DOI: 10.31038/JPPR.2019214

 

Quality Assurance will provide an understanding and importance for support in providing perspective and understanding from day to day activities and to provide effective and advocate a culture that supports commitment to customer integrity.

Index Terms

Delivery, Evaluations, Commitment, Consulting, Planning, Quality, Requirements, Audits, Evaluations, Verification and Validation.

Introduction

The primary purpose is to increase the implementation of Effective Processes for Quality Assurance for Companies and Institutions to increase communication, knowledge, and the visibility into the company operations. This journal will provide informative, interesting, and convey the methods for Quality Assurance to be more effective in current and future companies and institutions and could benefit as well by adopting these effective processes.

Driving innovation will help in controlling costs for companies, institutions, military programs, and successful businesses. Delivering complex products must have high quality to reduce customer problems and defects. Integration of Quality Assurance processes provides compliant work product management and gap analysis. The purpose of Quality Assurance is to provide a common operating framework in which best practices, improvements, and cost avoidance activities can be shared, and Quality Assurance responsibilities assigned results from converging on quality shared best practices are improved process execution and reduction of operational costs.

Quality Assurance personnel must support Business Companies by encouraging a cooperative, pro-active approach and ensure compliance through evaluations and management participation. All results are reported to management. Make sure that happens.

Quality Management

To have quality management in place it is simply, having documented paperwork, online instructions, execution with knowledgeable employees, monitoring or measuring and making continual improvements. The following improvements are to Plan and document to deliver results and Do implementation by a skilled work force. Always Check and Act to take actions and continually improve performance.

In order to have quality management implemented, the companies and institutions must be focused, process based, and improvement oriented. Say what you do, do what you say, prove it, and improve it. A quality management system can be used for internal application certifications and contractual purposes and the focus on the effectiveness of the quality management system in meeting customer requirements and expectations.

Do what you say: (Compliance): Follow all procedures and instructions that affect your work. You must say what you do (Documentation): Use current plans, procedures, and work instructions. Prove It: (Records): Demonstrate your work in accordance with compliant processes/procedures and provide objective evidence. Improve It: (Business Management/Continual Improvement and implement change based on information provided by Business Management.

“Managers do not control change but need to manage change.”

– Dr. Boyd L. Summers

Policy

A policy is the key element in business process and there are organizational, planning and control documentation and/or procedures to support key elements. The significant activities are defined in this book. To conduct a successful business, we should understand the scope of the work to be accomplished. A policy provides a mission statement of direction and guidance for companies and institutions. Policies are the highest level of authority and are consistent with the visions that should be used to be successful.

A very effective policy to review over and over is a policy for Quality Assurance. The policy states that we are the difference such as:

• I am personally responsible and accountable for the quality of my work.
• I acquire/use the necessary tools and skills needed to meet quality requirements.
• I know my objectives and needed process improvement goals.

Quality Engineering

Quality Engineering is associated with analysis, requirements understanding, and the importance of employer and/or consultant capabilities. Interfaces are defined externally and internal to ensure Quality Assurance is compatible supporting business activities and military programs. The Quality Engineering process methods are included in tasks or assignments to integrate all disciplines to meet all requirements and expectations. In years of working Defense and Space related to military and aerospace program technical Quality Assurance needs are very important.

Quality Engineering methods are used for application setting the ladder for rigorous business techniques to solve complex problems both technical and functional.

Driving innovation will help in controlling costs for companies, institutions, military programs, and successful businesses. Delivering complex products must have high quality to reduce customer problems and defects. Integration of Quality Assurance processes provides compliant work product management and gap analysis.

The purpose of Quality Assurance is to provide a common operating framework in which best practices, improvements, and cost avoidance activities can be shared, and Quality Assurance responsibilities assigned results from converging on quality shared best practices are improved process execution and reduction of operational costs.

Quality Assurance personnel must support Business Companies by encouraging a cooperative, pro-active approach and ensure compliance through evaluations and management participation. All results are reported to management. Make sure that happens.

