Quantifying Quality for GxP Compliance

April 8, 2012

quantifying quality GxP

Quantifying Quality

GxP professionals understand the need for quality and quality system and we discuss quality with one another on a daily basis. But how do we measure it? How do we quantify our results? Once again we turn to Len Grunbaum and Emma Barsky, regular contributors to GxP Perspectives, for their insight on how to quantify quality for the development manufacture, and distribution of health products such as drugs, medical devices, and biologics.

Quantifying Quality

In its simplest form, the definition of “quality” is “how good something is.” But what exactly does this mean for the life science industry, whose frame of reference is defined by regulations which are often vague and which provide little or no guidance regarding how they should be implemented?

In light of this, we would like to offer some ideas regarding how to measure – quantify – how good your “quality” is in tangible and practical terms. We contend that such metrics are useful in order for company management to make sound decisions regarding whether and/or where the quality system (i.e., the operational infrastructure that promotes and facilitates “quality”) requires improvement. The following key indicators are not all-inclusive (nor are the items mutually exclusive), but they provide meaningful ways to assess your “quality”:

• Number of successful external and internal audits as a percentage of the total number of external and internal audits: the higher the percentage of successful external audits (e.g., by existing/potential clients, regulators), especially when you have a large number of them, the better your “quality.” Passing one audit with flying colors is great but passing multiple audits with few minor or no observations is way better. It not only sets a trend regarding “legitimate” quality but it also validates the company’s degree of quality from different perspectives. This scenario allows any company to claim that its quality system has withstood scrutiny from a variety of companies and/or regulatory agencies over a long period of time.

While “looking good” to the outsiders is great, “feeling good” about what is under the covers is even better. Therefore, if thorough internal audits do not find any issues that either directly (critical observation) or indirectly (major observation) impact subject/consumer safety and/or data/product integrity, then “quality” is inherent to the operations.

GxP quality quantify

Measurements for Success

You may wonder how a subjective term like “success” is defined in this context. Fair question. A result of “no audit findings” (e.g., no FDA 483s, no audit observations) is the clearest measure of success. A relative handful of “minor/cosmetic” issues is not perfect but is certainly acceptable in this context. To the extent that the number of observations may be “critical” or “major,” as defined above, the audit will certainly be viewed as less successful or even unsuccessful. One should also remember that it is a common thing in the industry to consider a large number of minor observations as a major issue because this scenario gives an impression of a negative trend, the latter of which is not conducive to having quality operations.

Number of “directed” (i.e., “for cause”) audits as a percentage of total audits: because directed audits are performed to follow up on actual or perceived regulatory compliance problems, the higher the number of “directed” audits, the more questions will be raised about your “quality.” “Directed” audits could be external (i.e., performed by existing clients or regulatory authorities) or internal (i.e., performed by internal quality staff). The higher the number of problems confirmed, the weaker the quality system. Even if these types of audits indicate in general that there are no actual problems, or a minimal number of problems, a large number of such audits should prompt questions regarding why the perception exists that the degree of “quality” is such that an investigation is required.

quality

Number of Investigations

Number of investigations/CAPAs: an investigation is a formal and documented process performed to gather information (e.g., root cause, impact) regarding a specific problem encountered (e.g., a customer complaint, a missing controlled document) and which, depending on the outcome of the investigation, may lead to corrective and preventive actions. An “excessive” number (the definition of which is admittedly subjective in nature) of investigations, even if satisfactorily completed and closed, gives an impression that the underlying cause has never been properly identified and/or corrected.

Number of repeating issues as a percentage of the number of audits performed: repeating issues are symptomatic of a quality system that does not correct or otherwise effectively address problems. While isolated incidents are not necessarily a reflection on the company’s overall quality, incidents that span multiple project teams and/or departments and/or are observed more than once may be indicative of quality-related problems. It is very difficult to convince anyone of the quality of operations when problems that are systemic in nature become evident.

