GxP Audit Techniques & Etiquette

May 29, 2011

audit GxP

GxP Audit Techniques and Etiquette

Auditing for quality assurance purposes or for an independent quality assessment has become a necessity for GxP Professionals in the highly regulated life sciences industry. Many companies have highly developed SOPs for auditors but there is no consensus on the basic behaviors of auditors. In this Guest Commentary veteran GxP Consultants Emma Barsky and Len Grunbaum offer their perspectives on how auditors should behave when conducting audits that can easily impact people’s jobs and reputations. I firmly believe that auditors should take their approach very seriously. Recent experiences of my own indicate it is a topic well worth review.

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GxP Perspectives will be taking a break for a few weeks. Everyone should take a break now and then.
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Guest Commentary by Emma Barsky & Len Grunbaum

As consultants in the life science industry, we often serve in the capacity of audit hosts for companies and, as such, have a greater exposure than most to various audit behaviors. We therefore are rarely surprised by inappropriate audit conduct.

GxP audit technique and etiquette

"I put three people
in jail
."

But even our eyebrows were raised when a third-party auditor, who was representing a company doing business with our client, started the audit with, “I put three people in jail.” Was she showing off and justifying her credentials? Was she trying to intimidate our client and us? Both? The result was that no one in the room was impressed or made nervous by such an introduction. If anything, her attitude provided the inspiration for this blog Guest Commentary.

In light of having to conform to technical and ethical standards of one’s profession, an auditor represents himself/herself and group/department he/she belongs to for sure. More importantly, however, the auditor also represents his/her company as a whole, even if representing the auditing company in the role of a consultant. Given that the auditor is often viewed as the company’s due diligence “eyes and ears,” every word and every move that the auditor makes is a reflection on the company he/she represents and on the employees of that company.

So what should one consider when it comes to the audit preparation, conduct and follow-up? Based on our experience (both good and bad), the following tips regarding audit etiquette, if put into practice, will usually leave the auditee with positive impressions regarding the auditor and the company he/she represents, irrespective of the audit’s outcome:

Be prepared – learn as much as you can in advance about the company you will be auditing. At a minimum, this can be accomplished through:

1) reading about the company on its website,
2) having a discussion with those groups and/or individuals who intend to use the company to be audited,
3) doing an internet search to see if there is anything of interest regarding the company to be audited (e.g., warning letters, legal actions), and
4) reviewing previous audit reports if applicable and available.

audit technique GxP

Preparation:
"An audit agenda is the first document the auditee will see"

Stay focused – develop an audit agenda that will center on the business reason(s) for the audit (e.g., qualification/due diligence audit, “for cause” audit, follow-up of a previous audit, investigation). An audit agenda is the first document that the auditee will see, and from this will form an opinion regarding the auditor. Therefore, it is best to have a detailed agenda that is customized in terms of the basis for the audit. This will:

1) demonstrate the auditor’s understanding of the nature of the auditee’s actual and/or potential support as it relates to the auditor’s company,
2) be indicative of the fact that there is no hidden agenda on the part of the auditor, and
3) set the tone for the auditor’s own expectations regarding thoroughness of the auditee’s preparation for the audit.

Be timely – if possible (e.g., you are not conducting a “for cause” audit or an investigation), send the audit agenda to the auditee at least two (2) weeks in advance of the audit. While a company should be prepared for an audit at all times, a timely agenda:

1) allows the auditee time to gather correct and complete information in advance of the audit,
2) permits the auditee to identify and schedule the appropriate individuals who will provide information during the audit, and
3) establishes the auditor’s own standard regarding timeliness for the auditee to provide requested information.

Dress appropriately – while many companies have a casual dress code, we believe that an auditor should always be dressed in a suit because this is a sign of respect and professionalism even in today’s “less than formal” work environment.

GxP audit technique

Avoid Surprises

Avoid surprises – information regarding the number of people attending the audit should be communicated to the auditee as far in advance as possible. More than once, we have seen instances where more people than expected showed up for an audit without warning. Even if the number of people to be hosted changes at the last second, it is the auditor’s responsibility to let the auditee know about it. Anything less than that is viewed as unprofessional.