Lean and Agile

Coming from a software and Quality Assurance technology background, I have supported many software companies, military and aerospace programs that are Lean and Agile and have a competitive advantage. By implementing these two principles, practices, development deliveries of products to the customers will show Quality Assurance has been applied and with fewer defects.

The definition of Lean is a new concept in the software world. Lean principals establish clear priorities by getting rid of bad multitasking, focus, and not finishing the task assigned to an individual within a business companies, military and aerospace programs. Lean principals will eliminate the release of software being late and require an early delivery. One must prepare, start, finish, and use checklists to prevent software defects and risk. Teams will face issues and resolve them on timely basis and drive daily software execution and quality products.

Applying the Agile management model per Figure 1 implements software development, supports many initiatives, and provides a Business Company and Institutions a strong management approach to emphasize short-term planning, risk mitigation, and adaptability to changes as well as close collaboration with the customers.

Proactive Approach to Quality Assurance

The elements of basic standards require identification to plans and procedures for production and service which can affect Quality Assurance processes. There are elements that should always be addressed. These elements are:

• All plans and documents show how work is done
• Effective tools for handling work used in a working environment
• Compliance to monitor and control work products
• Approval of Quality Assurance processes

What Quality Assurance auditors should always assess the operations and where all the work is done. The auditors need to talk to personnel and ensure they have the training and experience and the knowledge for process control for all data documentation. The auditors will interview personnel and ask about the workmanship activities, specifications and tie them to records. Education and training of personnel are the required standards and mush always be correct. The standards offer ways to address specific processes by continuous monitoring of all processes.

All Quality Assurance auditors need to demonstrate the capability to deliver effective and efficient data. There should always be an ongoing program for training to stay current and show improvement to satisfy customer needs.

Quality Assurance consultants must support by encouraging companies, institutions, military and aerospace programs, and successful businesses to be cooperative and a pro-active approach to quality and ensure process compliance through evaluations and management participation.

Compliance verification is performed using quality evaluations, assessments, reviews, or appraisals. Quality Assurance consultant’s witnesses/monitors activities in accordance with the project-level reviews and meetings.

Quality Management System

The Quality Management System (QMS) is a requirement to have processes documented and execute with knowledgeable people and teams. At times metrics are reviewed and monitored to ensure processes are showing improvement. I will have a chapter that defines and talks about metrics and a very good understanding of the importance of metrics and how they come into play with Quality Assurance.

All customer focus should be QMS and provide the framework that is followed to say; what you do, do what you say, prove it, and show improvement. The Standards for QMS is AS9100 AS9100C, AS9100D, SAE AS9110, and ISO 900 and is the model for:

• Quality Assurance
• Design and Development
• Production and Delivery Results
• Business Compliances
• Customer Contracts

Biography

Boyd L. Summers has completed his Bachelor of Science (BS), Business Administration at Weber State University, USA. Areas of emphasis: Information Systems, Production and Operations Management, Quantitative Analysis and Methods, Human Resources, Economics, Business Management and Statistical Analysis and Computer Science.

He is a Software Technology and Quality Consultant for BL Summers Consulting LLC located in Florence, Arizona. With 30 years of experience in Software Engineering and a leader of multiple software development teams, Boyd continues to solve complex technical challenges to ensure that system and software engineering problems are addressed, resolved and include: System Design, Software Requirements, Software Design, Software Test and Evaluation, Configuration Management, Quality Assurance, Process and Product evaluations. Applies Processes in Agile, Lean and Six-Sigma including a Software Technology Speaker at conferences and member of the American Society Quality (ASQ).

Author of the three software and quality technology books titled; “Software Engineering Reviews and Audits.” and “Effective Methods for Software and Systems Integration. and Effective Process for Quality Assurance and Provides Software and Quality Articles to Journals and magazines.

