At the end of 2021, experiencing the surging uncertainty of Omicron as possibly a fifth coronavirus wave threatening a “Dark Winter” in the US and other countries, and anticipating advancing SMART factories making medicines called S.M.A.R.T Pharmaceuticals, this report spirals above the efforts on the ground supercharging the Industry 4.0 revolution to begin a professional journey to 2030.
Like some migratory birds navigate in the darkness using an internal “magnetic compass,” this migration to the next stage of development utilises feelings (experience) to guide progress in uncertainty and complements vision 2020, naturally corrected SMARTly.
To prepare for this journey, let us recall some lessons in process understanding as defined in the “PAT Guidance” (2004) to make sense of anticipated chaos and pandemonium in this decade of the 21st century and know what it will take to be a “good practitioner.” To be objective and evidence-based in our journey, let us select a predicated point of reference, the letter and spirit of the US Food, Drug, and Cosmetic Act of 1938, as amended in 1962.
Acknowledging that nothing is perfect, errors can occur but not repeat as mistakes. When necessary, course-correcting should be based on good and non-theory laden observations. Efforts to improve continually, based on continuing “scientific training and experience” is needed to “fairly and responsibly” deliver “substantial evidence of effectiveness.” Let us begin to explore how to make common sense of SMART as Industry 4.0 advances and take steps to understand options to align our natural and emerging artificial SMART – Self-Monitoring Analysis and Reporting Technology in how we manage systems with Specific, Measurable, Achievable, Relevant, and Timely (or Timebound) objectives.
“SMART Pharmaceuticals” invokes the notion of digital therapeutics and pills with embedded sensors that digitally track behaviours and medical surveillance and, broadly any pharmaceuticals made in a “SMART factory.” Pharmaceuticals manufactured in standard and a “SMART factory” are the subjects of this report. Continued professional development is essential to remain “current” in pharmaceutical product development and manufacturing. The suitability and capability needed to do so in this decade will increasingly be gauged in the context of managing fairly and responsibly, locally and broadly, across sociotechnical systems we live and work.
The ensuing narrative intends to objectively empower individuals to progress in their efforts to develop to their next stage of maturity via attention to and proficiency in a valid experiential learning process.
What does it mean to learn from the experience? Do we do so with an SOP or broadly when allowed to experience different viewpoints and encouraged to innovate? What if such opportunities are not offered – how to self-empower are some questions explored implicitly in this report. The exploration itself is an experiential journey in practising to take a migratory bird’s-eye view to observe events in the real world from different viewpoints including insights. Within our worldview or scope is the experiential learning at the initiation and evolution of PAT initiative at the US FDA, some twenty years ago and described in a journey from 2013 to 2020. How can this help to anticipate progress of the Industry 4.0 revolution in manifesting SMART factories by 2030 is considered.
We experience unfairness in life and at work (in new drug development, manufacturing, and all functions) as negative emotions such as anger and hate. To consider the relevance of “fairly and responsibly” in the regulatory context, this report reminds of practices such as “file [ANDA] first and figure it out later,” incentivised in the FD&C Act and habitually mandated in parts of the sector. Regulatory approval is often a reason to celebrate and grant bonuses to the development and regulatory departments. However, if or when the manufacturing and quality department struggle to reproducibly manufacture an “FDA approved” product with a process claimed to have been “validated,” the finger is pointed at who?
The Subject of this Report is Experience
The word “experience, derived from Latin experientia,” “means a trial, experiment knowledge gained by repeated trials”, and as a verb, it means having first-hand knowledge of states, situations, emotions and sensations.
In the regulated CGMP environment, processes are expected to be “validated,” and validity provides a high level of assurance of repeatability and reproducibility of predicted results. Hence, to be considered good, personnel must follow “valid” procedures, no matter the outcome.
Experiments to ensure repeatability are for the development phase exhibit batches. When transferring technology from development to operations, reproducibility by representative operators is verified as the process qualification, part of process validation as described, for instance, the FDA guidance. Adequacy of qualification, which is supposed to include the representative experience of the operators who will manufacture routinely. However, it is often difficult to assess the state of validation without continued process verification. Therefore, it is not uncommon to note lagging indicators of control and reactive events resulting in regulatory warning letters.
Such events can induce fear, and negative emotions are not conducive to learning. So, what does it mean to learn from experience in a CGMP facility and broadly when one must comply with Standard Operating Procedures (SOPs)?
As a good practitioner, responsibility, in part, is trustworthiness. With the “validation” of our professional development and maturity, albeit a subjective judgement, others should fairly and responsibly recognise individual “suitability” (for instance -to be fair) and “capability” to be responsible and, in the context of promotion, take on increasing responsibility. Can Artificial Intelligence (AI) as a SMART supervisor be more objective than a human supervisor?