Be sensitive – recognize the fact that audits are stressful in that they take away from the auditee’s ability to do billable work. Therefore, to maximize on your own effort while being conscious of the auditee’s availability, have all of your questions prepared in advance of interviews (e.g., after reading SOPs or other documents so the questions can be detailed and specific) to minimize the interview time and be flexible if the times for the interviews have to be changed on the spot.

Be fair – sometimes issues are very complicated and overlap multiple processes and/or organizational groups. Thus it is only fair to split the responsibility for misunderstandings/miscommunication and activities “going amiss” between the auditee and the company on behalf of which the audit is being performed.

GxP Audit techniques

Be Fair
'From what we have observed, the auditees often get all the blame'

From what we have observed, the auditees often get all the blame, even though the fault may not be entirely theirs. If you position yourself as someone who takes no sides and listen to all parties involved, you will be in a better position to identify the root cause of the issue(s) and, as a result, help the company you represent to resolve/mitigate them no matter whose fault it is.

Know your stuff – be well-versed with respect to the applicable regulations and be versatile in how regulations can be applied operationally, while still maintaining compliance, in the areas you are auditing.

Be open-minded – if you have not seen a regulation being addressed in a certain way, it does not mean that it presents a regulatory compliance problem. If it ever happens, your only job is to determine whether the unconventional approach, chosen by an auditee, may result in potential data integrity issues.

GxP audit technique

Professionalism:
"exhibiting a courteous and business-like manner during the audit "

Be polite and tactful – is essential. And, therefore, the usage of language becomes a critical part of the audit conduct. Not only should one stay away from inappropriate introductions (such as that described above), but also from 1) arguments, 2) accusations and 3) exhibiting lack of patience. Even if you think the company you are auditing is wrong, stay away from heated discussions. Instead, include your point of view and an explanation, along with the auditee’s position, in the audit report and let the company’s “Operations” deal with the rest.

Also, the auditor’s authority should not be misused – we have seen cases where, due to the auditor’s lack of understanding, the auditees were wrongly charged with something they have not done.

Be open – audit observations and potential audit findings should be discussed with the audit host throughout the audit, rather than just at the close-out meeting or even worse yet, mentioned only in the audit report that the auditee has to respond to.

GxP audit techniques

"Transparency throughout the audit"

Transparency throughout the audit will give the auditee a chance to present additional documentation, provide clarifications and collect supplementary evidence before the end of the audit. Not only will such an approach prevent the auditee from feeling “cheated” or “blind-sided,” but it will also give you, the auditor, a much better idea regarding where the auditee really stands.

Be sensible – unlike many seem to believe, “minimal or no observations” is not necessarily a reflection on your competency. So don’t be afraid to walk out of the audit with “no findings” where findings are not warranted. Remember that even the FDA itself is comfortable to close-out its inspections with no FDA-483s. Furthermore, there should also be a clear difference between auditor’s preferences (e.g., recommendations) and findings that present deviations from the regulations and have a potential impact on the quality of the product and/or process(es).

Be factual – when writing observations, provide enough facts and details to substantiate your findings. It is best to stay away from ambiguities and generalities when describing an issue because nothing frustrates an auditee more than all-encompassing statements that make the issue look worse than it really is.

GxP audit techniques

Review Audit Findings
in a Timely Manner

Be responsive – just like you expect the auditee to respond within thirty (30) calendar days (or business days, depending on the individual company’s requirements) to the audit findings, the auditee is also expecting reasonably prompt feedback from you regarding the audit findings and feedback to the respective auditee’s responses. Therefore, the audit findings, audit responses and any follow-ups should be sent out and/or reviewed in a timely fashion. Not letting the auditee know what the audit status is, even if responses are acceptable, is not an option because contracts often depend on the auditee successfully passing the audit.

The “morale of the story” is that the auditor has a big responsibility towards the company he/she represents and towards the company he/she is auditing. In our opinion, the biggest compliment and validation that the auditor can get is for the auditee to say “you were fair,” findings notwithstanding. In this case, everyone wins.