The higher the percentage of audits that contain repeating issues, the more likely that this may be viewed as 1) management indifference, 2) lack of management involvement, 3) inappropriateness of personnel qualifications and/or 4) inability/unwillingness to invest in “quality.”

quantify quality GxP

Lost Business

Number of business opportunities lost due to unsuccessful external audits as a percentage of the number of external audits: audits are sometimes performed as a basis for determining whether a business relationship should be consummated or continued (e.g., you will be chosen as a vendor/supplier, an existing relationship will be sustained) or expanded (e.g., a company will be awarded additional projects). Some life science companies (e.g. pharma, biotech) have to get clearance from the FDA prior to being able to market their product. Support companies (e.g., CROs, contract manufacturers) may have to undergo due diligence inspections to establish/maintain/enhance a business relationship. The higher the percentage of such opportunities lost (e.g., loss of a potential or existing client, project cancelled/not awarded, FDA did not grant an approval) because of poor audit results, as a percentage of external audits performed, the stronger the indication that your “quality” is dangerously weak. This, in turn, has a financial “bottom line” impact on the company: loss of business opportunities can also be translated into wasted R&D cost and/or lost anticipated revenue, both of which become a major risk to the company’s financial health.

In addition to the items listed above, there is another important quantifiable component to “quality,” which is too often being overlooked or not being considered at all. This component is what we define as “the monetary expenditure associated with ‘quality.’” Namely, we are talking about an operationally quantifiable parameter – cost of establishing and maintaining “quality” operations. Most will argue that “quality” is very expensive no matter what. We firmly believe that it does not have to be that way if the underlying causes, which directly and unnecessarily contribute to the extra cost of doing business, are either eliminated or minimized. Here are a few examples to give you a flavor of what can contribute to increased costs when it comes to meeting the regulatory responsibility of instituting and sustaining “quality”:

Regulatory compliance decisions that are not defined in writing and/or are not defensible.

Cumbersome and inflexible procedures that require more resources than necessary to execute them without “procedural deviations.”

Inefficient procedures that require the same activity to be done more than once in order to be in compliance.

Ineffective procedures that do not reach the desired objective of being in compliance after the first execution.

Unclear procedures that result in too many on-going corrections in order to inject “quality” into operations.

Too many procedures that company staff must follow without any value added.

Contradictory procedures that lead to generating Notes-To-File, CAPAs, deviations, investigations, etc. because compliance to one procedure results in non-compliance with one or more other procedures.

GxP Quality

The Costs and Benefits of Quality

The above-listed activities not only translate into the need to spend more time and money in an attempt to have operational quality, but a number of these items translate into further quality-related costs to the company. Examples of the latter include, but are not necessarily limited to, taking the time to respond to observations or even worse yet, an FDA-483 or a Warning Letter. We think the point we are trying to make is clear…

Our bottom line is that you can make both your QA and CFO happy by quantifying “quality” in terms that will be understood and appreciated by both. This means that sound decisions can be made regarding whether and/or where to apply precious company time and resources help ensure that your “quality” is as good as it can be without putting the business out of business.

Emma Barsky and Len Grunbaum
Partners of The Practical Solutions Group, LLC
609.683.0756
Practical Solutions

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In News from FDA: Yet another weight loss danger in Japanese “rapid weight loss” pills. Read the story: foodconsumer.org

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European Qualified Persons & New EU Anti-Falsification Legislation

February 7, 2012

qualified persons anti-falsification legislation

EU Anti-Falsification Legislation

In the European Union an EU certified “Qualified Person” or QP must certify that any batch of medicinal product is in compliance with applicable regulations before it can be released for sale or distribution. Although originally intended for Good Manufacturing Practice, the requirement for QP oversight is now in place for pharmacovigilance and drug products used in clinical trials. The QP is required to have extensive industry experience and the academic credentials, such as pharmacist or chemist, to provide robust, independent oversight of medicinal products.

