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MONTHLY UPDATE - MAY 2014

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INTERNATIONAL PHARMACEUTICAL QUALITY Inside the Global Regulatory Dialogue

VOL. 5, NO. 4

CMC/REVIEW

• Top Excipient DMF Problem Areas for FDA Include Authorization Letters, Paper Filings, and Annual Reports.......................................................................................................................................................................................3

GMP/INSPECTION

• Progress of FDA’s Compliance/Enforcement Data Transparency Initiative Will Be Spurred by Refined Road Map from Working Groups.........................................................................................................................................................7

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UPDATES IN BRIEF - p. 27

U.S. CMC: • Expedited Approval Guidance • eCTD Submissions • ANDA Stability Q&A • Generic Equivalency • Regulatory Research • Centers of Excellence • USP Organic Impurities • USP 2015 ResolutionsU.S. GMP: • Track/Trace Workshop • DQSA Distributor Compliance • Pew Track/Trace Study • Reimbursing Compounders • Compounding Warning Letters • Sun Integrity Warning • Anti-venom, Allergenic Product Warn-ings • Destroying Drugs at Border • ORA Specialization • FY 2015 User FeesEUROPE CMC: • EDQM Texts • EMA Annual Report • MHRA Early Access • EDQM Product Monograph • EU National PharmacopoeiasINTERNATIONAL CMC: • US-EU Reliance • Canada Biowaiver Guidance • FDA/PANDRH CooperationINTERNATIONAL GMP: • India’s Inspection Force • Re-Branding in India • India Charging Ranbaxy

EUROPE

GMP/INSPECTION • UK MHRA’s Compliance Management Upgrade Includes “Risk IntelligenceIT System” for Drug Inspection Targeting............................................................................................................................................................................13

INTERNATIONAL

CMC/REVIEW

• China’s FDA Voices Interest in Developing an Excipient DMF System at Meeting with IPEC China; India Among Countries Reviewing Excipient Regulatory Upgrades................................................................................17

• FDA and EMA Finalize Guidances to Help in Postapproval Change Management................................................22

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

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Top Excipient DMF Problem Areas for FDA Include Authorization Letters, Paper Filings, and Annual Reports

FDA wants the excipient industry to better understand the challenges that the agency faces in reviewing drug master files (DMFs) and to improve their filings so that they do not impede the drug application process.

At a DMF workshop held in conjunction with the IPEC/ExcipientFest conference in Raleigh, NC in late April, FDA DMF expert Art Shaw gave the participants an insider’s view of what the excipient DMF process looks like from the reviewer perspective and where and how shortcomings in the filings are making the process more difficult.

Key current DMF problem areas, he noted, include: ● the Letter of Authorization (LOA) ● paper rather than electronic filings, and ● annual reports.

In his presentation, Shaw offered valuable advice on how to avoid pitfalls and expedite reviews.

An update on the use of excipient DMFs and other excipient regulatory approaches around the world was also provided at the workshop by Lubrizol Global Manager for Regulatory Affairs and Strategies Meera Raghuram and Dow Corning Associate Scientist and Global Regulatory Compliance Manager Katherine Ulman (see story on p. 17).

Raghuram and Ulman, who served as co-chairs for the workshop, explained that IPEC is working on a redraft of its excipient DMF guide, and that one of the outcomes of the workshop would be to generate recommendations for the revisions.

Shaw is chairing the group working on a rewrite of FDA’s aging 1989 DMF guidance. He noted that the workshop discussions would also help inform the agency revision process, which is expected to be completed over the next year.

LOA Problems Can Delay Drug Applications

Shaw characterized the purpose and appropriate use of the LOA as “an important administrative, bureaucratic issue” that he has “been trying to get companies and reviewers to understand.”

The function of the LOA is to grant FDA authorization to review the DMF and the authorized party (AP) the right to incorporate the information by reference in a drug

application, although not to view it. The DMF will be reviewed by FDA only when it is referenced.

Shaw explained that the agency has “thousands” of DMFs that have been filed in the past ten years for which there have been no letters of authorization and therefore no FDA review.

The DMF expert stressed that the LOA submission and updating process is important to follow to ensure that reviews are conducted in a timely manner.

The holder must submit an LOA – two copies if it is in paper format – to the DMF team for entry into the agency database. It is then posted as part of the DMF. Following the posting, the holder sends an LOA to the authorized party. The AP then submits a copy of the LOA with their application.

“This is the only mechanism to trigger a complete technical review of the DMF,” Shaw explained.

The letter of authorization must contain a reference to a specific item in the DMF, which is “particularly important” for multi-item DMFs. The item should be specified by its code name, page number, and, “most importantly,” the date of the submission as it appears on the cover letter of the DMF submission – not an internal document date.

Shaw noted that while the regulations instruct inclusion of a volume number, “it is of no use to us, because your volumes are different from our volumes. For paper copies, we keep the folder until it is about two inches thick, and then we start another one. Or sometimes we will start another one if the volume is out for review. So you cannot count on your volumes being the same as ours.”

When changing authorized parties, the DMF holder should issue a new LOA to the agency and send a copy to the AP. Doing so ensures that the new party has authorization and that the agency is aware of it.

It is not necessary to resubmit an LOA on a periodic basis. However, the list of authorized parties should be submitted annually.

If authorization is withdrawn, “please notify your customer that you are withdrawing authorization and submit a

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‘Withdrawal of Authorization’ letter,” Shaw advised the workshop participants. “Do not just include it in the annual report.”

FDA Wants Electronic DMFs in eCTD Format

While not currently required, electronic filings offer distinct advantages for the agency and industry.

When an electronic application is submitted to the agency, it must follow the Electronic Common Technical Document (eCTD) format unless a waiver is granted. No waivers are granted for DMFs.

“So if you file it in electronic form, it must follow the eCTD, or it will be rejected,” Shaw explained. “Do not send in an electronic DMF by email. Do not send in a flat PDF file. It must be in the eCTD format, and it must either go through the gateway, or if it is in physical form, it must be sent to the Central Document Room.”

If a firm chooses to convert a paper DMF to electronic form, the FDA expects the document to be complete when it is converted and that all subsequent submissions be electronic, including the LOAs.

Shaw explained why electronic DMFs in eCTD format are much easier for reviewers to handle.

For each new paper submission, CDER staff must find the latest volumes on the shelves – volume A and volume B – place one copy of the paper submission in each volume, and return the volumes to the shelves. “This seems trivial,” the DMF expert commented, “but it is time-consuming when we get hundreds of submissions every day.

DMFs are filed by date of submission, and the paper copies are stored in a location that is remote from the reviewers. To view the file, the reviewer must find the date of submission on the LOA and request the paper copy from the document warehouse. Agency personnel must then locate the file in the warehouse, check it out, ship it by truck to the reviewer’s building, deliver the file, then reverse the process when the reviewer is finished.

Along with not having to handle paper copies, the advantages to FDA of the electronic filings include: ● having the entire DMF available in an organized fashion ● being able to copy information for inclusion in the review and analysis, and ● the ability for multiple reviewers to simultaneously examine the same document.

While the agency much prefers electronic DMFs, it cannot mandate the format since they are voluntary submissions. Other submissions to the agency are slated to become mandatory in electronic format under the current draft of the FDA Safety and Innovation Act (FDASIA) two years

after the final guidance is issued. FDASIA does recommend that DMFs be submitted electronically.

Transition to eDMF Has Challenges

From the filer’s point of view, for large paper DMFs, the cost of printing and mailing can be substantial, and an electronic DMF can be more effectively managed over its lifecycle. However, an electronic DMF can be costly to prepare.

At the workshop, Antoinette Azevedo from e-SubmissionsSolutions.com discussed the challenges of transferring from paper to electronic DMFs.

She echoed Shaw in stressing the agency’s strong preference that the excipient DMFs be submitted electronically and provided advice on addressing the challenges involved. “Be prepared to take six months to meet your deadline,” she advised.

The conversion process can be done in-house or outsourced. “If your volume is low and you do not have the staff to master the nuances of publishing, you may want to outsource,” she advised – a service her company is set up to provide.

Report AP Changes Annually

Two issues that generate “a lot” of questions, Shaw noted, are: ● the recommendation in the existing DMF guidance that the holder file an updated list of authorized parties (APs) annually rather than submitting a new list each time a firm is added, and ● the content of that filing vs. what aspects of the DMF should be filed immediately when they change is made.

Steps in the Paper-to-Electronic TransitionAt the IPEC workshop, e-SubmissionsSolutions.com’s Azevedo recommended that the following steps be taken in transitioning DMFs from paper to eCTD format:

● Consult with the agency on timing

● Perform a CTD-readiness assessment

● Determine whether the CTD will be put together in-house or outsourced

● Determine whether a document management system is needed

● Get a budget

● Implement the solution

● Participate in the pilots, and

● Enter production

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Shaw noted that he has seen “a lot” of cases where DMFs are in use for compendial excipients, although the excipients may not have been compendial at the time the DMF was submitted.

In many cases, excipient customers do not want to have filing problems, so they require the excipient manufacturer to file a DMF for the excipients they use.

Shaw commented that there would “probably” not be a filing issue for an excipient that is listed in the USP, but that companies will ask for a DMF filing “because they want to cover their bases.”

Workshop co-chair Ulman provided an example of an excipient Dow Corning produces that has a monograph in the USP – simethicone, an orally administered anti-foaming agent used to reduce bloating, discomfort or pain caused by excessive gas.

The monograph in the USP prescribes certain testing for simethicone. “But the truth is that we make six simethicones,” she said. “They all have different formulations. They all have different manufacturing processes. They all have different additives and different ingredients that would be reported but are not part of the simethicone monograph.”

The differing formulations have different compositions and impurity profiles, and it is important for a reviewer to have the DMF for the formulation referenced in the application. “We get requests for an LOA for our simethicone DMF more often than any other product that we have,” Ulman commented.

DMFs Misunderstood Overseas

Colorcon Global Regulatory Affairs Director and past IPEC chair David Schoneker turned attention toward Shaw’s statement in his presentation that FDA has thousands of DMFs that do not have letters of authorization and have never been referenced, and cited misunderstandings about the voluntary nature of DMFs overseas.

He noted that drug firms in China routinely ask to see a DMF or to be assured that one has been filed, and explained that in China, as well as in India and Latin America, firms think that DMFs are reviewed and approved by FDA and that “by having a DMF somehow it means that FDA has approved the excipient.”

Schoneker postulated that “many” of the non-LOA DMFs Shaw mentioned “probably” come from foreign manufacturers “who are trying to get into the business and

What the agency expects to see in the annual report is: a list of APs, including the date of the LOA; a list of parties whose authorization has been withdrawn, including the date of the withdrawal letter; and a list of all technical and administrative changes reported since the last annual report. If no changes have been made, a statement to that effect is expected.

