Data Talk—Opinions Walk: Justification vs. Rationalization

I was a judge for a junior high school science fair where young minds applied the scientific method to everything from bean sprouts to producing amino acids from primordial ooze. It was great to see creative minds at work as each explained their hypothesis, methods of observation, data collection and conclusions.

Of course, I took the opportunity to explain to each how their scientific skills would be of tremendous importance in helping sick people get better in the exciting industry of pharmaceutical manufacturing. Yeah—it was a real “sales job,” but I could not have been more serious.

So—what has happened to some people in our industry since they were in the eighth grade?

We work in a science-based industry. Sometimes you have to look hard to find a scientist in the day-to-day operational world of pharmaceutical manufacturing, particularly in the corner office.

Perhaps this explains the difficulty we often face when manufacturing problems occur that could potentially affect a batch of product. Rather than the response being: “Glad you caught that. Now, let’s gather all the data as quickly as possible to investigate the possible product impact,”—it’s “Dang! How in the world are we going to position this one?”

It is particularly disheartening when the role of QA deteriorates from data-driven decisions that provide scientific (and legal) justification, to unsubstantiated opinions. The former is science; the latter is creative writing. All too often QA is put into the creative writing business. The effect of a weakened role of QA has been noted recently in Warning Letters. (See The QA Pharm, 9/25/10.)

CGMPs use the term “justify,” not “rationalize” for a reason. So, let’s review the important difference between them:

Justify v. 1. To demonstrate or prove to be just, right, or valid. 2. To declare free of blame; absolve. 3. Law. To prove to be qualified.

Rationalize v. 1. To make rational. 2. To interpret from a rational standpoint. 3. To devise self-satisfying but incorrect reasons for (one’s behavior).

Your assignment, Class:

1.    What is the quintessential difference between “justification” and “rationalization?”

2.    Locate in the GMPs where the word, or some form of the word “justify” appears. What is the context, and why is justification important?

3.    From a patient’s perspective, which would you expect to be the modus operandi in the pharmaceutical industry: rationalization, or justification?

Remember: Without data—it’s just another opinion.

The QA Pharm

Contract Manufacturing Operations and You--the "You" Part

There's a saying that goes: “If it's left up to two people to water the horse, the horse will go thirsty.” So when it comes to the shared responsibilities between the sponsor and their contract manufacturer, it's important to ensure that the product does not die of thirst.

The growing trend toward outsourcing has not been lost on Rick Friedman, Director FDA Division of Manufacturing & Product Quality. From all indications, it is one of his inspection priorities to ensure the sponsor is carrying the water bucket.

He emphasized at the 2010 PDA/FDA meeting mid-September in Washington, DC, that sponsors should expect to hear questions during inspections about how their companies are making sure that their CMOs are actually being monitored.

There are tools at the sponsor’s disposal to help ensure that both parties are going into the relationship with their eyes open and to establish expectations. These include:

·       Due diligence audits to identify potential risks up front

·       Quality Agreements to establish who does what and whose procedures and standards apply

·       Supply Agreements to establish the business requirements and financial terms

However, after the dance is done and the CMO is integrated into the supply chain, remember “they” are “you,” and “you” are ultimately responsible for product quality.

This was made clear in the “lecture” portion of the Warning Letter to River's Edge Pharmaceuticals¹:

Although you have agreements with other firms that may delineate specific responsibilities to each party (e.g., quality control responsibilities), you are ultimately responsible for the quality of your products. Regardless of who manufactures your products or the agreements in place, you are required to ensure that these products meet predefined specifications prior to distribution and are manufactured in accordance with the Act and its implementing regulations, including CGMP regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Part 211.

So, in addition to the tools that initiate the relationship, there are also tools to ensure the sponsor exercises ultimate responsibility for product quality—and these must not be delegated:

·       Auditing (GMP) the contract manufacturing facility

·       Trending of product quality data and quality system performance

·       Approving changes that potentially affect the validated process and product

·       Approving batch rework, reprocessing, culling/inspection

·       Observing your product being manufactured

·       Deciding the final batch disposition (accept or reject)

Taking ultimate responsibility makes sense. After all, CMOs have their own problems. Their problems become incremental problems to you.

Take the most recent example of Contract Pharmacal Corporation², a full-service contract manufacture.

This firm received a Warning Letter on October 14 that ran the gamut and also cited repeated violations from previous inspections. FDA recommended that they engage a third party consultant having appropriate CGMP experience to assess their facility, procedures, and systems on a routine basis to ensure their drug products have their appropriate identity, strength, quality, and purity. (See The QA Pharm 9/25/10, When FDA Recommends a Consultant—Implications for the Pharma QCU.)