The EU has enacted new legislation regarding anti-falsification. In this Guest Commentary, Wolfgang Schmitt, Administration Manager European QP Association, discusses the implications of the legislation for Qualified Persons. The falsification of data is a primary concern in the United States as well. Last year FDA introduced a proposed rule for reporting the falsification of data in clinical trials. On both sides of the Atlantic regulators are increasing their anti-falsification enforcement.

Guest Commentary

The Anti-falsification Legislation: Potential Consequences for QPs

The 6th QP Forum of the European Qualified Person Association (EQPA) was held in Budapest, Hungary on 1-2 December 2011 with two parallel pre-conference sessions on 30 November. One Focus was on the new EU anti-falsification legislation and its potential consequences for Qualified Persons.

EU Qualified Person anti-falsification legislation

Tamper Resistant Seals

A first presentation on this topic was given by David Cockburn, Head of Manufacturing and Quality Compliance, European Medicines Agency (EMA) in London, U.K.. David emphasised the need for the directive to “secure integrity and authenticity of products”. The new safety features like serial numbers and/or tamper-evident seals will mainly have an impact on the QPs at parallel distributors as they need to make sure that the authenticity and the integrity is confirmed prior to the removal of original safety features. And this removal of course has to be done under GMP.

Regarding the more stringent rules for the importation of APIs, the QP needs to besatisfied that the supplier qualification procedures ensure verification that suppliers are registered and that the supplier has been audited. This has to be documented in the QP Declaration. After qualifying the supplier it needs to be ensured that the raw materials are actually received from the qualified sources. When it comes to excipients, the QP should at least check that a formal risk assessment has been performed and documented and that the suppliers are qualified accordingly. This should also take into account information in the EU database for excipient suppliers. However an audit is not mandatory but should be preformed for any excipient identified as critical. Regarding the delegated acts, industry and the QPs need to wait for further details. However the QP will need to be satisfied that procedures are in place to comply with the defined conditions for import of APIs e.g.

EU anti-falsification legislation

An Industry Perspective

The aim of the second presentation was to elaborate the industry’s perspective. As Senior Manager Quality & Regulatory Affairs at the European Generic Medicines Association (EGA), Julie Maréchal-Jamil was presenting different aspects. Julie asked the question, how long the overall implementation really will take. Besides the Delegated Acts, other steps need to be taken. It will be interesting to see, how the EC List of Equivalent Countries[1] will be implemented. In the implementation phase of the new Directive, existing guidelines need to be revised and even new ones need to be developed like for example to define risk-assessment principles for excipients or to describe the various confirmations. Julie stressed that currently, there is “no legally defined timeframe for the development and publication of delegated and implementing acts” only a legal timeframe for the entry into force of these legislative acts once they are adopted by the EC.

EGA’s main concerns with the implementation of the Directive on Falsified Medicines are:

1. The so-called “Written Confirmation” of compliance with EU GMP for APIs from non-EU origin. For this process no guidelines are foreseen. Amongst others, EGA sees necessity in having a transition period and a possible risk of heterogeneous supervision of pharmaceutical import and waiver granting in different Member States in the absence of a coordination effort. Here a common central approach will be needed.

2. Process for the establishment of the list of EU GMP “Equivalent Countries.” Here, EGA recommends to leverage existing and operating initiatives like e.g. PIC/S, or MRA and ACAA agreements but also on other similar successful initiatives (Food and Feed) where a staged approach to implementation led to a smooth transition towards a level playing field.

3. Registration of API-related activities for EU-based API manufacturers, importers and distributors (article 52a). For EU multi-sites companies, duplication should be avoided.

4. Pharmaceutical Excipients GMP/GDP. Here, Guidelines should provide a fair reflection of today’s best practices, focusing on cost-effectiveness and existing standards like ISO. Unnecessary over-regulationshould be avoided.