What does ‘exploration narrated is an experiential’ noted above mean? It means an objective process is followed to account for feelings (experience). Such a process guides the ensuing discussion. It emphasises unbiased, non-theory-laden observations, as illustrated in Figure 2.
Being wedded to our theories and plans can be comforting. Actively being aware of exceptions to expected results can take us outside our comfort zones, egos and self interest. When we do not acknowledge unexpected results, as often also observed with adverse reports and phase-IV commitment, it represents a conflict of interest. It takes away from our commitment to being fair and responsible.
In committing to being open to new data that may not be what we expected and practising to be a good observer, we test and challenge our plans, theories, and practices and go beyond our education and training to continuously experience and empower our development. So, then what is it that helps us to be SMART within, naturally?
Naturally, SMART within
In most corporations, it is a typical course of business for management to instruct how to set objectives for annual performance review. A SMART process of establishing and implementing performance objectives involves aspects of SMART as in self-monitoring progress, analysing deviations per plan, course corrections, remediation, and achievements, and providing periodic reports using accepted techniques such as reports, emails, etc.
In Table 1, the Specific, Measurable, Achievable, Relevant, and Timely (or Timebound) management objectives with Self-Monitoring Analysis and Reporting Technology in Column 2 as an interaction or an interrelationship and Column 1 a reminder to introspect on the previous performance (2021) and Column 3 performance considerations for learning from experience going forward (2022-).
The elements outlined in Table 1 are deceptively simple. What does it take to be SMART within, naturally in ways that ensure our commitment to the stated mission, vision, policies, and objectives we document? Sometimes or often as the case may be, it is hard to set SMART goals and be smart about these objectives and be committed? What “life experiences” are foundational to adult development and maturation? Some adults continue to mature, but at different rates; many do not. What are experiences relevant to professional development? How do these relate to experience as a mode of qualifying requirement for CGMP operations as in the US regulations at 21 CFR 211.25, education, training, and experience”? We can extend this question to other functions, for instance, experience as a qualifying criterion for new drug development in the context of the US Food, Drug and Cosmetic Act of 1938 as amended in 1962, the Kefauver Harris Amendment, or “Drug Efficacy Amendment.” This amendment is considered to have revolutionised new drug development, and among other things, stipulates “scientific training and experience” to “fairly and responsibly” evaluate “substantial evidence of effectiveness.”
Seeking experiential, not theoretical, insights to these and other questions, I embarked on a journey to 2020 (why 2020 is explained later) in 2013. As the core purpose, I sought answers on how experience interrelates and interacts with quality culture, management systems and good practices before the WHO declared the novel coronavirus (COVID-19) outbreak a global pandemic.
After providing an overview of this journey, the relevance of the insights collected is discussed in the context of SMART Pharmaceuticals 2021-2030.
The journey to 2020: “I can see clearly now.”
Serendipitously in mid-2012, I returned to the pharma sector when the attention of the US FDA was sharpening on BADI, a topic familiar since when I had moved to the US FDA, leaving behind the comfort of a tenured academic career. I chose the word serendipitously because I had not expected return to the pharma sector, given that I had crossed its boundaries to venture into the tobacco sector. Venturing into the tobacco sector and working on tobacco harm reduction had expanded my awareness of human behaviour, development, and behavioural economics, which informed my journey to 2020.
After a year with Wockhardt, I launched my consulting practice ‘Insight, Advice, and Solutions’ in July 2013. Soon, two topics – ‘Human Factors in GMPs’ and ‘Culture of Quality’ – dominated my teaching and public speaking engagements as a growing cluster of GMP deviations specifically breaches in the assurance of data integrity or BAD I dominated the sector. Given the opportunity to interact with pharma professionals up and down and across an organisational hierarchy of several companies, it was an opportunity to explore how experience interrelates and interacts with quality culture, management systems and good practices. The commitment to do so until the 2020 calendar year is my journey to 2020 literally and metaphorically – “I Can See More Clearly Now,” and it reconnected me to the launch of the Process Analytica Technology (PAT) Initiative at FDA, where in November 2001, I wrote a few statements to describe a vision of pharmaceutical quality in the context of the, and I titled it ‘Vision 2020’- “I can see clearly now.”
