Pfizer plant in Kansas repeatedly hit with form 483 infractions

In the last 6 years, Pfizer’s Hospira plant in Kansas has received eight FDA Form 483 citations, as well as other observations for regulatory bodies, such as this summer’s  from the MHRA.

The latest FDA 483 was in August 2018.

Comparing these observations with this year’s from Mylan certainly brings to mind a lot of thoughts about cleaning validation and contamination control.

All eight observations are repeat, some from multiple years. I find this troubling given the June 2018 Close Out letter to the 2017 Warning Letter.

Considerations when validating and auditing algorithms

The future is now. Industry 4.0 probably means you have algorithms in your process. For example, if you aren’t using algorithims to analyze deviations, you probably soon will.

 And with those algorithms come a whole host of questions on how to validate and how to ensure they work properly over time. The FDA has indicated that ““we want to get an understanding of your general idea for model maintenance.” FDA also wants to know the “trigger” for updating the model, the criteria for recalibration, and the level of validation of the model.”

Kate Crawford at Microsoft speaks about “data fundamentalism” – the notion that massive datasets are repositories that yield reliable and objective truths, if only we can extract them using machine learning tools. It shouldn’t take much to realize the reasons why this trap can produce some very bad decision making. Our algorithm’s have biases, just as human beings have biases. They are dependent on the data models used to build and refine them.

Based on reported FDA thinking, and given where European regulators are in other areas, it is very clear we need to be able to explain and justify our algorithmic decisions. Machine learning in here now and will only grow more important.

Basic model of data science

Ask an Interesting Question

The first step is to be very clear on why there is a need for this system and what problem it is trying to solve. Having alignment across all the stakeholders is key to guarantee that the entire team is here with the same purpose. Here we start building a framework

Get the Data

The solution will only be as good as what it learns from. Following the common saying “garbage in, garbage out”, the problem is not with the machine learning tool itself, it lies with how it’s been trained and what data it is learning from.

Explore the Data

Look at the raw data. Look at data summary. Visualize the data. Do it all again a different way. Notice things. Do it again. Probably get more data.  Design experiments with the data.

Model the Data

The only true way to validate a model is to observe, iterate and audit. If we take a traditional csv model to machine learning, we are in for a lot of hurt. We need to take the framework we built and validate to it. Ensure there are emchanisms to observe to this framework and audit to performance over time.

PIC/S Draft Guidance on Data Integrity

On 30-Nov-2018 PIC/S published the third draft of guidance PI 041-1 “Good Practices for Data Management and Data Integrity in regulated GMP/GDP Environments“. The first draft was published back in 2016, and the third draft is subject to a focused stakeholder consultation seeking substantive comments from trade and professional associations on specific questions relating to the proportionality, clarity and implementation of the guidance requirements. In parallel to this stakeholder consultation, the new draft is applied by PIC/S Participating Authorities on a trial basis for a new implementation trial period (3 months).

In short, you can expect inspectors to have reviewed and be reviewing against this. Do your gap analysis now and have plans in place to address the gaps. Yes, there will be a little while before this is finally published, but at this point this guidance neatly triangulates with other guidances on data integrity and we can expect most of this to be in the final version.

This document is a great place to start and can be used to develop whole sections of the quality management system. I find it very actionable. For example this table from 9.5 “Data capture/entry for computerised systems”:

pics data capture part 1pics data capture part 2

 

 

Building relationships is critical for tackling complexity

If we want to address the complex problem situations that the world is facing, being a smart systems thinker and innovator is not enough. We need to engage in new ways of collaborating that promote continuous, productive and collective learning and innovation. These collaborations require us to learn social skills, build social structures, and adopt attitudes of openness to learning, trust and responsibility, however hard it is to let go of the behaviours and structures that hold us back.

Mieke van der Bijl “Why being smart is not enough — the social skills and structures of tackling complexity

Good article on problem-solving and complexity that is very sympathetic with Donella Meadows Leverage Points. This article and my recent post on creativity are both coming from similar points by stressing many of the same solutions to solving problems.

