So…you’re the new QA person?

New heads of Quality Assurance come into pharma companies all the time for various reasons. If you are the new head of quality, hopefully you were able to get some sense for the reasons for the vacancy during the interview process. I recognize that this is not always easy in an interview situation.

I have heard such explanations as: we’re looking for a fresh approach; we’re looking for someone with more of a business perspective; we’re looking for a partnership with QA; we’re looking for an operations-oriented QA; or we’re looking for a more progressive QA.

Actually, these all sound very positive and a highly desirable situation for a new, enlightened head of QA looking for a challenge. But like the Rorschach test, these explanations could be interpreted various ways, some of which would be troublesome for the newbie who understands the regulatory role of QA.

Rarely is the expectation as clear as one example in my own career when a company president that interviewed me spoke very directly and took out all the guesswork.

The interview lasted three minutes—because I ended it. The president of the company said, “If you reject my product, blood will be let.” After a moment of nervous laughter I understood him to be quite serious, and that he was talking about my blood. I responded by plucking my resume out of his hand, tucking it back into my briefcase, and responding, “Would you please ask your admin to call me a cab?”

But there is no more popular reason for changing of the guard than being the incumbent on whose watch the company received a Warning Letter. The termination of the QA person is served up as a peace offering and symbol of turning over a new leaf.

The problem with turning over a new leaf is that sometimes it looks the same on both sides. The new QA head has the same struggles as the former head of QA, because the issue was not one of understanding and applying CGMPs, but facing a pervasive company culture of antagonism toward FDA regulations.

The FDA recognizes the possibility of antagonism when we read in recent Warning Letters: “QA was either unable, or not permitted to exercise its responsibility.” (See The QA Pharm 9/25/10.) However, neither is an excuse, because you had the option to resign.

As the new head of QA, you want to make a positive impression as a leader who can be trusted; who is a collaborator; who is a builder; and who makes mindful decisions. So here are some suggestions on what should you do before the honeymoon period is over.

1.    Know for yourself the state of compliance.

Gather your own intelligence on the effectiveness of the Quality Management System QMS) and the general state of regulatory compliance. This should include CGMP compliance as well as compliance to the Chemistry and Manufacturing Controls (CMC) of your drug application. Don’t rely on hearsay, or solely on the results of previous inspections.

2.    Establish a governance process.

Determine the appropriate performance metrics for each element of the quality system that reports both how well the system is working, as well as what the system is detecting. Report these in a decision-oriented forum of your peers. Solve the problems at a lower level, if possible. However, ensure that each problem rises to the appropriate level and person who has the approval authority for the cost of the solution. Be sure you have allies in the room. Document the decisions, even if the decision is to do nothing, or to postpone action.

3.    Build relationships with other functional heads.

Build trust with your peers. Work together to identify and resolve problems. Give credit to other areas when they identify problems and come forward to resolve them. Don’t blindside a peer in a public governance process. Offer to resolve problems that other areas have with inefficient quality system processes.

4.    Integrate the quality/ compliance plan into the business planning process.

Develop a quality planning process based on the problems and risks identified from the management review (governance) processes. Integrate the quality plan with the normal business planning process.

5.    Speak the universal language of money.

Resolving waste streams, rejections, and nonconformance, etc. all have associated cost. Resolving these issues not only save money, but improves quality and CGMP compliance. Never allow cost to enter your judgment when making a market release decision; however, keep focus on problems that improve the bottom line, and get the compliance for free.

6.    Use the fine art of writing proposals.

Write proposals to improve the way of working, to implement a new program, or to make a capital expenditure. Putting proposals in writing helps you to make the case to support. Be sure to capture the return on investment, cost avoidance, or risk mitigation. Shop your proposal to other functional heads, and allow them to sign on to the proposal to signify support.

7.    Strengthen the Quality function.

Make time to visit each functional head during the first month of your tenure to ask: What does the quality function need to do more of? What does the quality function need to do less of? Be willing to accept the feedback. Loop back with each one to let them know your assessment of the situation and the action you are taking.

I invite you to share your thoughts and experiences that would benefit our readers, especially the person walking into a new QA leadership position.

The QA Pharm

Who Owns the Quality System: Everybody, Somebody or Nobody?

I understand on a philosophical level that everyone owns “quality.” Much like safety, everyone has responsibility for following safe practices and calling attention to potentially unsafe conditions. However, there also is a Safety Department that is responsible for establishing safety policies and procedures, as well as conducting periodic safety inspections. They also report the safety metrics such as “OSHA Reportable” incidents and near misses. Members of the Safety Department keep current with the latest safety equipment, changes in the regulations, and benchmark against best industry practice. Management takes these reports and metrics quite seriously, because it is ultimately responsible for ensuring a safe work environment.

