Factors & solutions for manufacturers (Part 5 of the Recall of -sartans series)

The pharmaceutical companies involved in drug manufacture can be roughly classified into two: those who manufacture active ingredients and those who buy the active ingredients for producing drugs (sometimes both are the same company). The responsibility for detecting contamination and ensuring GMP normally lies with the manufacturers. Should a batch not meet criteria for quality, efficacy, and safety, the manufacturer has to document this and communicate this to the regulators who should (ideally) decide on the best response.

Indeed, manufacturers are best equipped to identify the source of the problem. Once a problem is detected (e.g. a contamination), they could backtrack each step of the production process and identify where the contamination took place, thereby removing the source of contamination.

However, as seen in previous posts, manufacturers (some, if not all) seem to engage in suppressing results and following suboptimal manufacturing practices - i.e. they consciously, unconsciously, or temporarily blindly decide to act unethically. Guido Palazzo, Professor of Business Ethics at the University of Lausanne, admits that, "What you see in some cases, also in the recent Boeing case, is that there are at one point quality controls, and they find something, but they overrule or they push the guy aside, threaten them, or they put them elsewhere. So it seems that the quality control does not really have the power to make decisions here." Some key reasons for this (gleaned from the -sartan recalls) are as follows:

At the company level

1. Financial motivations:  From the company point of view, suppressing results and making shortcuts might be tempting as drug manufacturing consumes resources and carries costs. As these companies exist in a competitive environment, their focus is on competitive advantage and financial performance.

2. Time pressure: Investigating the contamination requires time (and resources).

3. Reputational effects: Reporting the contamination to the regulator may affect the reputation of the company.

At the employee level

1. Performance pressure: Employees are expected to deliver a certain quantity of work each day.

Thus, they are motivated by reaching the quotas assigned for each day.

2. Cultural norms:  The work culture in some countries may not privilege following good manufacturing practices.

3. Laziness or reluctance: Even when investigations are done, employees are not diligent about filing reports or documenting the work they do.

4. Language barriers: A reason that often springs up is that employees may not have good language skills that prevent them from reporting in English.

Professor Palazzo urges examining the "role of quality managers or compliance and how can we strengthen it in a way that we can have speed, but not distort the quality". He points out that "from the ethical blindness perspective*, [...] speed makes everything invisible. So you focus on something and you don't see the rest. And this is getting worse with the whole debate on agility, we have the invitation to speed up even more."

Given this context, compliance managers can address the employee-level factors with training: on drug production process, GMP, regulations, and the consequences of suboptimal manufacturing practices and unethical behaviour. Ideally, third parties would conduct these, with the employees having to demonstrate excellent knowledge (perhaps certifications) that permits them to continued employment by the manufacturer. This training could be repeated every few years for refreshing the knowledge and accounting for changes in regulations and practices. Language tutorials could be given for those who need to utilise a language they are not proficient in.

Furthermore, employees should be motivated to prioritise ensuring the safety, quality, and efficacy of the products instead of achieving product output goals. This could be assisted by having a verification process for each step so that the onus does not lie on a single individual.

The company-level factors could be partly addressed by manufacturers benefit by having independent, third-party audits and being willing to address issues discovered by such audits. However, regulatory bodies are the key actors who can motivate manufacturers into compliance. This will be explored in the next post.

Image Source: RGtimeline

Sources:-
Bloomberg's previous articles:

https://www.bloomberg.com/news/articles/2019-03-27/tainted-generic-drugs-force-fda-to-tighten-safety-regulations

https://www.bloomberg.com/news/articles/2019-03-01/third-potential-carcinogen-found-in-blood-pressure-drugs

https://www.bloomberg.com/news/features/2019-01-31/culture-of-bending-rules-in-india-challenges-u-s-drug-agency

https://www.bloomberg.com/news/features/2019-01-30/chinese-heart-drug-valsartan-recall-shows-fda-inspection-limits

https://www.bloomberg.com/news/features/2019-01-29/america-s-love-affair-with-cheap-drugs-has-a-hidden-cost

https://www.bloomberg.com/news/articles/2018-08-09/red-flags-raised-at-chinese-heart-drug-maker-year-before-recall

*Palazzo G., Krings, F., & Hoffrage, U. 2012. Ethical Blindness. Journal of Business Ethics, 109, 323-338. 

Mayaro virus – the next Chikungunya?

Earlier in May, researchers at the Federal University of Rio de Janeiro announced that they had discovered patients infected by the Mayaro virus in the state of Rio de Janeiro.

What is Mayaro virus? It’s related to Chikungunya, and produces very similar symptoms - fevers and intense muscular pains. Mayaro had previously been thought to be restricted to areas of the Amazon forest, where it is transmitted primarily by the forest mosquito Haemagogas janthinomys. 

