Shruti Bhat PhD, MBA, Lean Six Sigma Black Belt
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Out of Specification Impurity and Non-Compliance to Manufacturing Standards Continue to Haunt Pharmaceuticals- The Lupin Story.  Here's One Way to Correct the Mess ...

1/29/2019

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Out of specification impurity continues to haunt pharmaceutical products. There is yet another USFDA report citing out of specification product impurity and inappropriate processing issues in a reputed pharma company!
out of specification impurity and non-compliance to manufacturing standards continue to haunt pharmaceuticals- the lupin story. Way to correct the mess
For the third time in four months, Lupin Pharmaceuticals has been admonished by the Food and Drug Administration for a series of troubling quality-control issues at a manufacturing facility.

In a recent inspection report dated January 25, 2019, the regulator cited the company for failing to thoroughly review unexplained deficiencies in batches of medicines and not taking ‘scientifically sound’ steps to evaluate samples.

Few other deficiencies include- OOS (out of specification) investigations not handled correctly, impurity levels in products exceed specification limits and detailed health hazard assessment for the presence of this impurity was not conducted as needed.

Further remarks include- failure to re-train analysts who were involved in the purported mis-identification of product impurity, CAPA (Corrective Actions Preventive Actions) not designed and implemented correctly, insufficient investigation of customer complaints.
​
Other observations include- Appropriate controls were not exercised over computers or related systems to assure that changes in master production and control records or other records are instructed only by authorized personnel; Equipment used in the manufacturing, processing, packaging or holding of drug products is not of appropriate design to facilitate operations for its intended use; Established lab control mechanisms are not documented at the time of performance, and a lack of oversight and training.

Related reading:

  1. Valsartan, Irbesartan, Losartan Product Recalls- What are the Lessons for Pharmaceutical Industry?
  2. Mistake-Proofing Pharmaceutical Products: What can we learn from Valsartan, Losartan and Irbesartan recalls?
  3. Mistake-Proofing Pharmaceutical Product Development, Manufacturing and Logistics, Cost Savings via Poka Yoke​​​.
​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.​
Ideally, pharma companies must structure a dedicated Continuous Improvement lead and team within its organogram.
​There are over eighteen different continuous improvement methodologies to choose from.
Kaizen can be an excellent start to sort out this mess.​

How to Employ Kaizen in Pharmaceutical Operations?

Though a combination of nine types of Kaizen would be most suited; for starters, Gemba Kaizen can provide maximum help.

Gemba Kaizen is a method of continuous improvement that involves real time action. It is commonly used to add valuable activities to an organization, which help to add to the quality of customer satisfaction. When a problem arises, Gemba Kaizen pinpoints the issue as promptly as possible. The solution to the problem is then used to deal with the same problem, if it should reoccur, but ideally stops the problem from reoccurring in the first place. 
​
This method also implements ideas used in lean manufacturing, which help to reduce waste and unnecessary procedures.

One of the main goals of Gemba Kaizen is to eliminate anything that is not valuable, or adds value, to an organization, whether it is systems, procedures, employees, business verticals, machinery, facility and others. 

​Kaizen Case Studies:

  1. ​​Reduced Variations in Eye Drop Dosage; a Continuous Improvement Case Study: Kaizen in Pharmaceutical Product Development
  2. Kaizen Improved Patenting and Patent Filing Process ~ 20% drop in Patenting Cost; a Continuous Improvement Case Study
  3. How to Speed-up Pharmaceutical Generic Product Development?: Continuous Improvement Case Study
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Keywords and Tags:
​#OOS #OutOfSpecification #ProcessExcellence  #ContinuousImprovement #QualityImprovement  #ManufacturingManagement  #Pharmaceutical  #LifeSciences    #Drugs  #RiskManagement  #Lupin
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Valsartan, Irbesartan, Losartan Product Recalls- What are the Lessons for Pharmaceutical Industry?

1/27/2019

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Since September last year, news of *SARTAN drug recalls are doing the rounds. Yesterday's CNN Health carried yet another story on recalls of tainted Valsartan, Irbesartan, Losartan drug products.
Valsartan Irbesartan recalls_ What are the lessons for pharmaceutical Industry
Valsartan, Irbesartan, Losartan product recalls- What are the lessons for Pharmaceutical Industry? 

Straight answer- Big Time Business Process issue which must be rectified ASAP...

And, these 'process issues' are at several areas viz. product development process, manufacturing process, outsourcing or procurement process, customer service process to name a few; though a
company-specific root cause investigation will indicate more business processes that might have fully or partially impacted this drug product recall mess.

