FDA IP Labeling Requirements

April 29, 2012

FDA labeling investigational product

Does FDA Require an Expiration Date for IP?

What are FDA’s requirements for labeling investigational drug and biological products (IP)? We are all aware of the required statement in 21 CFR 312.6, “(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement ‘Caution: New Drug–Limited by Federal (or United States) law to investigational use.'” However, is that the only requirement? What else, if anything, belongs? What labeling is against FDA requirements? Is this a GCP or GMP issue? This question came up recently in a discussion with a colleague. It was their opinion that an expiry date was not required. They had stability records for the IP and could show that the expiration date exceeded the length of the trial. Is this sufficient? I disagreed. I felt that the IP labeling should include a lot/batch number and the expiry date.

What Are YOUR Viewpoints? Please comment below.

FDA regulations for investigational new drugs tell us little about what goes on to an IP label. However, we know that IP must be manufactured under the GMPs. Just what do the GMP regulations say about labels? We can find it in § 211.137, Expiration Dating. It states in 211.137(g):

“(g) New drug products for investigational use are exempt from the requirements of this section, provided that they meet appropriate standards or specifications as demonstrated by stability studies during their use in clinical investigations. Where new drug products for investigational use are to be reconstituted at the time of dispensing, their labeling shall bear expiration information for the reconstituted drug product.”

FDA Drug Labels

Consultant's Don't Enjoy Being Wrong

It is clear that my colleague is correct. FDA does not require expiration dates if the IP meets the standards and/or specifications in stability studies. I don’t like making mistakes, but “the proof is in the pudding.” This is a very specific regulation that is easy for all of us to interpret. I would have appreciated it if FDA had referenced this in the IND regulation, §312. That is where most GCP professionals go to look for FDA’s GCP requirements. However, FDA frequently doesn’t appreciate what I appreciate, so we find the information in §211.

The second point that this regulation makes is very interesting. More and more drug products require very specific instructions on how to administer the drug or IP. A reconstituted test article can have a very short time period for dispensing. This regulation is equally clear that “their labeling shall bear expiration information for the reconstituted drug product.”

This can add up to a lot of information. Expiration information for a reconstituted drug product, storage temperatures and conditions, and adequate directions for dispensing the IP are all essential information for a label. How in the world do you fit it on one small container? For this, you need to understand FDA’s definition of “label.”

In conducting your clinical research program your ultimate goal is to attain a “label.” This is the physician’s insert that informs the clinician, among many other things, “adequate instructions for use.” Vials of parenterals are usually packaged and the packaging contains essential information that is also considered labeling.

FDA investigational product labeling

FDA Labels Must Not be Misleading

In addition, the handy “informational sheets” that some nutritional supplement or “neutraceutical” dealers keep under the counter at their stores and are given out to answer question from consumers also meet FDA’s definition of labeling. So when they hand you an informational brochure saying that “many studies find” that patchouli oil cures arthritis, yes that can be part of the label. Chances are that FDA would probably find it to be false and misleading.

That means you should have plenty of room for this information on the IP labeling. Referencing it on protocol-specific worksheets that the clinical site may, or may not, use for recording source data is not sufficient. The information needs to be part of the labeling or clearly stated in the protocol. It can also be part of pharmacy manual that is referenced in the protocol. The information needs to be readily available and part of the pre-study training that the sponsor documents before enrollment of subjects.

FDA Labeling

European Requirements

Finally, a European employee of the company my colleague works at informed me that it is an EMA requirement to include the expiry date. However, she had heard that in the U.S. there was no requirement, which she found strange. I find it strange as well. It is my viewpoint that in an era of globalized trials, we should aim for the highest standard. And harmonizing label requirements, when possible, will help the company develop a systematic approach to GCP compliance.

My personal opinion is that expiration dating is essential information for “adequate directions for use,” as required by Section 502 of the FD&C Act. I agree with EMA that the expiry date should be part of the label. However, I live in Tacoma, WA, not in Paris, Copenhagen, or Venice. So my personal opinion is just that, my personal opinion.

Carl Anderson, GxP Perspectives

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Please join your industry colleagues in completing the 2012 TMF Reference Model Survey, and use results to inform your TMF best practices.

https://www.surveymonkey.com/s/FPP8DCF

This fifteen minute survey is designed by members of the TMF Reference Model team to provide valuable insight into Trial Master File practices, both paper and electronic, to identify common problem areas, assess changes in practice and reveal opportunities for improvement. All respondents who complete the survey and provide contact information will be provided with the survey results.

Data collection closes June 1st; please join us today.

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What is Your viewpoint on IP labeling? Please comment and let us know.


