Every so often topic of Quality in pharmaceuticals rears its “ugly” head in conversation or print. It should not as products are for human use. There is conversation about quality culture and its existence. It is known that pharma’s quality levels are much lower than Six Sigma (1). Lack of pharma achieving six sigma for active pharmaceutical ingredient (API) and their formulators has been discussed for quite some time (2). Repeated discussion of less than quality products and out of specification excursions is manifestation of shortcomings of company’s process development, commercialization, manufacturing and resulting record keeping practices. Perspective presented is my own and not influenced by and profit making company or regulatory body.
There could be a simple explanation for pharma company’s quality level being stuck around 2-3 sigma. My conjecture that it is a case of seventy plus year old tradition and speed to market where every “t” is not crossed and every “i” in not dotted or lack of understanding of chemistry or chemical engineering practices and their application to produce quality products from the onset. Since in English alphabets “P” comes before “Q”, it seems that the companies are getting stuck at “P” = profit and not going to “Q” = quality. Once “P” is achieved there could be laxity in achieving “Q”. It could also be a case of every expense to achieve “Q” is paid for by the patient through higher prices.
We all know that competitive market leads to quality perfection. If we look at the Brand and Generic pharma, brand drugs during their patent life have no competition. These companies cannot afford to offer less due to public relation they cannot have less than quality product. They have to maintain an image. Their sell prices are high as patient also pays for quality so why worry.
Generic drugs are a different story. Multiple companies have their ANDA (abbreviated new drug application) approved. Some become the supplier to the developed countries. FDA approved drugs are placed on formulary lists. My conjecture is that “formulary lists” are an artificial barrier established by the Pharmacy Benefit Managers (PBMs) and associates along with US legislators to ration drugs to patients and maximize their profits through mutually subsidized healthcare systems.
Placement of a drugs on formulary list are most likely being used by the intermediaries to maximize their rebates, i.e. profits. Manufacturing companies may be cutting corners if they have not perfected their process from the onset and rely on “quality by analysis (3) (aggravation)” process.
All of the quality issues that keep popping their ugly head can be solved but will require a landscape change. There are too many players with vested interests and they would not let the change which is of benefit to US population happen. Pharma distribution landscape will have to change. Three distinct routes are reviewed.
If the current healthcare system is going to stay, steps stiffer than the current 483 issuances and correction have to be incorporated. PBMs and allies who acquire drugs from the manufacturers and distribute them should also be held accountable and responsible for any product that does not meet FDA approved and company agreed specifications.
Route TWO: Direct drug sales to customers: This route is being used across every sale item and supply chain members are held accountable except for in pharmaceuticals. These methods assure product quality and manufacturing technology innovation. It is time this route be considered for pharmaceuticals in parallel to the current method used by PBMs and their allies involved in distribution and sale of drugs. Direct sales to consumers i.e., competition will assure quality and lower prices.
Either of the proposed route if promulgated will change the drug distribution and sales in USA. However, there will be resistance from Legislators, USFDA, Pharmaceutical Research and Manufacturers of America (PhMRA), PBMs, their allies and anybody and everybody who can intervene.
Pharma companies for their manufacturing practices are stuck in practices from inception of drug manufacturing (5,6) and attempt to use better methods have been stifled by the companies due to speed to market and US FDA’s current approval processes. FDA needs to improve its approval practices. It talks about industry improving its practices but if FDA’s approval processes were labeled as a manufacturing process, FDA will completely fail. It’s practices are QbA (quality by analysis) vs. QbD (quality by design) and are an impediment to pharma manufacturing coming back to USA.
It is time USA adopts policies so that its population is not held hostage for lack drug supplies and shortages. Issues and remediation methods have been discussed over the years. They are:
1. Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity March 16, 2020
2. Long Term Drug Quality Supplies for US, FDA and A New Reality, Profitability through Simplicity April 3, 2020
3. Health and National Security Issues for the USA and Is The United States of America Prepared, Profitability through Simplicity May 8, 2020
4. Euphoria to Bring Pharma Manufacturing Home to United States its Reality and Challenges, Profitability through Simplicity May 23, 2020
5. Bring Pharmaceutical Manufacturing Back to USA: Additional Thoughts and Recap, Profitability through Simplicity May 29, 2020
6. US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions, Profitability through Simplicity March 31, 2022
7. Has US lost its Business Acumen, Creativity and Imagination for its Healthcare Needs? Profitability through Simplicity June 6, 2022
Route Three: Issues of product quality could easily and very quickly disappear if the process developers and designers operate the manufacturing processes in the plants they have commercialized for a designated time. This will get everyone firsthand information of the deficiencies of their commercialized processes. They will correct all of the issues and produce quality products first time and all the time. This proposal is bold and works as I have lived it. This route also protects intellectual property.
Combination of the above routes should be considered. Inclusion of bringing pharmaceutical manufacturing back to USA and eliminate the pervasive drug quality and shortages are the PRIME objectives. It is time US take bold and necessary steps to curtail drug quality discussion and at the same time bring manufacturing home. Quality should be expected and not discussed.
Girish Malhotra, PE
1. What is Six Sigma https://asq.org/quality-resources/six-sigma Accessed March 31, 2023
2. Shanley, Agnes: Will the Pharmaceutical Industry Ever Get to Six Sigma? Pharmtech.com July 12, 2017 Accessed March 31, 2023
3. Malhotra, Girish: “Quality by Analysis” cannot compete against “Quality by Design” Profitability through Simplicity March 15, 2008 Accessed April 10, 2023
4. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability (4) was proposed in December 2019. Profitability through Simplicity , December 6, 2019
5. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
6. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022