument with Reading, is designed to be a true alternative to the traditional argument (Williams 81). It complements students approach with unique broad examples and therefore responds soundly to reasoning around them. In most cases argument of evaluation provides profound decisions about someone's life through the involvement of certain standards (Williams 83). The particular standard required for an individual is an establishment of judgment within an individual. A person is required to judge anything that comes across his or her life. This judgment can be an idea, a work of art, a person or a product. It is this lack of sound argumentation that can lead to making a relevant judgment that makes girls susceptible to effects that comes from media imagery (Williams 85). According to Nachbar and Lause (119), the examination of these evaluation criteria such as an idea or art of work is enough to give a verdict that they have impounded on the adolescent girls both positively and negatively. The programs that are aired by the media can influence an adolescent girl to make a decision that leads to an explosive behavior to dangers. An adolescent girl may become frightened and violent with others such as suicidal commitment. Lundsford, Ruszkiewicz and Walters (54) assert that in as much as media provides education and entertainment, they can also result in aggressive attitudes and violent behavior. Violence in the media especially those programs that affect the psychological effect on children and women in advertising or merchandising in media are harmful to girls. As a result of self-image seen, they are therefore influenced to behave and try to imitate their behavior.

The Color Purple Essay Example | Topics and Well Written Essays - 1000 words

The Color Purple - Essay Example The story revolves round the protagonist Celie, a fourteen years old black girl, who is victim of the sexual assaults of her stepfather. The stepfather, not only rapes her continuously, but also impregnates her twice illegitimately. Celie is also rebuked and tortured by the obnoxious Alphonso, who does never have mercy towards the innocent little girl. Since she is unable to resist to the cruel and atrocious behavior of her stepfather, she writes letters to God out of the feelings of sheer disappointment and despair. Hence, she maintains unabated belief in the existence of the Supreme Being, Who would remove all her miseries one day. Thus, the elements of Christian religious belief sway throughout the book that consists of letters to God carrying prayers for the protagonist’s safety from the cruelties society committed on the weak stratum. She also looks nagging in her letter on the sad demise of her mother, which has deprived her of the affection and protection of a shelterin g tree in the person of the mother. She also makes complains through her writing to the Lord regarding the loss of her daughter and then son, both of which are snatched away from her lap as soon as she gives birth to them. Since the children are the product of her illicit relationship or rape by her stepfather, who gets the infant children lost in order to conceal his heinous crime he has been committing against her innocent stepdaughter. The little girl’s mourning and cries fill the hearts of the readers with gloominess. The author, in a highly moving though morbid way narrates the torture and battering Alphonso inflicted upon Celie. However, Celie’s unabated belief in the Lord does not waver altogether. On the contrary, her faith observes tremendous boost while her addressing the Lord through her innocent writing. help. Her letters further make complains from the Lord on getting married to the immodest and dissipated Mr.___. Although Mr. ___ had asked for the hand of Celie’s younger sister Nettie, yet Alphonso preferred to hand over comparatively â€Å"the ugly† Celie to the sweet and charming Nettie. Since she is unable to get rescued from the cruelties of Alphonso and then Mr. ___, her belief about God as a white male strengthens. Consequently, she starts believing that the deity belonging to male stratum as well as white racial group would not protect an ordinary, poor and helpless black girl at any cost. Thus, sense of alienation appears in the mind of the black girl. The elements of racial discrimination are also evident in the letters Celie writes to God, which are actually the reflection of the sentiments of