India: Quality for Clinical Trials

March 1, 2012

India clinical trials quality assurance

Quality Systems in India

Are Quality Systems in place in India, where the clinical trials industry is exploding?Do clinical trials professionals have the knowledge, skills and experience to run clinical trials where the rights, safety, & welfare of human subjects is protected and where data are reliable for submission to FDA and EMA> In this Guest Commentary QA professional Anusha Reddy demystifies the GCP process in India outlining her approach to quality in clinical trials.

This marks the first edition of GxP Perspectives as a monthly blog. It has been too much work for one person to keep up with a weekly schedule. I will be using the GxP Perspectives Linkedin Group to keep on top of current developments with FDA, as well as discussions by group members. Also, youcan subscribe to the blog on the button to your right on the sidebar.

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Improvising Quality in Clinical Trials

By Anusha Reddy

Over the last decade Clinical Trials in India have increased very rapidly in number. India has made a name for itself in the international pharmaceutical field as an ideal destination for worldwide companies to conduct clinical trials which is a test for both the government and the private sector to create a balance between ethics and trade The rise in the business brought sharp focus on the need to manage quality while conducting clinical trials.A need was, however, felt to develop our own Indian Guidelines to ensure uniform quality of clinical research throughout the country and to generate data for registration for new drugs before use in the Indian population. An Expert Committee set up by Central Drugs Standard Control Organisation (CDSCO) in consultation with clinical expert has formulated GCP guideline for generation of clinical data on drugs.

The Drug Controller General of India (DCGI) has introduced several guidelines and regulations, in an effort to maintain and ensure credibility, integrity, safety, well being and quality of clinical trials, some which includes guidelines on approval of clinical trials, CTD, Clinical trial Inspection, registration of clinical trials, CROs, and Ethics Committee’s. It constituted NDAC to review applications of new drugs and clinical trials, introduced prescreening of applications in order to expedite and streamline the process of application by ensuring completeness and has recently made compensation mandatory for injury or deaths during trials and which would increase the number of volunteers and patients going for a trial in India, according to experts.
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quality clinical trials in India

"Each Stage of Data Handling"

Quality in clinical trials should be applied to “each stage of data handling” to ensure that all data are reliable and have been processed correctly. Clinical trials are carried out to allow safety and efficacy data to be collected to provide information for industry and regulators to make decisions about the safety and efficacy of the interventions. Activities like monitoring and auditing are performed in order to ensure that the quality exists and the study is conducted in accordance with the SOPs, Protocol, GCP and applicable regulatory requirements. Pharma and Biotech firms are looking for several different strategies in clinical trials to ensure the highest quality of data. This article tries to discuss on describing and executing the quality in clinical trials.

A good quality clinical trial should, address an important question, have the potential to make an actual difference to patients, use the finest available research techniques, generate significant data, be scientifically and ethically sound. Recognition of GCP at the sponsor, CRO and the investigator site will improve the quality of clinical trials and finally leads to the acceptance of clinical trials.

clinical trials quality India

"Ability to Satisfy Stated or Implied Needs."

As per ISO (International Organization for Standardization) quality is defined as the features and characteristics of a product or service that bear on its ability to satisfy stated or implied needs. In clinical trials, poor quality has much more serious outcomes than discontented customers. Failure to ensure quality in clinical trials can result in undue harm to research participants, invalid data, and consequently, wrong conclusions about the safety and efficacy of the drug being tested. Additionally poor quality is a call for a regulatory inspection.

Determined efforts to improve quality in clinical trials have increased noticeably over the past decade. Recently the Department of Medical Education has imposed a temporary ban on clinical drug trials and research projects in all government and private medical colleges and hospitals in the Karnataka State, India; however, later it was assured that no such measures are being undertaken. The reason behind such decision was especially lack of guidelines to regulate drug trials. An expert committee was set up to study and frame guidelines to regulate and re-organise clinical drug trials, which is a step towards a quality clinical trials.

quality India clinical trials

The Consequences of Poor Quality

There are several reasons for poor quality in clinical trials and preventing them all is not an easy task. The objective should be to limit their number and their effect on the trial outcomes. This can be achieved by taking steps at the initial stage in protocol development and at the trial set up phase to obtain a high quality data in clinical trials; however, this alone does not result in high quality. Furthermore, planning should be accompanied by adequate oversight through proper routine monitoring and auditing of the trials with necessary corrective and preventive actions (CAPA) in place.

Measures should be taken to promote quality improvement in clinical trials by following standard operating procedures and implementing good documentation practices while performing study activities like drug accountability, Informed consent process, Safety reports, protocol deviations/violations and other protocol related activities which will provide reliable results and error free data when submitted to regulatory agencies for approvals.

