Dangers of De-Regulation

Nothing makes me decide someone is an unserious thinker than the line “There are too many regulations” when discussing drug development and manufacturing. Okay, which one? Point to me the regulation you want to get rid of? Because frankly they all exist mostly as reactions to the crap some corporation got up to.

I am going to be honest. I don’t trust corporations to do the right thing. Otherwise we wouldn’t have problems like we see in OTC and consumer goods. Just look at this recent article on cancer causing shampoos, sunscreens and tampons. And that is the tip of the iceberg if you ask me. Don’t even get me started on the risks in generics coming from China and India. Or the mess that is the supplement industry.

So definitely put me in the category of regulations are a good thing. Are some poorly written? Sure. Are there some that need updating? Definitely. But as a whole 21CFR chapter 1 is a pretty decent set of regulations (don’t ask me about the other chapters, I rarely use them). The European Eudralex, pretty straightforward (okay I would get rid of QPs and RPs and all the rest but that is a cultural thing).

I personally think we don’t go far enough. I want to write the regulation that requires every c-suite in every pharma, med device, OTC, consumer goods, supplement and food company to do an intense reading of the Jungle and then quarterly restorative justice sessions with victims of badly executed decision making. I want to see a regulation makes executives and board members truly accountable. I want to stop reading horror stories and seeing recalls.

Stop it with the 4.0 stuff

Industry 4.0, Quality 4.0, Validaiton 4.0. It is all absurd, so cut it out. Old man rant out.

Seriously though, let’s have a chat about this and why it is a bad practice.

When we put a number after something, we denote a version number. Version numbers have meaning, and individuals react to them in a certain way.

Understanding Version Numbers

A version number is a unique identifier assigned to specific releases of software, hardware, firmware, or drivers. It helps developers and users track changes, improvements, and updates in the product over time. Version numbers are crucial for maintaining software, ensuring compatibility, and managing updates effectively.

Structure of Version Numbers

Version numbers typically follow a structured format, often in the form of major.minor.patch or major.minor.patch.build. Each segment of the version number conveys specific information about the changes made in that release.

Major Version

  • Indicates: Significant changes or overhauls.
  • Example: Going from version 1.0.0 to 2.0.0 might indicate a complete redesign or the addition of major new features.
  • Impact: These changes might not be backward compatible with previous versions.

Minor Version

  • Indicates: Addition of new features or significant improvements that are backward compatible.
  • Example: Updating from version 2.1.0 to 2.2.0 could mean new functionalities were added without altering existing ones.
  • Impact: Users can expect enhancements without losing compatibility with previous minor versions.

Patch Version

  • Indicates: Bug fixes and minor improvements.
  • Example: Moving from version 2.2.1 to 2.2.2 might mean minor bugs were fixed.
  • Impact: These updates are usually safe and recommended as they resolve issues without changing functionality.

Build Number

  • Indicates: Specific builds or iterations, often used internally.
  • Example: Version 2.2.2.45 could indicate the 45th build of this particular version.
  • Impact: Helps in identifying specific builds, useful for debugging and internal tracking.

Semantic Versioning

One of the most widely adopted systems for versioning is Semantic Versioning (SemVer). It uses a three-part version number: major.minor.patch. This system provides a clear and standardized way to communicate the nature of changes in each release.

  • Major: Incompatible API changes.
  • Minor: Backward-compatible functionality added.
  • Patch: Backward-compatible bug fixes.

Importance of Version Numbers

  1. Tracking Changes: Helps developers and users keep track of what changes have been made and when.
  2. Compatibility: Ensures that users know whether new versions will work with their current setup.
  3. Support and Maintenance: Facilitates efficient troubleshooting and support by identifying the exact version in use.
  4. Update Management: Allows users to determine if they need to update their software to the latest version.

Why I Dislike Quality 4.0, Validation 4.0, and the Like

It is meant to denote a major version, but it’s not, for a lot of reasons:

  1. These concepts are more growth of design boxes than major changes. To use version control lingo, there is a lot of backward compatibility.
  2. They are not definitive. There are absolutes and best practices and onward progression.
  3. Each company tends to be in different places in different ways, and there are many maturity scales, not just one.

Maturity models are a better option. Each of these buckets has multiple scales, each of which needs to be evaluated and improved.

This is why I like cGMP

The “c” in cGMP stands for “current,” which signifies that the Good Manufacturing Practices (GMP) being referred to are up-to-date with the latest standards and technologies. This differentiation emphasizes that companies must use the most recent and advanced technologies and systems to comply with the regulations set forth by the FDA. The term cGMP ensures that manufacturing practices are not only good but also current, reflecting ongoing improvements and updates in the industry.

ICH Document Structure, a Call for Change

The International Conference for Harmonization (ICH) has guidelines categorized into four main categories:

  1. Quality (Q) Guidelines focus on the chemical, pharmaceutical, and biological quality standards, including stability testing protocols to ensure the longevity and consistency of drug products.
  2. Safety (S) Guidelines address non-clinical and preclinical safety evaluations, guiding the toxicological assessments necessary to protect patients’ health.
  3. Efficacy (E) Guidelines cover the clinical aspects of pharmaceutical development, providing standards for designing, conducting, and analyzing clinical trials to ensure therapeutic benefits.
  4. Multidisciplinary (M) Guidelines encompass guidelines that do not fit neatly into the other categories, dealing with genomics, terminologies, and technical aspects of drug registration.