5. Authority/inspectorate funding of the implementation. Details on EGA’s point of view will be published in a White Paper. Both the Forum and the pre-conference workshops were rated very positive by the almost 220 delegates. A survey amongst the delegates resulted in an overall rating of 1.56 (where 1 was the best rating and 6 the worst).

anti-falsification legislation for qualified persons

Budapest

Again very much appreciated was the social event on Thursday evening. Four busses with well selected guides took the QPs for an interesting sightseeing tour through Budapest, the famous capital of Hungary. Followed by a dinner in a traditional restaurant on top of Gellért Hill, the participants were able to continue their discussions and share their experiences with their colleagues in a relaxed atmosphere.

The 2012 QP Forum will be held in Hamburg, Germany on 22 – 23 December with preconference sessions on the 21 November. At the EQPA Advisory Board on 02 December 2011 in Budapest, a structure was defined and first presentations and parallel sessions identified.

Wolfgang Schmitt
Administration Manager
European QP Association, an Interest Group of the ECA Foundation
P.O. Box 10 21 68
69011 Heidelberg
Germany
EMAIL: info@qp-association.eu

U.S. Conference on European GMPs and the role of the QP

There will be a conference in Bethesda, MD on 27-28 June 2012. The conference goals are: “The European Compliance Academy ECA and the European QP Association, recognising this need for further professional knowledge development, intend to support the pharmaceutical industry outside Europe in understanding the European approach and legal framework in this respect. Therefore the QP Association has set up the programme at hand on European GMP requirements and the role of the QP.”

European Compliance Academy

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GxP Perspectives is Thankful

November 24, 2011

GxP Perspectives is Thankful

GxP Perspectives
is Thankful

Today is Thanksgiving in the U.S., a day to be thankful for what we have. It is my favorite holiday. I enjoy eating and I think that saying “thank you” is pretty important. I’m thankful for the readers of GxP Perspectives on the Blog’s third Thanksgiving. I am in particular very thankful for the Guest Commentaries that have been submitted to the Blog. This year they have been great. I am also thankful for the ability to take a break once in a while (which I have been doing). And finally I’m thankful to my family and friends who seem to put up with me. OK- this is a short post but it does have two important announcements, one on the TMF Reference Model from Co-Chairs Lisa Mulcahy and Karren Redding and the other about the GCP CAPA Conference that GxP Perspectives is a media sponsor.

Carl Anderson – GxP Perspectives –
24 November 2011

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TMF Update:

Eighteen months ago, the only guide to the contents of the trial master file (TMF) was ICH-GCP, specifically section 6. Today we have the TMF Reference model, created by a wide variety of experts across pharmaceutical companies, CROs and technical vendors. Version 1.1 was released in February 2011, and has been adopted by many companies – pharmaceutical and CRO alike. The TMF Reference Model has also received positive feedback from the Regulators, with recent comments about what a great reference it is and how much hard work must have gone into it!

Version 1.2 will be released in December – The exciting addition is the adaptation for the contents of Investigator Site Files, facilitating alignment between trial master file contents at the Sponsor or CRO, and Investigator site file contents at the Investigator site. If this part of the model has the same uptake as the main TMF Reference Model, imagine how much easier it will be for the Investigators in terms of standardisation.

Watch this space closely – version 2 will be released early in 2012, to include device studies, process-based metadata and Investigator initiated studies. This is not the limit of the group developments – we are also looking at intra-operability from an electronic perspective, document destruction (a huge area of interest which extends way beyond the TMF) and even quality aspects of the TMF (a new idea put to us just yesterday!)

Karen Redding
Lisa Mulcahy
Co-Chairs of the TMF Reference Model

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2nd Annual Developing CAPAs in the GCP Environment 19-20 January 2012 in Arlington, VA. The keynote speaker is Dr. Leslie Ball, FDA, with a regulatory update on FDA’s Expectations for Clinical CAPAs and Reponses to FDA Warnings. For more information:

GCP CAPA Conference

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FDA 483s: Effective Responses to Avoid Warning Letters

October 16, 2011

Responding to FDA 483

Effective Responses to Form FDA 483

An FDA inspection can result in a Form FDA 483, Inspectional Observations, being issued by the FDA field investigator. How you respond can determine whether the 483 will result in a Warning Letter, the primary form of FDA enforcement actions. How to respond to a 483 is a topic of discussion for regulated industry since the 483s arose in the early 1950s, originally as an attempt by FDA to respond to industry complaints that FDA didn’t inform industry about the field investigator’s findings prior to initiating an enforcement action (at the time primarily seizures, injunctions, and prosecutions). In this Guest Commentary regular GxP Perspectives contributors Emma Barsky and Len Grunbaum list the problems that FDA has found with responses to 483s and some proposed solutions.