A quality system proposition to good clinical practice conformance will establish quality in clinical trials by identification and setup of standards, applying them by those involved in the conduct of clinical trial, tracking the areas that are non-complaint with the standard procedures or applicable regulatory requirements, take actions to prevent the recurrence in future in the identified areas.

quality in India

Developing Metrics

Developing and using metrics that are meaningful within an organization facilitate in measuring the quality in clinical trials. For example, preparing a protocol from the stage of drafting to finalizing, here with increase in amendments the time increases and quality is reduced (but number of amendments is often not the reflection of protocol quality). Other example for measuring the quality includes the number of data clarifications forms (DCFs) raised per case report form (CRF); increase in the number of data queries indicates the poor data quality. Based on these metrics one can measure the quality and can improve those areas.

In Conclusion, systems with procedures or measures that assure the quality of every aspect of the clinical trial should be implemented. Quality should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. This extent of transparency and accountability of clinical trial processes ensures ongoing quality control and quality assurance, but in addition, makes it easy to assertively address inquiries from regulatory agencies.

Useful Links:

Indian GCP

Clinical Trial Registration

Prescreening Checklist

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Training Opportunity:

The 3rd Proactive GCP Compliance Conference taking place April 2-4 in Arlington, VA – GCP Conference Website. Leading GCP experts from Lilly, Pfizer, J&J, Novartis, Shire and many more address risk-based approaches to clinical quality that meet requirements and ensure patient safety. Special 15% discount off of the standard registration rate for GxP Perspectives readers. Register online at: GCP Conference and use discount code: P439GXP

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DIA Regulatory Conference this April in India

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In News From FDA:

FDA has issued the final guidance, “IRB Continuing Review after Clinical Investigation Approval.” GCP Guidance Documents may be found here: FDA GCP Website. The new guidance is on the right in the section “In The News.”

From: A Message from the Commissioner
Sent: Wednesday, February 29, 2012 04:14 PM
To: FDA-Wide
Subject: Announcement re Chief Counsel

Dear Colleagues,

I am thrilled to announce the permanent appointment of Elizabeth Dickinson as the Chief Counsel of the Food and Drug Administration, effective Monday, March 12, 2012.

As many of you know, Liz has had a long and distinguished history at the Agency; she joined the Office of the Chief Counsel in 1994. Over the years, Liz has served as legal counsel to the Center for Drug Evaluation and Research and the Office of the Commissioner on innovator and generic drug review issues, orphan drug development, and biosimilars; has implemented pediatric exclusivity and pediatric drug development programs; has worked closely with the Department of Justice on dozens of cases addressing Waxman-Hatch issues and preemption; and has coordinated the development of the Office of the Chief Counsel’s flexible workplace program.

A graduate of the University of Massachusetts and Northeastern University School of Law, Liz is highly regarded by both her internal colleagues and those across the food and drug bar. Over the years, Liz has received numerous awards for distinguished service, leadership and her outstanding legal skills.

Liz has been serving as Acting Chief Counsel since August 2011, and we have been grateful for her hard work and dedication each day that she has been on the job. It is terrific to know that she will be serving the Agency in this role permanently as we move forward. Please join me in congratulating Liz.

Sincerely,
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

We have some excellent comments on this post. Please join the discussion and add your own thoughts


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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FDA Warning Letters for International APIs in 2011

January 8, 2012

API FDA Warning Letter International firms

API Warning Letters to International Manufacturers

FDA issued at least ten Warning Letters to international manufacturers of active pharmaceutical ingredients in FY-2011. Manufacturers in both China and India, the world’s largest exporters of APIs, received three Warning Letters each from FDA. Manufacturers in Spain, the UK, Canada, and Japan each received one Warning Letter from FDA. These metrics show both the domination of China and India in the API market as well as the continued dependence on international manufacturers for APIs destined for the U.S. market.

Deficiency Categories:

The violation that dominated the charges cited by FDA in FY-2011 related to quality control, cited in four Warning Letters, two to China and one each to Canada and Japan.

FDA API Warning Letters in 2011

Failure to Have Procedures for Cross Contamination

Another violation that is sure to cause concern with FDA is the failure to prevent cross-contamination. When I attended FDA API inspection training in 2000 cross-contamination, particularly with anti-biotics, was a major concern. It continues to be with API manufacturers in both India and China being cited for the “Failure to have appropriate procedures in place to prevent cross-contamination.”