So be involved and develop not only a legal relationship, but also an active partnership that works well together all the way down to the shop floor.

But can there ever be “too involved, or too controlling?”  That depends.

The worst case I ever saw was the outright bullying of a CMO by a big name, global pharma company—because they could. The CMO that was hungry for business took their regular beating—because they had to.

So, to the sponsor who likes to throw his weight around, I say—Be careful what you ask for, you might get it. Demanding unreasonable launch dates; constantly making last minute schedule changes; and insisting that it be your exact SOPs adopted as their quality system infuse volatility throughout the CMO. For this you get happy smiles and unwanted variation in the form of half-baked processes, last-minute training of the operators, and complexity due to “one more difference” in the way something has to be done at the CMO.

To the CMO, I say—Be careful what you promise. You may get the business, but are you truly engineered for the sponsor’s products? Does the sponsor expect shortcuts? Are you staffed to deal with the inefficiencies as a result of mercurial sponsors that make demands much better than they can forecast and plan?

Ether way, you are in it together—but the sponsor is the “Responsible You.”

¹ River's Edge Pharmaceuticals, LLC, Warning Letter 10-ATL-05, May 20, 2010.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm220315.htm.

² Contract Pharmacal Corporation, Warning Letter 10-ATL-15, October 14, 2010.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm229354.htm.

The QA Pharm

When All Else Fails, Lower Your Standards

My definition of “specification” is rather simple: it’s a promise.

Just like any other promise—you’d better be sincere when you make it and able to keep it. Failure to keep a promise brings disappointment. Frequent failure leads to distrust. And consciously breaking a promise is nothing less than deceitful.

Just as in our personal lives, the pharma industry makes a promise to its healthcare professionals and patients every time it establishes a product specification.

Whether it is a raw material or component from a supplier, in-process material, or final product, a specification is your promise to provide a product that possesses the attributes known to make it work.

Anything outside of the specification range is either unknown because it has not been studied, or known to have some probability of a negative effect. Neither is acceptable.

The same could be said for process control ranges. Although they are applied to the manufacturing process and facilities, they nonetheless are “promises” based on a scientific field of study with respect to product quality.

Thus it seems to be particularly egregious when specifications and process controls are capriciously established or changed.

Take for example River’s Edge. The Warning Letter¹ stated that Lidocaine HCL 3%/ Hydrocortisone 0.5% lots were released and distributed even though they failed the initial release and stability viscosity testing at 3, 6 and 9-month time points. The firm responded by revising the specification range.

Additionally, after failing to investigate over 30 complaints of discoloration of Hydroquinone 4% Cream, River’s Edge responded that it would address the issue by revising the labeling to describe the cream as “tan to slight brown on storage.”

Another example is Gilead. The Warning Letter² stated that their aseptic processing room was not adequately constructed to meet design specifications. The room, in which partially-opened sterile drug is transported, failed to meet ISO design criteria.  The firm responded by reclassifying the room to a lower standard.

FDA was not amused in either case.

Quality Assurance is responsible for being the guardian of specifications and making sure that systems are in place and followed for developing and changing specifications.

It is a system based on statistical analysis of experimental studies, which is part of the process and product knowledge base. You know—the institutional knowledge of the scientific and technical aspects of what you make, how to make it and why your specifications are what they are.

I am aware of some shoddy specification-setting practices, like—taking the highest and lowest values on record, plus or minus your shoe size—just to file the NDA quickly to beat the competition.

But this always causes problems. Manufacturing processes are not efficient and varied product attribute results are obtained. It all adds to a high nonconformance rate and adds cost to the operation.

So a specification is not only a promise, but established properly you get something in return. It’s the “sweet spot” for economical operations.

¹ River's Edge Pharmaceuticals, LLC, Warning Letter 10-ATL-05, May 20, 2010. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm220315.htm

² Gilead Sciences
, Warning Letter 44-10, September 21, 2010. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm227649.htm

The QA Pharm

"We have reviewed your firm's FDA483 response, however..."

I remember a class exercise in "Quality School" in which you counted the number of F’s in a paragraph. Remember? The one where you got a different number with each try? The point was to illustrate: one hundred percent inspection does not detect defects one hundred percent of the time.

That exercise came to mind again when I tried counting how many times some form of the word "inadequate" appeared in the recent Gilead Warning Letter¹. I think it was eighteen times. But—I’m not absolutely sure.

Most likely eighteen is not the record, but the point is not lost on the reader: the Gilead response to their FDA483 was—shall we say—inadequate. This prompted the Warning Letter.

