Pharmaceutical Quality: Concepts, Misconceptions, Realities and Remedies

By Girish Malhotra, President of EPCOT International

Pharmaceutical companies have a moral and ethical obligation to ensure that their products meet regulatory standards and are

Pharmaceutical companies have a moral and ethical obligation to ensure that their products meet regulatory standards and are therefore fit for human consumption. But in reality, the quality of any given pharmaceutical often shows too great a variation, which ultimately puts patients at risk. In this article, Girish Malhotra, President of EPCOT International, explores how API quality can be greatly improved by the adoption of continuous manufacturing and how regulatory bodies can ensure high product quality with stronger punishments for non-compliant players.

Pharmaceutical quality, especially for generic drugs, has been and is going through its cyclical ups and downs. Discussion heats up and then goes dormant until the next major quality issue appears. One would expect that every pharma manufacturer (API and their formulator) would be on their toes and prevent regulators from issuing 483 or equivalent citations and prevent news reporters from writing about out-of-compliance issues. Unfortunately, oversights at companies keep occurring and the press is forced to report this.
For most of us, product quality reflects a company’s integrity, intelligence, knowledge and ability to manufacture products that are the best in their class. The irony is that the cost incurred to achieve first-time quality is very low or nothing if done right the first time. Properly designed and executed manufacturing processes are supposed to deliver quality products. Recurrence of quality issues (deviation from established specifications, lack of data integrity and cGMP practices), especially in pharm,a have a common theme. They are a reflection of a shortfall in the company’s integrity, management, knowledge and manufacturing practices. Every oversight can result in an issue.
It is critical that we understand pharma’s manufacturing landscape as it affects product quality. Every company knows what is needed, but the ultimate question is ‘do they produce repeat quality product that meets established specs using cGMP practices?’
Financial model
Companies have to follow a criterion that gives them acceptable financial return. This also applies to pharma’s older cousin, fine/speciality chemicals. However, pharma’s profitability criterion, in my conjecture, is based on how to maximize profits irrespective of the processes used. I believe that their criterion of maximizing revenue and profits is based on exploiting the emotional need of humans to extend life. Lack of affordable drugs for mass populations have resulted in companies increasing revenue and profits through year-on-year price increases and pharma has not explored increased profitability through continued process improvements. My conjecture is that the regulators are the obstacle in this process.
Again, pharma’s profit model is based on a tradition of capitalizing on a financial opportunity rather than based on manufacturing excellence. Current practice may have been derived from initial limited drug availability and a dire need for the branded drug. Once a drug is widely sold, companies’ tradition of using multiple manufacturing sites (inefficient processes), similar to the time when the drug had limited distribution, has been continued. It seems the value of alternative or efficient processes has not been explored. As explained below, too many API producers and formulators could also be part of current quality variations and problems.
Batch vs continuous process
Improved quality is being touted as one of the benefits of using continuous processes rather than batch. This is true if there is such a process for the manufacture of APIs and their formulations which would produce the same product for about 7,500 hours per year. However, volume is needed to have a steady run from the same equipment. If the process is stop and go, it is no different from any batch process. In addition, significant understanding of the chemistry involved, component interaction and execution control is needed. This can present formidable and different challenges for manufacturing APIs and their formulations. If all were easy, then continuous manufacturing, especially for formulations, would have been adopted in pharma manufacturing 60+ years ago.
Drug dose and product demand determine API and formulation needs. Table 1 illustrates API and tablets needed to satisfy the needs of 50 million patients per year. If principles of economics and chemical engineering were applied, the most likely needed API (dose 1 milligram) could be produced in a single plant. Formulation of this API could also be done at a single plant requiring multiple parallel formulation lines operating year-round. For a 50 milligram dose, a single plant using a continuous process would be sufficient to meet the global API need. However, in reality multiple plants are used to produce the API and their formulations. This is an extremely important point, as quality from each (API and their formulations) facility can vary even if every plant were an exact replica of each of the others. This is due to a myriad of factors (people, raw materials, equipment and even execution).
Table 1. Theoretical API and formulation needs.
Number of days per year
API, kilo per year
Tablets per year
Table 2 is an illustration of the  reality for some of widely used drugs. Process economics should dictate process selection but that is not the reality and the fundamentals of engineering and economics are not applied in manufacturing process selection. It is interesting to note that Pfizer produced 200 tons of Atorvastatin API at three sites but now it is being produced at 44 sites and is being formulated at over 800 sites (by different companies). Every product will not be exactly the same. We can all draw our own conclusions about batch-to-batch and site-to-site quality variations. Another interesting fact we have to recognize is that the FDA or any other regulatory body does not have adequate manpower to do even risk-based inspections just for these six drugs.