This is fairly analogous to the Quality Management System (QMS). Everyone has personal responsibility for following CGMPs in general and procedures in particular. The Quality Assurance Department is responsible for establishing and measuring the effectiveness of the QMS. They periodically conduct internal audits and report quality system performance metrics. The findings are reported to management, because they are ultimately responsible for ensuring that products are manufactured in a state of control and in accordance with CGMP regulations.

But allow me to break away from generalities and get very specific, because it is in the specifics where I believe the QMS falls apart in practice. It has to do with the notion of “ownership” and having a person—by name—for each element of the QMS who “owns” that particular element and exhibits defined “ownership behavior.”

In my opinion, creating an environment where “ownership behaviors” are defined and expected is a powerful part of a compliance sustainability strategy.

What are some “ownership” behaviors? Take these for example:

·       Own the (System) Procedure: The Owner is responsible for ensuring that the procedure or set of procedures for his/her particular element of the QMS remains current with regulatory expectations and best industry practice. The Owner does not wait for negative feedback from a regulatory agency or corporate audit to identify the problems or to be motivated to improve to the system. For example: the Owner is the first to know that an identity test is required for each drum of active ingredient and is the driver to ensure that the procedure is changed.

·       Own the Implementation: The Owner is responsible for ensuring that the particular element of the system is deployed. It is in the Owners best interest to know that all the employees required to be trained on the procedure have been identified and the procedure is incorporated in the employee’s curriculum. For example: the Owner of the Complaint Handling system ensures that anyone who could possible receive a product complaint has been trained. It would not be unusual for the Owner to conduct the training as the subject matter expert. In fact, the collective Owners in the company should be the focus of a “train the trainer” program.

·       Own the Performance Metrics: The Owner is responsible for identifying the best possible performance metrics that would indicate how well the system is being managed, as well as what problems the system is detecting. It is the Owner who first detects an unacceptable trend and calls it to management attention. It will be the Owner who presents the system metrics to the management review forum. For example: it is the Owner of the CAPA system who reports to management about the significant backlog and the associated regulatory and product quality risk.

·       Own the Recommendation: The Owner is responsible for knowing what the solution to the problem is. The Owner will have consulted with the users of the system to understand implementation issues and identify targeted action to address the problem. When the Owner presents metrics to the management review forum, recommendations are suggested. In many cases, it will not be necessary for management approval to proceed with the solution. For example: it is the Owner of the preventive maintenance system that first detected the backlog, but has also determined with the production manager that an integrated PM-Production Schedule is required. So they just do it and inform management.

·       Owns the Knowledge: The Owner is the subject matter expert (SME). The company has supported the continuing education for the Owner to ensure that he/she remains current in the field. The Owner takes the initiative to identify educational opportunities. When companies cut back on the training budget, they certainly want to “red circle” the Owners to ensure that they are exempt from the budget cut. The Owner shares the knowledge to continually raise the competency bar. The Owner is the person who represents the system for problem solving, as well as addresses questions during regulatory inspections.

“Ownership” does not mean isolated or autonomous. But in this world of managing the business and decision-making through teams and consensus, “ownership” and personal accountability tends to get lost or totally diffuse.

Just imagine the organization strength if “ownership behaviors” were expected and nurtured within an operating site, as well as across the company sites.

Just imagine the framework for continuous improvement at the site and company network levels to turn the Owners loose to drive best compliant practices.

Your Assignment:

(1) Make a list of the elements of your quality system (e.g., deviations, CAPA, batch record review, incoming inspection, etc. and enter the name of each Owner. 

(2) Develop a strategic plan to support and enhance ownership behaviors.

Watch awesome things happen!

The QA Pharm

Cartoon: Myrtle the Change Control Coordinator

Okay, okay...Be gentle. This is my first attempt to draw a cartoon. My inspiration is Scott Adams who draws from the daily experiences that we all identify with in his "Dilbert" world. This cartoon draws from everyday experience in the pharma world.

Please share your experience if this cartoon from down on the QA Pharm resonates with you.

The QA Pharm

P.S. See the continued cartoon story on June 27, 2013.

FDA Inspections: Being prepared when you know you have problems

I am often asked how best to prepare for an FDA inspection when you know that you have problems. My first response is that they have already taken the first step: acknowledging that there are problems. Believe me. That is a huge first step. Just like AA’s 12 step program, it’s not until you are willing to admit this aloud that you are on the road to recovery. But just knowing that problems exist is not enough to survive an FDA inspection.

Here are the various positions that firms find themselves when the FDA comes knocking. You can decide which of these scenarios is the best possible position.