Presence of a potential carcinogen impurity in the drug as well as drug product clearly shows flaws in 'development and manufacturing processes'.
Companies that purchased this potentially contaminated API (active pharmaceutical ingredient) obviously have huge flaws with their 'procurement / outsourcing process' and need immediate process re-design!
​
​The fact that, carcinogen-contaminated drug products were consumed by patients show huge issues with 'customer service processes' of pharma companies and pharmacies. The issue with 'customer service process' gets further augmented because of the drug product shortage scenarios patients must now deal with.

As these recalls are not just with native irbesartan, valsartan, losartan products, but also extended to their fixed dose combinations i.e. *sartan combined with other drugs such as amlodipine, hydrochlorothiazide etc., the
product shortage mess gets sticky. Further, since these products are consumed daily, the impact of product shortages on patients (i.e. customers) is more intense...

Related reading:​

Mistake-Proofing Pharmaceutical Products: What can we learn from Valsartan, Losartan and Irbesartan recalls?
Mistake-Proofing Pharmaceutical Product Development, Manufacturing and Logistics, Cost Savings via Poka Yoke
​
Recommended steps to solve this problem:

  1. A logical thing to do in such cases is to study the Value Stream Map and identify all business processes that might have contributed to this mess.
  2. Next take a call on where these 'problematic' processes must be improved or re-designed. You can learn more about business process improvement and redesign here.
  3. Improve or redesign process(es) by using appropriate business improvement methodologies. There are over 18 different business improvement methodologies to choose from. Note that, selection of correct business process improvement methodology is very important too. 
  4. Once the problematic process(es) have been improved or redesigned as the case may be, conduct a robust risk-management exercise with FMEA and install a CAPA.
  5. ​Supplementing CAPA with Error-proofing mechanisms via Poka Yoke highly guarantees a 'no risk' scenario.​​
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​
#Kaizen   #BPM #ContinuousImprovement  #QualityImprovement     #ManufacturingManagement #Pharmaceutical  #LifeSciences #Drugs #FMEA   #RiskManagement  #ErrorProofing #Losartan  #Irbesartan  #Valsartan
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Mistake-Proofing Pharmaceutical Products: What can we learn from Valsartan, Losartan and Irbesartan recalls?

11/3/2018

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First Valsartan, now Irbesartan formulations are going thru a recall. As these product recalls are happening world-over, the chaos is enormous...
Mistake proofing pharmaceutical products_ what can we learn from valsartan losartan and irbesartan product recalls
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?
​

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?
A thumb rule whenever a 'defect' occurs means, underlying 'processes' are faulty and must be revisited- improved or re-designed. 

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).​
Secondly, the whole concept of 'Mistake-Proofing' pharmaceutical products must be revisited ...
​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' ...
A comprehensive Continuous Improvement methodology such as Kaizen must be rooted into pharmaceutical company operations 
Thirdly, stronger risk-assessment and risk-control tools must be adopted during development and processing of pharmaceutical products. Additionally, multiple risk-assessment and risk-control tools must be employed as standard operating procedure.

​Besides CAPA, FMEA, QbD, ICH and compendial norms, a structured 'Mistake-Proofing' methodology such as Poka Yoke- a Japanese concept for 'Mistake-Proofing', must be adopted as an integral part of Drug Discovery and Drug Product Development programs.​
Poka Yoke based Mistake-Proofing must be customized by companies for their line of business and product mix.
Practicing such 'Mistake-Proofing-by-Design' principle will imbue pharmaceutical products with quality to face any rainy day. It main rain tomorrow!

You may also like:

Mistake-Proofing Pharmaceutical Product Development, Manufacturing and Logistics, Cost Savings via Poka Yoke
Book on Kaizen for Pharmaceutical, Medical Device and Biotech Industries; released as Paperback and Digital editions!
Improved Productivity of Pellet Manufacturing: 28% rise in output per shift: Continuous Improvement Case Study
Follow Shruti on Twitter, Facebook, YouTube, LinkedIn 

#Manufacturing #Lean #ContinuousImprovement #Kaizen  #QualityImprovement  #Losartan #Valsartan #Irbesartan #USFDA   #Quality  #eLearning  #ManufacturingManagement #Pharmaceutical  #LifeSciences   #LeanManagement  #KaizenLeaderMasterclass    #RiskManagement  #Impurities
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Mistake-Proofing Pharmaceutical Product Development, Manufacturing and Logistics, Cost Savings via Poka Yoke

11/1/2018

0 Comments

 
Do you have any of the following complaints:
  1. R&D is slow, doesn’t give out products on time?
  2. Too many backorders, products don’t leave factory on time?
  3. Too many failed batches in pilot plant during tech-transfer?
  4. Too many failed bio-studies?
  5. Accidents at workplaces?
  6. Cost of logistics is high; denting bottom-line?

