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Process Analytical Technology And The Search For Quality By Design In Bio-Manufacturing
Process Analytical Technology And The Search For Quality By Design In Bio-Manufacturing
Table of contents
TOC o “1-3” h z u 1Introduction PAGEREF _Toc370560847 h 32Discussion PAGEREF _Toc370560848 h 43PAT Tools PAGEREF _Toc370560849 h 53.1 Multivariate data acquisition and analysis tools PAGEREF _Toc370560850 h 53.2Modern process analyzers or process analytical chemistry tools PAGEREF _Toc370560851 h 63.3Process and endpoint monitoring and control tools PAGEREF _Toc370560852 h 73.4Continuous improvement and knowledge management tools PAGEREF _Toc370560853 h 84Applying PAT tools in bio-manufacturing PAGEREF _Toc370560854 h 95Conclusion PAGEREF _Toc370560855 h 96References PAGEREF _Toc370560856 h 11
IntroductionProcess Analytical Technology (PAT) is a revolution in the pharmaceutical industry that was originated around two decades ago by United States Food and Drug Administration to minimize the risk of producing poor quality products. Shresth et al (2009, p. 225) defines PAT as “ a system for designing, analyzing, and controlling pharmaceutical manufacturing through timely quality measurements and performance attributes of materials and processes.” PAT is a framework that allows for continuous improvement of the quality of a product throughout the manufacturing process. As Shresth et al (2009, p. 225) explains, PAT involves physical, risk, biological, chemical and mathematical analysis which is carried out in a systematic manner. It is a process that requires clear understanding of all the processes that are involved in the process of manufacturing a product. PAT uses real time information to enhance manufacturing capability and to reduce processes variation. In other words, PAT involves real-time testing and using the information acquired to make the right adjustments based on clear understanding of how all activities and processes involved affect the final product (Streefland et al, 2013, p. 212; Shresth et al, 2009, p. 225).
In the manufacturing of chemical drugs, PAT is applied in relatively simple process phases such as drying, milling, granulation or tableting. However, bio-products and their production processes are more complex than chemical drugs and their production processes. Thus, application of PAT in bio-manufacturing processes is relatively more difficult. Despite the challenges, the quality of biochemical products can be enhanced through the use of PAT tools during production processes (Streefland et al, 2013, p. 214). This paper reviews some of the PAT tools that are available currently and examines their applicability in designing and in operating bioprocesses.
DiscussionAccording to Scott (2006a, p. 21), the key objective of developing PAT framework is to design and create processes that guarantee the manufacturer predefined quality of products. The procedures and activities involved enhance efficiency, safety and quality, which may vary depending on the product (Scott, 2006a, p. 21). The aim of introducing PAT framework is to:
Improve material and energy use and increase capacity
To use dedicated manufacturing equipments
To replace large-scale equipments with small-scale ones in order to solve some issues associated with large-scale equipments
To consider continuous processing to manage variability and to improve efficiency
To increase automation in order to reduce human error and enhance operator efficiency
Where possible, to enhance real time production
To prevent re-processing, reject and scraps
To introduce certain measurements and controls that can help to reduce cycle times during production (Scott, 2006a, p. 22).
PAT framework can also be applied in enhancing quality, efficiency and safety in bioprocesses. For instance, in a convectional cell culture bioreactor setting, samples are taken manually several times a day to monitor process performance. The samples are then analyzed using bench-top equipment and the results are finally entered into batch records. The monitoring process can be automated by applying online analyzers that have been developed recently (Streefland et al, 2013, p. 214). Generally, available PAT tools can be modified and applied in bio-manufacturing to achieve desired level of efficiency and quality of bio-products.
PAT ToolsThere are numerous tools that have been developed and implemented in improving efficiency, safety and quality during production of pharmaceutical products. When used within a system, the tools provide efficient and effective ways for gathering critical information regarding processes and materials. As well, the tools facilitate achievement of continuous improvement, development of risk-mitigation strategies and sharing of information and knowledge. Studies have shown that when implemented correctly, the tools can help to achieve monitoring and control goals and to reduce variability in bioprocesses (Streefland et al, 2013, p. 212). The currently available PAT tools can be grouped into the following categories
Multivariate data acquisition and analysis tools
Modern process analyzers or process analytical chemistry tools
Process and endpoint monitoring and control tools
Continuous improvement and knowledge management tools (Roggo, 2007, p. 685).
