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All opinions are my own.

Thursday, May 23, 2019

Opportunities for Generic Pharma to Clear the Quality Stigma

Recently there has been significant press (1)in the United States about quality of generic drugs. India and China were singled out. Increased exposure (recalls and FDA citations) are par for the course. These are indications that issues of varying degree are there and they need to be addressed. Press in general looks for opportunities to get on the band wagon. It is ironic that many in press might not have any clue of what a drug is, how they are developed, costed or for that matter what the manufacturing processes entail but are riding the news horse. They have power of the pen. We must remember that negativity sells and influences. 

The current negativity unless harnessed is going to cause increasing damage and the publicity will not end soon. I consider this an opportunity for various companies to re-work/re-look the current business model/plans to see how and what can be done to improve the affordability of generic drugs to the largest global market while producing quality drugs. If nothing is done to excel in product quality eventually lack of action will come back and haunt generic pharma. 

होजायेगा(Ho Jaye ga) or 着什么急呀! (zháo shénme jí ya!) loosely translated what’s the hurryattitude must be shed. Quality must be delivered today as tomorrow never comes. If for any reason quality demanded by the customer is not respected and delivered, business in the long term will suffer. In this effort, it is possible that many egos may have to be shelved as lives are stake. Onus to correct perception of questionable quality, perceived or actual, is on the generic pharma companies.

Again, bottom line, the current negativity is an opportunity to harness and rein in the quality horse. Some costs may be there but done right they should be minimal or none and will be offset and will add to the bottom line. Long-term survival of generic pharma depends on quality and undeniably it must be their highest priority. First time quality should be the goal. It is well known that to re-work the product to achieve quality can cost as much as 40% (2, 3)that simply translates to lower profits. 

Presented is my perspective/perception which is based on the current landscape. There is no vested interest of any for-profit or non-profit entity. In addition, this is also not a solicitation or a recommendation but a suggestion that companies must overcome the prevailing negativity by using talent that can and does think out of the box and can resolve issues. Talent that can “walk the talk” rather than “talk the walk” is needed.

Acknowledgement and Capabilities:

Generics must acknowledge their quality issues internally and must take the bull by horns to fix the current negativity. Companies that are excelling need not worry but will have to stay the course and continuously improve. There will be internal denials and challenges that could be hard to swallow. That is to be expected. Change is needed. If anyone thinks that it is difficult and expensive to achieve quality, that notion needs to be challenged. They need to be asked “would they risk to take the medicines produced by their own company?”   

Chemists and chemical engineers are taught to produce quality the first time. It seems that somewhere between the university doors and plant floors, they faltered and have accepted and/or succumbed to the prevailing practices. I am not sure how they have lost their mojo. Doing right is cheap and fixing the wrong is costly and in pharma wrong can cost lives, an unacceptable occurrence. Again, lack of first-time quality is expensive (2, 3)

Frugality and creativity are the cornerstone of India’s ingenuity as exemplified by its extremely low-cost mission to Mars. Similar attributes are true for China. My question is why these traits are not being applied to pharma. 

What is needed for quality drugs? 

Most pharma plants operate are at about TWO Sigma level (3, 4), a significant opportunity to improve. This might not hold true for every company but based on publicly available information, fragmented manufacturing could be the root cause of poor quality. 

Even though drug manufacturing is understood, it is good to re-visit the process. Every produced drug is a two-step process. An active pharmaceutical ingredient (API) is formulated with inert excipients to produce a dispensable dose. Method of API manufacture is dependent on the chemistry and volume needed. Since APIs are toxins that kill the disease-causing bacteria they are used in minute quantities. Thus, small quantities of API are needed to meet the needs as exemplified by the fact ONE kilo of API will produce ONE million tablets of one milligram @ 100% conversion. Table 1 is an illustration of API needed and tablets produced per year for 50 million patients. Needed API could be produced at a single plant but formulation most likely would be done at more than one plant.

Patients
milligrams
#/yr.
API, Kilo/year
Tablets/yr.
 50,000,000 
1
365
    18,250 
  18,250,000,000 
 50,000,000 
10
365
  182,500 
  18,250,000,000 
Table 1: Theoretical API and Formulation needs 

If I were to produce the needed API (Table 1 Illustration) for 50 million patients it will produced at a single plant. Multiple lines at the same site or multiple sites would be needed for formulation. In today’s landscape multiple plants will produce it. Multiple plants or lines would be need for formulations. it is imperative that the product quality meet established specifications and follow cGMP. 