“For some reason,” Shaw commented, “people seem to think that the list is a list of people who work for the holder or their agent who are authorized to add this list to the DMF. No – it is a list of parties that are authorized to reference the DMF.”

Other changes, such as those in technical or administrative information, including updates to stability data, must be reported as amendments when they occur (21 CFR 314.420(c)).

Although technical information can be submitted at the same time as the annual report, it should be specified in the header to call the agency’s attention to it and allow the reviewer to more readily see what has changed.

Technical and administrative changes must be reported at the time they occur, “because the DMF can be reviewed at any time when a review is triggered by reference in an application,” Shaw explained. “If there are changes made and not reported, the reviewer can waste valuable time reviewing obsolete information. We do not want that. You do not want that. And your customer does not want that. Because all of us are on a clock.”

Compendial Excipients Pose Challenges

One of the issues drawing attention during the discussion period that followed the presentations at the workshop was DMF use for compendial excipients.

Prepared Questions for Q&AThe following is a list of questions presented for dis-cussion at the DMF IPEC workshop.

● Have you established DMFs for both compendial and non-compendial excipients?

● Is your DMF in a paper or electronic format? If elec-tronic, is it in eCTD format?

● Any general feedback on DMFs?

● Would you support a fee-based system such as the one in Canada?

● Is there support for a system like in the EU where there is a split between confidential and non-confidential infor-mation?




who filed the DMF with no intentions of ever referencing the DMF simply so that they can say they have a DMF number. And that in many countries is taken to mean that it is a good quality excipient.”

Schoneker also pointed to Shaw’s statement that the agency may close a DMF if an annual report is not received for three consecutive years and a letter sent to the holder is not responded to.

That approach is “something we have kicked around in other IPEC discussions with FDA in the past,” Schoneker commented. He expressed support for closing a DMF if it does not have an LOA after some period of time. “What purpose is it serving other than maybe someone’s misguided marketing effort?”

A conference participant cautioned that it is important to “be careful about that expiration time, because it takes seven years minimum to get a new drug to market, and if you have a novel excipient as part of that application and it expires after three years, that is a problem.” She pointed out that “a lot” of manufacturers will not use a new excipient without a DMF, and it is important that the file stays active.

Schoneker commented that there needs to be some mechanism to deal with that possibility. “It is not an easy fix. But that is an area that needs to be looked at.” He maintained that continuing education is needed and that “having it written in guidance rather than coming from an individual will make a difference.”

eDMF Conversion Issues Draw Discussion

Conversion of paper DMFs to electronic format drew further discussion during the Q&A.

FDA’s Shaw pointed out that the agency would like the complete history to be available. If a DMF is submitted electronically with a new number, the agency will not know whether it has been reviewed before unless the history is presented in the DMF.

In addition, it is “useful” to indicate that an electronic DMF is replacing a paper copy and provide the DMF number. He noted that it is beneficial to use the same number from the customer perspective as well.

Schoneker commented that it could be “quite a hassle” to convert to electronic format and include all of the history if the DMF has “been around for decades.”

An audience member maintained that although it is time-consuming, the conversion exercise can be useful as it causes a review that may find issues that need corrected. Shaw agreed, noting that as he has found DMFs that were different

than what the DMF holder thought they submitted.

Schoneker asserted that there are a “large” number of companies that will not convert to electronic format because it is “a fairly complicated thing requiring a significant investment.”

Included are companies with a DMF “that could care less whether they sell to the pharmaceutical industry.” The firms put the DMF together “because their user wanted confidential information that the company was unwilling to supply.” He noted that firms will create the DMF as “a favor” so that the customer company can use it in a filing.

“There is going to be a sizeable percentage of DMF owners who are not going to do something that will cost a lot and is complicated,” Schoneker pointed out. He asked whether the agency would consider exploring whether some mechanism could be put in place for “peripheral excipient suppliers” that have DMFs to get relevant information to the agency electronically that will help improve the review but involve less work than a full electronic DMF.

“I would say probably not,” Shaw responded. “The reason is because…so much effort has gone into making sure that submissions are in a reviewable format. He characterized reviewing applications that are not in eCTD as a time-consuming “pain in the neck.”

“For many of those DMF holders, the DMFs are not reviewed anyway,” Shaw commented. “And we have no way of saying that, given the regulations, we are going to prevent someone from filing a DMF on paper. In order to get a regulation changed there has to be enough, let’s say, money, behind it. That is why GDUFA came into place after many years of industry saying that they did not want user fees for ANDAs. There was enough interest to make it work.”

Also put on the table was the question of whether excipient makers would support a system like EU’s, where there is a split between the confidential and non-confidential information in the DMF.

Schoneker commented that if the purpose is to separate the information that the firm wants to give to the user from what it does not want to give them, creating a new DMF system is unnecessary. “Why do you need a DMF for that? Why not just give it to the user? The US system really only covers the information that is restricted in the EU.”

Highlights Understand European GMPs Understand the Role of the QP

Plus:Clinical Trial Supplies: IMP Handling in Europe and the Role of the QPThe Role of PIC/S in a globalising WorldThe View of the FDA

ECA

ACADEMY

Delegates’ Voices:“The chemistry between speakers and delegates was great.” “Very interactive conference, very informative with real life examples.” “Great broad coverage on topics relating to the QP.” “I really enjoyed a conference that also addresses IMPs ! Thank you!”

Organisation / Contact CONCEPT HEIDELBERGP.O. Box 10 17 64D-69007 Heidelberg, GermanyPhone +49 (0) 62 21/84 44-0 Fax +49 (0) 62 21/84 44 [email protected]

Speakers

Richard M. Bonner Chairman of the ECA Foundation and the European QP Association

Dr Rainer GniblEU-GMP Inspectorate, Germany

Tor GråbergMedical Products Agency, Sweden

Dr Bernd RengerImmediate Past Chair of the European QP Association, Germany

Martine TratsaertJohnson & Johnson, Belgium

Mark Tucker, Ph.Dform. FDA Investigator and Compliance Officer, USA

FDA Speaker invited

European GMPs and the Role of the Qualified Person (QP)The Impact of EU Directives and Guidelines on the Supply Chain

Jersey City, NJ (New York City, Metro Area), USA, July 8-9, 2014

You will find more details at www.qp-association.eu

http://www.qp-association.eu

mailto:[email protected]

Will you play on our Team? IPEC-Americas is part of a global federation that brings together manufacturers, distributors and users of pharmaceutical Excipients to set-the-bar on quality standards. We strive to achieve harmonization of pharmacopeial monographs and cGMP-regulatory guidelines for world-class qualification of Excipient suppliers.

Key Players Wanted

www.ipecamericas.org I Tel: 571-814-3449

3138 10th Street N. Suite 500 I Arlington, VA 22201

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The impact of FDA’s compliance/enforcement data “transparency initiative” will continue to increase with the help of a road map released by the initiative’s working groups in late April.

One place where the impact of the initiative has already been clearly manifested is in a comprehensive public database of FDA interactions with pharmacy compounders (see IPQ “Monthly Update” March/April 2014, pp. 36-39).

The database is updated in nearly real-time and contains a list of all compounding firms that have been inspected since the agency’s inspection blitz began in the wake of the meningitis outbreak (see IPQ “Monthly Update” March 2013, pp. 30-34).

Included are links to all associated: ● 483s ● warning letters ● recall notices ● FDA and company press releases, and ● referral letters to state boards of pharmacy with recommended follow-up actions.

Improving internal software tools to facilitate data quality, promote more rapid reviews and posting of compliance information, and make the data more user-friendly, is one of eight facets of the transparency initiative that separate teams have been working on.

The late-April report outlines the progress the teams have made and provides their recommendations on how to advance the various facets.

Included in the report are three appendices that contain: ● a comparison of the current status of each of the agency’s centers regarding what data it makes available, how it is presented, whether graphics are used, and the availability of mobile access ● a survey of the current database structure that each center is using and the associated reporting capabilities, and ● a detailed listing of the web addresses where the various compliance and enforcement information currently resides.

Public Comments Help Inform New Roadmap

In late 2011, FDA issued its first report on the transparency initiative, labeled as “Draft Proposals for Public Comment to Increase Transparency by Promoting Greater Access to the Agency’s Compliance and Enforcement Data.”

The report put forth eight draft proposals for making FDA’s “publicly available compliance and enforcement data more

accessible and user-friendly.” Increased transparency of the data, the 2011 report explained, is intended to enhance the public’s understanding of FDA’s decisions, promote its own accountability, and “foster an understanding among regulated industry about the need for consistently safe and high-quality products.”

Following “extensive” public comment on the report and internal deliberation, FDA Commissioner Margaret Hamburg, for whom the initiative is a high-priority, adopted the eight proposals and created separate working groups with representatives from all of the agency’s centers and several of its offices to develop plans for addressing each of them.

Each of the groups has refined the plans for their piece of the initiative, which were compiled into the new report. In addition to the overarching proposal on improving internal software tools to facilitate data quality, rapid reviews and posting of compliance information, the remaining seven facets of the initiative explore the feasibility and benefits of:

● including additional communication tools on theagency website such as buttons to help promote stakeholder reporting of website or data errors

● using more graphics in agency reports and thedevelopment of mobile applications

● presenting data in a way to make it more user-friendly

● improving website search capabilities

● posting more data compilations and analyses inaddition to those already provided

● increasing the use of social media and othercommunication tools such as webinars, and

● providing context with the posted data to reduce thepossibility that it is not misused or misunderstood

[See below for more detail on the eight proposals along with recommendations on how to proceed from each of the agency working groups.]

In its report, FDA emphasizes that “the agency’s ability to analyze, design, implement, test and document these recommendations depends on the availability of resources.”

Progress of FDA’s Compliance/Enforcement Data Transparency Initiative Will Be Spurred by Refined Road Map from Working Groups

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Transparency High on Hamburg’s Priority List

At the opening session of the Food and Drug Law Institute (FDLI) annual meeting in Washington, D.C. in late April, FDA Commissioner Margaret Hamburg described how the transparency initiative – which she launched shortly after becoming Commissioner – fits in with her overall priorities for the agency (Hamburg’s full remarks on this topic are provided below).

A core part of her agenda has been to “bring new clarity and understanding to what we do, how we do it and why – for the general public, industry and other key stakeholders,” she explained.

Along with embarking on “important, new” public-private partnerships in various areas, “we have upgraded our communications, including a far more accessible web site, with more timely and useful postings, and more recent ventures with social media, from blogs to Facebook to

FDA COMMISSIONER HAMBURG ON THE TRANSPARENCY INITIATIVE

At the opening session of the FDLI annual meeting in Washington, D.C. in late April, FDA Commissioner Hamburg described how the transparency initiative fits in with her overall priorities for the agency.

When I was first appointed, more than a few people, some of whom were quite well informed in the ways of Washington, offered me the advice – unsolicited, of course – that I should plan to limit the expectations of what I could accomplish in terms of change or reform. The agency is just too big, the Washington bureaucracy too difficult and intractable, and I was further reminded that I would also have to deal with Congress.