FDA told the company dominating the HIV treatment market that their response was inadequate because:

           

·       Your rationale was incomplete

·       You do not have justification

·       You provide no timeframe

·       You provide no details

·       You did not specify how you intend to document

·       You did not provide the scientific rationale

·       You did not describe how you will evaluate

We should have a pretty good idea of how to respond to FDA483's by now, since the FDA has been publicly pointing out inadequate responses to FDA483s in Warning Letters on their website since 1996.

More specifically, Anita Richardson, Associate Director for Policy, Office of Compliance and Biologics Quality, has given suggestions for writing an effective response.²

It's like being given the answers in the back of the book, except it's not just for the odd-numbered problems.

So take notes, class. Ms. Richardson says:

1.    Include a commitment/ statement from your senior leadership

2.    Address each observation separately

3.    Note whether you agree or disagree with the observation

4.    Provide corrective action accomplished and/or planned. Tell the FDA the plan.

a.     Be specific (e.g., observation-by-observation)

b.    Be complete

c.     Be realistic

d.    Be able to deliver what you promise

e.     Address affected products

5.    Provide timeframes for correction

6.    Provide method of verification and/or monitoring for corrections

7.    Consider submitting documentation of corrections where reasonable and feasible

8.    BE TIMELY (Ms. Richardson’s emphasis.)

Unfortunately, by the time an FDA483 response filters through layers of management and the legal department, some industry responses read as though the following principles had been applied:

1.    Have the communications department write a sincere cover letter for the president to sign.

2.    Never agree with the observation, as this will be interpreted as admitting guilt.

3.    Respond as generally as possible to allow maximum flexibility.

4.    Don’t look anywhere else other than the specific problem cited in order to limit our liability.

5.    Don't give lot numbers of potentially affected product, since this will provide the seizure list to FDA.

6.    Don’t put anything in writing because documents are legally discoverable.

7.    Don't provide additional documents, as this gives the FDA more material to find objections.

Ms. Richardson’s advice is excellent, and my parody—although used at some firms—just calls fire on your position.

In summary, count the F’s:

For faring fine in the future with our federal friends, firms must faithfully follow forthright fundamentals. Felonious firms finesse and finagle forgetting that forthwith our federal friends will find and fine them.

¹ Gilead Warning Letter, San Dimas, CA, September 21, 2010

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm227649.htm

² Richardson, Anita, Writing an Effective 483 Response

http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM102921.pdf

The QA Pharm

http://theqapharm.blogspot.com

Root Cause Analysis: the 5 "Who's" Behind the 5 "Why's"

I think it is time to add the "Five Who's" to the "Five Why's" in the Quality Tool Box. The “Five Why’s” is a common technique used to derive the root cause for a problem. The idea is if one keeps asking "why" enough times—like a persistent child—the layers will peel off and the true reason will surface.

But sometimes the reason for a “why” is a “who.” For example:

“Inadequate training” really means: "Joan said he likes they way he does it better."

“Equipment failed” really means: "Ted did not want to shut down for preventive maintenance."

“Inadequate mixing” really means: "Fred said that mixing studies were not necessary."

“Leaking tanks” really means: "Jane didn’t want to spend the money to replace them."

Some say that the problem is always with the system, never a person. I doubt that, unless we run our businesses with robots. Even then, someone had to program them. Decisions don’t make themselves. And as long as fear reigns supreme in a punitive organizational culture, getting at “who”—and true root causes—for learning and accountability purposes will be elusive.

This is one reason the BP investigation into the Deepwater Horizon rig explosion was less than satisfying to Najmedin Meshkati, a professor at the Viterbi School of Engineering at the University of Southern California.

He said of BP's nearly 200-page internal accident report, "How could you call this great work accident investigation...(without) addressing human performance issues and organization issues, and decision-making issues?"¹

As far as the FDA is concerned, the question of personal accountability has already been asked and answered by the U.S. Supreme Court. (See The QA Pharm 9/11/10).

It is interesting to watch hearings in Congress--or Whoville--over pharma failures lately. There is more interest in who was in charge and who made the decision than operatives who were in the room at the time of the incident.

To quote Dr. Seuss: Today you are you, that is truer than true. There is no one alive who is youer than you.

It's time to be honest, direct, and create a supportive and learning culture, if we are ever to really excel and compete.

¹ Associated Press, 9/29/10, Engineering Expert Takes Issue with BP’s Oil Spill Report, submitted by Jessica Durando.

John Snyder
The QA Pharm

http://theqapharm.blogspot.com