At the beginning of the 21st-century, the US FDA launched initiatives to contribute in several ways to improve efficiency and reliability of pharmaceutical operations, and then via ICH these efforts were extended internationally. Operational challenges continue to be visible in external failures such as drug shortages, recalls, Warning Letters and Import Alerts; and the FDA has recently taken additional steps to achieve the goals it had outlined in the 21st Century initiative. Over the past couple of years’, a growing cluster of deviations - breaches in the assurance of data integrity - have gained prominence, in part due to improved detectability, and this has led to an erosion of trust. Why is compliance with the Good practices such as a significant challenge? Reflecting on insights accumulated over the past two decades, from when at US FDA to currently in the private sector, suggest that we – as a community of professional practitioners - are not adequately accounting for certain human behaviors in our business and regulatory practices. This article seeks to improve awareness of this urgent and pressing need, and it invites a discussion on ways to improve human-centricity in the pharmaceutical industry’s operational practices. Additionally, progress and trends in Process Analytical Technology (PAT) and in the adoption of pharmaceutical Quality by Design (QbD) methodology, that are part of the solution, are discussed.

Compliance or Adherence to CGMP Regulations: Choices of words matters
The words we use influence the way we think, organize information, make decisions and the way we behave Consider two commonly used words in our vocabulary - compliance and adherence. In pharmaceutical operations, compliance is used to describe the behavior of following written instructions or operational routines (SOPs). In healthcare, the noun adherence is preferred to describe the behavior of following written instructions for taking medications (prescriptions). In the CGMP context would you consider compliance and adherence to be synonymous?

On the US-FDA website, it is stated that Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications to adequately control manufacturing operations9. In this context is adherence synonyms with compliance? Alternatively, is it a subtle reminder of an important principle?

Note: The noun adherence is related to the verb adhere, meaning “to stick”; faithful support for a cause. Compliance is what you do when you try to fit standards set down by someone else. The act of submitting; usually surrendering power to another.

In healthcare, the noun adherence is preferred because compliance suggests that the patient is passively following the doctor’s orders and that the treatment plan is not based on a therapeutic alliance or contract established between the patient and the physician10. Adherence to medications is squarely in patients’ self-interest.

The rate of adherence to prescriptions, particularly in chronic conditions, are dismal10. Changing this behavior is incredibly difficult; as if humans have an innate immunity to change:

“…. when doctors tell heart patients they will die if they don’t change their habits, only one in seven will be able to follow through successful...Our individual beliefs – along with the collective mindsets in our organizations – combine to create a natural but powerful immunity to change.” Robert Kegan and Lisa Lahey.

So, should it surprise us that deviations from established pharmaceutical operating routines (SOPS) are widespread and such a significant challenge?

So why did the FDA write-up on CGMP use the word adherence? It is to emphasize that adherence to CGMP regulations provide ample flexibility to design and implement policies and procedures. Such systems are required to assure the identity, strength, quality, and purity of drug products in any facility and should account for, among other things, specific human factors therein.

It is the responsibility of management and leaders of a company to design and implement processes and procedures that are easy to comply with and, yes, joyful. Unfortunately, in some companies, Quality Management System (QMS) is just a folder of policies and procedures; often put together using a ‘cut-paste’ approach; i.e., without design or system thinking. Such disregard can eventually trigger a regulatory demand for CGMP remediation; sometimes with the help of external CGMP experts (“Doctors” -remember compliance suggests that the patient is passively following the doctor’s orders. Are we not underestimating human immunity to change?

Reasons for medication non-adherence?
A considerable amount of research has been conducted to identify correlates and predictors of adherence and nonadherence. It would be useful to summarize what we have learned and consider its relevance to non-compliance with SOPs in pharmaceutical operations. The table below lists five interacting dimensions of non-adherence and draws a parallel to factors relevant to the failure to comply with SOPs. Clearly, the list of factors is not comprehensive; it is only to highlight some similarities between the two challenges.