DOI: 10.31038/JPPR.2019213

 

In this limited space I intend to make a few observations and opinions, and raise some questions, in order to stimulate thinking about future treatments for envenomation, mainly but not exclusively for the benefit of newer investigators and investigators new to this field. There is no way to be definitive completely in this short opinion piece. It seems fair to disclaim that while not all questions have simple answers, the process of consideration, including debate, stimulated in part by controversial statements and open questions, can lead to improved understanding, and hopefully better clinical outcomes.

Envenomation is a significant health challenge worldwide. Aside from medically serious hypersensitivities to venom peptides/proteins from envenomation that would not otherwise be medically serious, e.g. by insects, the main concerns are snake and spider envenomation. The effects range from significant tissue loss to death. Traditional treatments have been the use of antisera in severe cases, and supportive care. The importance of treating envenomation and conducting research toward better treatment has periodically been specifically addressed by the World Health Organization.

Some time ago it was held in this country that you might acquire public research funding for a variety of projects, but not for a better understanding of the pathology of envenomation. The entrenched approach included reliance on antisera, and led to the Wyeth product for snake envenomation, helpful but with limitations for which it was difficult to impress many scientists that these existed and a better product was needed. Now it is no longer deemed safe and efficacious for human use, supplanted by a newer and more satisfactory product from abroad. Concerns limiting commercial development for many years, arguably with some validity, considered profitability of the development of such products. The recent involvement of at least one company in Mexico to develop products is another encouraging step, as has recent investment by the NIH, after a checkered history in this area. For neurotoxic snake venoms, one opinion expressed was that if the patient received timely supportive care in hospital, including respiratory support, they generally recover with minimal effects, without the use of anti-venom. Those are a lot of qualifications. One might ask what does real data say, both overall and for locales, and how uniformly is supportive care available.

We may also ask “Given the toll on populations in Africa and Asia, is the expenditure on research toward therapies for their envenomation at an appropriate level?”, and if this is an economically disadvantaged area, “Is there a responsibility by the more economically advantaged countries to engage in meaningful contributions?” The less common the envenomation, and less profitable the market, the lower the likelihood of product development. “What is the value to humankind of the development of an effective, accessible treatment, that if found will be useful in the future in perpetuity?”

As has been often mentioned including in print, traditional treatments have had limitations. In the context of snake envenomation, hospitalization is not universal, antisera if locally available are expensive and perishable, and effectiveness varies. It is not always clear which species of animal was responsible, and the composition of venoms can vary substantially within a species, making the targeting of therapies a challenge.

Is there a single path of knowledge development, a single research approach to develop the new therapy, acceptable to the general body of researchers? I have had a reviewer indicate as much. But historically no; and for the future there seem developing options and pitfalls. A substantial volume of work has been to deconstruct venoms, with detailed in vitro enzymology, pharmacology and lately proteomics, studies of each toxin present, with much less of the venom’s pathology in vivo. How comparable are studies done in vitro with reactions in simple buffers, occasionally with simple cell systems, compared to the clinically relevant in vivo complicated microenvironments of plasma and parenchymal tissue? For tissue destructive venoms, if a therapy to arrest tissue damage is found, can additional insights from wound management be applied to control excessive acute inflammation and hasten recovery, perhaps with tissue regeneration?

Lessons from and methods in drug development, from high throughput screening to lead optimization seem directly applicable. But to what extent are researchers trained in the study of purified enzymes in model reactions ready to consider the inhibition of the mixture of toxins, often enzymes in venoms, as is the actual clinical challenge, broadening their experimental systems, approaches and expectations, both in their own work and as grant or manuscript reviewers? Will established investigators adapt to new methodologies?