On this journey, I sought to take a development stance via adaptive and experiential learning focusing my attention on insight as a symbolic “internal magnetic compass” to notice patterns of interactions and inter-relationships between observations, feelings, thoughts and intention to make sense of experience, what it meant, an insight, which I recorded contemporaneously and my learning shared with my network on social media such as LinkedIn (e.g., blog posts and articles) and broadly with the community of pharmaceutical practice and knowledge via industry news and update media such as Express Pharma and Biopharm Asia, industry experts panels such as CPhI community, publication of professional associations such as Indian Pharmaceutical Association’s (IPA) Pharma Times, and the American Association of Pharmaceutical Scientists Journal AAPS PharmSciTech and also a public-private partnership with US FDA – the National Institute for Pharmaceutical Technology and Education (NIPTE). Table 2 lists the dates and titles of some of these reports to provide a glimpse of how the journey progressed.
Beyond daily posts, over 45 articles are posted on LinkedIn; only the “end of the year” articles are listed. In December 2014, when insight into the value of social media posts to experiential learning was noted, the journey from 2015 to 2020 was named-‘Schrödinger’s Cat & My Journey From 2015 to 2020.’ Further, not listed in Table 2 are recordings and posted slides of conference presentations (if in-terested, see: YouTube https:// www.youtube.com/chan-nel/UCRkXTgz4kZ7WQdYO1uf9RyQ and SlideSharehttps://www2.slideshare.net/a2zpharmsci/).
It is beyond the scope of this report to summarise all insights collected. So, in this section, a few topics are elaborated.
What is a good quality culture? A sentiment (force) permeating the environment to help us expand our awareness and simultaneously empowers all to continue their development and maturity from their current capability and suitability. The commitment and message credibility of founders, promoters, corporate board and officers to generate quality culture is a social force, as is fairness and responsibility to pursue the stated mission and vision per formulated quality policies and incentives. These forces permeate horizontally and vertically with “peer involvement” and “employee empowerment” via formalised and informal interrelationships and interactions we call reporting and meetings. Intentionally becoming aware of and leveraging this force, horizontally and vertically, in any hierarchy is how the enablers interact and interrelate to share their source code openly so that others can assess and, when convinced, use it to build their executable continuous development programmes – stand-alone or aligned with an enterprise-wide system.
We sustain and build a quality culture in moments that can be gauged in the choices of words to report minutes of meetings. A pledge of commitment can be a reinforcing interaction to understand a quality policy that typically hangs on a wall.
Recruitment and onboarding (~ IQ) and orientation (~OQ) are socialisation processes that should carefully transform outsiders into insiders to build teams and prevent “groupthink” by actively remover fear, expanding awareness and empowering mastery to be internally validated to self-author procedures and plans to be self-assured in their responsibilities and demonstrate suitability and capability of taking on increasing responsibility. To give others assurance with integrity, we first must be self-assured. The relevant interactions and interrelationships to achieve these objectives should formally be a part of the pQMS such that metaphorically anybody can dance – ABCD. We recognise knowledge and risk management as key enablers of pQMS; ABCD calls for a formal, systemic effort to acknowledge and manage uncertainty and expectations on deviations, OOS, CAPA, continual improvement and continuous professional development. In the letter and spirit of the FD&C Act, theory to practice takes us to commercial operations, commitment to being vigilant, good observers, and experience is essential to sustain credibility and develop professionally.
The PAT initiative, which opened the door to FDA’s Pharmaceutical CGMPs for the 21st Century: A Risk-based Approach and to Pharmaceutical Quality for the 21st Century at the International Conference for Harmonisation, ICH – which now is the International Council for Harmonisation, resulted in several “guidance documents” and this process continues to spiral with a draft ICH guidance on continuous manufacturing and a concept paper to spiral back to update ICH Q2 in the framework of analytical quality by design to facilitate real-time control and product release. In a highly heterogeneous sector spread across developed and emerging economies, converting this information to knowledge in practice remains a perpetual challenge. Efforts to educate and train need to be complemented with experiential learning to overcome this challenge.
To facilitate experiential learning, we must change how we feel and think, and act synchronously. A quality culture needs to simplify interactions and interrelationships between management systems and practitioners to make it normal, easy and rewarding.
The pharmaceutical sector is a heterogeneous collection of small and large corporations. Recruiting, onboarding and orientation programmes vary considerably – from “walk-in hiring” to elaborate orientation with programmes for continuous professional development.