However, the recent cases followed analysis of 3 workers in Niteroi, a city next to Rio, diagnosed with Chikungunya, but whose subsequent tests were negative. Significantly, none of the patients had been to Amazonia, implying Mayaro was circulating in the local population. 

James Gathany - PHIL, CDC, Public Domain,

The route of transmission in these cases is unknown, and one possibility is that the virus was again carried by Haemagogas janthinomys, which although traditionally a mosquito of the Amazon, has been detected in forest areas near cities in the south of Brazil, and has been implicated in an outbreak of Yellow Fever in 2016 (de Abreu et al 2019). 

There is however a more worrying possibility. It has been previously reported (Long et al 2011) that Mayaro can be transmitted by the mosquito Aedes aegypti, which is both much more common in urban areas, and more homophagous. 

There are doubts about how good a vector Aedes aegypti would be for Mayaro (Brustolin et al 2018), and it should be stressed that Aedes aegypti was infected in the laboratory, and no wild caught individuals have yet been found with the disease. However, if it does turn out to be an urban vector this is a matter for serious concern.

Sources

Pesquisadores da UFRJ anunciam que descobriram virus mayaro no estado do Rio. Globo. 16 May 2019.

https://g1.globo.com/rj/rio-de-janeiro/noticia/2019/05/16/pesquisadores-da-ufrj-anunciar-que-descobriram-virus-mayaro-no-estado-rio.ghtml

Virus Mayaro, transmitido pelo Aedes aegypti, chega ao Rio. Globo. 17 May 2019. https://globoplay.globo.com/v/7622100/

Anopheles mosquitoes may drive invasion and transmission of Mayaro virus across geographically diverse regions. Brustolin, M. et al. (2018). PLOS Neglected Tropical Diseases 12(11), e0006895.

Haemagogus leucocelaenus and Haemagogus janthinomys are the primary vectors in the major yellow fever outbreak in Brazil, 2016–2018. De Abreu et al. (2019). Emerging Microbes & Infections, 8, 218-231.

Experimental transmission of Mayaro virus by Aedes aegypti. Long, K.C. (2011). Am J Trop Med Hyg., 85(4), 750-757.

Et tu, ...? (Part 4 of the Recall of -sartans series)

If tweets were indicative of general option, then the recall of blood pressure medications is owing to faulty manufacturing practices in China. However, this recall is only part of a far bigger problem in the global pharmaceutical industry: contamination of active ingredients/drugs and not following good manufacturing practices (GMP). As we will see from Bloomberg's investigative pieces, the issue is also not restricted to production in China. Several production facilities in neighbouring India had/have substandard laboratory practices, which came to light during the Food & Drug Administration (FDA) inspections.

• In 2016, Hetero Labs Ltd./Camber Pharmaceuticals Inc. was found following substandard GMP for cleaning and maintaining equipment and having products with potential carcinogens. Two months ago, they too detected a potential carcinogen in their losartan batches. 
• In 2017, employees at Dr Reddy’s Laboratories Ltd. plant in Andhra Pradesh were caught destroying computer files and documents (suspected to be relating to the production process).
• Ranbaxy Laboratories Ltd was found to have falsified data at two factories and was fined $500 million by the US Justice Department.

Such examples being from India and China, there arises an argument for boycotting products manufactured in such countries. However, the problem of contaminated drugs and bad GMP is not restricted to the economic South.

• In 2016, an inspection by the FDA found that production staff at the West Virginian facilities of Mylan (the second largest producer of generics) had recorded passing scores for drugs that failed tests and had destroyed documents (again relating to the production process). In 2018, they found evidence of bad manufacturing practices. 
• Illinois-based Akorn was found to have submitted falsified data to the FDA when requesting an approval of their generic version of the antibiotic azithromycin. In addition, they did not follow good GMP, particularly in following cleaning, testing, and storage procedures for ensuring drugs are not contaminated. 

This then leads to a potential hypothesis that the problem has to do with the manufacturers of generics. However, brand names are not immune, as seen when Pfizer Inc.'s Hospira facility in Tamil Nadu recorded wrong (passing) data regarding the quality of some active ingredients. When these failed when retested in front of FDA inspectors, Pfizer paused manufacturing and later ceased production due to "significant long-term loss of product demand".

Thus, the problem of contaminated drugs and active ingredients is not one specific to manufacturing in certain countries or the nature of the manufacturer (generics or brand name). How then can the problem be solved? The three remaining blog posts of this series will offer pointers to the main stakeholders concerned: regulators, pharmaceuticals, and the general public.