I liked the discussion on creating the right organization structures to allow problem-solving to happen. As someone who is very worried that can contribute to laying the bricks in Kafka’s castle and the bars in Weber’s Iron Cage, I am always striving to push for better ways of working, of creating structures that both amplify freedom and responsibility, that drive for innovation. Applying basic principles is pretty important to ensure we build for now and the future.

Prominent Doctors Aren’t Disclosing Their Industry Ties in Medical Journal Studies. And Journals Are Doing Little to Enforce Their Rules

Prominent Doctors Aren’t Disclosing Their Industry Ties in Medical Journal Studies. And Journals Are Doing Little to Enforce Their Rules
— Read on www.propublica.org/article/prominent-doctors-industry-ties-disclosures-medical-journal-studies/amp

People need to realize the only way to truly build trust is through transparency. If there is nothing to hide, don’t hide it.

Creative teams

The secret to unlocking creativity is not to look for more creative people, but to unlock more creativity from the people who already work for you. The same body of creativity research that finds no distinct “creative personality” is incredibly consistent about what leads to creative work, and they are all things you can implement within your team. Here’s what you need to do:

Greg Satell “Set the Conditions for Anyone on Your Team to Be Creative”  05Dec2018 Harvard Business Review

In this great article Greg Satell lays out what an organization that drives creativity looks like. Facilitating creativity is crucial for continuous improvement and thus a fundamental part of a culture of quality. So let’s break it down.

Cultivate Expertise

In order to build expertise our organizations need to be apply to provide deliberate practice: identify the components of a skill, offer coaching, and encourage employees to work on weak areas.

Bring knowledge management to bear to ensure the knowledge behind a skill has been appropriately captured and published. To do this you need to identify who the expert performers currently are.

It is crucial when thinking about deliberate practice to recognize that this is not shallow work, those tasks we can do in our sleep. Unlike chess or weight-lifting you really do not get anything from the 100th validation protocol or batch record reviewed. For work to be of value for deliberate practice it needs to stretch us, to go a little further than before, and give the opportunity for reflection.

Geoff Colvin in Talent is Overrated gave six traits for deliberate practice:

  • It’s designed to improve performance. “The essence of deliberate practice is continually stretching an individual just beyond his or her current abilities. That may sound obvious, but most of us don’t do it in the activities we think of as practice.”
  • It’s repeated a lot. “High repetition is the most important difference between deliberate practice of a task and performing the task for real, when it counts.”
  • Feedback on results is continuously available. “You may think that your rehearsal of a job interview was flawless, but your opinion isn’t what counts.”
  • It’s highly demanding mentally. “Deliberate practice is above all an effort of focus and concentration. That is what makes it ‘deliberate,’ as distinct from the mindless playing of scales or hitting of tennis balls that most people engage in.”
  • It’s hard. “Doing things we know how to do well is enjoyable, and that’s exactly the opposite of what deliberate practice demands.”
  • It requires (good) goals. “The best performers set goals that are not about the outcome but rather about the process of reaching the outcome.”

Encourage Exploration

The Innovators DNA by Dyer, Gregersen, and Christensen state that creativity is a function of five key behaviours

  • Associating: drawing connections between questions, problems, or ideas from unrelated fields
  • Questioning: posing queries that challenge common wisdom
  • Observing: scrutinizing the behavior of customers, suppliers, and competitors to identify new ways of doing things
  • Networking: meeting people with different ideas and perspectives
  • Experimenting: constructing interactive experiences and provoking unorthodox responses to see what insights emerge

Exploration can be seen as observing outside your sphere of knowledge, networking and experimenting.

Empower with Technology

Sure, I guess. Call me a luddite but I still think a big wall, lots of post-its, markers and some string work fine for me.

Reward Persistance

Remember this, we are always in this for the long haul. I think remembering the twelve levers can help give perspective.