At most, the notion of system and systems thinking and quality culture can be amorphous and “brand” identity at few corporations. The frequency at which the US FDA CGMP inspections are the only objective assessment of quality system effectiveness can be unacceptably high. Therefore, this journey aimed to collect insights to facilitate individual empowerment of continuous professional development and maturity. Facilitation means removing barriers, blind spots, sharing know-how and acknowledging that – “You have to do your own growing no matter how tall your grandfather was.” -Abraham Lincoln. The opportunity to take a development stance while interacting and interrelating within (novice, seasoned professional, and at the board level) and across systems (multi-university collaboration, regulatory and political systems), i.e., taking a “system of systems” (review articles and reports in Table 2) perspective was indeed an experience worth wring and learning. The process of experiencing in practice remains similar; the challenge we confront varies, and what we experience, changes. For instance, we worry that we will look bad (to others), seek validation of our opinions, proposals, etc., or we seek to belong to a group, we feel self-assured (internally validated), or we can see the potential to do good in others despite their failures. Although our development and maturity occur in many dimensions – the emotion in seeking to look good (to others) to be (considered) good by others point to a development stance in which we are seeking external validation, whereas “do good” and “see good” in others point to internal validation.
The following observations on human experience in interaction with smartphones are worth mentioning here. SMART’s addictive, enslaving power is troubling in trend and scope. “Aiyo! my SMART phone is developing more efficiently than I, a phrase I wrote in 2020 in an article entitled “Pharmaceuticals Beyond 2020: Professionals and Artificial Intelligence.”
Given that artificial SMART is a human invention, it should be obvious that it is manifested from within; obviously. Far from it, it seems to be hidden in plain sight, and for a large segment of the population, far from being obvious. Our dependence on SMARTs can retard our ability to feel in ways to empathise.
The feeling (experience) can be an inner compass, and learning using it objectively is essential to development and maturity. Like a migratory bird, the ability to simultaneously attend to details and panorama during planned introspection and integrate feelings helps to make good sense in uncertainty; this is “Vision 2020+” elaborated in the article (see Table 2) “Digitisation in Pharma and Digital Therapeutics: A Migratory Birds Eye View for Charting a Path Forward.” Such a journey can be transformative, expanded awareness and appreciation of the need to emphasise professional development, which we will discuss further in the current (2021) context and look forward
Journey for 2021 to 2030: S.M.A.R.T Pharmaceuticals
A key lesson learned is that vision 2020 was necessary, but not sufficient; Vision 2020+, analogous to the bird’s eye view with left-right lateralisation and a built-in magnetic compass to migrate in darkness, is needed to be suitable and capable in chaos – an unpredictable system showing extreme sensitivity to initial or starting conditions.
Amidst the chaos and pandemonium in multiple systems, which are disrupting our supply chains, we must become aware of the S.W.O.T (strength, weakness, opportunities, and threat) of [our] development and maturity in today’s realities to prepare to plan and keep these current in being ready to modify the our plans smartly. Concerted effort to “reset” the financial and economic systems and political “build back better” mandates intending to accelerate the revolution we refer to as Industry 4.0 can pose threats and present opportunities which we miss out with lingering weakness and leverage in our maturity, which is now a key strength. To begin such an analysis, we need to know our current state, the leading edge of competition, and the time it takes to be competitive per corporate mission and vision.
The stages in the adult development and maturity model for a SMART factory are illustrated in Figure 4. The leading edge of a digital plant is stage III- the Connected Plant. It is anticipated that several plants will be at maturity stage V – end-to-end automation, machine-to-machine communication and automated actions.; i.e., “humanfree” and “carbon-neutral,” etc. Regulators in the US, EU and others are politically charged to promote and accelerate the Industry 4.0 revolution; perhaps at disadvantage to traditional manufacturing,. it seems that challenges to regulatory inspections, given the lockdowns, social distancing and travel restrictions, are here to stay in to the future.
Do not underestimate the exponential growth of AI technology; beyond machine learning, natural language processing, a third-generation emotion chip can understand 64 trillion possible emotional states every 1/10th of a second at any moment. We are in an epoch of unprecedented changes in working and living. In the emerging new world, technologies will dominate more the markets and business; many (humans) engaged today in manufacturing will need to mature quickly or risk becoming victims to the “mean meaning-making” by profiteers and AI.
We need to smartly go beyond our education an training to continuously learn from experience and empower our development in moments. Note that we sustain and build a quality culture in moments and feelings and intentions are in the words we choose to think and report as in meeting minutes. Learn what you can do to be SMART within, naturally. Prepare for an unprecedented journey to 2030; this is your journey. I wish my journey to 2020 makes a contribution to expanding your awareness to articulate your Vision 2030. Remember – “You have to do your own growing no matter how tall your grandfather was.” -Abraham Lincoln.
 US FDA White Paper: Innovation and continuous improvement in pharmaceutical manufacturing: pharmaceutical CGMPs for the 21st Century. The PAT team and manufacturing science working group report: a summary of learning, contributions, and proposed next steps for moving towards the “desired state” of pharmaceutical manufacturing in the 21st Century. September 2004.