Out of specification (OOS) laboratory results are always a concern of FDA and landed on Warning Letters to manufacturers in India and Spain. Other citations include:

= Water purification for APIs used in parenterals

= Failure to establish a stability program to monitor APIs

= Failure to perform at least one identity test of each batch of incoming material

= Validation of analytical methods used to test APIs

There are no big surprises here but it shows that regular surveillance of API vendors is an absolute necessity for the manufacture of quality drug products. What is of interest is that GxP Perspectives couldn’t find any domestic Warning Letters for APIs. That doesn’t mean they don’t exist, only that they couldn’t be easily located. Unfortunately, FDA lists API Warning Letters in any number of classifications for GMPs for finished pharmaceuticals. However, they don’t seem to list them for APIs. With all the razzle-dazzle taking place on FDA’s website, you would think they could come up with a consistent way to list API Warning Letters. Who knows, maybe next year.

by Carl Anderson, GxP Perspectives
Research by Francesca Carreras-Perez, GxP Perspectives

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Two articles of interest regarding APIs:

Indian API Manufacturers want anti-dumping duties

API Product List (note countries of origin)

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Clinical Labs & GCP

June 12, 2011

FDA lab GCP

GCP for Clinical Laboratories

How to assess clinical laboratories for GCP compliance is one of the more difficult issues facing GxP professionals. Is CLIA the gold standard? How do the good laboratory practice (GLP) regulations impact clinical labs? Isn’t there a handy checklist out there somewhere? What do people mean by “GCLP?” I have been dealing with this issue a lot of late and people are really all over the map. Here are some of the approaches I take, along with a handy-dandy reference list at the bottom of the post.

First, let’s look at the easy part. The primary regulation dealing with clinical laboratories is the Clinical Laboratory Improvement Amendments (CLIA). Wow, that’s simple. However, CLIA specifically states that it does not have jurisdiction over research. CLIA covers the day-to-day laboratory tests that your doctor orders to check up on your cholesterol or hematocrit. For these routine tests, FDA recognizes CLIA certification as an acceptable standard. FDA also recognizes other certifications such as from the College of American Pathologists (CAP). However, FDA does not have its own laboratory program. No, the GLP regulations (Part 58) just don’t apply here. My advice is to keep them on the shelf.

GCP Lab FDA

Research Continues into New Laboratory Methods

However, things can get more complex. Not all laboratory tests are CLIA certified, there is a whole lot of research going on out there. Research methods are being developed every day. To make matters worse, just because a lab is CLIA or CAP certified, it does not mean that they have clinical trial experience and knowledge of kit building or blinding procedures. You need to go to their laboratory and see if they are equipped to perform the tasks in your statement of work. You need to perform a chain-of-custody tour to determine that your samples will be handled and analyzed in an appropriate manner, if there is “quality control at each stage of data handling” (ICH E6 Section 5.1.3).

One document that will come in handy is the FDA Guidance for Industry: Bioanalytical Method Validation. If you have a new laboratory method, it should be validated. What about an audit plan? I use the European Medicines Agency (EMA) GCP Inspection Guidance on Clinical Laboratories (Annex II). Links to both of these documents are listed below. The important thing to remember is that you have critical safety and efficacy endpoints being evaluated by the lab and they are highly importance to your study. Give the laboratory the attention it deserves.

GCP lab clinical trials FDA

Tour the Laboratory

Chronological order is a useful tool in assessing a laboratory. Follow the route of the samples starting with kit building, shipment to the sites, receipt from the sites and how they make it through the laboratory. Remember, the majority of laboratory errors take place Before sample analysis, in the pre-examination phase (source: CDC). In addition, there are more errors reported in the post-examination phase than the examination phase itself. Reporting is of critical importance. Your NDA or PMA might depend on the accuracy of those reports.

I have seen many checklists for conducting clinical laboratory audits. Most of them have issues that can impact their effectiveness. Your audit should be protocol-specific. The lab needs to be able to conduct the analyses required by the protocol. That’s why I use the EMA GCP Inspection Guidance for Clinical Laboratories as a basic audit plan. EMA has a GCP inspection program for clinical labs. Another important point is that not only do you need to pre-qualify a lab, you need to go back during the trial and audit live data. This is true for any critical vendor.

GCP Lab

There are a number of resource documents available

Many organizations are working on the clinical laboratory dilemma. You will hear the term “GCLP” quite a bit (for good clinical laboratory practice). It is important to remember that there is not one consistent standard on what GCLP is. Wouldn’t it be nice if we did have a consistent GCLP standard recognized by the world’s regulatory authorities? Here are some important references for clinical labs and GCP. Feel free to make additions to this list in the Comments section below.

EMA GCP Inspection Guidance for Clinical Laboratories

FDA Guidance for Industry: Bioanalytical Method Validation

College of American Pathologists Website

Clinical Laboratory Improvement Amendments (CDC)
(This site has links for genetic testing and Waived Testing)

GCLP – UNICEF, UNDP, World Bank, & WHO

MHRA: Good Clinical Practice for Clinical Laboratories – (Please see the comments/discussion on this.)

On The Blogroll: Dark Daily: News for Clinical Laboratories & Pathology Groups

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Draft Guidance: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. This guidance is open for public comment for 60 days (approximately August 7).
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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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FDA

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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 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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