3.1 Multivariate data acquisition and analysis toolsFrom a biological, physical and chemical perspective, bio-pharmaceutical processes and products can be regarded as complex multi-factorial systems. As Shresth et al (2009, p. 225) explains, numerous developmental programs have been invented which help in identifying and in gathering in-depth information during formulation and processing of these systems. The information gathered using the programs is used in the development and improvement of product and process design. In some cases, producers use multivariate approaches, such as response surface methodologies, statistical design experiments, pattern recognition tools and process simulation. Usually, such approaches are used in conjunction with knowledge management systems. The applicability and reliability of each approach or model is assessed by statistically evaluating the model predictions. As Rathore, Bhambure and Ghare, (2010, p. 138) explain, methodological experiments based on statistical standards of randomization, reference distribution and orthogonality provide effective means for studying and identifying the impact and the results and the interaction of process and product variables.
As Rathore et al (2010, p. 138) explains, experiments that are based on the traditional one-factor-at-time model are not effective in assessing interactions between process and product variables. Experiments that are carried out during process and product development help to identify critical areas of improvement. A higher degree of complexity in the life-cycle of a product is achieved as the information gathered through continuous experiment grows. Information gathered from such experiments is utilized in the development of knowledge system for production process and products. As well, such information can become part of the overall organizational knowledge base. As the information grows in the organizational knowledge base, it can be mined to come up with useful patterns for current and future project. As Kamble (2013, p. 52) explains, information kept in experimental databases can also be used in development of simulation models which can help to significantly reduce overall development time and to facilitate continuous learning.
Modern process analyzers or process analytical chemistry toolsAs Mendhe, Rathore and Krull, (2012, p. 16) noted, the concept of process analytical chemistry has received significant attention over the last several decades. This has largely been caused by an increasing appreciation for the importance of collecting process data during production. Modern tools that measures physical attributes and chemical components during production have been developed from simple process measurements, such as pressure, temperature and pH (Mendhe, Rathore & Krull, 2012, p. 16). The tools provide effective measurements that contain data related to both chemical and physical attributes of materials used in the production process. The measurements are carried out in the following manner:
Off-line in a laboratory
At-line when the manufacturing process is set to begin
On-line during the manufacturing process. The measurement system is connected to the process and a sample is diverted for measurement. The sample may be returned back to proceed with processing after measurement
In-line where the production process may be stopped to allow adjustments or probe. Measurements after the correction are done in real time.
Noninvasive and nondestructive when the sensor for the measurement system is not in contact with the material being processed. Thus, the production process is not disturbed (Mendhe et al, 2012, p. 17)
Process and endpoint monitoring and control toolsThe following steps can be incorporated within the PAT framework for the optimization and development of design for manufacturing processes and drug formulations.
Identification and measurement of crucial process and material attributes relating the quality of a product
Development of a process measurement system to facilitate real-time monitoring of all crucial attributes
Develop process controls that aid in the collection and adjustment to enhance control of all crucial attributes
Developing mathematical relationships between measurements of critical process and material attributes and product quality attributes (Challa & Potumarthi, 2013, p. 67).
Generally, as Challa and Potumarthi (2013, p. 67) explain, a strong link between process development and product design is essential to ensure that all critical quality attributes are effectively controlled. The control and monitoring strategies applied to the production process are intended to closely monitor the process and to manipulate it in order to achieve a predefined outcome or to maintain a desired state. While developing strategies, it is vital to consider all information related to reliability and ability of analyzers to measure crucial process and material attributes, the attributes of input materials and the expected achievements at the endpoints of all phases within production process. This helps to ensure that consistent quality of materials is achieved at all endpoints of phases within production process (Challa & Potumarthi, 2013, p. 67). Within the PAT framework, the endpoint of a phase may not be necessarily tied to specific time fame; rather a phase can end after achievement of a desired material attribute. However, this does not imply that process time should be ignored. As Kourti (2006, p. 259) explains, there is need to develop a range of acceptable process times. The production process should be evaluated and considerations be made to address deviations from the acceptable process times. According to Kourti (2006, p. 259), it is essential to emphasize that process end points that are meant for real time release and more critical in comparison to those that are simply used for in-process control.
Continuous improvement and knowledge management toolsAs mentioned earlier, information collected during production process is quite important for continuous learning. Such information can be used to justify proposals for changes prior to the commencement of the production process (Alford, 2013, p. 40). For instance, such information can justify a proposal for change in technology. It is therefore essential for producers to develop knowledge management systems and approaches that support acquisition of such information. As Alford (2013, p. 40) explains, the knowledge management systems can also facilitate communication between manufacturers and regulatory agencies.
