All opinions are my own.

Monday, August 1, 2011

Pharmaceutical Quality: Is it a Company or Regulatory Responsibility?

A recent report (1) by a committee of Board of Directors essentially gives Johnson & Johnson a clean bill of health for the following incidents at McNeil OTC. I have not reviewed other issues discussed in the report.

·       Motrin dissolution
·       B. Cepacia issue
·       Musty odor
·       “Super potent” Tylenol

Fortunately no one died but what makes the report interesting is how it lays the partial blame on FDA for some of its guidelines, exonerates J&J from its quality lapses on self-induced manpower shortages and does not discuss company’s inaptitude which is obvious to anyone who is experienced with manufacturing operations.

Whatever the reasons of the problems, problems were created at the company and not by the regulatory agencies. Johnson & Johnson is globally known for quality. It seems attaining profits and bonus targets took precedence over product quality.

My conjecture is that for the Motrin and Cepacia problems are raw material issues. If J&J's suppliers did not supply material to spec or supplied contaminated materials they should be held accountable and responsible. Other question that could be asked to J&J is that were proper raw material specifications in place.

Strangely the “musty odor” is still around J&J and I wonder who is being held accountable for it. May be “Mr. Product Recall” should be called to the rescue or whitewash.

Since details of dissolution issue are not elaborated, one can conjecture that the dissolution problems happened due to material that was used, was different from the specified material. Thorough analysis of off-spec material would have identified the problem and it should have been part of the report. Why this is omitted is an interesting question?

Cepacia problem occurred due to contaminated raw material from the supplier. This suggests that either the specifications were not tight or some error happened. It should have been caught at the supplier’s lab or J&J lab during quality check before the product got used. FDA guidelines suggest that the companies check their incoming raw materials. I guess the company did not follow the regulatory guidelines.

Production of “super potent” Tylenol is not only a failure of “good manufacturing practices (poor scale-up)” but also a failure of “good accounting/business practices” especially as it happened over a period of time. During the five-month period J&J produced 10 batches. Error of overcharge (between 11-24% over specifications) should have been caught as soon as they happened through material and cost variances, a standard practice of inventory and cost management controls. Since they were not caught immediately is suggestive of McNeil had issues with their operation and management systems. Since it took about five months, if it is true, to find out over charges it is suggestive that the whole Tylenol profit center needs a thorough scrutiny. It makes one wonder how many other things are being hid under the carpet?

The following excerpt from the report needlessly points J&J’s problems to FDA regulations. It should not have been included as it basically suggests that US FDA’s cGMP guidelines are vague. It is like making FDA partially responsible for whatever happened at J&J. Similar implication could be extended to other global regulatory bodies.

US FDA or any other regulatory body should not be blamed for J&J’s inaptitude. These regulatory bodies are not in the business of designing processes and methods for companies’ products and processes. It is the responsibility of the companies to ensure they have processes and methods that deliver quality products based on good science and engineering principles.

The FDA is responsible for enforcement of the FD&C Act, and has promulgated regulations that require drug product manufacturers to employ “systems that assure proper design, monitoring, and control of manufacturing processes and facilities.” The FDA’s cGMP regulations are intended to “assure the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. This includes strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories.” The FDA does not differentiate between the manufacture of OTC medications and prescription medications, treating both as drugs subject to the same cGMP requirements.

The FD&C Act and the FDA regulations are sparse on the specifics of what constitutes cGMP. The FD&C Act states only that manufacturers of drug products must employ cGMP. The FDA’s implementing regulations, in turn, are only marginally more specific -- requiring, for example, that laboratory facilities be “adequate,” that manufacturing facilities be “of suitable size, construction and location,” and that certain equipment be used “when appropriate.” The FDA asserts that this level of generality provides a flexible approach “to allow each manufacturer to decide individually how to best implement the necessary controls . . . .”

Report citing “sparse on specifics” is really questioning the intelligence of every chemist and chemical engineer. Experienced chemists and chemical engineers while working at regulatory bodies have suggested cGMP guidelines that will allow the processes to produce quality products. Process developers at companies have to understand the intent of the regulations and develop and commercialize processes that will deliver quality product. If the feedback to the report writers is that the regulations are vague even then it is the responsibility of the company to use processes that produce quality products.

Regulatory bodies are not in the business of suggesting how each process should be designed and operated. It is the responsibility of the personnel at each company to ensure that the produced drugs meet established quality standards. If the members of Board of Directors of a company are suggesting that the regulatory bodies should design and specify equipment, operations and methods then the report writers do not understand the intent of CFR 21 Parts 210 & 211. Is it not the responsibility of the every company (public, private or government held) to ensure that their products are safe for their customers?

In this report J&J’s independent board members (many question their independence) are suggesting that lack of manpower caused the problem. It is management’s responsibility to make sure that they are staffed properly and the company delivers quality products to its customers. If the management is not responsible then the Board of Directors should be held responsible and accountable for company's actions or they should make sure that the right people are managing the company. Reoccurrence of odor issue is suggestive of that company has not learnt from past experiences.   

Lately reoccurring drug quality problems have become part of our life. This is because companies are using the least technologically advanced and economic manufacturing methods to produce their products. Having fancy equipment does not guarantee quality product.

To ensure product quality pharmaceutical companies are relying on repeated quality by analysis (QbA) using technologically advanced analytical methods. Even with such technological sophistication they have had issues that have resulted in product recalls. We are all familiar with Baxter’s Heparin issue. Chinese raw material suppliers had adulterated their product with an inert.

Not understanding and/or having the right process should be a cause of concern. Analytical methods will only tell the after the fact problem. These instruments do not fix problems. Unless companies have command on their process and its raw materials the problems will persist. Regulatory bodies should not be blamed.

When the reason of quality problem is being passed on or an excuse is given and no one gets prosecuted, it might be time to change the laws. Tiered heavy fines could be levied. These fines could be at different points of the distribution chain with the heaviest being if the product gets to the pharmacy shelf. Penalties could include monetary fines along with prosecution of progressive levels of management.

The report mentions lack of attention by certain non-quality control workers such as  “engineering and operations”. With such implication one would expect detailed investigation. Why did the board not explore this area and detail this lack of attention. It is fascinating that the word “engineering” has been mentioned only ONCE in the whole report but they are blamed. If it was operations that did not pay attention, it is suggestive that proper procedures were not put in place by the company management.

All of the above suggests that J&J has significant opportunities with their total business systems. Above issues may be just the tip of the iceberg. J&J is relying on post analysis (QbA) methods to produce quality products. A complete audit of their manufacturing processes and methods will unearth many issues that can save J&J significant monies. QbD (Quality by Design) methods could be implemented in many cases thereby assuring high quality and improving profitability. This is necessary and should be done if J&J wants to prevent future embarrassment.

I wonder how James Collins would feel today about J&J if he had to re-write his “Good to Great” book. Would J&J be part of the book?

Girish Malhotra, PE 
EPCOT International

(1) http://freepdfhosting.com/bc85fe20b1.pdf

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