They suggested that I pick a few issues or initiatives I thought were really important and where I might be able to get something accomplished in a couple years’ time. Now there was nothing especially wrong with that advice. But, as someone who had spent my professional life committed to strengthening structures and mechanisms to improve public health, it went against my basic nature and experience.

More significantly, as I took stock of the agency, its vast responsibilities, and its enormously talented and committed workforce – I came to the conclusion that if FDA was truly to fulfill its mission in the modern era, this was a critical time to reposition in several fairly fundamental ways, addressing substantive issues as well as structural changes. And so, the priority areas I have focused on have involved underlying institutional change and have revolved around three main themes: engagement, science and globalization.

Perhaps most importantly, I felt it was critical that we open ourselves up as an agency. To ensure that our vital work at FDA is done with the best possible input from stakeholders, and with the trust and confidence of the public we serve, it was imperative that we increase transparency, enhance stakeholder engagement, and strengthen partnerships across sectors, disciplines and components of government. This is essential to ensuring that we make the best possible decisions, extend our reach and impact, and make the most efficient use of resources possible.

We have been approaching this in many ways. Through the transparency initiative, launched soon after my arrival as Commissioner, we sought to bring new clarity and understanding to what we do, how we do it and why – for the general public, industry and other key stakeholders. We have embarked on important new public-private partnerships in many domains of activity. And we have upgraded our communications including a far more accessible web site, with more timely and useful postings, and more recent ventures with social media, from blogs to Facebook to Twitter.

We also have been undertaking regular listening sessions – hearing from various leaders, experts, and advocates, seeking ideas and feedback, as well as our recent efforts on patient-centered medicine, including holding dozens of public meetings with patient advocacy groups for specific diseases.

If you look across our many accomplishments in the past year, and there were many – they all build on this model. Our ongoing conversations with stakeholders informed the rollout of these important initiatives. With strong stakeholder engagement and being very clear and transparent about what we wanted to do and why, there was better information flow and fewer surprises.


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FDA TRANSPARENCY INITIATIVE PROPOSALS

The following are the eight proposals as described in the late-April working group report on FDA’s transpar-ency initiative and the working groups’ recommendations. The recommendations reflect the public com-ments on the preliminary 2011 initiative report.

Initiative 1: FDA will explore different ways to improve data quality and facilitate more timely data disclosure by expediting data entry, expediting inspection review and classification, and/or updating the data more frequently. Tools to improve data quality and speed data disclosure may include, for example, providing new technologies to investigators, introducing other process improvements, and/or implementing administrative incentives. To implement these types of tools effectively, FDA also will explore how frequently data should be updated in order for it to be useful to stakeholders.

Recommendations:

FDA should:

● continue efforts to consolidate basic facility information in one place, establishing a single authoritative source for facility identifying information,

● embrace Master Data Management as an implementation priority,

● expand and standardize the electronic tools and procedures available to FDA staff,

● continually assess the utility of its electronic tools to support enhanced investigator efficiency,

● consider system changes that enable facilities to submit their compliance and enforcement information electronically, and

● consider using standardized investigator forms to help promote reporting consistency.

Twitter,” Hamburg said.

The transparency initiative aims to enhance stakeholder engagement and strengthen partnerships across sectors, disciplines and components of government. The commissioner characterized these actions as “essential” to ensuring that “we make the best possible decisions, extend our reach and impact, and make the most efficient use of resources possible.”

While not specifically referenced in the April report, FDA’s metrics effort reflects the priority the agency is giving to increasing communication and transparency with industry in the GMP compliance arena with the goal of creating a more informed and better targeted regulatory process.

The development of objective and transparent metrics is intended to help FDA shift from an inspection to a more flexible surveillance-oriented mode based on a better

understanding of the compliance risks, and the agency has been dialoguing with industry on what metrics would be viable (see IPQ “Monthly Update” January 2014, pp. 13-20).

EMA has also been focusing on increasing the accessibility of its compliance information (see IPQ “Monthly Update” Jan./Feb. 2013, pp. 48-49). In December, EMA launched a new version of the EudraGMDP database which includes, among other changes, the making public of statements of non-compliance with EU GMPs, along with the list of companies that have been issued GMP certificates (see IPQ “Monthly Update” January 2014, p. 33).

DOWNLOAD FROM THE STORY: • FDA April 2014 transparency initiative report

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http://www.ipqpubs.com/issues/ipq-monthly-update-jan-feb-2013/

http://www.ipqpubs.com/issues/ipq-monthly-update-jan-feb-2013/

http://www.ipqpubs.com/wp-content/uploads/2014/06/FDA-Transparency-Initiative-April-2014.pdf


WWW.IPQPUBS.COM MAY 2014 10


. Initiative �: Although FDA’s inspections database web page currently provides an e-mail address where stakeholders can submit questions about the database, FDA will explore whether (1) reporting buttons, or other tools specifically focused on error reporting, would allow stakeholders to more easily identify potential errors in compliance and enforcement data, and (�) the agency can implement procedures for investigating potential errors and correcting data, when appropriate, that would enable the agency to remedy the errors more expeditiously.

Recommendation:

Because tools and processes were considered adequate, Working Group 2 has no recommendations at this time.

Initiative �: FDA will explore how to present its compliance and enforcement data graphically and better utilize mobile web applications to draw more users to its compliance and enforcement web pages and to encourage data analysis.

Recommendations:

● A centralized entity should be responsible for the knowledge management required for transferring lessons learned from ongoing initiatives that graphically present compliance and enforcement data, develop mobile web applications, or support data analysis.

● Modifications and updates to ORA’s Inspection Observation Database should be assessed and modifications made to encourage and assist users in data analysis. Currently, the site provides information on inspectional observations by fiscal year and in a downloadable data set.

● FDA should consider additional usability efforts to enhance the navigation of its web sites and make compliance and enforcement data more accessible.

● A stakeholder needs assessment should be performed to determine which data would benefit from graphical display or a mobile web application.

● Additional feedback should be solicited from regulated industry and other stakeholders before moving forward with the development of mobile applications.

● Now that it has developed a mobile web site, FDA should evaluate the use of QR codes [Quick Response Code is the trademark for a type of matrix or two-dimensional barcode]

● The Working Group for Initiative 3 also adopts and incorporates by reference the recommendations 1 and 4 advanced by the Working Group for Initiative 4.

Initiative �: FDA will explore whether it can better integrate its compliance and enforcement data, as well as its other publicly available data on regulated firms, to make the data more user-friendly and easier to analyze.

Recommendations:

FDA should:

● implement a dashboard tool to enable presentation of compliance and enforcement data in a user-friendly manner,

● provide additional funding for the Office of Regulatory Affairs Reporting, Analysis, and Decision Support System (ORADSS, a data mart) to enhance integration of the compliance and enforcement data available in its siloed data universes,

● empanel a board to study and advance recommendations to enhance navigation of the web sites that make compliance and enforcement data available, and


MAY 2014 11


● establish and support an editorial board for the agency-wide compliance and enforcement web page (i.e., www.fda.gov/iceci) to improve access to all of FDA’s posted compliance and enforcement data.

Initiative �: FDA will explore whether additional, or more specific search criteria (e.g., criteria that would enable individual product-specific or violation-specific searches), or more sophisticated search capability (e.g., predictive name searches) would make the inspections database more user-friendly and the data easier to analyze.

Recommendations:

FDA should:

● implement the use of dashboards to enhance search capability,

● expand the use of application programming interfaces, and

● make predictive search/predictive text capability available.

Initiative �: FDA will explore whether posting additional data compilations or analysis, such as the agency’s most common inspections observations or the warning letter compilations, both of which it already posts, would increase transparency or better inform the agency’s own compliance efforts.

Recommendations:

FDA should:

● update data regularly, and

● expand the amount of compliance and enforcement data it makes available in the form of compilations and analyses.

Initiative �: FDA will explore ways to make better use of social media, such as Facebook and Twitter, as well as agency-sponsored webinars and automatic e-mail notifications to better communicate with the public about its compliance and enforcement efforts.

Recommendations:

FDA should:

● establish and implement a strategy to increase the dissemination of and audience for FDA compliance and enforcement data through social media, and

● enlist the assistance of its subject matter experts when responding to questions using social media.

Initiative �: FDA will provide appropriate context for the compliance and enforcement data that it discloses to help ensure that the data are not misinterpreted or misused. Depending on the circumstances, appropriate contextual information may include, without limitation: ● information regarding how frequently the data are updated ● information regarding the reliability of the data ● information regarding the average lapse of time between the inspection and the posting of inspection classification information ● definitions of inspection classification types (i.e., official action indicated (OAI), voluntary action indicated (VAI), or no action indicated (NAI)), and ● a statement explaining that the web site’s lack of information regarding a particular facility does not imply compliance or non-compliance (i.e., users should not infer that facilities that have not been inspected recently, or at all, are (or are not) in compliance with FDA laws and regulations).

Recommendations:

FDA should:


WWW.IPQPUBS.COMMAY 2014 1�


● create a frequently asked questions (FAQ) guidance document to provide appropriate definitions and contextfor compliance and enforcement data,

● make the compliance and enforcement data it discloses more prominent on its web site, and

● improve the organization and consistency of its posted compliance and enforcement data and develop aneditorial board dedicated to the main compliance and inspection data web site (www.fda.gov/iceci). This web page should be clearly accessible from the primary FDA web site and contain links to all such available data FDA discloses.

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MAY 2014 1�


UK MHRA’s Compliance Management Upgrade Includes “Risk Intelligence IT System” for Drug Inspection Targeting

EUROPE

U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) is creating a comprehensive “Risk Intelligence IT System” for determining where to deploy its inspection resources that captures and analyzes a wide variety of inputs from industry, public, and agency information sources.

Data feeding into the revamped risk-based inspection planning system will include: ● agency inspection reports ● network market intelligence ● media reports – for example, dramatic shifts in company share prices ● information from whistle-blowers, and ● information from other government regulatory agencies such as FDA or Australia’s TGA.

The new system complements a broader MHRA effort that is aimed at improving its interactions and communication with industry and getting a better handle on where compliance and drug shortage risks are located before they manifest themselves.

At a PharmaLink conference in March in Cincinnati, Ohio, co-sponsored by FDA and Xavier University, MHRA GMDP Inspections Group Manager Mark Birse reviewed his agency’s initiatives in these areas.

The new Risk Intelligence IT System has three different statistical models that interlink, and by analyzing data over time, will make a recommendation on how soon the next inspection of a site should take place.

Birse pointed out that, previously, manufacturing site compliance information did not all reside in the same place, and thus was not considered in a holistic manner.

“If I had information and one of my colleagues had information, unless we spoke, we wouldn’t link that up,” he commented. “Now as long as I have put it in the system and they have put it in the system, the system will bring those two pieces together and perform the correlation.” [Birse’s complete remarks on MHRA’s new risk-based inspection scheduling model are provided below.]