Emma Barsky
Len Grunbaum
Partners
The Practical Solutions Group, LLC

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FDA has announced a new draft guidance document. Public comment is due by 25 July 2011:

Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators

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On the blogroll: ‘The Hill’ on defunding the health reform law: CBO States Danger to Medicare Drug Funding

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FDA Proposes User Fees for Biosimilar Products

May 22, 2011

FDA biosimilar user fees

FDA Proposal on Biosimilars

Biosimilars or “add-on biologics” have been making the news of late. These are replacements for patented biological drugs developed by biotechnology companies like Genentech and Amgen. Are they the same as generic drugs? No, large molecule biologics products are far more complex than a tablet of aspirin. They can’t be exactly reproduced in the manner of a generic drug which is why they are called, “biosimilars.” How can they be regulated by FDA? That’s a good question that veteran consultant Michael Hamrell discusses in this Guest Commentary. It is a complex and difficult issue and Hamrell does an excellent job of explaining FDA’s Proposal.

User Fees for Biosimilars

FDA Biosimilars User Fees

Differences in Large Molecule Products

The FDA recently issued it proposed plan for user fees for the new biosimilar products that were authorized under the Healthcare Reform Act in the subsection on Biologics Price Competition and Innovation Act of 2009. This law added a new section (351(k)) to the Public Health Service Act that gives the FDA the authority to approved product biosimilar and interchangeable with a licensed reference biological product. As part of the implementation of the law and regulations for the development of these biosimilar products, the FDA is preparing a proposal for how user fees will be assessed and collected for these products. These fees are proposed to begin with the next reauthorization of the User fee program in FY2013 (October 1, 2012).

Under the initial plan, the user fees for the new biosimilar products will overall be the same as for new biological products. Since FDA expects that marketing application review, preapproval facility inspections, and safety issues will be comparable for 351(k) and 351(a) applications, for the initial 5-year authorization, the Agency proposes to maintain the same PDUFA fee levels for 351(k) marketing applications, manufacturing establishments, and products. However, the Agency proposes to modify this structure to provide resources in the near-term because, as noted in section I of this document, there is no existing inventory of marketed products that would generate fees.

biosimilar FDA user fees

Differences in the Biosimilar Pathway

One key difference is the planned inclusion of a Biosimilar Product Development Fee, a part of the user fee to be paid upon submission of the IND and annually thereafter while the molecule is under active development that is intended for a single 351(k) application. The initial product development fee is estimated to be around $150,000 per year. Failure to pay the development fee on initial IND submission or annually as required would result in the IND being placed on Full Clinical Hold. The other difference is when the applicant submits the associated 351(k) marketing application, the sum of the previously paid annual Biosimilar Product Development fees would be deducted from the 351(k) marketing application fee.

This is a major difference, at least initially from drug development under the NDA regulations, where no user fee or partial fee is paid during the development phase. The only user fee is paid upon submission of a marketing application. Since the development fee is payable annually during active development, it will be critical that the development program proceed in a logical and efficient manner. Delays in clinical trials, due to GCP problems or other issues will now cost money by extending the IND development phase and having to pay another annual IND development fee.

FDA Biosimilars

FDA is Seeking Input on Biosimilars

This is still a proposal at this point and the FDA is seeking input and comment on the proposal in order to move forward to finalize a plan. Anyone interested in commenting on the proposal should review the requirement for submitting comments contained in the Federal Register notice regarding the plan (76 FR 27062-27067).

Guest Commentary – Michael Hamrell

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On the Blogroll: RegBlog on all things regulatory from the University of Pennsylvania Law School. Covers much more than FDA

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=== Read more on biosimilars:

The Economist on Biosimilars

Read from Genentech on Biosimilars

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FDA Issues 5 New International Warning Letters

May 15, 2011

FDA international warning letters

FDA's Increased International Presence

The “Most Recent Warning Letters” section of the FDA website lists five Warning Letters to international firms. The Warning Letters were posted on May 10 and will disappear into the Warning Letter labyrinth on the website in a few days (see previous post). They are to firms in both Europe and Asia and come from four different centers: the Center for Devices and Radiological Health; the Center for Drug Evaluation and Research (Active Pharmaceutical Ingredient (API); the Center for Biologics Evaluation and Research; and the Center for Food Safety and Applied Nutrition (two Warning Letters for Seafood HACCP).