Table 2 (5 ,6, 7) is an illustration for some named drugs. Potential of products being perfectly same is unlikely but it is necessary that they meet the accepted specifications. 

Drug
Number of API Sites
Number of FDF Sites
Ciprofloxacin
22
536
Atorvastatin Calcium
44
865
Omeprazole
87
768
Modafinil
29
70
Metformin HCl
77
752
Metoprolol
41
338
Table 2: Number of sites for APIs and Formulations

Since most APIs are manufactured and formulated at many plants (Table 2), based on my experiences and I am sure of others, ensuing processes have significant cost variations. Due to lack of economies of scale most of the processes are not optimum. Global API demand of ciprofloxacin, omeprazole, modafinil, metoprolol can be fulfilled from a single plant. FDF facilities for these products could be lot fewer than the current number. API and FDF plants for atorvastatin and metformin can be significantly lower the current numbers. 

If a company is producing many products in the same equipment, cGMP issues can result. Short production runs test operating personnel’s metal. This can happen across the board for generic drugs. Combination of above can result in two sigma quality. Due to nature of the processes and method of execution, quality in current manufacturing methods is most likely tested in rather than built in, an expensive process (3,4). These processes also can be a leading cause of quality infractions. Companies who rely on “after the fact quality” aka “quality by analysis/aggravation” rather than QbD, could apply fundamental of process design which every designer of a chemical process is expected practice. They could explore methods to have command of their processes (8, 9). Internal resistance is very possible. Regulations also intervene to make such improvements.  

Another alternate to retain quality is through consolidation and taking advantage of economies of scale. Processes will be optimized. Quality will be consistent. Such processes will have significantly higher profitability than the current processes. Every chemist and chemical engineer knows and understands these fundamentals. It just behooves me why they don’t practice what they have learnt. Is it the corporate culture? As said earlier regulators do not facilitate process improvements either. 

Generic companies like any other profitable company have to continuously do self-evaluations of their operating and business practices and strategies. However, it seems not much has happened (10,11). Increasing 483s and recent issues e.g. valsartan are telling us that quality issues are persisting and things need to change.

USFDA due to repeated generic pharma quality issues could succumb to political and social pressure and could take significantly drastic stand of stopping import of these drugs. That would an unhealthy situation for the generic pharma and US populous. Health of Generic Pharma like any human patient is in their own hands. They can fool the doctor (FDA) some of the time but eventually when reality hits home, results can be pugnacious and difficult to handle. By ignoring quality generic pharma is playing with its own existence. Thus, it is in the interest of generics to stay on top of their quality game. 

Girish Malhotra, PE

EPCOT International 

  1. Eban, Katherine: Bottle of Lies, Harper Collins Publishers, May 14, 2019 
  2. Cost Of Quality: Not Only Failure Costs https://www.isixsigma.com/implementation/financial-analysis/cost-quality-not-only-failure-costs/
  3. Hussain, A. S.: Pharmaceutical 6-Sigma Quality by Design, The 28thAnnual Midwest Biopharmaceutical Statistical Workshop, Ball State University, Muncie, IN, May 23-25, 2005, Page 20, Accessed May 19, 2019
  4. Shanley, Agnes: Will the Pharmaceutical Industry Ever Get to Six Sigma? Pharmaceutical Technology, July 2017
  5. Malhotra, Girish: Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs) on Drug Shortages and Affordability Part 2, Profitability through Simplicity, April 3, 2019
  6. Berndt, Ernest R., Conti, Rena M. and Murphy, Stephen J: The Generic User Fee Amendments: An Economic Perspective, NBER Working Paper 23642, August 2017
  7. PharmaCompasshttps://www.pharmacompass.com 
  8. Malhotra, Girish:  Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
  9. Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization” in  Quality by Design-Putting Theory into Practice co-published by Parenteral Drug Association and DHI Publishing© February 2011
  10. Malhotra, Girish: US FDA citations to Ranbaxy are an excellent opportunity, Profitability through Simplicity, September 17, 2008
  11. Malhotra, Girish: What do the Ranbaxy Citations Teach US? Profitability through Simplicity, February 4, 2014

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