Compliance Management Team Formed

Efforts underway to address supply chain and compliance risks before they occur and improve agency communication of compliance information and consistency of interpretation will be under the purview of a Compliance Management Team (CMT), formed recently by Birse in his inspections group at MHRA.

The three primary functions of the team are to: ● anticipate supply chain and compliance risks, especially for sites

that are the single source of critical medicines, and put together mitigation plans ● improve compliance-related communication with industry, and ● implement a risk-based escalation process regarding inspection results within MHRA.

The process used to anticipate compliance risks that may lead to drug shortages begins with seeing GMP problems at a manufacturing site, then creating a list of the products manufactured at the site and determining whether any of those products are classified as a critical medicine in the U.K. or in any of the 27 EU member states.

If the site is manufacturing a critical medicine, a decision must be made that balances the extent of the compliance issues with the needs of patients.

The decision may be that the site is unacceptable and that its GMP license should be cancelled. Alternately, Birse noted, the GMP certificate may be modified to allow the manufacture of only specific products that are critical if the agency determines that “it is better for the patients to have that medicine than no medicine.”

The next step is to work with the marketing authorization holder to formulate risk mitigation plans to bring the plant back into GMP compliance.

Industry Team to Support Compliance Info Sharing

Also under the purview of the CMT is an effort to improve communication of compliance-related information to industry. To help in the improvement efforts, it has pulled together a team from industry with the help of various trade associations that includes representation from the U.S., Europe, India, and the U.K.

The aim is to take information on non-compliance uncovered during inspections and share it with industry in a way that serves to communicate agency expectations.

In addition to sharing “critical” and “major” findings, the agency is exploring a way to capture the findings classified as “other” and arrange all three categories together in a way such that underlying trends may be revealed. One format being discussed is a pyramid that would relate the more numerous but less serious “other” findings at the base to the major and critical citations at the top.

“We are looking at ways that we can collect that information, and rather than us just putting it in a nice pie chart or a nice tick-off box showing that we have done something – actually providing industry with some raw data that you can take away and manipulate as you like to help you improve your




own businesses,” Birse commented.

MHRA is also looking at using the inspection information to create a system that compares drug manufacturers’ compliance positions, as FDA is trying to do with its quality metrics initiative (see IPQ “Monthly Update” June 2013, pp. 12-20 and January 2014, pp. 13-20).

Under discussion is the level of stratification that the agency will employ – for example, the population of all companies the agency inspects vs. by dosage manufacturer in a particular region or country.

The objective is to be able to assess how companies compare to their peers and provide “almost a health check to see how your performance is,” Birse explained.

Agency and Industry Training Underway

Training that includes regulators in less-developed countries as well as industry is among the specific actions MHRA is taking to better communicate its compliance expectations.

A recent example of regulator training took place in January in India, provided by a team that included Birse and representatives from WHO and FDA’s India office.

The team traveled to three different regional Indian FDA offices and trained the local regulators on international harmonization efforts along with EU, WHO and FDA GMPs, with the goal of helping them “get more appreciation of what we are looking for and what we view as important,” Birse explained.

For the last several years MHRA has conducted an annual symposium for industry in London, providing one day each of updates regarding GMP and GDP expectations. The most recent session was held in early December, and included about 1,000 participants.

The U.K. agency is also exploring increasing its use of social media to convey compliance expectations – for example, using news feeds or twitter tocommunicate real-time examples of recent non-compliance findings.

Under consideration is the use of YouTube or a similar medium to provide training in lieu of conveying expectations during inspections. Birse provided an example regarding wholesalers, noting that the U.K. has about 1,800 wholesale license holders with nearly 4,000 sites, and a team of 18 inspectors to cover them.

“So if you do the math, it is going to take a long time to get around to all them,” he pointed out. “If we want to tell them something, it is not via inspection. Because in” the six years between inspections, “the message has probably changed.”

Conveying expectations to the wholesalers may take the form of producing short videos and mandating that the firms watch them and provide

documentation that the training was delivered and understood.

Confirmation of the training would be filed by MHRA and the firm’s understanding would be confirmed during the next inspection. If the issues discussed in the training are discovered during the inspection, “then there are probably data integrity issues,” Birse commented.

Risk-Based Escalation Process Taking Shape

An MHRA escalation process for compliance findings that in some ways mirrors an FDA warning letter, instituted by the agency in 2013 (see IPQ “Monthly Update” July/August 2013, pp. 16-21), is being further formalized with the formation of an Inspection Action Group (IAG).

When an MHRA inspector finds a compliance problem that is deemed “critical,” the finding goes to the IAG, a cross-functional team that includes a broad range of disciplines within the agency.

If potential supply issues are present, U.K.’s Department of Health is also included in the discussions. In turn, the Council of Europe may also be consulted to determine of the medicine that may go into shortage is has been deemed essential in a member state other than the U.K.

Prior to the IAG taking action, a letter is sent to the CEO of the firm in question to explain the issues in an attempt to head off regulatory action. Birse provided a nautical analogy on how the process is envisioned to help companies in trouble (see box below).

“We are trying to see how we can help companies really stay away from the problems that come from non-compliance. It is not good for us as regulators. It is certainly not good for patients and shortages. It is not good for your shareholders. And it is certainly not good for your either staff if they lose their jobs.”

MHRA Warning Letter AnalogyAt the Xavier/FDA conference, MHRA’s Birse pro-vided the following analogy to illustrate how his agency envisions that its use of “warning letters” will help a firm avoid major compliance pitfalls:

“There are two ships setting sail for the Americas from the UK. There is a problem on the horizon. It is there and they can see it.

Now let’s say that one ship decides to do nothing about until it gets closer. It is a huge problem. It is ‘game over’ for them really. It is too late for them to do anything.

But if the other ship runs into the exactly the same problem on the horizon and we write to that captain and say ‘there is a problem here. We know that for other people that has caused a real problem. Just change directions slightly. Just try to bring your ship back on course and let’s see what we can do.’ And that is one of the sister ships of the Titanic that did make it.”

http://www.ipqpubs.com/issues/ipq-monthly-update-june-2013/


http://www.ipqpubs.com/issues/ipq-monthly-update-%E2%80%93-julyaugust-2013/



MAY 2014 1�


MHRA’s MARK BIRSE ON THE RISK INTELLIGENCE IT SYSTEM

At the Xavier/FDA conference in March 2014, MHRA’s Mark Birse discussed his agency’s Risk Intelligence IT System for inspection planning. Birse describes the inputs to the system, the statistical decision-making models it uses, and the impact to inspection frequency at both company and individual site levels.

This is a very complicated slide and I will try to explain it. This is how we have adapted our risk-based inspection program last year. We have had one since 2009. But this year we have a new system that tries to do a bit more with it.

Let’s break this slide down into three sections: the dark blue on the left, the middle section in the pale blue, and the dark blue on the right.

Take the left hand section first of all. The top-left hand corner is the kinds of information we gather from industry stakeholders. It is the information we get via regulatory sources from within companies, information we get from manufacturing sites, or what we get from self-assessments and data inputs.

We have a system where if we have inspected you as a facility, we may tell you that we are not going to come back for a couple of years. Then something significant happens at your site. Maybe you make a change. It may be that you decided to put in a night shift. Or you halve the workforce. Or you have taken on a whole new agreement that means you are quadrupling production. We want you to tell us those types of things. And we have a system, a self-assessment form that you use to tell us about those types of things. So all of those we have as data entries.

Then we also have stuff from other stakeholders, such as: ● network market intelligence ● what we see in the media – the share-prices could be going up or down dramatically ● information from whistle-blowers, and ● what we hear


WWW.IPQPUBS.COM MAY 2014 1�


from other government agencies – so what we hear from the FDA or the Australian TGA. All of that becomes information.

How our new system works – looking at the first white box moving across the slide – is we have some inspectorate information. So we perform an inspection, and based on the findings, depending on how many criticals and majors we have, we decide when we are going to re-inspect. That goes into our system. Our system is called Sentinel. I think I mentioned that Accenture designed that for us a few years ago. It captures everything that we have and how we work as an agency.

What we now do is that all of the information that is coming from industry and the other stakeholders, gets put into a program called the ‘risk information case folder.’ We assign a risk to that piece of information between one and five. It can be one to five on a scale going bad, or one to five on a scale going good. A good piece of information isn’t just that the FDA came to us and said ‘we have been to this site and it was terrible.’ If they have been to a site and said it was good, this is a good piece of information that can allow us to adapt our inspection schedule.

We have then worked with Oracle, which has developed a program called ‘Empirical Risk.’ We have a long-standing relationship with them as an agency back through two various guises of the company that is now Oracle. All of our pharmacovigilance monitoring across the whole agency and the way we have the yellow card system and how adverse reactions are reported, the way the whole of that statistical model works has been designed by this company that has been bought twice since it was part of Oracle.

Empirical Risk that we are now using has three different statistical models that interlink. It takes that data and over time. Rather than us say we will only go back in two years, the system will now take all of the data we put in and start to make those decisions to say whether we should be going earlier or going later to that site. The other good thing with this system is previously, if I had information and one of my colleagues had information, unless we spoke we wouldn’t link that up. Now as long as I have put it in the system and they have put it in the system, the system will bring those two pieces together and perform the correlation.

We can also view risk across different levels. We can look at individual sites and ask what the risk is of that individual site, or we can widen it and ask what the risk is at that company. We can also look at a company with different arms and different areas and then bring it up to the top corporate level and look at the risk within that organization as well. So it helps us with all of those decisions.

The bit in the right-hand side in the dark blue is just explaining that business process. We are collecting information in this process, we have standard business rules against that. But the outcome is that we have a risk-based inspection program that is now adaptable depending on the risks we are seeing from industry.

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MAY 2014 1�


China’s FDA Voices Interest in Developing an Excipient DMF System at Meeting with IPEC China; India Among Countries Reviewing Excipient Regu-latory Upgrades

INTERNATIONAL

China is among countries giving consideration to Establishing a drug master file (DMF) system for excipients, as regulators world-wide seek to rationalize and improve their approaches to excipient oversight.

Interest in an excipient DMF system was expressed by China’s FDA (CFDA) at meetings in late April with the International Pharmaceutical Excipients Council (IPEC) China and the U.S.-China Joint Commission on Commerce and Trade (JCCT).

IPEC China is planning to sponsor a workshop for CFDA on excipient DMFs in late 2014 or early 2015 that would include participation of the U.S. FDA.

An update on the use of excipient DMFs and other excipient regulatory approaches around the world was provided by Lubrizol Global Manager for Regulatory Affairs and Strategies Meera Raghuram and Dow Corning Associate Scientist and Global Regulatory Compliance Manager Katherine Ulman at a workshop held on April 28 in conjunction with the IPEC/ExcipientFest conference in Raleigh, NC.