Applying PAT tools in bio-manufacturingAs Shresth et al (2009, p. 225) explains, implementation of PAT tools in bio-manufacturing means applying the collect sensors or tools to measure critical process parameters and critical quality attributes of a bioreactor process. There are numerous tools that can be applied in bio-manufacturing, depending on the critical attributes that need to be monitored or controlled during processing. Examples of available PAT tools that can be applied in bio-manufacturing are; optical spectroscopic tools (near infrared spectroscopy, infrared and RAMAN spectroscopy, photoacoustic spectroscopy, 2D fluorescence spectroscopy, UV spectroscopy and real-time imaging), biomolecular tools (biosensors/biochips, transcriptome and proteome measurements) and other tools such as bio calorimetry, on-line HPLC, flow cytometry and soft sensors (Shresth et al, 2009, p. 225). The PAT tools described above have different uses in bio-manufacturing processes. Some tools, such as on-line HPLC, allow online measurements for critical quality attributes and critical quality parameters. Some of them, such as near infrared spectroscopy, produce multivariate data that requires chemometric processing before use. Some tools such as deoxyribonucleic acid (DNA) microarrays cannot be used directly for process monitoring and control. However, such offline tools provide essential biological information about materials being processes.
ConclusionIn conclusion, the use of PAT can provide numerous benefits in biomanufacturing industry by improving product quality, enhancing efficiency and delivering financial value and superior asset utilization. PAT enables manufacturers to acquire in-depth knowledge of law materials and production processes. Critical information about raw material is acquired by characterizing it biologically, chemically and physically. PAT framework also provides an opportunity to understand manufacturing parameters. Combined together, the information acquired is used in making adjustments and corrections at various points within the production process. Any variations in the expected outcomes at endpoints of production phases are identified and corrections are made in real time. As a result, the PAT framework facilitates the achievement of a predefined product quality attributes. If they are applied in bioprocesses correctly, the available PAT tools can result in better products, huge time saving, better process control and more robust process. Ultimately, this may bring some benefits to a manufacturer, such as unique brand image and enhanced reputation for the organization, reduction in production costs and increase in profits.
ReferencesAlford, J. S. (2013). “Understand the Basics of Process Analytical Technology.” Chemical
Engineering Progress, Vol. 109, Iss. 8, p. 40
Challa, S. & Potumarthi, R. (2013). “Chemometrics-Based Process Analytical Technology
(PAT) Tools: Applications and Adaptation in Pharmaceutical and Biopharmaceutical Industries.” Applied Biochemistry and Biotechnology, Vol. 169, Iss. 1, pp. 66 – 76
Kamble, R., Vaidya, I., Gawai, A. & Jangam, R. (2013). “Process Analytical
Technology: A Review.” International Journal For Pharmaceutical Research Scholars, Vol. 2, Iss. 1, pp. 49 – 55
Kourti, T. (2006). “Process Analytical Technology. Beyond Real-Time Analyzers: The Role of
Multivariate Analysis.” Critical Reviews in Analytical Chemistry, Vol. 36 pp. 257–278
Mendhe, R., Rathore, A. S. & Krull, I. S. (2012). Tools for enabling process analytical
technology applications in biotechnology: the authors review the various analytical methods that can enable use of PAT.” Pharmaceutical Technology, Vol. 36, Iss. 11, p. 16-18
Mhatre, R. & Rathore, A. S. (2011). Quality by Design: An Overview of the Basic Concepts.
Quality By Design For Biopharmaceuticals, New York, NY: John Wiley & Sons
Rathore, A. S., Bhambure, R. & Ghare, V. (2010). “Process analytical technology (PAT) for
biopharmaceutical products.” Analytical and Bioanalytical Chemistry, Vol. 398, Iss. 1, pp. 137 – 154
Roggo, Y. (2007). “A review of near infrared spectroscopy and chemometrics in pharmaceutical
technologies.” Journal of Pharmaceutical and Biomedical Analysis, Vol. 44, Iss. 3, pp. 683-700.Scott, P. (2006a). “Process analytical technology in the pharmaceutical industry: a toolkit for
continuous improvement” PDA Journal of Pharmaceutical Science and Technology, Vol. 60, Iss. 1, pp. 17-53
Scott, P. (2006b). Process Analytical Technology: Applications to the Pharmaceutical Industry,
Quality Assurance Analytical Services. AstraZeneca, Westborough
Shrestha, B., Basnett, H., Raj, P. M., Patel, S. S. Das, M. & Verma, N. K. (2009). “Process
Analytical Technology: A Quality Assurance Tools.” Research J. Pharm. and Tech, Vol. 2, Iss. 2, pp. 45-67
Streefland, M. Martens, D. E., Beuvery, E. C. & Wijffels, R. H. (2013). “Process analytical
technology (PAT) tools for the cultivation step in biopharmaceutical production.” Engineering in Life Sciences, Vol. 13, Iss. 3, p. 212
The Foreign Corrupt Practices Act
The Foreign Corrupt Practices Act
Contents
TOC o “1-3” h z u The rationale for the Act (i.e. why was it implemented) PAGEREF _Toc377398209 h 1What the Act prohibits PAGEREF _Toc377398210 h 1How the Act impacts businesses nationally, and internationally PAGEREF _Toc377398211 h 2The penalties that are imposed for violating the Act PAGEREF _Toc377398212 h 3The “real” impact and significance of the Act on U.S. commerce PAGEREF _Toc377398213 h 3Enforcement (who is responsible for enforcing the Act) PAGEREF _Toc377398214 h 5
The rationale for the Act (i.e. why was it implemented)The act is a federal law and enacted in 1977. It is based on the premise that business entities should earn their position in the society and therefore should not be engaged in soliciting for favours from government officials and politicians by the use of bribes (Weiss, 2009). This means that under this act of law, bribing by companies and corporations is termed as illegal and is punishable by law. The act covers all citizens of the United States whether by birth or by registration (Posadas, 2009). It also includes other citizens of a country so long as the act is committed while one is in the boundaries of the United States. The only exception is for diplomats for from other countries.