Guest Commentary: One Way to Avoid a Warning Letter … Maybe

The following sentence fragments represent but a very small sample of trumpet calls heralding that a firm may have fumbled an opportunity to avoid a Warning Letter after receiving an FDA-483:

• “We have reviewed your response and have concluded that it is not adequate because…”

• “The adequacy of the response cannot be determined because the response did not include…”

• “Your response does not address…”

• “We have reviewed your firm’s response and note that it lacks sufficient corrective actions regarding…”

• “We have reviewed your firm’s responses; however we continue to have concerns related to your firm’s compliance…”

• “The adequacy of your firm’s response cannot be determined at this time…”

• “Your response is inadequate because…”

We say this because of the following: while a response to an FDA-483 is not mandatory and does not represent a final Agency determination regarding firm’s compliance, a firm’s voluntary response often does impact the Agency’s conclusion of the need for follow-up actions, one of which may be the much feared and dreaded Warning Letter. How so, you ask? Here is how….

FDA 483s and Warning Letters

"FDA will conduct a detailed review"

As the FDA indicates in section 5.2.7 of the Investigations Operations Manual, “If FDA receives an adequate response to the FDA-483 within 15 business days of the end of inspection [emphasis added]”, FDA will conduct a detailed review of the response before determining whether to issue a Warning Letter. Alternatively, responding late negates any chance that the FDA will consider the firm’s responses in its resolution regarding whether a Warning Letter is warranted and not responding at all, of course, has the same outcome as responding late.

This brings us to the quality of the response itself. In this context, the higher the “quality” of the response, the more likely the FDA will consider the response as “adequate” and, as a result, may not issue a Warning Letter. Since the firm’s management controls the quality and timeliness of everything that goes on, we suggest that the following guidelines be used to craft the response to the FDA-483 to increase the firm’s chances of avoiding the Warning Letter:

Train the individuals involved in the FDA-483 response effort regarding what information should be included in the response and the format chosen to present the response.

Assign someone to review recent FDA Warning Letters to identify those items where the FDA indicates that the response to the respective FDA-483 was not adequate and include these items in the training to ensure that known mistakes/failures are not repeated.

FDA 483 response

Focus Your Response

Focus on evaluating the extent of the observation in terms of whether the issue could have potentially impacted data integrity, and, if so, whether the issue is systemic (e.g., how many studies, batches, sites, etc. could be possibly affected). This is the most important point to address in terms negating the observation or softening the impact of the observation. If an observation points to actual data integrity issues, these issues need to be brought to the attention of the respective sponsors, where applicable, and responses to the FDA should be discussed with them first.

Establish the true root cause of the observation. In doing so, look for the operational gap (e.g., inefficient project management oversight) that resulted in the regulatory deficiency (e.g., lack of timely document reviews and/or approvals) so that it can be fixed properly and permanently.

Provide specifics regarding any corrective actions taken or proposed. It is not adequate to state that the problem was or will be corrected. Details regarding 1) what was/will be corrected (e.g., development of a remediation plan), 2) when it was/will be completed and 3) if applicable, the timeframe for training (e.g., as in case of a revised procedure) should be provided.

Describe preventive actions that will minimize or eliminate the chance of recurrence of the problem in the future.

Provide supporting documentation for every claim made.

Show commitment regarding implementing all of the proposed activities by 1) specifying activities to be taken and target dates for their completion, 2) assigning accountability for the actions, 3) ensuring proper completion of each respective activity though internal audits.

effectively responding to a 483

The Importance of a Quality Response to FDA 483s

The quality of the response to the FDA-483 is also important for another reason: groups like FOI Services request the Establishment Investigation Reports (EIR) and FDA-483s through the FOIA, so this information eventually winds up in the public domain.