Raghuram and Ulman, who served as co-chairs for the session, explained that IPEC is working on a redraft of its excipient DMF guide, and that one of the outcomes of the workshop would be to generate recommendations for the revisions.

Also presenting was FDA DMF expert Art Shaw, who discussed the content, management and maintenance of excipient DMFs at the agency. Shaw is chairing the group working on a rewrite of FDA’s aging 1989 DMF guidance. He noted that the workshop discussions would also help inform the agency revision process, which is expected to be completed over the next year.

A fourth presenter at the workshop was Antoniette Azevedo from e-SubmissionsSolutions.com, who discussed the challenges of transferring from paper to electronic DMF systems. She echoed Shaw in stressing the agency’s strong preference that the excipient DMFs be submitted electronically and provided advice on addressing the challenges involved.

Receiving particular attention from Raghuram and Ulman were the excipient regulatory approaches in

China, Japan, Canada, Australia, Russia, and India.

One problem facing excipient manufacturers when filling out an Import Drug License (IDL) for China is the requirement for submitting a “free sale certificate,” which certifies that a firm is free to sell the excipient in the country in which it was manufactured. Most regulatory agencies, including FDA, do not issue such a document. Raghuram commented that acceptable documentation can sometimes be obtained from the U.S. consulate in China.

While Japan is one of three countries that have excipient master file systems – along with the U.S. and Canada – the voluntary submission process is not straight-forward.

Japan requires an in-country “caretaker” of the DMF that is located in Japan to take ownership of the file and provide it in Japanese. In addition, DMFs in Japan cannot be submitted independent of a drug application. For the DMF to be submitted, a sponsor needs to reference the DMF.

Canada’s system is very similar to that in the U.S. One

China Import Drug License RequirementsThe current “Import Drug License” in use in China requires the following information to be submitted for excipients. The expectations are very similar to those for APIs under the ICH CTD:

● Certified documents: - Statement of commitment to compliance to cGMP - Free sale certification - Certification of DMF, including product name, DMF registration number, and current DMF - Authorization to local entity to submit dossier - Warranty of patent and its ownership status● Production Process: - Chemical synthesis, process flow diagram, quantities of reactants, yield at each step, critical process steps, controls - Production equipment and specifications - Control of critical steps and intermediates - Process Validation - Batch size● Chemical structure, including analytical methods and rel-evant literature information● Prescription of product if marketed in the U.S. or EU● Packaging insert (assumes a drug product with dosage and use information● Pharmacology/toxicology studies● Clinical studies




difference is that a charge is incurred for each DMF that is submitted. During his talk, Shaw pointed out that for the first time, the latest reauthorization of the Generic Drug User Fee Amendment (GDUFA) also requires fees, but only for certain types of DMFs.

Australia’s Therapeutic Goods Administration (TGA) does not have an excipient drug master file. Instead, it has a “register of therapeutic goods,” and maintains a public list of what kinds of applications specific ingredients can be used for. Ingredients must be entered on the Australian Register of Therapeutic Goods (ARTG) before they can be lawfully supplied in or exported from Australia.

Brazil does not have a DMF system. However, in May 2012, its regulatory agency ANVISA published a draft resolution for GMP compliance by manufacturers of pharmaceutical excipients. The requirements were largely based on the IPEC-PQG excipient guide (see IPQ “Monthly Update” July/August 2013, pp. 38-49).

Interest in excipient DMFs in Brazil will also be a topic of discussion at a Pharmaceutical Products Manufacturers Union in the State of São Paulo, Brazil (Sindusfarma) “Excipient Workshop” it will be holding in Brazil on August 26, 2014.

Russia is another country without a DMF system. It does require all APIs to register, but excipient registration is voluntary. If an excipient is registered, the same type of information is requested that is generally submitted in a drug application or an API registration. In general, drug companies in Russia avoid using materials that are not registered.

India Lacks DMF System; Expectations Unclear

India’s lack of a DMF system along with different sets of rules for excipients that are or are not listed in the Indian Pharmacopeia (IP) makes getting the materials approved for use in India a challenge, particularly for companies that are not physically located in the country.

At a session of the IPEC ExcipientFest conference, Colorcon Global Regulatory Affairs Director David Schoneker – a past chair of IPEC who has been instrumental in expanding the association’s global presence – reviewed the history of excipient regulations in India and provided insights into the complexities of the Indian regulatory system.

Current drug and excipient regulations are based in large part on the Indian Drug and Cosmetics Act of 1940, and their interpretation and enforcement are divided between central and provincial agencies. These include the Central Drug

Standards Control Agency (CDSCO) – generally referred to as the India FDA – and the Drug Controller General of India (DCGI) as well as drug agencies in each of India’s 28 provinces.

Excipient regulatory requirements are “hard to find,” Schoneker, adding that there are no specific regulations for excipients other than having to comply with the IP or other international compendia.

“If an excipient has a precedence of use in India or any other country – for example, appearing on FDA’s IID [Inactive Ingredients Database] list, in a compendial listing, or even an FCC [Food Chemicals Codex] listing – that would justify the use of that material as an excipient in India,” at least in principle. In practice, requirements for the use of excipients into India gets more complex.

IP Materials Regulated by India FDA

Schoneker explained that only excipients claiming IP status are controlled by the India FDA. The manufacturer of the IP excipient is required to be registered and have a drug manufacturing license, which is subject to inspection and is renewable every five years. “That works for an Indian manufacturing company,” he commented. But for a firm outside of India there is no mechanism for claiming IP conformance “because there is no mechanism to issue a manufacturing license” to a foreign firm.

However, for the registration of imported drugs, which include atypical actives – known in India as “dual purpose” substances – there is an importing process.

The process includes payment of a $2500 registration fee and requires inspection of the manufacturing facility by Indian regulators, with an inspection fee of about $5,000, which the excipient manufacturer must pay. Also needed is a one-time “special clearance” from DCGI.

There is no registration certificate required if the material is simply an inactive bulk substance such as an excipient for use in a pharmaceutical formulation.

“This is where the confusion begins, because it starts to create problems at customs,” Schoneker emphasized.

“What is the material? It is coming in. It could be used as an active. It could be used as an excipient. There is a process for the active. There is no process for the excipient. What does the customs guy do?”

Schoneker pointed to attempts at Indian ports to reclassify excipients as food additives, especially if they claim to




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interpretations that Schoneker characterized as “critical” to resolve (see box below).

The affiliate’s first public event in India will be an excipient control conference, targeted for late 2014 or early 2015.

IPEC currently has four other independent regional associations in its federation: IPEC-Americas, IPEC Europe, JPEC in Japan and IPEC-China. A working arrangement with Brazil’s Sindusfarma, through which similar functions are being performed, is also in place.

Hamburg’s India Visit Triggers Reactions

In mid-February, FDA Commissioner Margaret Hamburg traveled to India to meet with government officials on quality and other regulatory topics (see IPQ “Monthly Update” March/April 2014, pp. 19-29). This visit included the signing of a “Statement of Intention” to clarify the points on which both countries will cooperate, such as: ● sharing of CGMP compliance and facility information, ● India observing FDA inspections, and ● enhancing communication and public meeting collaboration.

Schoneker commented that during the commissioner’s visit to India she made “good, needed statements” regarding the quality that drugs need to possess to be exported to the U.S.

“There has, unfortunately, been a very significant reaction to her trip,” he said, “and not necessarily the reaction that we would have hoped for. You would hope that people would look at that kind of statement and say, ‘we have some issues. We need to fix some things. Let’s move forward.’”

Instead, “many” companies in India interpreted the statements as FDA protecting U.S. businesses. “That is not so,” Schoneker emphasized. “It has nothing to do with it.” He also noted that some Indian regulators have made “some interesting statements.”

Shortly after Hamburg’s visit, “all of a sudden a number of regulatory requirements started to change.”

Some of the requirements relate to excipients, and “the requirements we are seeing now would be very difficult and costly for us to meet as global excipient manufacturers and even as users.” Schoneker pointed specifically to “new interpretations” regarding mandatory micro testing and expiration dating requirements for excipients (see box below). His remarks on the situation in India speak to the vagaries that the pharmaceutical community faces in excipient regulation around the world.

meet FCC criteria. There is a “much higher duty” on food additives than on excipients, he noted.

If there is an IP monograph for the material, it is required by law that it meets the criteria of the monograph to be used in drugs. If, however, there is no IP claim from the manufacturer – such as would be the case for an excipient imported into India – then the user has full responsibility to ensure the excipient’s compliance to the IP monograph.

“That means in every case, full testing on every batch” the Colorcon exec explained. “If you are importing into India and have no ability to claim IP, but there is an IP monograph, your customer is going to have to test every batch for every test in the IP monograph.”

Registration/Change Expectations of Concern

Schoneker explored what excipient information must be submitted in Indian drug applications and the approval processes required for a drug manufacturer to make changes to excipients in approved products.

An application for drug approval needs to list the excipients that are used in the drug preparation and include the “approximate” composition of the drug product and the master formula, including the quantity and compendial status of the excipients used. It does not require the name of the excipient manufacturer or the country of origin.

Regarding change notifications, none are required for changing an excipient supplier unless the specification has been changed. A change of excipient or level used can be made with a notification to India’s FDA and do not need pre-clearance. Changes in the color or flavoring agent requires prior approval.

While the API and coloring must be listed on the product label, excipients are not listed. There are no maximum levels prescribed for excipients, unlike in FDA’s case (see IPQ “Monthly Update” November/December 2013, pp. 16-27).

IPEC India Established

At the IPEC conference, Schoneker announced that an IPEC affiliate in India has now been officially launched. While it was incorporated in mid-January, the affiliate is still in its infancy, and just acquired the ability to begin accepting membership applications in early April.

In addition to sharing IPEC guidelines and providing excipient manufacturers and users a voice in excipient regulation, the affiliate will initially tackle recent regulatory

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COLORCON’S SCHONEKER ON CHANGES IN EXCIPIENT EXPECTATIONS IN INDIA

At a session of the IPEC ExcipientFest conference in late April, Colorcon Director and IPEC past chair Dave Schoneker reviewed recent changes to Indian regulators’ interpretation of micro testing and expiration dat-ing requirements for excipients. He explained the new interpretations, the impact they will have on excipient manufacturers importing into India and the firms using them, and the role the newly-formed IPEC-India may play.

A couple of weeks after Hamburg’s visit, several of us in IPEC happened to be at a meeting and [compared notes]. All of a sudden, customers in India started calling us asking for all kinds of information. We asked, ‘what is going on?’ We think [Hamburg’s] visit is what triggered it.

So what am I talking about? Let’s start off with the Indian Pharmacopeia microbial limits chapter that is very similar to the USP. According to the IP, in an announcement that came out after Margaret Hamburg’s visit, their new interpretation is that the parameters of this chapter are mandatory and must be reported by the raw material or excipient manufacturer on the certificate of analysis [C of A] for every lot. That means that we – the excipient manufacturer, not the user – have to do micro testing on every lot and put it on the C of A, otherwise it will not get through customs.

