PIC/S Guidance on Data Integrity is final

This week, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) finally announced that its new guidance on good practices for data management and integrity for pharmaceutical manufacturers and distributors has come into effect.
 
This final version is of a draft document originally introduced in 2016 and re-issued as a draft in 2018. It’s been a long road to get final version. Final version here.

Quality Bookshelf – Upton Sinclair

One of the ideas in my mind when I first started this blog almost three years ago was to explore some of the literature that asks the hard questions that reading will make us better quality thinkers. Neuroscience suggests that reading literary fiction helps people develop empathytheory of mind, and critical thinking. All critical to our success.

Unfortunately, other than a sporadic appreciation for Kafka – the source of the name of this blog – I haven’t done a great job at that. So, as an early birthday present to myself I bring you this piece written by Catherine Hamilton.

Upton Sinclair on the Working World and his Accidental Push for a Regulatory State

In 1906, socialist writer and political activist Upton Sinclair published his novel The Jungle, which became an instant bestseller and resulted in a major societal shift towards the modern regulatory environment seen in the US today.

Sinclair’s The Jungle follows the story of an immigrant family, who moved to Chicago in search of a better life, only to be met with poverty, death, and despair, in large part because of the terrible working conditions they endured, and the meagre wages they were afforded.

A novel written to illuminate the inhumane working conditions endured by the proletariat working in industries such as the meatpacking industry, Sinclair hoped that his expose of the unjust treatment of workers – those who would now be described as ‘blue collar’, an evolution of the phrase ‘white collar’ that Sinclair himself coined – would incite Americans to embrace Socialism. Indeed, when peer and fellow socialist writer Jack London received a copy of the novel, he predicted that it would turn “thousands” to socialism as it depicted “what our country really is: the home of oppression and injustice, a nightmare of misery, an inferno of suffering”.

Contrary to his objective, however, the publication of The Jungle lead to public outrage about the unsanitary conditions depicted in the meat production industry – a description that lasted only twelve pages in an over four-hundred-page novel – rather than a commentary on the injustice endured by the working class. As Sinclair himself stated in response to the outrage, “I aimed for the public’s heart, and by accident I hit it in the stomach.” This effect was perhaps understandable when we consider that Sinclair’s readers were faced with graphic images of dead meatpacking workers being ground up into the meat that they believed they were being fed; alongside these horrors, the greedy corrupt leaders – and the exploitation of their workers – that Sinclair was trying to expose, took a back seat in the public consciousness.

As such, rather than a novel – and a commentary on capitalism and the injustice of the inhumane working conditions suffered by the proletariat – the public viewed The Jungle as an expose on the meat industry, perhaps fuelled by the revelation that Sinclair spent seven weeks working undercover at one of these factories as research for the novel. As a result of this unrest, the government was pressured to enact laws to regulate the industry – the primary purpose of which was to appease the public, rather than increase the safety and sanitation around meat production – which culminated in the introduction of The Meat Inspection Act (1906) and the Pure Food and Drug Act (1906).

The former stated that the slaughter and processing of meat would be strictly regulated, and that edible meat products could not be mislabelled or misbranded. Meanwhile, the latter required the inspection of food and drug products, banned interstate and international traffic of adulterated or mislabelled food products, required active ingredients to be listed on the label of a drug’s packaging and stated that drug purity levels could not fall below the purity specified by the US Pharmacopeia/National Formulary.

These laws were the first in a series of consumer safety laws enforced by the state and lead to the founding of the Food and Drug Administration (FDA) – the US organization that regulates consumable products, including food, tobacco, supplements, pharmaceuticals, cosmetics and more, to ensure that these products aren’t harmful (or at least that their benefit outweighs the potential harm) to human (or pet) health. Thus, Sinclair’s novel became one of the most significant cogs in the foundation of the modern regulatory state.