The Warning Letters do not state if the inspections were conducted by one of the FDA’s new International Resident Posts- but it is likely that the FDA’s increased global presence contributed to the enforcement actions. FDA now has offices in China, India, Belgium, and Costa Rica. This is addition to FDA’s International Inspection Cadre which is primarily drawn from FDA Field Investigators (Consumer Safety Officers) working for the 20 FDA District Offices across the country. The fact that different offices are issuing Warning Letters around the world at the same time gives a clear indication of FDA’s increased international enforcement efforts.

FDA International Resident Posts

Read the Warning Letters:

Hong Kong – Medical Devices

Spain – Active Pharmaceutical Ingredients

Sweden – Biologics cGMP

Korea – Seafood HACCP

On the Blogroll: Last week we had the FDA Lawyer’s Blog. This week I want to highlight a recent article on the FDA Law Blog on “FDA Warning Letter ‘Close Out’ Process Not Working.”

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FDA Warning Letters: How to Navigate FDA’s Website

May 10, 2011

FDA Warning Letter

One of the Many Exhibitors at the
ACRP Conference

FDA Warning Letters, and some thoughts on critical and creative thinking, conclude my reporting from the Global Conference for ACRP – the Association of Clinical Research Professionals – held last week at the Washington State Convention Center in Seattle. During the conference it became apparent that many people, including FDA employees, have a difficult time searching for Warning Letters on FDA’s website. The Warning Letter section is an absolute mess. So I thought I would provide a few simple search tips to help find Warning Letters for GCPs. Unfortunately cGMP Warning Letters are more difficult, but the tips still help. Then I would like to tell you about an interesting session I attended on critical and creative thinking.

When searching for FDA Warning Letters, the link is below, scroll down and choose to “Browse Warning Letters by SUBJECT.” You will be presented with the alphabet. Click on “C” and then scroll down past all the “cGMP” categories until you reach “Clinical Investigator” where you will find the majority of GCP Warning Letters.

FDA Warning Letters

Searching for FDA Warning Letters

They will be listed in alphabetical order. There is a “Sort by:” option. Choose “Letter issued DESC” from the drop down menu. You will then have most of the GCP Warning Letters with the most recent listed first. You can also choose as subjects: Clinical Investigator – Sponsor; Bioresearch Monitoring; IRBs; Sponsor Obligations; and “IDE….” for medical device Warning Letters. There are several ways of listing for each category. You can sort by “Letter Issued DESC” for each category. There are five GLP categories plus Good Laboratory Practices. Go figure.

FDA Warning Letters

There were a number of interesting sessions that I attended at the ACRP meeting. I wanted to tell you about Critical Thinking in a Regulated Environment, because it can be so darn difficult. Kirk Mousley described critical thinking as producing ideas and then evaluating ideas. Citing Iris Verdi he described creative thinking as original, imaginative, and uncommon. He discussed that creative thinking comes through different avenues: it is often a revisement of something that already exists (evolution); a combination of two or more ideas (synthesis); or just a different way of looking at things, asking yourself, “how else can I look at this?”

FDA Warning Letters

How Can I Look at This Differently?

Mousley also discussed the barriers to creative thinking including “not part of an approved process” (SOPs). He noted that the regulatory process itself discourages critical thinking by imposing a “process mentality.” He countered that by suggesting that you build into a process the encouragement of critical thinking. And he pointed out the myth that “every problem can only have one solution or one right answer.” One of the points that I emphasize when doing a root cause analysis of a problem identified during a CAPA process is that you should Always Look for More Than One Root Cause.

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On The Blogroll: The FDA Lawyers Blog discusses a variety of interesting issues including bioequivalence data, litigation tactics, and Victory for Embryonic Stem Cell Researchers.

