The health ministry of Indonesia has temporarily banned the sale of all syrup and liquid medicines, citing the risks to children (according to a BBC news report). In a statement, the ministry explained that acute kidney injury (AKI) has been linked to syrup medicines. The government cited a sharp increase in AKI cases among children, most of them under five years of age. However, the number of acute kidney failure cases could be much higher than reported.
 
Higher than accepted levels of diethylene glycol and ethylene glycol were found to be present in the products recovered from patient’s homes. Children suffering from AKI had allegedly been using syrups that contained diethylene glycol and ethylene glycol in very small amounts. Currently, there are 206 confirmed cases of AKI in Indonesia, of which 99 were fatal. However, the true number is likely to be higher.
 
As per the BBC news report the Indonesian authorities have so far not disclosed the brands or types of syrup medicines linked to sick children; instead, just temporarily banned the sale and prescription of all syrup and liquid medicines.
 
Earlier this month, cough syrup-linked child deaths were reported from African country The Gambia. The reason then was higher than accepted levels of diethylene glycol and ethylene glycol in syrups. ( A report in India's one of the leading newspaper Economic Times stated that the Medicines Control Agency MCA, has not yet found definitive links between the deaths and the cough syrup).

Unfortunately, we have been witnessing such tragedies since 1937, when the first elixir tragedy was reported in the United States.
 
Further to that, compliance procedures and regulations were strengthened, and for a few decades, it has helped bigtime in curbing such fatalities.
 
Over the years, pharma operations have graduated from ‘quality control’ to ‘quality assurance’ and now ‘quality-by-design’. One of the fundamental principles of quality-by-design (QbD) while formulating drug products is that safety is built-into the product by design. But then a quick question that pops up in my mind is- Are syrups safe?
 
In my view and I'm sure you will agree with me, there can be no justification to such tragedies. As an operational excellence leader, I believe that in addition to ensuring cGMP and quality compliance while manufacturing drug products, it is probably the need of the hour to re-think formulation strategies for syrup medications.
 
Go for syrups sans propylene glycol!
 
This is surely a challenge for pharma formulation development scientists, but it will be efforts worthwhile. Firstly, it will stop such potential tragedies and secondly, syrups shall truly become patient-friendly!

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Dozens of child deaths have been reported recently in African country The Gambia. The deaths are allegedly linked to cough syrups containing unacceptable levels of diethylene glycol and ethylene glycol.
 
Diethylene glycol and ethylene glycol are known toxic items and are ‘source-related’ impurities of the solvent used in the cough formulation. At the outset, for those new to this topic, let me briefly explain what is meant by ‘source- related’ impurities- There are broadly two types of impurities in drug products- (1) Source-related impurity and (2) Impurities arising as a result of product manufacturing and/or generated during the shelf-life of a product. These impurities are referred to as degradation products.
 
The source-related impurities are traces of substances in the raw material in lieu of its manufacturing. These source-related impurities cannot be totally avoided but must be controlled and must be within permissible limits mandated in the pharmacopoeia. Further, these source-related impurities must be within acceptable limits in the finished formulation (whenever that raw material is used) at all times until after the expiration of that finished formulation.
 
Same goes for the degradation products, they too (if present) must be within limits stated in the product monograph. If the impurity levels get higher than accepted limits, it can cause minor to critical safety concerns.
 
Coming back to this unfortunate incident…

​Deaths linked to diethylene glycol from cough syrup was first reported in the year 1937 in the United States, the ill-famous ‘Elixir Tragedy’.
 
Since that incident, regulators and pharma companies worldwide have put in stringent cGMP (current good manufacturing practices) criteria in drug product development thru manufacturing as well as post-marketing surveillance. The fundamental objective of cGMP is to ensure quality, efficacy and safety in drug product at all times until after its expiration. An incident such as this one, prima facie means a break-off from the norms i.e. non-compliance to the cGMP process.
 
Also, cGMP does not mean ‘best practices’ implemented only during manufacturing. cGMP is a wide-spectrum best practice and is applicable to all upstream and downstream processes of a product’s lifecycle. Non-compliance in adhering to these ‘best practices’ at any stage of the upstream and/or downstream processes can lead to mishaps, even fatalities.
 
So, what happened in this case? Why so many people died after taking a cough syrup? Why did the syrups have unacceptable quantities of diethylene glycol in them? As a member of the pharma fraternity such questions came my way (from friends and acquaintances) for the past few days. Since this matter is under investigation by competent authorities, we'll know in the coming days. But our objective as responsible pharma professionals, is not to just find out what happened in this unfortunate case, but also proactively ensure that such situations do not happen in the future.
 
In fact, I shall say- selling a safe product to the consumer is the seller’s prime responsibility, no two ways about it. Hence, not just drug products, but all products must have the desired quality attributes and must be safe in the hands of the user.  But how can companies ensure this?
 
There are several ways to achieve this. But the surest and fastest route is to- Start implementing QbD (quality-by-design) in the product’s value chain, and mistake-proof all processes in the product’s supply chain.
 