This was not the socialist writer’s intention, however, and Sinclair was strongly against the imposition of these laws, as the only bodies they served at the time were the big meatpacking companies. In fact, large meatpacking corporations welcomed the regulation laws, as they knew that their smaller competitors would be eliminated by the expense of adhering to the regulations. As such, these laws – which can be directly attributed to Sinclair’s novel The Jungle – acted as an agent of capitalism, the exact opposite effect that Sinclair had hoped his novel would have on US society. To add insult to injury, the implementation of these laws also resulted in the taxpayer paying $3 million to bring about their enforcement. As thoughts on health, safety and quality of consumable products has progressed, however, it is likely that the change in public thought about food quality in 1906 – and the subsequent laws enforced – has had a net positive effect on the sanitation and safety of food and drug industries.

As a writer in the progressive era – who wrote to expose corrupt leaders and institutions and to raise public awareness and sentiment towards poverty – Sinclair was considered a ‘muckraker’, seeking to expose the injustice of capitalist society through his writing. Consequently, Sinclair wrote a large body of work charged by these ambitions, though none that had such a marked (and misdirected) effect on US society as The Jungle.

Though The Jungle was Sinclair’s most notable socialist work, Sinclair penned over one hundred books in his lifetime, and many of these sought to criticize capitalism and an array of specific industries. In 1913 and 1914 for example, Sinclair visited the Colorado coal fields, which inspired his novels King Coal and The Coal War and likewise exposed the harsh working conditions suffered by coal miners. Furthermore, he ‘exposed’ the oil industry with the novel Oil! and the auto industry with The Flivver King, though none of these works became commercial successes.

 Moreover, Sinclair stepped outside the world of industry to criticize the ‘free press’ in his novel The Brass Check, highlighting the benefits of the press to the rich and the drawbacks to the poor. In this novel, Sinclair also criticizes the office, describing ‘white collar’ workers – a term Sinclair himself coined – as “the petty underlings of the business world, the poor office clerks, who are often the worst exploited of proletarians, but who, because they are allowed to wear a white collar, and to work in the office with the boss, regard themselves as members of the capitalist class”.

With this quote, Sinclair illustrates his frustration that, due to the ‘white collar’ workers’ perceived elevation of their own status, and the marginally better working conditions they enjoyed – compared to their fathers who may have worked in factories or coal mines – they allowed themselves to be exploited. Describing these workers “petty underlings” he also assigns some of the blame of the propagation of capitalism to these workers, despite his acknowledgement of their exploitation.

Another of Sinclair’s most famous quotes states that “it is difficult to get a man to understand something when his salary depends upon his not understanding it”. Though this statement pertained to discussions Sinclair had with the publishers and editors of major newspapers about publishing articles in favour of pensions and other progressive reforms, it can also be related to his feelings about ‘white collar’ workers. Namely, because these ‘white collar’ workers relied on capitalism to provide their wage – but also because the capitalist class had given them the perception of obtaining a higher class – they would not risk their comparatively comfortable position in the office to seek something more just.

Evidently, then, Sinclair harboured as much contempt for the office – and for the leaders heading these businesses – as he did for the industrial workplace, as an unjust product of capitalist society, an inadequate place of work, and a new avenue with which to oppress the proletariat.

Despite over a century having passed – much to Sinclair’s probable dismay, were he still alive – offices are still the status quo, with over 80% of Americans reported to sit all day at their place of work, the majority of whom will do this in an office or equivalent space. Providing support for Sinclair’s disapproval of the office, multiple studies have shown the harmful effects of office environments on human beings. In 2020, for example, a Perkbox study showed that that work-related office politics were the number one cause of work-related stress, while lack of interdepartmental communications came second, and concerns about others’ work performance came third, which are all stressors bred by the office environment.

Sinclair would likely philosophize that because their salaries depended on these workers not understanding the injustice of working within a capitalist system – harboring a significant proportion of the workload, and enjoying an insignificant slice of the profit – they would not consider a system in which the means of production was shared by the community, and where the rewards were, likewise, shared equally.

Jeremiah’s comments

I love Sinclair for his prose and his politics. He wrote these amazing novels that are still fun to read today. He basically drove the creation of my entire profession. He focused on a lot of the workplace aspects that form such a huge part of my practice. Whether you can agree or not with his socialism, he will greatly reward your time.