If you have any of the above complaints (and more), then this post is for you. Do keep reading…
Mistake_proofing pharmaceutical product development manufacturing and logistics cost_savings via poka yoke
​Usually a defect is construed as a product defect. Pharmaceutical cGMP norms and other FDA regulations bring check to product defects from happening, as well as in most cases, check defective products reaching the patients.

A point to note is that, defects and rework happen in all areas of a pharmaceutical business, be it- R&D, Manufacturing, Logistics or Office work zones.  ​
In any business, including pharmaceuticals, defects and rework amount from 5% to as much as 30% of overhead expenses. Imagine what if your business could save all those dollars?
Implementing Poka Yoke allows you to 'Mistake-Proof' processes/ products, stop defects and rework. Poka Yoke is a Japanese term which means Mistake-proofing or Error-proofing inadvertent errors. Its purpose is to- eliminate product defects, stop re-work and save overall costs of operation or running the business.

Poka Yoke concept was first formalized and adopted in the auto industry to draw attention to human errors as they happen. It was originally described as Baka Yoke; ‘Baka’ in Japanese means an idiot or a fool. Baka Yoke meant idiot-proofing or fool-proofing. The name was later changed to a milder term- Poka Yoke; ‘Poka’ in Japanese means disengaged. Poka Yoke means mistake-proofing or error-proofing. Poka Yoke aims to prevent errors because of actively disengaged employees.

Poka Yoke is preventing errors caused by absent-mindedness. Baka Yoke is preventing errors when process standard is beyond human ability. Poka Yoke distinguishes between concept of inevitable errors (professing Murphy’s Law) and defects that happens because of lax processes and/or absent-mindedness of employees.

The consequence of defects in pharmaceuticals is grave when defective products reach the market- C&F agents, wholesalers, retailers, doctors, patients. Maximum damage is done when defective products are consumed by unsuspecting patients; while damage is minimal when defects are detected no sooner than they occur. 

The aim of Poka Yoke is to design the process (within a company) so that mistakes can be prevented or at least detected and corrected immediately so that it is eliminated at source. Poka Yoke can be implemented at any step of a R&D, manufacturing, logistics or office process, that is, all processes where something can go wrong or an error can happen.
​

How to do Error-Proofing?


Error-proofing in traditional pharma companies can be primarily done via three techniques, namely:
  1. Contact Method technique: contact method identifies defects by testing and inspection.
  2. Fixed-value or Constant number technique: This method alerts the employee if a certain number of movements are not made.
  3. Motion-step or Sequence technique:  This technique determines whether the prescribed steps of the process have been followed.

​In above instances, the employee is alerted when a mistake is about to be made (referred as warning Poka Yoke) or the Poka Yoke device actually prevents the mistake from being committed (referred as control Poka Yoke). By eliminating defects, the cost of mistakes within the company is reduced/ eliminated.

​
Note that the error-proofing fronts increase if the organization is a smart factory, industry 4.0, operates as a multi-national or has many product mixes in its portfolio.

Poka Yoke is most effective when processes are accurately mapped. So, how to install Poka Yoke at your workplace?​

You may also like to read:

How to develop a culture of Continuous Improvement with your organization?
Decision making tool: Process Mapping
Continuous Improvement Case Study: Improved eyedrop dropper design and its process of making

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.
 
​

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

​
​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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#Manufacturing #ContinuousImprovement  #QualityImprovement #Quality  #Impurities   #ManufacturingManagement   #Pharmaceutical  #LifeSciences  #RiskManagement​  #Valsartan #Losartan #Irbesartan   #MistakeProofing
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    Shruti Bhat
    PhD, MBA
    Certified Lean Six Sigma Black Belt

    ​Shruti is a ​Global Leader in Operational Excellence, Lean Innovation, Lean Manufacturing, Business Transformation and Continuous Improvement; Best-Selling Author and Speaker.

    Shruti is a Go-To Scientific Expert and Management Leader within Pharmaceutical, Health Care, MedTech, Biotechnology, Retail, Chemicals, Engineering and Telecom industry  verticals.

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