Table 2. Number of sites for APIs and formulations.
Number of API sites
Number of FDF sites
Atorvastatin calcium
Metformin HCl
Given the current profits landscape, many companies will enter the market to fill its needs. As stated earlier, to assure profits, it is very likely that shortcuts will be taken and quality could be compromised. Pharma companies have not explored increased profitability through continued process improvements and my conjecture is that the developed country regulations are the obstacle in this process. Too many filings are needed to comply with current regulations and companies may not have the time to improve processes. Thus, continuous process improvement effort is minimal at best.
A possible solution
Ethical practices, integrity and quality products are expected from companies. Every company that produces health-related products, including drugs, has to make sure that their products meet established quality specifications and follow cGMP practices. Companies know very well that non-compliance with FDA regulations will have negative consequences besides bad publicity. They will have to spend monies for remediation. Doing things right the first time has minimal financial costs but somehow they miss this important fact.
Under the current regulations, manufacturing companies are given an opportunity to correct their non-compliance but companies could be abusing this privilege. Repeat-offence companies are still in business. The pharma lobby’s behaviour, siding with less-than-quality manufacturers, should be considered shameful and unethical.
The FDA needs to change the rules of the game but it seems that the FDA/regulators are afraid of the ensuing shortages that could result. Repeated non-compliance with the FDA’s requirements and guidelines should be a reason to forbid shipments to the US. It is my conjecture that API manufacturers and their formulators in China and India have taken advantage of lack of sufficient producers in the developed countries and some might have a ‘take it or leave it’ posture. Developed country regulators have to take a tougher stance.
A combination of polite and drastic pathways needs to be used by the regulators to convince manufacturers to abide by the current regulations and quality standards. Companies could be given single-site exemption with the stipulation that they deposit $200,000 (refundable) after the first deviation from FDA’s expectations. A second offence on the same site should be the cause for forfeiture of the deposit and the company should be barred from exporting their product(s) to the US.
The FDA has taken bold and drastic steps to withdraw ANDA approvals in the past but this has not been publicized much. Recently, the FDA withdrew ANDA approvals for Apotex, essentially stopping its export to the US. The FDA should withdraw ANDAs from companies if they have not produced the product at the declared site for more than one year. They have no clue whether approved ANDAs are being produced. Basically, the FDA has had a big stick it has not used properly. Maybe it is time to use it as often as possible. There could be some shortages, but they could become an opportunity for others.
Going forward
The pharma landscape needs to be reviewed and changed to assure quality drugs from the get go. I believe regulators themselves are reluctant to adopt ‘continuous improvement’ (which they expect companies to practice) in their own operations. They need to practice what they preach. FDA, instead of preaching QbD (quality by design), needs to practice it. It relies on QbA, (quality by analysis).
The current ANDA filing process is complex, as most of the application involves multiple reviews and submissions, taking as much as three years. FDA’s ANDA approval process should be such that any application filed by its own personnel should be approved by a fellow reviewer on the first review in 90 days. If it can’t, this suggests that the ANDA filing and approval process needs to be simplified and perfected. Complexity of the current process is confirmed by the recent Government Accountability Office (GAO) Report. Since certain drugs are given an expedited approval, it suggests that a 90-day approval is possible, if the effort is made.
ANDA applications that can be reviewed and approved in 90 days will demand that companies filing such applications have a complete command of every facet of the manufacturing process, product quality, labeling and whatever else is needed by USFDA. Many will say ‘this cannot be accomplished’. Such conjecture is unfathomable from successors of a generation that can send a human to the moon and bring him back.
Approval of a product and its manufacturing process is equivalent to a binding contract between two parties (manufacturing company and the FDA). If a company does not live up to its contract, the FDA should exercise its power to withdraw ANDAs. The FDA has a stealth weapon, withdrawing approved ANDAs, but has been reluctant to use it. Recently, it has used it and has publicized this. It is an indication of ‘wall handwriting’ to the companies to get their act together if they want to be player in developed-country markets. No one, including the legislators, should be surprised that ANDA withdrawal could become frequent practice in order to stop less-than-quality drugs being offered to large populations. The EMA and other regulators have similar options. ANDA withdrawals could lead to temporary shortages but could also be an opportunity.
The possibility of companies losing their profitable markets will force them to stay on top of product quality through economies of scale and better manufacturing technologies. If they succeed, their revenues and profits will improve. In the light of regulators withdrawing ANDAs or potentially imposing fines for repeat violations, companies have to look again at their operations and technologies. Some might have to consider whether it pays them to be in the business.
Companies have choices to make but supplying drugs that do not meet established quality and regulatory standards should not be the choice.