Is there a potential for enzyme inhibitors as a major component of anti-venom therapy, an idea that appears in print from the nineteen eighties? This idea has had a surge of interest recently, I hope in at least some small part due my own modest contributions, but recently by many others as well. Under what circumstances would the enzyme inhibitor approach have the best chances of success? Is the best target pathology due to venom with a single enzyme as the main virulence factor? Is the composition of venom across related species, within a species at different locales and developmental age of animal, sufficiently consistent a target for us to construct a simple yet effective cocktail of inhibitors, which if used in a single or brief dosing, will be effective but minimally toxic to the patient? Will it be possible to devise better, rapid, accurate diagnostic tests for the clinical lab to identify which venom is harming the patient, and point to specific therapies? The challenges are substantial, but equally so are the opportunities.

DOI: 10.31038/JPPR.2019212

 

Recent years have brought great progress in our understanding of the pathogenesis of inflammatory and immunologic diseases, thereby uncovering novel therapeutic targets. One of these newly identified targets is the Janus Kinase (JAK) / Signal Transducer and Activator of Transcription (STAT) pathway.

Janus kinases are a family of intra-cellular tyrosine kinases that are activated after stimulation of several cell surface receptors by their specific growth factors, growth hormones, chemokines and cytokines. After activation, they phosphorylate STAT transcription factors, resulting in the transportation of these STATs to the nucleus and affecting expression of specific genes. These transduced cytokine-mediated signals via the JAK-STAT pathway are pivotal for the downstream signaling of inflammatory responses and their desired, as well as pathologic affects. As such, JAK kinases are a critical conduit for translating information from a cell’s extracellular environment to its nucleus, resulting in gene expression profiles corresponding to these extracellular cues.

There are four known types of JAKs: JAK1, JAK2, JAK3, and TYK2, which are predominantly, but not exclusively, expressed in hematopoietic cells. As such, JAKs can contribute substantially to the immunologic processes involved in inflammatory diseases, and with autoimmune pathologies in particular. There are currently three FDA approved oral JAK inhibitors in clinical use: Tofacitinib (Xeljanz), Ruxolitinib (Jakafi) and, most recently, Baricitinib (Olumiant). There are also a significant number of additional JAK inhibitors, with varying JAK selectivity profiles, currently undergoing clinical trials for a number of indications.

Tofacitinib (a JAK1/3 inhibitor) and Baricitinib (a JAK1/2 inhibitor) are approved to treat moderate-to-severe rheumatoid arthritis, with Tofacitinib also approved for ulcerative colitis, and active psoriatic arthritis. Ruxolitinib (a potent JAK 1/2 inhibitor) is approved for the treatment of myelofibrosis and polycythemia vera in cases where specific mutations lead to constitutive activation of JAK 2, contributing to dysregulated JAK signaling in the JAK/STAT pathway and growth factor hypersensitivity/independence.

Rheumatoid Arthritis (RA) is a well characterized autoimmune disease that affects a large patient population. Additional treatment options to methotrexate and TNF blocking injectable biologics are desirable for patients that don’t respond well to these therapies, so it made sense for first-in-class JAK inhibitors that can attenuate a dysregulated immune response to initially target RA. Other prominent autoimmune indications, in addition to ulcerative colitis and inflammatory bowel diseases such as Crohn’s, are currently being studies in clinical trials. A significant number of these targeted indications are dermatologic in nature, such as psoriasis (especially plaque psoriasis), atopic dermatitis, and vitiligo [1].

However, beyond these above stated indications for JAK inhibitors, there are other potential therapeutic utilities that have emerged. For example, Alopecia Areata (AA) (spot baldness), was identified as a possible indication for treatment with JAK inhibitors when a patient being treated with Tofacitinib for plaque psoriasis also saw improvements in his alopecia, which did not occur when on corticosteroids [2]. Thus, both oral and topical treatments for AA are currently being studied in clinical trials [3].