Patient-focused manufacturing, quality and regulatory solutions
The FDA initiative on Pharmaceutical Quality for the 21st Century aimed, in part, to reduce the reactive aspects of regulatory compliance ingrained within the system1. Although there is some progress – many challenges remain. Early in 2016, the FDA’s new Office of Pharmaceutical Quality was stood-up, and it is expected to achieve, more comprehensively, the goals outlined in the FDA’s 21st Century Initiative. The FDA has noted some challenges that have continued:

• Product recall and defect reporting data demonstrate unacceptably high occurrences of problems attributed to inherent defects in product and process design
• Alarming shortages of critical drugs over the past few years
• Rapidly growing numbers of Post-Approval Supplements; which inhibit industry’s ability to optimize and improve
• Current regulatory review and inspection practices continue to be “one size fits all”; i.e., not considering specific risks to the consumer from product failure modes
• There are no formal benchmarks for the current state of pharmaceutical quality; inadequate quality surveillance adds to the challenges that make it difficult to make decisions on risk
• Inspection and Review functions remain disjointed; inspections not well-connected to knowledge gained from product application review and vice versa.

In the Federal Register Notices dated March 12, 2015, the US FDA announced its participation in a conference entitled ‘‘Mission Possible: Patient-Focused Manufacturing, Quality, and Regulatory Solutions’. It should be obvious that patient-focused manufacturing, quality, and regulatory solutions demand an adequate emphasis on staff/ operator-centric quality management system, policies, and procedures. Are we adequately emphasizing staff/ operator-centric quality management system, policies, and procedures? Not adequately.

A case in point is our casual attitude towards the regulation 21 CFR 211.25...education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions5. Shouldn’t staff and their supervisors reliably comply with written SOPs when provided with appropriate education, training, and experience? Given that, pharmaceutical processes are required to be “validated”; complying with SOPs should yield predictable outcomes. How often does it occur? 70-90% of the time? That is not often enough!

When a manufacturing process is not predictable; human error is (almost often) the immediate “cause” and which requires no further thought (what is the root-cause?). Sufficient correction then generally is to: retrain or to modify a SOP and retrain.

When this occurs repeatedly - either an operator loses his/her job, or it can open the door to individual and/or systematic set of irrational behaviors, and sometimes this leads to breaches in the assurance of data integrity.

Confronting our immunity to change
The immunity to change was described by the following three dimensions:
Employee empowerment is in need of attention (Feeling system). It begins with senior leaders making adherence to CGMP regulations and compliance with SOPs the Normal thing to do, Easy thing to do and also Rewarding Junior employees are looking towards the leaders to guide and support them.

Good practices include management actions to provide support, resources, asking questions to ensure optimal design and effective implementation of SOP’s which should be designed conjoint with targeted training. Given a set of starting conditions (e.g., raw material COA, and equipment), a complicated process should be reproducible, and deliver results expected (we are in Operations not in Research mode). Processes that do not – are complex.

Interactions and emergence characterize a complex process. Following a SOP will not reproducibly achieve expected results. Right-first-time (RFT) rates for pharmaceutical processes can be small (i.e., suggesting process complexity).

A failure rate of 5% should not be considered small – because in certain environments (e.g., a weak culture of quality) batch failure can have a devastating impact on behavior. Management which does not openly acknowledge the need for high RFT rate (during development) is perhaps trapped in “file first and figure it our later” mindset. Then when they do not recognize the actual RFT (whatever it might be) during routine operations (the change-preventing system), it can lead to rationalization within an organization. Phrases such as “this is FDA approved” or “process is validated” when heard in company discussions should raise a red flag!

The knowing system (epistemology; how do you know what you know?) is critical. It calls for leaders to ask the right question at the right time. Traditional regulatory defaults such as a scale-up factor of 10X, three batches for process qualification, can be an easy reminder to ask the right questions; how do you know that 10X is the optimal option for a particular product/process? The knowing system should cover the entire life cycle – from proper development and regulatory review to effective process validation, technology, and knowledge transfer and continued process verification. The knowing system should include a special reminder to improve awareness of how adherence to CGMP and compliance with SOPS addresses residual-uncertainty.

Getting it right-first-time in the 21st Century
The FDA “getting-it-right” is critical; in particular with its emphasis on One Quality Voice. Commitment to achieve the goals of the 21st Century initiatives requires concerted efforts in multiple dimensions – on the stubborn immunity to change (as discussed above), our methodologies and our technologies. Progress in these three dimensions is palpable.

Integrating Generic CMC review within OPQ/CDER/FDA is already changing the questions to sponsors; questions on patient-related-failure modes and manufacturability are now more prominent and a surprise for some companies. Issues now being raised by FDA during CMC review - on product failure modes and manufacturability - is a signal that the methodology for Quality by Design should be a more serious focus during development and, perhaps, a strong message against the practice of “file first and figure it out later”.