This new interpretation was announced in March, and went into effect on April 1. So we are currently in this situation. If you are exporting to India, do not be surprised if you start getting questions about where your micro results are.

The IP policy on testing each lot prior to quality release and reporting the results on the C of A is different than similar chapters we see in the USP and the EP, where, in fact, it is allowable to do periodic checks or process controls or other types of things were you have assurances that you do not have a microbial situation going on. For some materials, you do have to test every batch or test on a periodic basis. For other materials, you can justify that you do not really even need micro specs, depending on the material. That is not the case here….

In discussions within IPEC already, it is pretty clear that most excipient manufacturers do not perform routine micro testing on every lot unless their excipient has a significant likelihood for microbial growth. Since this new policy has come into effect in India, it will certainly have a huge impact on a manufacturer’s ability to supply to the Indian market.

We are working with IPEC India, now in its infancy, saying, ‘your first project needs to be to go meet with the IP commission and talk to them about what is going on and how we can come up with a better resolution.’ I believe that meeting was scheduled for last week. I have not heard back yet on how that went.

Let’s switch gears to another expectation that has changed. All of a sudden excipient manufacturers have been receiving requests from customers saying, ‘you cannot send something to us, or you cannot import it, if it doesn’t have at least 60% of the remaining shelf-life on the product. If it is below 60%, you will not be able to import it, or I do not want it as a customer.’

This requirement, from what we understand, is based on the 1940 Indian Drugs and Cosmetics Act, which states that this requirement applies to all drugs. Excipients, by definition, fall into this category. There was a notice dated March 4 – right after Margaret Hamburg’s visit – that was issued to industry by CDSCO. It appears that notice is being used to enforce provisions in the act that have never been enforced before for excipients and APIs, which now have to meet this requirement.

In many cases, manufacturers have been advised that expiration dates are required for all excipients, and that a re-test or re-evaluation date – which is what we have in the IPEC guides – is no longer accepted. Even though it has been acceptable all along, everything now has to have an expiration date. And if the product is less than 60% from that expiration date, you are not going to get it in.

The Indian Drugs and Cosmetics Act does not provide any distinction between the shelf-life for an excipient or a finished drug product. Many other countries have differentiations as to how those are handled.

They are now taking these provisions into account, and the concept of re-test intervals is not acceptable any more,

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although that is what we use in many other countries.

This is a critical situation. Fortunately, IPEC-India has been formed, and can hopefully start to have some influence. But remember that we are in our infancy. We just got to a point where we can accept membership applications about two weeks ago. We are trying to get involved in the situation to hopefully change the outcome.

If we cannot get this changed, there will be a significant impact on the availability of high-quality excipients for use by the Indian pharmaceutical industry for the domestic market. Hopefully, IPEC-India will be able to negotiate some sort of modifications in the implementation of the regulations that may work for the excipient industry and ultimately for the pharmaceutical industry that uses these materials and has a significant need for them.

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FDA and EMA have issued final guidances intended to help industry better understand and manage the regulatory expectations for postapproval CMC changes.

In both cases, the final versions were impacted by a plethora of comments that came in on the drafts – reflective of the level of industry concern with the global filing burdens when making CMC changes.

The two guidances and the changes incorporated based on the comments, in turn, bear witness to the effort the two agencies are making to reduce those burdens and bring the CMC review paradigm into closer alignment with the continuous improvement orientation on the GMP/quality systems side.

[Editor’s Note: An in-depth review of the problems that global manufacturers face in making postapproval changes and the current industry/regulator dialogue around what can be done to address them is provided in IPQ’s February 2014 Monthly Update.]

FDA’s Guidance Fosters Annual Reporting

In March, FDA released the final version of its guidance on “CMC Postapproval Manufacturing Changes to be Documented in Annual Reports,” which had appeared in draft form in mid-2010. The guidance provides further clarity around the changes that FDA has deemed to be of low risk to product quality and able to be handled in an annual report.

The “background” section explains the basic structure of FDA’s risk-based, three-tiered change reporting system: “major,” requiring a prior approval supplement (PAS); “moderate,” requiring a changes-being-effected supplement submitted 30 days prior to making the change (CBE-30) or at the time of distribution (CBE-0); and minor, requiring notification in an annual report.

The “discussion” section explains how the increasing supplement workload and application of the risk-based regulatory principles in FDA’s 21st Century GMP initiative is reflected in the guidance. FDA’s evaluation, it notes, has found that many of the changes being reported in supplements present low risk and can be better handled in annual reports.

Key to the guidance are the two appendices, which constitute about half its length.

Appendix A provides specific examples of the various categories of changes that may be filed in an annual report, which were not specified in other FDA guidances. Appendix B, in turn, provides a summary of changes that are covered

in the SUPAC or “Changes to an Approved NDA or ANDA” guidances, and generally understood to not require supplements.

Appendix B was not included in the 2011 draft and is the most significant change made to the final version.

In conjunction with Appendix B, a “resources” section was also added that lists the other agency guidances that discuss reporting of CMC postapproval changes. These include the five SUPAC guidances released in the late 1990s, and the two guidances and Q&A issued between 2001 and 2004 on NDA/ANDA changes. Also cited is the overall compilation of the guidances applicable to the CMC section of drug applications on the agency’s website.

FDA notes that all of these documents should be referred to when making changes in addition to the new annual report guidance.

Labeling Changes Added to Appendix A

Appendix A is particularly significant because uncertainty around the listed changes may have prompted industry in the past to file them as a PAS.

In turn, the discussion section of the guideline cautions industry, before submitting a supplement based on recommendations the agency made in previous guidances, to “refer to the list of risk-based recommendations provided in Appendix A,” which indicate whether an annual report may be appropriate instead.

The guideline stresses that FDA’s change filing expectations are ultimately based on the evaluation by the NDA or ANDA holder of the risk to product quality.

A statement was added to the discussion section to clarify that “when a risk-based evaluation shows that the proposed change would have a minimum potential to have an adverse effect on product quality, the change can be documented in the next annual report.”

In a revised footnote, the agency explains further that it is “asking applicants to use scientific data from appropriate studies and risk analysis to determine whether changes should be submitted in a PAS, CBE-30, CBE-0, or annual report.”

The discussion section goes on to stress that “compliance with the CGMP regulations is required regardless of how the change is reported to the agency,” highlighting some of the key CGMP change control requirements that come into play.

FDA and EMA Finalize Guidances to Help in Postapproval Change Management

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A few additional clarifications were also added to the section in the guidance on the contents of annual reports.

Along with the names of the drug products involved in the change, the agency explains that it wants the description to include a reference to “any previously approved grouped supplements if the change affected multiple products.”

Related to the CGMP compliance dictates, the contents section adds the statement that “executed batch records, SOPs, and data from studies and tests performed to assess the effects of each change should be kept on file and made available to the agency on request (e.g., during an inspection).”

Both Appendices Deal With Component, Site, Process and Spec Changes

Categories addressed in Appendix A are drug substance and product post-approval changes related to: ● components and composition ● manufacturing sites ● manufacturing process, batch size, and equipment ● specifications ● the container/closure system ● labeling to revise information related to CMC changes, and ● stability testing.

The labeling change section (6) was added to the final version. Subsection 6.1 focuses on drug product labeling to reflect changes in the coating formulation, and 6.2 covers the issue for all changes in drug product labeling due to CMC changes. In both cases, FDA wants the Structured Product Labeling (SPL) reflecting the change, if revision is needed, to be submitted concurrently so that the information in the eLIST is correct.

A few of the examples in other sections of Appendix A were removed or condensed in response to industry comment on the draft.

The convenient consolidation of the existing agency

guidances provided in Appendix B focuses on the first four categories included in Appendix A: ● components and composition ● manufacturing site ● manufacturing process, and ● specifications.

Center for Drug Evaluation and Research (CDER) Small Business and Industry Assistance (SBIA) held a webinar in May to review the final guidance. Presenting at the webinar was Raj Uppoor, who heads up the CBE supplement review team for CDER’s Office of Pharmaceutical Science (OPS).

Uppoor commented that Appendix B includes annual reportable changes that “are well recognized and well-practiced. The reason we put it in this final guidance is to summarize them based on the common changes that we see.”

In general, FDA wants applicants to submit enough detail in the annual report to judge that the applicant has studied and understood the change and its effect. “There is some subjectivity here,” the CDER reviewing official said, but the agency wants industry to take “a common sense approach [and] communicate just enough detail to allow the agency to efficiently determine whether the appropriate reporting category has been used.”

The guidance revision, Uppoor summarized, is intended to make the annual reporting expectations “very specific and clear, and increase the list” of eligible changes.

Stability Testing at Issue for Excipient Changes

While industry in general is very appreciative of FDA’s effort to create more flexibility around post-approval changes and lessen the regulatory constraints around those that are lower risk, higher quality ingredient suppliers are sensitive to the need for assuring that the risks of changing suppliers based solely on cost are not underestimated or ignored in the regulatory process, creating an unlevel playing field.

The issue was raised in particular by excipient manufacturers in addressing the component section (section 1) of Appendix A in the draft. The section addresses the changing of coating formulations and more generally of inactive ingredient suppliers via annual reporting.

Colorcon was among those cautioning that the change of an excipient supplier of coating and other inactive ingredients can be of relatively high significance, and that “meeting acceptance criteria,” derived, for example, from a monograph, does not assure that the interaction of the components will not affect product performance and stability over time. For the supplier change to be annual reportable, the stability should be evaluated prior to making the change, the firm maintained – otherwise problems will not be found until the products are on the market.

Colorcon supported its comments by submitting examples

Added Guidance Clarification on Use of Annual Reports

The following was added to the discussion section of the final guidance to clarify its precedence over previous agency guidance on the use of annual re-ports.

To the extent that a recommendation in this guidance to document a single change in an annual report is found to be inconsistent with previously published FDA guidances, the reporting category recommended in this guidance would apply, assuming that the applicant’s proposed change would present a minimal potential to have an ad-verse effect on product quality.

For changes not addressed in this guidance, or for multiple related changes implemented simultaneously, applicants should refer to other CDER guidances (see Section V. Re-sources), as well as Appendix B, to determine the appropri-ate reporting categories (i.e., PAS, CBE-30, CBE-0, or annual report) for notifying the agency of the changes.




to FDA where stability was impacted by changing the ingredients in a coating system. In response to the industry input, the final guidance clarifies that the coating formulation change must be shown not to alter specifications (“i.e., tests, analytical procedures, and acceptance criteria for test results”) and stability as well as drug release.

FDA also put more specificity into subsection 1.3 on changing inactive ingredient suppliers via annual reporting, including provisions that the original supplier was listed in the approved application and that the inactive ingredient’s specification remains unchanged.