Sources:

https://www.bloomberg.com/news/articles/2019-03-27/tainted-generic-drugs-force-fda-to-tighten-safety-regulations

https://www.bloomberg.com/news/articles/2019-03-01/third-potential-carcinogen-found-in-blood-pressure-drugs

https://www.bloomberg.com/news/features/2019-01-31/culture-of-bending-rules-in-india-challenges-u-s-drug-agency

https://www.bloomberg.com/news/features/2019-01-30/chinese-heart-drug-valsartan-recall-shows-fda-inspection-limits

https://www.bloomberg.com/news/features/2019-01-29/america-s-love-affair-with-cheap-drugs-has-a-hidden-cost

https://www.bloomberg.com/news/articles/2018-08-09/red-flags-raised-at-chinese-heart-drug-maker-year-before-recall

Image source: Dreamstime

Manufacturing and regulatory pitfalls (Part 3 of Recall of -sartans series)

A previous post on the -sartan recalls refers to the contamination process that occurred in the production/manufacturing process. In last week's post, I mentioned the existence of problems in US Food & Drug Administration's (FDA) verification process of drugs/active ingredients sold in the US. This week, I summarise findings from several of Bloomberg's investigative pieces (references at the base) that highlights the four manufacturing and regulatory pitfalls behind the recall of valsartan, losartan, and irbesartan.

1. Reduced number of inspections by FDA: Obtaining the approval of FDA involves visits of the production facilities by FDA's own inspectors. Whilst the number of approved generics increased (for meeting the election promise of the current Trump administration), the number of FDA inspections (both international and domestic) dropped in the fiscal year of 2018. In the 2018 fiscal year, FDA inspections in China (having a market share of around 8% in the US) decreased by approx. 11%. On the other hand, FDA inspections increased by 18% in India (having a market share of 38% in the US and is the world's largest exporter of generics).
This reduction-increase was justified by the FDA as the strategic targeting of facilities that had a certain risk score based on past inspections. Furthermore, FDA's agreements with EU counterparts ensure there is no duplication of work. However, the agreement does not cover India and China.

2. Production of substandard active ingredients: In May 2017, an FDA inspector pointed out the production of substandard active ingredients at the Linhai (China) factory of Zhejiang Huahai Pharmaceutical Co. Ltd, a supplier of active ingredients to big pharma and generic pharmaceuticals (e.g. Teva). These active ingredients did not meet FDA's criteria.

3. Malpractice by manufacturer: The manufacturer had obtained results showing that some batches did not meet the FDA's criteria and contained unknown contaminants. Their responses were to ignore the results, omit the results from the official records, and record falsified data that indicated the products meeting FDA's criteria. Regarding the contaminants, they are supposed to attempt at identifying and rectifying these and communicate the presence of such contaminants to the FDA. The FDA inspector discovered these faux pas and noted that this was not the first time they did so. Furthermore, in 2016, Chinese regulators directed Zhejiang Huahai to withdraw applications for selling new drugs, should the application be based on false or incomplete data. Consequently, Zhejiang Huahai withdrew its applications for epilepsy, blood pressure, and depression generics and blamed flawed testing by a local contract research organisation.

4. Questionable decisions by FDA: The FDA inspector recommended penalising the manufacturer by making the approval of the sale of new drugs/active ingredients in the US contingent on the inspected products and manufacturing facility addressing the shortcomings or meeting quality criteria. However, FDA managers decided not to follow the recommendations of the FDA inspector, claiming that previous inspections of the facility came up with nought.

The end result of these manufacturing and regulatory pitfalls is the consumption of contaminated medicines by patients for at least four years. No one would have been any wiser had not a company who purchased valsartan from Zhejiang Huahai spotted the contamination.

My next post will disentangle the implications of such manufacturing and regulatory pitfalls.

References:
All of Bloomberg's investigative pieces listed below:-
https://www.bloomberg.com/news/articles/2019-03-27/tainted-generic-drugs-force-fda-to-tighten-safety-regulations
https://www.bloomberg.com/news/articles/2019-03-01/third-potential-carcinogen-found-in-blood-pressure-drugs
https://www.bloomberg.com/news/features/2019-01-31/culture-of-bending-rules-in-india-challenges-u-s-drug-agency
https://www.bloomberg.com/news/features/2019-01-30/chinese-heart-drug-valsartan-recall-shows-fda-inspection-limits
https://www.bloomberg.com/news/features/2019-01-29/america-s-love-affair-with-cheap-drugs-has-a-hidden-cost
https://www.bloomberg.com/news/articles/2018-08-09/red-flags-raised-at-chinese-heart-drug-maker-year-before-recall

Image source: Shutterstock