Furthermore, it has recently been demonstrated that chronic itch is dependent on neuronal JAK1 signaling in a conditional JAK 1 KO mouse model of itch, as well as efficacy in a mouse model of itch with a small molecule JAK inhibitor [4]. Approximately 15% of the general population suffers from chronic itch, which has been shown to be equivalent in terms of impact on quality of life as chronic pain. In contrast to pain, there are currently no FDA-approved treatments for chronic itch. Patients with recalcitrant itch that failed other immunosuppressive therapies showed marked improvement when treated off-label with the JAK inhibitor Tofacitinib [4]. In this case, signaling mechanisms attributed mainly to the immune system may represent novel therapeutic targets within the nervous system as well.

Graft-versus-Host Disease (GvHD) is a major and sometimes life-threatening complication of bone marrow transplantation in the treatment of blood cancers and in whole organ transplants. There are over 20,000 allogenic Hematopoietic Stem Cell Transplantations (allo-HSCT) performed annually, and approximately 30–60% get GvHD, which can result in death or significant decrease in quality of life, carrying a 50% mortality rate. Additionally, more than 30,000 solid organ transplants are performed in the US alone, of which 25–40% experience episodes of organ rejection. Current therapies to treat GvHD include intravenously administered glucocorticoids, which are often not effective and can have serious side effects such as chronic and life threatening infections. These complications limit wider application of allo-HSCT as a therapeutic approach to patients with high risk hematologic malignancies. Thus, new, safer and more effective therapies to treat GvHD are needed. Recent advances have shown that JAK inhibitors can, in animal models and small clinical trials, reduce graft-versus-host disease while maintaining their anti-cancerous effects against leukemia [5,6,7]. Optimization of such inhibitors as a therapeutic option for GvHD and whole organ transplant would provide clinicians with a much needed alternative to current standard of care.

Other potential uses for JAK inhibitors include Multiple Myeloma (MM) (in combination with other chemotherapeutic regimens), and Peutz-Jeghers syndrome.

In the multiple myeloma case, it is the tumor bone marrow stromal cell microenvironment that stimulates a JAK-STAT proliferative program in myeloma cells [8]. In another case, it was shown that a JAK-STAT pathway stimulated in an IL-6 environment down regulated CD38 expression on multiple myeloma cells, thus making patients on the anti-CD38 antibody daratumumab become resistant to this therapy. In vitro experiments with MM cells from these relapsed patients demonstrated that significant recovery of CD38 expression on these cells could be achieved following treatment with the JAK inhibitor Ruxolitinib, co-cultured with supernatant from bone marrow stromal cells [9].

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant genetic disorder characterized by the development of benign hamartomatous polyps in the gastrointestinal tract. Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in PJS patients and in mouse models. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, the stated STAT3 activation, and increased expression of inflammatory factors associated with cancer progression. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/− animals [10]. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor Ruxolitinib dramatically decreased polyposis [11]. These data indicate that the cytokine mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.

Lastly, it was recently reported that a JAK 1 inhibitor delivered locally to the lungs via inhalation suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyper responsiveness in mice. In a mouse model driven by human allergens, this inhibitor had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor reduced lung pathology, without affecting systemic Jak1 activity in these rodents [12]. Thus local inhibition of Jak1 in the lung has the potential to suppress lung inflammation without significant exposure to Jak inhibition systemically, a strategy that might be effective for the treatment of asthma if this pre-clinical data translates to humans.

These examples highlight how seemingly disparate diseases with different patho-mechanisms may be affected positively by a single agent, in this case a JAK inhibitor. This illuminates the interplay between advances in basic science and clinical therapeutics and provides a compelling narrative of the ways in which an increasingly complex understanding of medicine and ingenuity in new treatment designs can benefit patients.

Chronic inflammation has been suspected to play a contributing role to disease progression in cancer, cardiovascular disease, neurodegeneration, and organ fibrosis, to name a few. The obvious beneficial effects of the immune system in neutralizing invading pathogens, wound healing, etc. are essential to overall well-being. But when optimum homeostatic control mechanisms go awry, and dysfunctional and pathogenic inflammatory signaling mechanisms stay locked in a perpetual “on” position, such chronic, unregulated signaling leads to non-homeostatic and disease enabling gene expression profiles. A number of key cytokines that are drivers of inflammation signal through the JAK-STAT pathways. If JAK inhibitors could be dosed and utilized in such a manner as to attenuate this dysregulated signaling and reset conditions back to a more reasonable homeostatic state, then perhaps JAK inhibitors can become a more versatile therapeutic tool in the treatment of multiple diseases driven in part by chronic inflammation.