The firm can request that its FDA-483 response be published along with the FDA-483 itself, in which case the response should be such that it gives confidence not only to the FDA but also, where applicable, to existing and potential clients, that non-conformities have not and do not impact data integrity.

The bottom line is this: Do not ever get yourself in trouble with the FDA. But if you do, avoid unforced errors by 1) taking the time and making the effort to respond to the FDA-483, if you get one, in a timely fashion, 2) using the guidelines above in doing so, or 3) consulting with an expert to assist.

By Emma Barsky and Len Grunbaum, the partners of The Practical Solutions Group, LLC

Contact Emma & Len

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ExL Pharma has announced that FDA’s Dr. Leslie Ball will give the Keynote Address at the 2nd annual Developing CAPAs in the GCP Environment conference held 19-20 January in Arlington, VA. GxP Perspectives is a media sponsor.

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Read FDA Warning Letters A suggested practice is to search Warning Letters by topic or issuing office. Then sort by “Letter Issue Date – Desc” to find the most recent Warning Letters.

19 October 2011 update: FDA posted a Warning Letter to SmithKline Beecham (GSK), West Sussex, UK for serious cGMP violations stating: “Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile.”

Read the Warning Letter

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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

GxP Perspectives LinkedIn Group

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On The Blogroll: Rebar Interactive (twitter: @rebarinte) has an excellent blog for clinical sites. If nothing else you MUST check out their post on:
Patient Recruitment: Think That You Might Be Wrong,”
if for nothing else than the photo. A great blog post by Rahlyn.
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GxP Perspectives: Summer Reading

July 25, 2011

GxP Summer Reading

Summer Reading for GxP Professionals

GxP Perspectives firmly believes that summertime means more vacations, less work, and some different recommendations for your reading list. I am actually going to NOT be traveling for the entire month of August. I have weeds to pull, a fence to paint (can Tom Sawyer give me a call), Some hiking to do, and a blog to keep up (to a certain degree). Like most of you, I also enjoy reading. So here are some of my favorite sites for your perusal. Some are industry, some are not. All of them are good. I have really been enjoying the Harvard Business Review “Management Tip of the Day.” If you have other suggestions, please let us know.

UPDATE: Dr. Hamburg’s Op/Ed article printed in the Wall Street Journal.

7 August Update: Not to be missed is the Essex IRB Warning Letter. Earlier this year FDA warned of a fictitious submission to central IRBs. Essex took the bait and approved the fictitious submission.

Harvard Business Review Management Tips is a daily, very brief, “tip of the day.” I find them useful, well-written, and usually making sense. They have many products that they would like to sell you.

What I watched Last Night is a periodic, non-commercial blog about movies. No, not current Hollywood fare, but movies that this acclaimed video maker and film critic actually enjoys. It’s summertime and what better season to watch a movie.

MedCity News A weekly compilation of articles on this commercial website.

AbsoluteArts Because we all need some art in our life.

GCP works The twitter account of GCP Professional Tina Avanzato Chiodo.

NYRblog The blog of the NY Review of Books. If I could only subscribe to one print journal it would be the New York Review of Books.

PharmTech Talk is the blog of Pharmaceutical Technology. All play and no work…

Guardian.co.uk from London. The Guardian provides a different news perspective for readers from the U.S. who can see what others think of us. I like the column from Hadley Freeman on the ratings downgrade. The Guardian has a lot of very good writers.

Science 2.0 Now featuring “Decapitation and the Wave of Death” (now how cool is that?)

Value Added Connects: This blog from India discusses the inspections of CROs by the DCGI (Drugs Controller General of India). A good way to learn more about clinical trials in India.