1.    We know what our problems were, but they have been resolved.

Let’s say an FDA investigator stumbled upon a manufacturing work order system that allowed changes to production equipment without a review by QA on the impact on the state of validation. The best position to be in is to say that you were made aware of the problem; the system has been revised and employees trained; a retrospective review of maintenance work orders was conducted for product impact and appropriate action taken.

It engenders confidence when an inspector can see evidence that a problem has been resolved and a product impact analysis has been performed. It portrays the firm as being responsive to self-detected problems as a normal course of business.

2.    We know what our problems are; we have a comprehensive plan; we are executing the plan on schedule.

A common strategy for firms that anticipate a Warning Letter or a Consent Decree is to have a third party conduct a thorough systemic audit and to develop a comprehensive corrective action plan. It’s a way of saying to the FDA, “You can’t force us do anything that we aren’t already forcing ourselves do.” The plan is in writing, deliverables defined, reasonable target dates are established, responsibilities assigned, and management is tracking accomplishments versus the plan.

It can diffuse an otherwise nasty inspection when management demonstrates that it is taking the initiative to deeply understand its state of compliance and holding itself responsible for timely results. The FDA inspector may still give you observations, but the Establishment Inspection Report (EIR) will note the initiative you have taken. Also, the FDA may quibble over the scope of the plan, or the timetable for completion, but it is far better to have the plan be the center of discussion than inaction.

3.    We know what our problems are; we have a plan.

The difference between this position and the one above is the failure to execute according to the schedule provided in the comprehensive corrective action plan. In my opinion, failure to execute is one of the most significant issues that separate the wheat from the chaff. Some companies just cannot get out of their own way to accomplish meaningful change. Administration substitutes for real work; team meetings substitute for personal accountability; and production schedules take priority over executing the comprehensive compliance plan. Something else always is more important—there is no discipline, no organization alignment, and no leadership.

It becomes evident during an FDA inspection that it is all talk and no action. FDA cites repeated observations from previous inspections. With FDA on record that there will be no multiple Warning Letters, this places you in the crosshairs of increased enforcement action.

4.    We know what our problems are; we have no plan.

This is perhaps the most dangerous position to be in. Consciously not taking action when there are known problems is irresponsible. When faced with an issue during an inspection, you are either forced to say that you were not aware of the problem, or that you were aware of the problem and have not taken action. Neither response is very pretty. One is actually a falsehood.

This signals to the FDA inspector that CGMP compliance is not considered to be important to the firm, and that the dots have not been connected between regulatory compliance and patient safety. To be clear, management is personally legally liable for knowing its problems and resolving them. This is a real slippery slope.

5.    We don’t know what our problems are.

What problems? This describes companies that rely on FDA inspections to tell them what the problems are, and the firm is always aghast to learn about the problems and ready to call someone on the carpet. This describes management that thinks an FDA483 with five observations is an improvement over the previous one with ten. This also describes the company that does not have established processes to take responsibility for the effectiveness of the quality management system such as: management review of quality system performance metrics, internal compliance audits—or just generally thinking that it is someone else’s job to worry about it.

You would be surprised at the number of senior management who can’t even tell you what their top five problems are. FDA calls this “inspecting into compliance,” and they have very little patience for this unenlightened perspective. These are the bottom feeders in our industry.

So, which position would you rather be in during an FDA inspection when you know you have problems?

The QA Pharm

When All is Said and Done, there is More Said than Done

I couldn’t help but contrast the claims made by NexgenPharma on their website¹ with the responses to observations cited in the recent FDA Warning Letter about their operation.²

Website: Each pharmaceutical product undergoes rigid process validation…

Observation: Your firm has not conducted adequate cleaning validation or provided scientific justification.

Response: We’ve done it this way for the past [redacted].

Website: We test and analyze raw materials, products in production and finished goods using advanced analytical techniques…

Observation: Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance…including the identity and strength of each active, prior to release.

Response: …are closely related in structure and thus, do not necessitate individual testing for strength…We will test each drug product component at least once a year…

Website: Each pharmaceutical product undergoes rigid… stability…

Observation: Your firm does not have a written testing program designed to assess the stability characteristics of drug products…

Response: …stability studies are only performed if the customer pays to conduct the studies…(we) rely on stability data recorded in the years before and after to support the label expiry…

Website: Nexgen adheres to the strict standards of the current Good Manufacturing Practices (CGMPs) established by the US Food and Drug Administration…

Observation: …we remind you of your responsibility for ensuring that your firm’s drug manufacturing operations comply with applicable requirements, including the CGMP regulations. FDA expects NexgenPharma, Inc. to undertake a comprehensive and global assessment of your manufacturing operations to ensure that drug products conform to FDA requirements.

Response: None. (What can possibly be said after that?)

It’s a really impressive website. But it reminds me of the adage: “An ounce of image is worth a pound of performance.” On behalf of all the patients dependent upon their performance, good luck.