Any Q document is instantly and rightly viewed as a GMP guideline. This includes the quality trio, which, while they have a good philosophy, are still written specifically for GMP purposes. So, if you write your paper, good practice guide, standard, article, or what-have-you and refer heavily to the Q trio, you are either writing a GMP-centered piece or losing most of your audience.

The frustrating thing is that quality-by-design (Q8), risk management (Q9), and quality system management (Q10) are core concepts that apply across the pharmaceutical lifecycle, and there are best practices across all three that can and should be universal, especially Q9(r1), which can really better define risk management as defined in E6, and Q10, which can really shore up parts of E8.

What I would love to see the ICH do is write a technical reference document on risk management. Then, E6 and Q9 would have specific implementation aspects related to their focus. Put all the shared approaches in one place and build on them. The amusing thing is that they are already doing that. For example, Q13 applies the Q trio to continuous manufacturing, and Q14 applies it to the analytical lifecycle.

But for now, if you are writing and just referring to Q9 and Q10 don’t be surprised when all your clinical and safety colleagues tune you out.

Terms Matter and Differentiate the GxPs

About once a year, I find the need to criticize the GAMP5 writing teams for their use of terms. Seriously, change the name already.

This year’s rant is triggered by reading a good practices guide designed to be pan-GxP and getting frustrated by its utter GMP focus. I knew I was in trouble when it specifically discussed “Product and Process Understanding” as a critical factor and then referenced ICH Q10. Use those terms with ICH Q10, and you just announced to the entire world that this is a GMP book. It is important to use a wider term and then reference product/process understanding as one subcategory or way of meeting it.

I rather like the approach of ICH E6 and E8 here, which is to use the wider term “Critical to Quality,” which in the broader sense can be expanded to mean the key factors that must be controlled or monitored to ensure the quality, safety, and efficacy of pharmaceutical products from development to clinical studies to manufacturing and distribution and beyond. It’s a risk-based approach focused on what matters most for patient safety and reliable results.

Biotech Employees in Short Supply, a rant

The Boston Globe reported this past weekend “In the region’s booming biotech industry, workers are in short supply“, which is both good news and bad for me.

Good news is that my career prospects are always good.

Bad news is that I am hiring and building teams within quality.

also affect the quality of work as key positions become harder to fill and lower-level workers jump from company to company in search of a better compensation package.

For compensation package, read total cash. Sure there can be a difference on how good other benefits can be, but they all kind of get blurred together and I don’t think I noticed any difference between benefits packages until I went to a small startup, and I definitely knew what I was getting into there. The article later goes on to say some biotech is starting to offer some of the benefits seen in more computer-driven fields, but maybe folks should pay attention to how that is usually a trad to entice people into longer hours.

Notice the emphasis on lower level workers. Read that for “We don’t really offer good development programs and the only way to get promoted in this title-obsessed field is go to another company.”

According to the latest report from industry association MassBio, nearly 85,000 people work in the state’s life sciences sector, up 55 percent from 2008.

And sometimes you feel like you know all 85k, and have worked with most of them.

“You can’t walk two blocks around Kendall Square without receiving a job offer,” said Jeanne Gray, chief people officer at Relay Therapeutics in Cambridge, only half-kiddingly. “I get the sense that a lot of candidates know the market is hot.”

And she only made it 2 blocks because of the pandemic. Seriously, this joke has existed for over a decade.

About 16.5 percent of life sciences employees in Massachusetts voluntarily quit their jobs last year

Wouldn’t you if you keep getting better offers, often unsolicited from other companies and your current company gave you a measly 2-4% raise? Companies want folks to stay, start giving real raises commensurate with the market increase. As a manager, looking someone in the eyes (or vaguely at their eyes because we are both on camera) and telling the best the company can do is a 3% raise is pretty damn problematic. Especially if the employee knows how to read a SEC filing (if your company is public make sure you read these at every update).

There’s also a sense that employees are easily swayed by “title inflation,” a phenomenon that occurs when people climb the corporate ladder faster by bouncing around.

This is a problem in a field where title is everything. Where people where their MDs and PhDs as holy vestments. Where title is tied to autonomy and with ability to influence. This is a complex systematic problem, and few companies are even thinking of how to fix it, and probably can’t because the problem starts at the C-suite. No the problem starts with the regulators. See it’s complex, it starts in a lot of places.

I’m doing my little experiment here, I went to a company started by two incredibly earnest guys who had just graduated from Brown. Is everything perfect? Never is. But the experiment itself is fascinating to participate in.

the talent pool has not matured enough to fill key areas from the C-suite and clinical development, all the way through to the commercial launch of products.

Yes, expertise matters. However, we prize years-in-seat more than we should sometimes, and we do not spend enough time building talent. And let’s be honest, that leads to a lot of director levels who do not know how to actually do the thing they are supposed to do beyond the last time they did it.

This is definitely a ranty post.