Mistake-proofing means you don’t leave any scope for errors to happen while working the process. For example, try putting a two-pin or a three-pin plug into a socket. It won’t fit-in unless inserted the right way. Another example of process mistake-proofing is a washing machine. If you were to flip open a washer’s door while it was running its cycle, the machine immediately stops. But the moment you shut back the door it re-starts! Such mistake-proofing with a plug's or washer's design and operation is to prevent accidents i.e. consumer safety.
 
Pharma companies must couple cGMP with mistake-proofing; that is, apply appropriate error-proofing measures to all its technical and business processes.
 
Some of the promising and time-tested error-proofing tools are Poka Yoke, FMEA, Visual Management, CAPA etc. I’ve separate posts on Poka Yoke and Visual Management, do check them out …

1. Improve Process Efficiency with Visual Management
2. Mistake-Proofing Pharmaceutical Product Development, Manufacturing and Logistics, Cost Savings via Poka Yoke
3. Mistake-Proofing Pharmaceutical Products: What can we learn from Valsartan, Losartan and Irbesartan recalls?
4. Valsartan, Irbesartan, Losartan Product Recalls- What are the Lessons for Pharmaceutical Industry?

News update- Subsequently, a report in India's one of the leading newspaper Economic Times stated that the Medicines Control Agency MCA and The Gambian drug regulatory authorities have not yet found definitive links between the deaths and the cough syrup, and that the cause of child deaths is still unknown.

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​A detailed root cause analysis shall of course open avenues of true ‘problem areas i.e. disjointed business processes’ which need correction, followed by a neat process improvement strategy and its flawless execution.​

​There are over eighteen different continuous improvement methodologies to choose from.

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Keywords and Tags:
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For the affected patients, it is horrifying to learn that they have unsuspectingly consumed a medicine that contains a potential carcinogen. In addition they have now to deal with product shortages; a product they consume daily to keep their blood pressure in check!

For pharma companies, this is a huge hit to their brand image as well as to their bottom-line. 

Even though Impurities in drugs and drug products are a part of manufacturing process, drug companies strive hard to keep them at minimal and within specifications; be it as per ICH, FDA or company's internal standards. So what happened in case of Valsartan, Irbesartan? Are compendial testing procedures adequate? How were these impurities missed?

Several such questions arise... A root cause analysis will dig into reasons for the lapse, but prevention is better than cure … this is more so true for defective pharmaceutical products. Lesson learnt from *SARTAN mishaps is as a wakeup call !

Recalls will surely stop patients from taking defective batches of Valsartan, Irbesartan. But what about the damage already done to patients who have consumed these defective products? And what is it that we must do to prevent something similar from happening again; not only for *SARTANs but any other drug or drug product?
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Impurities in drug/drug products: How NOT to miss them?

Pharma R&Ds follow rigorous procedures to keep impurities/ degradation products at minimal possible levels. Drugs and drug products are developed using high standards and elaborate regulated procedures, yet how were these impurities missed out? And what to do to NOT miss them?

Here's the starting point-

Drug and drug products are developed using ICH Quality norms, QbD (Quality-by-Design), PAT (Process Analytical Techniques) and similar such sophisticated guidances which facilitate 'risk-assessment'. Based on *SARTAN scenario, a logical question that pops up is- Are these 'risk- assessment' tools good enough? Or is there an application failure? In the former case, guidance documents need overhaul, while the later, points to inadequate training (around appropriate implementation of these guidances).​

​Impurities are consequence of drug/ drug product manufacturing process. Any potential carcinogenic impurity carry overs into medicinal products and patients is no doubt hazardous; but it doesn't end there. What about these carcinogenic impurities getting into effluent systems and perhaps into the environment? This puts a larger population at risk!

Existing IPQC, QA monitoring norms are not good enough when we deal with complex small molecule drug candidates. All processes (technical and/or operational) leading to the products must be studied comprehensively,  supervised, modified and improved 'Continuously' ...

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How to install Poka Yoke in your organization?

A methodical approach to build up Poka Yoke countermeasures consist of three steps-

1. Identify the need.
2. Identify possible mistakes, mistake avenues
3. Manage mistakes before satisfying the need.

 
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Benefits of Poka Yoke implementation:

A foremost benefit of Poka Yoke solutions is that they don’t let an error happen in a process. Other benefits include:

1. Eliminates rework.
2. Reduces cost on employee training.
3. Reduces product analysis cost.
4. Reduces QA/ QC workload.
5. Improved productivity from R&D, manufacturing and other divisions of the organization.
6. Improved safety at workplace- no personal injury, prevents machine/ facility damage.
7. Motivated employees.
8. Promotes product innovations and defensive designs: Defensive design is building contingencies in the design to anticipate all potential ways an end-user could misuse or make a mistake. For example, power sockets are often keyed in such a manner to prevent the transposition of live and neutral. The plug is inserted into the socket in a specific orientation; hence the plug is designed so that it is physically impossible to insert the plug incorrectly.
9. Immediate action when a problem occurs.
10. Unburdens employees from repetitive operations, makes processes ‘Lean’ and efficient- Saves Cost

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​Learn more about ‘How to mistake-proof your R&D, Manufacturing, Logistics and Office processes and gain quick cost-savings’. Contact Us

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