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Please leave your comments on summertime reading


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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GxP Audit Techniques & Etiquette- Please Comment


FDA & EU Requirements for Documentation & Approval of GMP Procedures

April 23, 2011

FDA documentation requirements

FDA Requirements for Signatures & Documentation

What does the FDA require for the documentation, signature, and approval of standard operating procedures (SOPs)? Are the requirements the same for Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP)? As it turns out, the answer is no. FDA has different regulatory requirements for GCP, GMP, and GLP regulations. In this Guest Commentary Kathie Clark describes the FDA and EU requirements for documentation and approval of GMP procedures. And understanding the basics of good documentation helps in any area of FDA regulated industry.

Guest Commentary:

Approval & Signature Requirements for GMP Documents, by Kathie Clark

Complete, accurate and clear documentation is key to maintaining compliance in a Good Manufacturing Practices (GMP) environment. Documentation is needed to define quality management principles, describe specific procedures, and maintain records that demonstrate that procedures were followed. Together, these directives, procedures and records demonstrate that a manufacturer is operating in a state of control, defined as “A condition in which the set of controls consistently provides assurance of continued process performance and product quality” .
GMPs specifically require that “The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.” But what does this mean in terms of required signatures?

Some people may be surprised to find that the US GMPs only require signature (or initials) for a handful of documents. The following are the specific GMP signature requirements:

FDA documentation GMP signature

What Procedures are Required?

§ 211.182 Equipment cleaning and use log. The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under § 211.68, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed.

§ 211.186(a) Master production and control records. …master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.

§ 211.186(b)(8) Master production and control records. A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling.

§ 211.194(a) Laboratory records. The initials or signature of the person who performs each test and the date(s) the tests were performed. The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

§211.188(a) Batch production and control records. An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed

documentation and signatures for FDA requirements

Review and Approval Process for GMPs

What’s the impact? Although some documents require signature according to regulations (CFR) in the US, a closer read indicates that the real emphasis is on defining and following a sound review and approval process, and being able to provide evidence of this, for all documents. There is no indication that you are out of compliance if an SOP or specification does not display handwritten or electronic signatures, as long as a valid process was followed for the document.

In Europe, GMPs would initially seem to set the bar higher as they state that “Documents containing instructions should be approved, signed and dated by appropriate and authorised persons.” However, a closer look at recent revisions made to EudraLex, The Rules Governing Medicinal Products in the European Union Volume 4, to support electronic signatures for GMP indicates that electronic signature requirements in Europe (for GMP documents) are less stringent that in the US:

Electronic records may be signed electronically. Electronic signatures are expected to:

a. have the same impact as hand-written signatures within the boundaries of the company,
b. be permanently linked to their respective record,
c. include the time and date that they were applied.

documentation and approval for FDA

Documentation for
Review, Approval,
& Release

Since there is no explicit requirement for the signature to appear in the document, this could be interpreted as an electronic approval recorded in a document management system. In summary, recommendations based on a review of the guidance include:

• Ensuring that the process to review, approve and release any GMP document is clearly defined in writing and followed consistently.
• Reviewing the signature requirements in the region in which you operate and determine the most efficient way to meet them.
• If you are not already using an electronic system to manage your documentation, considering the return on investment you may be able to achieve from cost reductions in the “Four Ps” of paper, printing, postage, and processing. If you must print, courier and archive paper documents to comply with the regulations, the cost can be significant.

Kathie Clark is Director, Product Management at NextDocs Corporation, where she is responsible for NextDocs’ Quality Management and Regulatory SharePoint-based document management solutions.

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READ THE GMP DOCUMENTS:

PHARMACEUTICAL QUALITY SYSTEM Q10, International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use, 4 June 2008

21 CFR 212.22 Responsibilities of quality control unit

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Chapter 4: Documentation, Revision January 2011

EudraLex The Rules Governing Medicinal Products in the European Union Volume 4, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 11: Computerised Systems, Revision January 2011

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On the Blogroll: The AssurX Blog recently posted this interesting article about FDA Inspections

Barry A. Friedman discusses FDA Warning Letters for APIs in China and clinical trial materials in the U.S..

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FDA EU documentation

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