A factor now in the equation is the provision under Title VII of FDASIA for listing excipient suppliers and their manufacturing locations, etc., in applications, which was not previously a requirement.

The issuing of the new annual report guideline has generated discussions at the International Pharmaceutical Excipients Council (IPEC) about the term “specification” not being well-defined between industry and regulators and not necessarily interpreted to encompass the critical stability testing piece of the equivalency determination. The suggestion has been made to FDA that some additional guidance could be provided in a Q&A to clarify that meeting the specification would include a stability evaluation.

Type II Variation Examples in EMA 2014 Guideline

● manufacturer of a starting material, reagent or intermediate for an active substance where no Ph. Eur. Certificateof Suitability is part of the approved dossier

● manufacturing process of the active substance that may have a significant impact on the quality, safety or effi-cacy of the drug product

● immediate packaging of the active substance for sterile and non-frozen biological/immunological active sub-stances

● excipient composition of the finished products that may have a significant impact on safety, quality or efficacy

● coating weight of oral dosage forms for modified or prolonged release pharmaceutical forms where the coating isa critical factor for the release mechanism

● concentration of a single-dose, total use parenteral product, where the amount of the active substance per unitdose remains the same

● replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product

● manufacturing process that include the introduction of a non-standard terminal sterilization method orintroduction/increase in the overage that is used for the active substance that may have a significant impact on the quality, safety and efficacy of the drug product

● batch size for pharmaceutical forms manufactured by complex processes

● immediate packaging of the finished substance for sterile medicinal products and biological/immunological me-dicinal products, or changes that result in a less protective pack where there are associated changes in storage con-ditions and/or reduction in shelf life

● shape of the container or closure that may have a significant impact on the delivery, use, safety or stability of the finished product, and

● fill weight/fill volume of sterile multidose (or single-dose) parenteral medicinal product, includingbiological/immunological medicinal products.

The following is a list of the type II variations addressed in the final version of EMA’s 2014 guideline. Bolding has been added to indicate the general category into which the specific change falls.


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From the supplier perspective, the new guideance opens the door for the introduction of new coating materials for older marketed products that can improve them and their manufacturing. The concern is that the impact on functionality and stability is well-evaluated and the evaluation is a regulatory expectation to assure the quality of the marketed product and a level playing field at the supplier level.

EMA Clarifies Variation Stability Expectations

EMA, meanwhile, also in March published the final version of its “guideline on stability testing for applications for variations to a marketing authorization,” which encompasses the extensive comments received on a draft released in mid-2011.

The EMA guideline explains in general terms what the agency expects for type IA and IB variations, and provides specific examples elucidating the stability data requirements for type II variations.

The revision reflects the industry concern with lack of clarity in the agency’s 2005 guideline regarding type II variations – those defined as having a “potentially major impact on quality, safety, or efficacy of medicinal products” – which industry felt was not sufficiently addressed in the 2011 draft guideline focused on the stability implications of variations. The concern was that lack of clarity was leading industry to default to the most conservative filing category.

In its general comments on the 2011 draft, the European Federation of Pharmaceutical Industries and Associations (EFPIA) was among those requesting more specificity in the variation example descriptions, allowing industry to better understand when the example is applicable to a particular situation.

In response to the industry’s request for more clarity around the agency’s expectations for type II variations, EMA added more examples and more specificity to those it had provided in the draft.

The 2005 guideline addressed only three general areas of type II variations – in the manufacturing process of the active substance, in composition of the finished product, and in the immediate packaging of finished product – giving little in the way of the specifics for these changes. The 2011 draft contained 9 examples of type II variations, expanding to 19 in the 2014 final version (see box on previous page).

The specific examples added to the final version help clarify the degree of stability testing needed depending on the change.

When a change in the manufacture of an active substance occurs, three months of stability data is required for products known to be stable. The guideline defines an active substance as stable “if it is within the initial specifications when stored

at 25◦C/ 60 % RH or 30◦C/65% RH, respectively, (2 years) and 40◦C/75 % RH (6 months).”

For less-stable products, or if there are changes to the quality characteristics of the active substance, six months of data is required.

The guideline also requires six months of stability data following changes made to: ● excipients that may impact quality ● dosage forms ● batch size, or ● fill volume.

Along with the final guideline, EMA released a 75-page review of the various comments received from six industry associations and four pharma firms.

The comments are organized into categories, and each is dispositioned as “not accepted,” “noted,” “partly accepted,” or “accepted.”

In addition to the general EFPIA comment on the need for more specificity in the type II examples, other comments that the agency accepted included a request to standardize terminology that appears conflicting, a recommendation that the examples given relating to type II changes be carefully worded to avoid confusion, and clarification that stability data can be submitted from batches “of at least pilot scale.”

EC Q&A Updated Regarding Stability Studies

The EU also has a Q&A, issued by the European Commis-sion’s “Coordination Group for Mutual Recognition and Decentralized Procedures – Human (CMDh),” to help clarify the expectations for variation submission, classification,

Changes in Type II Example HeadingsThe following are two examples of the changes made to the headings in the examples provided in the 2011 draft of EMA’s guideline to make them more specific.

Draft: “Introduction of a new manufacturer of the active substance that is supported by an ASMF” Final: “Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suit-ability is part of the approved dossier: Introduction of a new manufacturer of the active substance that is supported by an ASMF” Draft: “Change in the manufacturing process of the active substance” Final: “Changes in the manufacturing process of the active substance: Substantial changes to the manufacturing pro-cess of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product”




approval, implementation, grouping, and worksharing.

The Q&A was updated in April to address notifying the agency regarding confirmatory stability studies for production scale batches after stability data for pilot scale batches had already been accepted.

A new question (2.13) notes that “it is not generally foreseen that these data are submitted…either via variation or simple notification” except in cases where issues arise during the studies with production-scale batches – for example, unexpected impurities or trends towards out of specification results.

DOWNLOADS FROM THE STORY: • FDA “CMC Postapproval Manufacturing Changes to

be Documented in Annual Reports,” �01�• EMA “Guideline on Stability Testing for Applications

for Variations to a Marketing Authorization,” �01�• Comments on EMA �011 Draft• CMDh Q&A on variation submissions

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MAY 2014 ��


Updates in Brief

CMC/REVIEW

FDA Releases Final Guidance on Expedited Drug Approval Pathways

In late May, FDA released a final guidance for industry on expedited programs for serious conditions, which reflects comments that came in on the draft released in June 2013 (see IPQ “Monthly Update” September 2013, pp. 2-12 and 11-23.). The guidance acts as a single resource for policies and procedures related to the four FDA programs designed to expedite approval: ● fast track ● breakthrough therapy ● accelerated approval, and ● priority review. The guidance contains definitions of the concepts surrounding expedited approval, as well as the qualifying criteria and features of each of the different programs. Also included are general considerations and appendices discussing the processes of the programs. [An analysis of the changes to the final version of the guideline will be included in IPQ’s upcoming coverage of the evolving dialogue on the CMC implications for the breakthrough therapy pathway.]

FDA Issues Documents Supporting Submission of eCTD

In mid-May, FDA announced the availability of four documents designed to support the submission of the electronic Common Technical Document (eCTD). The documents are: “The eCTD Backbone Files Specification for Module 1, version 2.3,” “The Comprehensive Table of Contents Headings and Hierarchy,” “Specifications for eCTD Validation Criteria,” and “Example Submissions using eCTD Backbone Files Specification for Module 1.”

CDER Releases Q&A on Stability Testing for ANDAs

In mid-May, CDER’s generics office issued a Q&A “to more effectively address the public comments” related to the September 2012 draft guidance on “ANDAs: Stability Testing of Drug Substances and Products” (see IPQ “Monthly Update” September 2012, pp. 32-37). The Q&A is organized into a general section and specific sections addressing drug master files, drug product manufacturing and packaging, amendments to pending ANDA applications, and stability studies. CDER finalized the ANDA stability guidance in June, 2013.

FDA Equivalency Testing of Generic Cardio Drugs Starts with Metoprolol

In early May, FDA began an initiative to compare the bioequivalency of generic blood pressure medicines with innovator products. Starting with metoprolol succinate, the initiative will test nineteen other generic cardio products.

FDA Requests Regulatory Research Proposals

In late May, FDA issued a solicitation for research proposals into improving the drug review process. Included in the request for research proposals on: ● ensuring FDA readiness in evaluating innovative emerging technologies ● new approaches to improve product manufacturing and quality development ● post-market evaluation of generic drugs, and ● the development of new analytical methods.

Johns Hopkins, UCSF-Stanford Tagged as FDA Centers of Excellence

In early May, FDA designated Johns Hopkins University and the University of California at San Francisco-Stanford University as “Centers of Excellence in Regulatory Science and Innovation” (CERSI), joining the University of Maryland and Georgetown University. The centers receive support from the agency to “promote cross-disciplinary regulatory science training, scientific exchanges, and leading-edge research focused on FDA science priority areas.”

USP Proposes New Standards for Organic Impurities

Appearing in the May-June 2014 issue of the Pharmacopoeial Forum (PF) were a draft chapter proposal and a draft chapter revision updating USP’s coverage of organic impurities. The revision of general chapter <1086> on drug substance/product

UNITED STATES

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf

http://www.ipqpubs.com/issues/ipq-monthly-update-september-2013/

https://www.federalregister.gov/articles/2014/05/15/2014-11178/documents-to-support-submission-of-an-electronic-common-technical-document-availability?utm_campaign=subscription+mailing+list&utm_medium=email&utm_source=federalregister.gov






http://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-024.html

https://www.fbo.gov/index?s=opportunity&mode=form&id=8342f2f11a7417829dbdd4c33276065e&tab=core&_cview=0

http://blogs.fda.gov/fdavoice/index.php/2014/05/johns-hopkins-and-uscsf-stanford-join-fdas-centers-of-excellence-in-regulatory-science-and-innovation/

http://www.usp.org/usp-nf/key-issues/monograph-modernization/organic-impurities-drug-monographs




WWW.IPQPUBS.COM MAY 2014 ��


impurities and the proposal for the addition of a chapter <476> on drug substance/product organic impurities, which will align USP with ICH Q3A and Q3B, are open for comment until July 31, 2014. Included in the PF issue was a stimuli article detailing the rationale, scope, and implementation of the changes.of issues, to ensure the stability and quality of supply chain.” By being able to map all facilities that manufacture drug products, FDA will be able to quickly locate trouble spots and deploy resources.

USP Begins Call for 2015 Resolutions

In late April, the USP Council of the Convention began its call for resolutions to be deliberated at the 2015 Convention. The pro-posal period for resolutions is open until February 6, 2015. However, proposals made before October will be considered for the Preliminary Resolutions Report. Information on the review process as well as frequently asked questions can be found at the USP Resolution Submission website.