And Upton’s work so highlights the woes of unintended consequences.

EU Annex 21 Published in Draft

On 20 March the new Annex 21 to the EU-GMP Guidelines was published as a draft. The document is entitled “Importation of medicinal Products”. The “Concept Paper” was published on 13 May 2015 (EMA/238299/2015) and the consultation phase ended in August 2015. The first draft for regulatory consultation was published in November 2016. Since then, no further activities or versions have been issued.

The Guidance is aimed at Manufacturing and Importation Authorisation holders (MIA holders) who import human or veterinary medicinal products from third countries. It does not cover products that do not have a marketing authorisation in the EU/EEA and are directly re-exported. The following points are to be regulated by the new Annex:

  • Physical transfer from the third country to the EU/EEA
  • Certification by the Qualified Person (QP) (link with the requirements of Annex 16)
  • Requirements for equipment and facilities
  • Required documentation
  • GMP requirements for manufacturers and exporters in third countries
  • Qualification and audits under the responsibility of the importing company and the Qualified Person (QP)
  • Import testing
  • Contractual regulations between all companies or persons involved in the import

Not much new here, but folks should be aware.

Rocky Road to ICH Q12 Implementation

Prior to the adoption of Q12 in Singapore at the end of 2019 there was a lot of rumbling from regulatory agencies on how Q12 would be more aspirational in many ways. In the last few weeks we’ve started to see just what that will mean.

FDA to release a guidance

The FDA’s Mahesh Ramanadham, from the Office of Pharmaceutical Quality in the FDA’s Center for Drug Evaluation and Research, provided an update on the agency’s implementation of ICH Q12 in the US on 25 February at the annual IFPAC meeting in North Bethesda, Md. He started that the FDA will soon be issuing guidance implementing the International Council on Harmonization’s Q12 guideline in the US that will, among other things, translate ICH post-approval change classification categories to FDA supplement categories, and address how to file established conditions (ECs).

This Q12 guidance will replace the agency’s 2015 draft guidance for industry on established conditions and reportable chemistry, manufacturing and controls changes to approved drug and biological products. It is expected to be issued in May 2020. The guidance will also discuss the relationship between FDA comparability protocols and the post-approval change management protocol (PACMP) established by the ICH Q12 guideline.

EU says not so fast in their adoption

However, additional scientific risk-based approaches to defining Established Conditions and
associated reporting categories, as described in Chapter 3.2.3, and the Product Lifecycle
Management (PLCM) Document, as described in Chapter 5, are not considered compatible with the
existing EU legal framework on variations.

It is important to note that the legal framework always takes precedence over technical and
scientific guidelines. More specifically this means that the definition of Established Conditions and
their reporting categories must follow the requirements laid down in the current EU Variations
Regulation and associated EU Variations Guidelines. With respect to the Product Lifecycle
Management (PLCM) document, in case such a document is submitted, it cannot be currently
recognised in the EU due to the fact that it is not referred to in the EU legal framework.

EMA/CHMP/ICH/78332/2020

In an explanatory note accompanying the adoption of ICH Q12 and related annexes, the European Commission and the European Medicines Agency point out that there are “some conceptual differences” between the ICH guideline and the EU legal framework on managing post-approval changes, ie, the variations regulation (Regulation (EC) No 1234/2008).

The EU authorities offer no clarity on when and how ICH Q12 would be fully implemented in the EU. The note merely states that the new “tools and concepts in the ICH Q12 guideline that are not foreseen in the EU legal framework will be considered when this framework will be reviewed.” The EU regulators said they would continue to work on the implementation of the ICH Q12 within the existing EU legal framework. The explanatory note also points out that despite some conceptual differences between ICH Q12 and the EU framework, there is also considerable common ground. In fact, some tools and concepts in ICH Q12 tools can already be applied by industry by following the current EU variations framework.

Next Steps

Companies should be ensuring that their knowledge management and risk management processes and understanding continue to grow. ICH Q12 will be a rocky road and I’m not sure we’ll see some of the potential streamlining of regulatory processes for a long time.

ICH Q12 pathway for established conditions