What the Act prohibitsThe act is divided into two provisions: the first provision is the anti-bribery provision which is supposed to be enacted by the department of justice. The provision prohibits any form of bribery to government officials and political parties by an individual or a company in order to get commercial related favours. In this act there is a clear distinction between bribery and grease payments to politicians and government officials (Weiss, 2009). Even though in some states both are considered as illegal, the act allows for grease payment as they are said to expedite the person however it must be clearly recorded and known to the supervisor in charge. This is to ensure that there is transparency.
The second provision is the accounting provision which is overseen and enacted by the Securities and Exchange Commission (SEC). The provision allows for clear financial statements on the spending of a firm (Posadas, 2009). This provision also states that all companies that have their securities listed by the United States should record all the financial transactions that the company participates in. This means that from time to time the books are to be checked and compared to the current financial position of the companies. In the case of any irregularity the firm can be fined or even worse closed down.
Generally the act prohibits government employee and politicians from receiving bribes from companies and individuals in order to be able to get favours that may lead to commercial flourishing. It also prohibits companies from poor accounting in terms of their finances. All financial transactions should be clearly recorded and stored for analysis by the government agents. The company should always pay its taxes and avoid transferring money to anybody as a bribe.
How the Act impacts businesses nationally, and internationallyNationally the act ensures that all officers of the state are not involved in any activities that would allow a company to continue engaging in any illegal activities. It ensures that all companies are registered with the government before they can start on their operations (Weiss,, 2009). Accounting is checked not only to ensure that the firm is recording all the financial transactions but also to know whether there are frauds in terms of tax evasion and in corporate payments. This is also used to deter any kind of fraudsters from attempting as there are regular checkups.
Internationally it ensures that fraudsters from other countries do not come to the United States and start illegal businesses by bribing their way up. It also ensures that all international organizations in the country like the UN are legally framed and have transparent financial records that cannot act as a breading point for any illegal commercial activities (Rich, 1994). In general internationally the act protects the United States from international criminals that may be interested in establishing companies in the country.
Internationally it also protects other countries from American citizens who would like to bribe their way into commercial activities in the country or to avoid accounting transparency as well. A good example is that of WalMart, a US based firm is: that was found guilty and charged for bribing officials in Mexico in order to acquire business premises and permits. This led to the closure of the premises and the revocation of the permits by the US government in conjunction with the government in Mexico (The Washington Post, 2012).
The penalties that are imposed for violating the ActThe penalties can go as high as a fine of $450million like the one charged by the courts to Siemens Ag, when the company was found guilty of bribing some public officers and not maintaining correct books of account. This was the beginning of the investigation into the company and it uncovered a lot (Funk, 2010). In other circumstances the bribed party is imprisoned to a sentence of not more than three years in a state penitentiary, while the one who bribed gets a sentence of five years. They are also liable to a fine or both a fine and imprisonment. The fine is to be decided by the court depending on the reasons behind the bribery. The company that would be found guilty of bribery would be dissolved as per the specifications of the case and at times it would become state owned.