GMP/INSPECTION

FDA Holds First DQSA Track-and-Trace Workshop

The first public workshop to discuss the implementation of track and trace provisions of title II of the Drug Quality and Security Act (DQSA) was held May 8-9. The workshop was designed to gather information, current practices, research, and ideas on the standard documentation that should be conveyed as products move down the supply chain. The public comment period closed June 9. [See IPQ “Monthly Update” January 2014 pp. 13-20 for more on DQSA’s track and trace provisions.]

HDMA Publishes Guidance on Distributor Compliance with DQSA

In late April, the Healthcare Distribution Management Association (HDMA) published a guidance meant to help distributors comply with the drug supply chain security provisions of DQSA.

Pew Releases Study Findings on Implementing a Track-and-Trace System

In order to better understand the difficulties related to the implementation of a track-and-trace supply chain system, Booz Allen Hamilton and The Pew Charitable Trust conducted an assessment of perspectives across the US pharmaceutical supply chain in 2013 and issued a report in late April 2014. Key findings from the study included the lack of clear regulatory expectations and a uniform system design.

HHS Looks for Transparency in Compounding Drug Reimbursement

In late April, HHS made available its study designed to determine the costs and oversight for compounded drugs under Medi-care Part B. Based on the lack of existing information related to Medicare and compounded drugs, the study recommends: ● that the Center for Medicaid and Medicare Services (CMS) establish a method to identify Part B claims for compounded drugs ● the possibility of requiring providers to identify the pharmacy that produced a compounded drug, ● and potentially conducting de-scriptive analyses of Part B claims for compounded drugs. The impact of reimbursement on pharmacy compounding is one of the factors getting more attention as compounding operations come under greater regulatory scrutiny (see brief below).

Sterile Compounding Warning Letters Continue

FDA’s warning letter stream to sterile drug product compounding pharmacies continued in April and May with letters to: Blue Ridge Pharmacy and Compounding Center, Grandpa’s Compounding Pharmacy, Brookfield Prescription Center, and Nature’s Pharmacy & Compounding Center. Drug approval and sanitization issues remain top concerns [See IPQ “Monthly Update” April 2014 pp. 36-39 for an update on FDA’s crackdown on sterile compounding operations through Q1 2014).

Warning Letter to Sun Cites Integrity Issues at Indian Plant

FDA issued a warning letter to Sun Pharmaceuticals in early May in the wake of a November 2013 inspection that found data integrity problems at the firm’s Karkhadi, India API facility, which resulted in it being placed on FDA’s import alert list in March. Integrity concerns cited at the facility included: lack of raw data, “unofficial testing” of samples, and failure to identify raw mate-rials. Earlier this year Sun bought Ranbaxy, which had also been enmeshed in data integrity problems with the agency. [See IPQ “Monthly Update” April 2014 pp. 19-29 and July/August 2013 pp. 2-8 for more on FDA’s findings of data integrity problems in India.]

http://resolutions.usp.org/

http://resolutions.usp.org/

http://www.fda.gov/Drugs/NewsEvents/ucm388993.htm


http://www.rxtrace.com/2014/04/just-released-the-hdma-edi-asn-guidance-for-dscsa.html/

http://www.pewhealth.org/uploadedFiles/PHG/Content_Level_Pages/Other_Resource/booz-allen-hamilton-report.pdf

http://oig.hhs.gov/oei/reports/oei-03-13-00270.pdf

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm398298.htm













MAY 2014 ��


Warning Letters Go To Anti-venom and Allergenic Extract BLA Holders

In mid-April, FDA issued warning letters to Instituto Bioclon’s Mexico City anti-venom facility and Greer Laboratories allergenic extract plant in North Carolina. Both biologics facilities were cited for deficient environmental monitoring and failure to conduct investigations.

FDA Proposes Reg on Drug Destruction at Border

In early May, FDA proposed a rule spelling out its right to destroy drugs at the border as part of its implementation of section 708 of FDASIA (see IPQ “Monthly Update” October 2013 pp. 7-11 and January 2014 pp. 13-20). In order to better meet the needs of a secure supply chain FDA would now be allowed to destroy misbranded or counterfeit drugs of low value when they are shipped into the US.

Dep. Com. Sklamberg on Specialization Needs Within ORA

In an early May blog post on FDAVoice, Deputy Commissioner Howard Sklamberg emphasized that the shifting regulatory en-vironment is creating an increased need for specialization within the agency’s Office of Regulatory Affairs (ORA), and noted the need for experts to contribute to that specialization.

FDA FY 2015 Product and Establishment Fees

A “dear colleague” letter was issued by FDA in early May, detailing the plan to issue user fee invoices for FY 2015. The agency requests information regarding invoice contacts, as well as a list of products and establishments subject to user fees.



https://www.federalregister.gov/articles/2014/05/06/2014-10304/administrative-destruction-of-certain-drugs-refused-admission-to-the-united-states?utm_campaign=pi+subscription+mailing+list&utm_medium=email&utm_source=federalregister.gov

http://www.ipqpubs.com/issues/ipq-october-monthly-update-october-2013/


http://blogs.fda.gov/fdavoice/index.php/2014/05/building-expertise-and-crossing-boundaries-to-improve-oversight-2/

http://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM396194.pdf



WWW.IPQPUBS.COM MAY 2014 �0


EUROPE CMC/REVIEW EDQM Publishes List of Texts Adopted at the March 2014 Session of the Ph. Eur. Commission

In mid-May, EDQM released the list of texts that have been adopted by the European Pharmacopeia for implementation in April 2015. The new and revised texts contain monographs as well as general chapters and will be published in Ph. Eur. Supplement 8.4.

EMA Issues 2013 Annual Report

In late April, EMA published its 2013 annual report, which notes the recommending of 81 medicines for approval for human use, compared to 57 in 2012. The annual report also highlights some of the initiatives and achievements from 2013, including its implementation of the Falsified Medicines Directive [see IPQ “Monthly Update” July/August 2013 pp. 16-21].

MHRA Announces “Early Access to Medicines Scheme”

In early April, MHRA announced its fast-track pathway for drug approval, known as the “Early Access to Medicines Scheme” (EAMS), which “aims to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorization when there is a clear unmet medical need.” The MHRA notice came a few weeks after EMA’s announcement of its pilot project on “adaptive licensing” (IPQ Updates in Brief March 25, 2014).

EDQM Drafts First Finished Product Monograph

In mid-May, EDQM published a draft of its first finished product monograph, covering sitagliptin phosphate tablets, for com-ment. The monograph is available in the online forum Pharmeuropa. EDQM notes that “finished product monographs will be elaborated according to the same general principles as for other monographs in the Ph. Eur. to ensure the same high scientific quality.”

Annual Meeting of the National Pharmacopoeia Authorities (NPA) of the Ph. Eur.

In late May, the annual meeting of the National Pharmacopeia Authorities (NPA) of the European Pharmacopoeia took place in London. According to the EDQM press release, following the event, the main topics discussed were: ● the implementation strategy for the future ICH Q3D guideline on elemental impurities ● current quality topics that have a potential impact on the Ph. Eur., ● collaboration between pharmacopoeias and quality assessors, official medicines control laboratories and GMP inspectors, ● and the current situation of national pharmacopoeias in member states and sharing best practices. It was noted that most of the participating NPAs had discontinued their national pharmacopoeia and were fully focused on contributing to the Ph. Eur.

http://www.edqm.eu/en/List-of-texts-adopted-at-the-March-2014-session-of-the-Pheur-Commission-1583.html?mbID=196

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/04/news_detail_002090.jsp&mid=WC0b01ac058004d5c1


http://www.mhra.gov.uk/Howweregulate/Innovation/EarlyaccesstomedicinesschemeEAMS/index.htm

http://www.ipqpubs.com/cmc-review-policy/ema-to-launch-drug-approval-fast-track/

http://www.edqm.eu/en/First-draft-finished-product-monograph-with-chemically-defined-active-substance-published-for-comment-1587.html?mbID=195

http://www.edqm.eu/en/Annual-meeting-of-the-National-Pharmacopoeia-authorities-of-the-European-Pharmacopoeia-1587.html?mbID=197


MAY 2014 �1


INTERNATIONAL

CMC/REVIEW New US-EU Mutual Reliance Collaboration

As announced by Deputy Commissioner Howard Sklamberg in the FDAVoice blog in mid-May, FDA has plans to begin a “mu-tual reliance initiative” with the EU. The stated goal of the initiative is to increase the exchange “of information that is critical to making decisions that protect the public health.” In cooperation with EC and EMA, FDA will aim to deepen reliance on trusted regulators who provide equivalent safety and quality protection and become” more efficient and effective in targeting our resources for inspecting pharmaceutical operations.”

Health Canada Issues Guidance on BCS-Based Biowaiver

In late May, Health Canada released a final guidance document on its “Biopharmaceutics Classification System (BCS) Based Biowaivers.” The guidance is intended to inform industry on when biowaivers may be obtained.

FDA and PANDRH Begin Work on Regulatory Competencies

In late May, FDA and the Pan American Network for Drug Regulatory Harmonization (PANDRH) began developing a set of regulatory competencies by which to drive regulator training. Another objective of the collaboration will be to analyze data from evaluations of regulatory systems in the region to decide on future activities and benchmark success.

GMP/INSPECTION

India Looks to Double Drug Inspectors

In mid-May, the Indian government announced plans to double the number of drug inspectors and install quality testing facili-ties at ports within the next three years as part of a $500 mil. plan to increase India’s drug regulatory capacity. The increase in its oversight program follows in the wake of recent compliance actions taken by the US and Europe against some of India’s key manufacturers, including import bans, warning letters, and a consent decree against Ranbaxy. [See IPQ “Monthly Update” March/April 2014 pp. 19-29]

India to Partner with Private Firms in Re-Branding Indian Pharma

In the Economic Times of India in early May, Commerce Secretary Rajeev Kher laid out a plan for a “Brand India Pharma” cam-paign, designed to reinvigorate the international view of pharmaceuticals made in India.

Ranbaxy Facing Criminal Charges in India

In early May, Ranbaxy faced criminal charges brought against it by the Indian state of Kerala due to subpotent amoxycillin and the labeling of an osteoporosis drug as a dietary supplement.

http://blogs.fda.gov/fdavoice/index.php/2014/05/ensuring-pharmaceutical-quality-through-international-engagement/

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/bcs_guide_ld_scb-eng.php

http://blogs.fda.gov/fdavoice/index.php/2014/05/fda-and-pan-american-partners-work-to-strengthen-regulatory-systems/

http://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/government-to-spend-rs-3000-crore-to-set-up-labs-double-drug-regulators/articleshow/35438329.cms



http://articles.economictimes.indiatimes.com/2014-05-01/news/49551880_1_rajeev-kher-kpmg-india-indian-pharmaceutical-industry

http://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/two-criminal-cases-await-ranbaxy-pharmaceuticals-in-kerala/articleshow/34657149.cms

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