The QA Pharm

¹ http://www.nexgenpharma.com

² http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm233276.htm

Routine Problems, Routine Explanations

Here I am at a foreign airport with time on my hands due to a significantly delayed flight. Usually I roll with the punches when travel is disrupted, and I have even grown accustomed to routine, scripted explanations. Same problems; same explanations. This time it was the ubiquitous "delayed incoming plane." The gate agent started to get annoyed when I said that “delayed plane” is a symptom, not a root cause. (It’s not her fault.)

This triggered a thought about disruptions—or more to the point—manufacturing problems that become commonplace, and routine ways I recall having seen them handled—or not.

One clever approach to handling a particular recurring deviation was to have a pre-printed form. The investigation was already written with the exception of the slight nuances, which were accommodated by blanks. This "Mad Lib" approach was completed in a matter of minutes, and a QA approval was handily secured.

Another very "efficient" approach was to use a "planned change" system to work around the recurring (planned?) problem. Another variation on this theme was an "emergency change" system used to document the quickie permission to urgently deviate from the established process—as it had many times before for the same emergency.

I would be the first to acknowledge that "things" happen, and that there needs to be a mechanism to efficiently and expeditiously handle the unusual. CGMPs would not have provided for a deviation investigation system if we lived in a perfect world.

But when the "unusual" becomes standard practice, and when quickie methods routinely substitute for permanent technical solutions, then we are buying into form over substance; ad lib over defined; accommodation over discipline; rationalization over justification. Our patients, which is to say—our business—deserve better.

Warning Letters are replete with observations about recurring problems. So, why do we tolerate habitual humans errors, aging equipment, half-baked processes, retro facilities, and uncoordinated support services that cause problems that are more predictable than our processes?

You tell me.

The best practice I've seen is the "Three Strikes You're Out." When a recurring deviation and obviously ineffective CAPA happens the third time, you no longer own the deviation/ investigation/ CAPA—your boss does. Each time thereafter, it goes up the chain of command. Now that is taking solving problem seriously—or a reaction out of frustration.

Besides, isn’t “repeat CAPA” an oxymoron?

I see the premium members queuing at the gate. I just might get stateside today.

The QA Pharm

FDA Enforcement Inflation: What's Next?

I grew up in a home where just a cast of my mother's glance was enough to cause me to stop dead in my tracks. I knew "the look" quite well. There were no raised voices.

When a parent doesn't follow through on the gentlest of correction, then the parent is communicating that an appropriate response is optional. Out of frustration, parents often up the ante by resorting to yelling and making idle threats. Nothing really changes, because nothing has to. There is more yelling than consequences.

Such has been the history of FDA regulatory enforcement. The threats had to escalate. Their voice had to get louder. The stakes had to get bigger to get industry attention.

I remember the day (now I sound really old) when an FDA483 caused you to clutch your chest and wonder whether your career was over. Over time the FDA483 just became a "calling card" as we used to call it. It was just evidence that the FDA paid a site visit. “It’s just a short one,” we’d say. “No biggie.”

Then Warning Letters became more prolific because FDA483s just didn’t get sustained compliance. “Everyone takes their turn in the barrel,” we’d say. “It was just our turn.”

Then the yelling started.

Eli Lilly (1989), Warner Lambert Consent Decree (1993) and American Red Cross (1993) ushered in a new era and a new FDA enforcement lever. There are now over sixteen major Consent Decrees, not counting those from the swath cut through the medical gas industry in early 2000.

Rather than the "pay-as-you-go" investments in improving the manufacturing operations and ensuring the state of control, some apparently have chosen profits over control until one day all goes wobbly and the FDA finally blows its stack. Even so, a fine of multi-millions of dollars is a drop in the bucket to the company. (The cost, of course, is passed on to patients.) “A blip in the stock price. A one-time hit,” we’d say.

But last week things started getting personal, and the FDA is threatening to up the ante again. Now mom is throwing the china to get attention.

Although the Parke Doctrine had been at the FDA's disposal since 1975, apparently it is being dusted off because, well—it has to be.

The Parke Doctrine is all about personal accountability. Individuals—not corporations—are personally charged with a crime. Their careers are over, and a criminal record taints them for life. (See The QA Pharm 9/11/10.)

Unfortunately, this just might be what it takes for the management at some companies to take their personal role seriously in assuring that they are in compliance with FDA regulations enacted to ensure public safety.

Thankfully, not all pharmaceutical companies are recidivists. Hopefully, reading the trade news about Consent Decrees will not become passé. 

Threat of personal prosecution needs to grab industry attention—like Consent Decrees, ah…like Warning Letters, um…like FDA483s used to.

The QA Pharm

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