The “real” impact and significance of the Act on U.S. commerceCommercial activities form the backbone of any country; this is because the only way to establish if there is development in a country is by the increase in its GDP and Income. These are all factors of commercial activities. This is the reason why the government has to protect the sector by enacting federal laws that ensure that all people are equal. The law is placed there to level the playing field so that nobody can oppress the other. This is because if such a law was not enacted the rich would always bribe their ways into contracts and permits at the expense of the poor. The disparity between the rich and the poor would increase and what was termed by Karl Marx as an army of unemployed and under-employed would become the fate of the poor.
The real significant of the act is to ensure that there are no short cuts and that everybody follows the correct means. The state should reward people in form of income from business activities that were earned from qualification due to experience and exposure but not because of being able to bribe someone somewhere to get ahead. If buying favours is allowed, then it means that the people of the country would be allowed to consume substandard goods and services (Funk, 2010). This is because the provider of these goods and services will be allowed to do so not because they are qualified but because they had the initial money to bribe their way there.
The backbone of the act is to protect the citizens of the country: to protect the education system so that the children can know that people get to the top by having the necessary technical qualification and not by bribing their way there (Rich, 1994). It is meant to protect the everyday citizen who has a hard time making the ends meet, so that he can work even harder because he knows that there will be a reward for his hard work. It is meant to encourage the youths to invest in businesses and make them legitimate and after a given period of time they will be able to grow and flourish because the law is there to protect them.
Enforcement (who is responsible for enforcing the Act)The US Securities and Exchange Commission is responsible for investigating for any inconsistencies in accounting books of all firms (Funk, 2010). This means it is in conjunction with the IRS in determination of corporate tax payments. It also analyzes the transfer of funds from the corporate bank accounts to any other bank account around the world.
The Department of Justice is the federal body of criminal investigation, it is headed by the attorney general of the government. In this case it is responsible for investigating the government employees and their involvement in any favouring after a grease payment was made or after bribery by a company. It is allowed to open and start investigation into individuals on their conduct at the work station and any other place. This allows them to investigate companies that are based in American and venturing into the emerging markets. The conduct of the firm should be as per the laws of the United States and any violation of them can lead to immediate shut down and dissolution of the mother firm in America.
References
Funk, T. Markus (September 10, 2010). “Getting What They Pay For: The Far-Reaching Impact Of the Dodd-Frank Act’s ‘Whistleblower Bounty’ Incentives on FCPA Enforcement”. White Collar Crime Report (Bureau of National Affairs) 5 (19): 1–3.
Posadas, Alejandro. (2009) “Combating Corruption Under International Law” . School of Law, Duke University.
Rich, Ben R. and Janos, Leo. (1994) Skunk Works: A Personal Memoir of My Years at Lockheed. New York: Little Brown & Co., , p. 10.ISBN 0-7515-1503-5.
Barstow, David (April 21, 2012). “Vast Mexican Bribery Case Hushed Up by Wal-Mart After High-Level Struggle”. The New York Times.
The Washington Post, (April 22, 2012), Mexican watchdog group says Mexico’s federal government should probe alleged Wal-Mart bribes, Associated Press..
Weiss, David C. (2009), The Foreign Corrupt Practices Act, SEC Disgorgement of Profits, and the Evolving International Bribery Regime: Weighing Proportionality, Retribution, and Deterrence, 30 Michigan Journal of International Law 471
The Force Awakens
The Force Awakens-Replicate reaching into the box
While the scene has many more shots, we are looking at seven unique shots and replicating four.
Entire Shot List:
BOX #1 Wide, Low Angle, tracking Rey as she walks through the space; camera booms up to reveal the box (as Rey walks left); Camera pushes past Rey to an OTS of the Box
Lens: Normal
Essence: shifts from Rey to the Box through camera movement
Camera Support: Jib, Dolly, & track
Box #2 Medium Tracking-Rey; Rey walks toward the camera
Lens: Normal/Portrait
Essence: shifts from Rey to the Box through camera movement
Camera Support: Jib, Dolly, & track
Box #3 Note: this is likely an extension of Shot #1
Box #4 Bust-Rey; Booms down to reveal the box, tracking Rey as she kneels
Lens: Normal
Essence: shifts from Rey to the Box through camera movement
Camera Support: Jib
Box #5 Profile; Push-In past OTS to Box INSERT; Push-In the box slightly; Push-In/Boom
Down as Rey reaches in for the box
Lens: Slightly long
Essence: shifts from Rey to the Box to the Light Sabre through camera movement
Camera Support: Jib, Dolly, & track
Box #6 MCU Rey from behind the box; Push-In; reframe with talent movement
Lens: Short Telephoto
Essence: Rey’s responses
Camera Support: tripod
Box #7 Bust Rey from behind the box; boom up as Rey stands; float left as Rey turns
Lens: Short Telephoto
Essence: Rey
Camera Support: Jib