If this trend continues (and regulator heterogeneity sufficiently minimized), it can offer a significant competitive advantage for those companies that have advanced their business practices to implement QbD methodology (e.g., as per FDA PAT, ICH Q8-11, and Process Validation 2011 Guidelines) efficiently in their development program. The business impact should be most significant for new drugs categorized as a Breakthrough (where product development and CMC review can often be on a critical path; time crunch), Complex Generics, and First Generics.

The FDAs strong support for application of new technology in pharmaceutical manufacturing – particularly as it pertains to the continuous production of pharmaceutical is broadly evident. The Summary Review of Regulatory Action on Vertex’s NDA 20603814 provides a hint as to why marking this approval in 2015 the “Tipping point” would not be an exaggeration.

“The manufacturing process for product employed Quality-by-Desing (QBD) process for the development of the product, manufacturing process, and control strategy. A fully continuous drug product manufacturing process was applied to the manufacture of the product, which is a unique and a new process”

A new manufacturing process included in an NDA submission is a pleasant surprise, indeed! Moreover, it also provided for a rapid QbD development of product, manufacturing process and control strategy! These two aspects, taken together, justify the label – Tipping point. The ability to manufacture continuously (24/7) is important but which, I suggest, is a business decision.

The NDA 206038 implicitly provides reassurance that PAT based manufacturing and control strategy can address several ontological and epistemological gaps that exist today (in FDA’s Inactive Ingredient Guide, USP and broadly). PAT provides a way to measure, monitor and control physical quality attributes such as excipient functionality, and, offers efficient solutions for many frustrating issues such as blend uniformity testing.

Vision 202015 appears to be on track; significant business opportunity is within grasp in the next 3+ years. This includes technical capabilities to get pharmaceutical manufacturing right the first time. Perhaps, the growing number of cases of breaches in data integrity help here by reminding us that we are prone to our cognitive biases and blind spots15; more so because we can not dismiss the possibility that the growing number of cases may just be due to improved detectability. This realization should prod us to overcome immunity to change, pay more attention to human factors and to do so look for practical solutions in disciplines such as behavioral economics to improve our practices16.

The lure of the rapid, comprehensive QbD development of solid dosage forms, process, and control system in a PATbased continuous manufacturing system is an attractive option for both industry and regulators. Fully integrated drug substance and product continuous production systems are also expected to gain momentum. Improved assurance of quality, smaller footprint, material saving and a relatively lower environmental impact are among the important reasons why adoption of these systems will increase with continued regulatory encouragement. Broader adoption of PAT-based continuous manufacturing systems (which need not be 24/7 operations) by brand and by a couple of major generic and CDMO’s should be more prominently evident in the next three years. Perhaps a bigger incentive may turn out to be the “C” in CGMP which has started to trend in the direction of process control, statistical confidence, and continued process verification. When process stability and capability are important factors in an FDA’s risk-ranking of facilities, it would be a significant driver for “Six-Sigma” level of assurance for pharmaceutical quality.

An excellent opportunity for continuous manufacturing of injectables exists and there is an urgent need for it so as to mitigate the risk of shortages. Although not prominent today, we should expect to see more progress for injectable manufacturing over the next three years.

The pharmaceutical education and training systems in the USA and Europe have been advancing anticipating this transition. It needs to do more to expand educational offerings and training opportunities. Efforts to support educational and training programs in India, China, and other regions should also be a high priority.

Summary
Adherence to CGMP regulations provides ample flexibility to design and implement effective policies and procedures that are easy to comply with and can be improved when necessary. Such systems assure the identity, strength, quality, and purity of drug products. Regulatory requirements are minimal requirements. This means companies need to go beyond a regulatory check-the-box and ‘cut-paste’ exercise. Aiming high and taking ownership & responsibility for quality is essential.

To “get-it-right” in the 21st Century, let’s remember Einstein’s challenge that we will never solve the problems tomorrow with the same order of consciousness we are using to create the problems of today! When we chose to take off our blindfolds, and we commit to recognizing that pharmaceutical quality is like an elephant in the dark; Rumi’s centuries old strategy can still work for us - If each of us held a candle there, and if we went in together, we could see it.