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FDA & OHRP Hold Regulatory Forum at ACRP Meeting in Seattle

May 1, 2011

FDA OHRP regulatory forum

Jerry Menikoff of OHRP & Jean Toth-Allen of FDA

FDA and OHRP both presented at a Regulatory Affairs Public Forum at the ACRP Global Conference on Sunday, May 1st.Speaking for FDA were Leslie Ball, MD, Director of the Division of Scientific Investigations (DSI) which initiates the majority of Bioresearch Monitoring inspections at FDA. Also from FDA was Jean Toth-Allen, PhD, Biophysicist, Office of Special Medical Programs. Jerry Menikoff, MD, JD, spoke on the panel as the Director of the US Office for Human Research Protection. The Association of Clinical Research Professionals hosted the forum in a setting more reminiscent of a TV game show than a professional panel that was complete with theme music and multi-colored columns highlighting the stage. However the questions posed were the ones on everyone’s minds and the speakers gave some good answers.

Please note that the Plenary Session on the Regulatory Affairs Public Forum was recorded and is available on the ACRP website for free.

One question brought up the issue of sponsor oversight of outsourced clinical trial responsibilities. Toth-Allen said that the sponsor is ultimately responsible for all of the clinical trial responsibilities and only CROs are specifically mentioned in the regulations. She emphasized the need to have SOPs in place covering how they are going to oversee contracts of vendors and what the contracts should cover. Leslie Ball said that DSI had an increased focus on sponsor and CRO inspections.

Dr. Ball said that she thinks sponsors should look at three qualities when selecting vendors:

1. The overall capability of the organization and staff.

2. That contracts clearly point out who is responsible for specific responsibilities.

3. That the sponsor oversees the vendor’s activities while the trial is ongoing.

OHRP FDA regulatory forum in Seattle

When Does FDA Inspect?

Another area of interest was when and where FDA would inspect. Both Leslie Ball and Jean Toth-Allen said that FDA was focusing more on inspections during the actual conduct of the study and not just when a sponsor makes an application to the agency.

Dr. Ball said that with the shift to more sponsor/CRO inspections that FDA inspections were looking at sponsor oversight of ongoing trials. She also said that DSI was developing a risk-based site selection tool that looked at three different levels. First, at the application level, did the application pose certain risks that FDA needed to consider. Then at the trial level, tending to focus on pivotal trials. Then at the site level, were there complaints or a history of non-compliance. She also said that they were looking at data from the application such as the rate of subjects dropping out or very high or very low rates of adverse events.

FDA OHRP regulatory forum

Dr. Leslie Ball, FDA

Dr. Ball also emphasized that FDA looked at what they considered important, specifically data integrity for primary efficacy endpoints or key safety indicators, and oversight by the sponsor. She noted that many things that are routinely listed on a Form FDA 483, Inspectional Observations, such as study drug accountability sometimes didn’t find their way to a Warning Letter that focused on items of significance to the approval of the application.

Another interesting discussion was on the topic of online informed consent forms, which are beginning to appear. Jerry Menikoff said it depended on the nature of the study when an online consent might be appropriate. Jean Toth-Allen spoke of the need for a verification process, that the online consent was given by a real person.

FDA regulatory forum Seattle

Discussion on Electronic Medical Records in
Clinical Trials

Finally the panel discussed electronic medical records (EMRs). All three panelists supported the use of EMRs. Toth-Allen said that if an EMR is used in a clinical trial then the institution needs to provide access to verify the record, that it was not acceptable to for monitors to be told that you can’t see it, which elicited a hearty round of applause from the many monitors in attendance. Dr. Ball noted that there were a lot of advantages to EMRS. “You can actually read them,” she said. She also emphasized that EMRs should have the same criteria for clinical trials, that they should be ALCOA– Attributable, Legible, Contemporaneous, Original and Accurate. She also said that although they may not need to be Part 11 compliant, they did need to have an audit trail so that all changes to the record could be traced.

To view the Regulatory Forum visit the
ACRP Website on the Plenary Sessions

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On the Blogroll: RegBlog on all things regulatory from the University of Pennsylvania Law School. Covers much more than FDA

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On The Blogroll: Applied Clinical Trials Blog discusses,
“It Takes a Village: Recruiting Latino and Hispanic Patients.”


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