Much of the positioning of such drugs will eventually also depends on the safety profile of JAK inhibitors. Increased susceptibility to opportunistic infections, sometimes fatal, is an obvious drawback to suppressing the immune system, and this has been observed with current JAK inhibitors. Other side effects will present themselves with increased usage over time, some being related to off-target effects specific to an inhibitor’s particular chemical structure. Clearly, the safety of long-term use will need to be assessed in follow-up clinical studies and safety registries. It is possible that strategic dosing regimens, where drug holidays are employed, can reduce pathologic inflammatory conditions to a satisfactory degree without significantly impairing immune surveillance abilities. Topical or other localized delivery options would further reduce systemic exposure and limit unwanted side effects. Also, JAK inhibitors with different chemical structures may have similar JAK inhibition profiles, but may interact variably in a heterogeneous patient population in regards to efficacy and, as implied above, side effect profiles. Thus, with the promise that JAK inhibitors can play a therapeutic role in the treatment of a wide range of diseases with an inflammatory and autoimmune pathology, development of multiple and chemically diverse JAK inhibitors would be desirable.

References

1. Shreberk-Hassidim R, Ramot Y, Zlotogorski A (2017) Janus kinase inhibitors in dermatology: A systematic review. J Am Acad Dermatol 76: 745–753. [Crossref]
2. Craiglow BG, King BA (2014) Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. Journal of Investigative Dermatology 134: 2988–2990.
3. Laita Bokhari, Rodney Sinclair (2018) Treatment of alopecia universalis with topical Janus kinase inhibitors – a double blind, placebo, and active controlled pilot study. International Journal of Dermatology 57: 1464–1470.
4. Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, et al (2017) Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell 171: 217–228. [Crossref]
5. Jaebok Choi , Matthew L. Cooper, Bader Alahmari, Julie Ritchey, Lynne Collins, et al (2014) Pharmacologic Blockade of JAK1/JAK2 Reduces GvHD and Preserves the Graft-Versus-Leukemia Effect. PLOS ONE 9: 109799.
6. Choi J, Cooper ML, Staser K,  Ashami K, Vij KR (2018) Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32: 2483–2494. [Crossref]
7. Madan Jagasia, Robert Zeiser, Michael Arbushites, Patricia Delaite, Brian Gadbaw, et al (2018)Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 10: 391–402.
8. Christine Lam, Ian D. Ferguson, Margarette C. Mariano, Yu-Hsiu T. Lin, Megan Murnane, et al (2018) Repurposing Tofacitinib As An Anti-Myeloma Therapeutic To Reverse Growth-Promoting Effects Of The Bone Marrow Microenvironment. Haematologica 103: 1218–1228.
9. Daisuke Ogiya, Jiye Liu, Hiroto Ohguchi, Yu-Tzu Tai, Teru Hideshima,et al (2018) 4440 JAK-STAT3 Pathway Regulates CD38 Expression on Multiple Myeloma Cells. ASH Annual Meeting, San Diego Convention Center, San Diego, California, USA.
10. M. C. Poffenberger, A. Metcalfe-Roach, E. Aguilar, J. Chen, B. E. Hsu (2018) LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis. Science 361: 406–411.
11. Saara Ollila,  Eva Domènech-Moreno,  Kaisa Laajanen,  Iris P.L. Wong, Sushil Tripathi, et al (2018) Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway. J Clin Invest 128: 402–414.
12. Dengler HS, Wu X, Peng I, Rinderknecht CH, Kwon Y, et al (2018) Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma. “Science translational medicine.” Sci Transl Med  10: 468. [Crossref]