INTERNATIONAL PHARMACEUTICAL QUALITY Inside The Global Regulatory Dialogue VOL. 1, NO. 1 WWW.IPQPUBS.COM MONTHLY UPDATE –JULY 2010 EDITOR’s NOTE: Welcome to the inaugural issue of IPQ’s “Monthly Update” on key CMC/GMP developments in the US, Europe, and internationally. The IPQ family of publications has been expanded this Spring to include breaking stories “In the News ” on our web site, “Weekly News Alerts ” sent via e-mail, and the “Monthly Update .” These now accompany our uniquely valuable in-depth “Special Reports ” on emerging areas of concern drawing particular attention from industry and regulators. IPQ’s new offerings will bolster our mission of helping readers understand, engage in and respond to the dialogue and developments around evolving and harmonizing the reg- ulation of pharmaceutical and biologic quality and manufacturing. Subscribers and license holders to IPQ have access to all of these sources of cutting-edge news and in-depth analysis as well as to the full IPQ archives. Visit IPQpubs.com for further information. UNITED STATES CMC/REVIEW • Bioassay Coverage Being Upgraded in USP . . . . . . . . .2 • Biosimilar Public Discussions Tabled by FDA . . . . . . .3 • CMC Change Draft Guidance from CDER . . . . . . . . . .4 • Monograph Modernization Help Sought by USP . . . .5 • Nanotechnology Under the Microscope at FDA . . . . .6 • Particulate Standards Targeted for Biotech . . . . . . . . .7 • Sponsor/Contractor Transparency Urged by FDA . . .7 GMP/INSPECTION • Cargo Theft of Drugs Addressed by FDA . . . . . . . . .10 • Consulting Firms are Busy, Lachman Reports . . . . . .11 • Genzyme Consent Decree Includes $175 Mil. Fine . .12 • Health Protection Is FDA Chief Counsel’s Focus . . .14 • J&J’s Recall/GMP Problems Draw In Congress - McNeil Shuts Down Plant, Recalls Product . . . . . .15 - House Holds Hearings on McNeil Issues . . . . . . . .16 - J&J CEO Asked to Supply More Information . . . . .19 - Contractors Also Queried on Recall Role . . . . . . . .20 • Pre-approval Inspection Compliance Guide Updated . .20 • Propofol at Issue in Teva/Hospira Warning Letters - Drug Shortage Follows GMP Regulatory Actions .21 - Teva Discontinues Propofol . . . . . . . . . . . . . . . . . . . .21 • States Partnering to Help FDA Enforcement . . . . . . .22 • Supply Chain cGMP Upgrades Coming Soon . . . . . .23 • Transparency in Reg Docs Proposed by FDA . . . . . .25 EUROPE GMP/INSPECTION • Annex 2 for Biologicals Redrafted by EU . . . . . . . . . .27 • Anti-counterfeit Initiatives in EU, Cambodia . . . . . . .27 • Counterfeiting Tackled by European Associations . .28 • Inspection Procedures Updated by EMA . . . . . . . . . .29 • MHRA Requires Interim Inspection Updates . . . . . .30 • Outsourcing/Supply Controls Tightening in EU . . .30 INTERNATIONAL CMC/REVIEW • ICH Q8-10 Implementation Workshop in Estonia - Industry/Regulator Input Helps Steer IWG . . . . . .32 - Senior Management Role Stressed by Regulators . . .33 - Generics Industry Outreach Urged . . . . . . . . . . . . . .34 - Criticality Assessments Among Concerns Raised .36 • Novo Nordisk QbD Initiative on Fast Track . . . . . . .39 • Pfizer Finds QbD a Value Proposition . . . . . . . . . . . . .41 GMP/INSPECTION • WHO Sterile Processing Guide Updated . . . . . . . . . .43 Bill Paulson, Editor-in-Chief
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INTERNATIONAL PHARMACEUTICAL QUALITYInside The Global Regulatory Dialogue
VOL. 1, NO. 1WWW.IPQPUBS.COM
MONTHLY UPDATE–JULY 2010
EDITOR’s NOTE: Welcome to the inaugural issue of IPQ’s “Monthly Update” on keyCMC/GMP developments in the US, Europe, and internationally. The IPQ family ofpublications has been expanded this Spring to include breaking stories “In the News”on our web site, “Weekly News Alerts” sent via e-mail, and the “Monthly Update.”These now accompany our uniquely valuable in-depth “Special Reports” on emergingareas of concern drawing particular attention from industry and regulators. IPQ’snew offerings will bolster our mission of helping readers understand, engage in andrespond to the dialogue and developments around evolving and harmonizing the reg-
ulation of pharmaceutical and biologic quality and manufacturing. Subscribers and license holders to IPQ haveaccess to all of these sources of cutting-edge news and in-depth analysis as well as to the full IPQ archives.Visit IPQpubs.com for further information.
UNITED STATES
CMC/REVIEW
• Bioassay Coverage Being Upgraded in USP . . . . . . . . .2
• Biosimilar Public Discussions Tabled by FDA . . . . . . .3
The US Pharmacopeia (USP) is upgrading its coverage related tobioassays to keep pace with the evolving science and technology.
In the July/August Pharmacopeial Forum, USP is proposingrevisions for public comment to General Chapters <1032>,<1033>, and <1034>, which address the design, validation,and analysis of bioassays respectively.
In its announcement of the proposed changes,USP explained that three ad hoc advisory panelshave created “a comprehensive suite of bioassayguidance chapters that have emanated from USP’score compendia bioassay standards.”
In March 2008, USP had proposed a comprehensive revisionto its General Chapter <111>, which covers the analysis ofbiological assays. The proposed revision elicited three pri-mary concerns: 1) the evaluation of curve similarity, 2) theutility of equivalence testing as an effective statisticalmethod in several areas of bioassay data analysis, and 3) thebest means for combining data from multiple assays.
Based on the comments received, USP shifted its focus to creat-ing a new General Chapter <1034> to focus specifically on theanalysis of biological assays and address the concerns raisedabout Chapter <111>. A new General Chapter <1032> toaddress the design of biological assays is also being proposed.
The revision to USP’s existing Chapter <1033> on the valida-tion of biological assays reflects the comments received on anoriginal proposal to revise the chapter released in March 2009.The new general bioassay chapters will be accompanied bya minor revision to the currently official <111> to bring itinto alignment with them. A more comprehensive revision
of <111> is planned, once all product- and monograph-spe-cific references in the chapter have been addressed.
The entire suite of the four chapters (<111>, <1032>, <1033>,and <1034>) will eventually be accompanied by a newGeneral Chapter <1030> that will provide a "roadmap" tothe chapters including a unifying glossary of terms. Thechapters will ultimately be accompanied by example datasets that would be made available on USP's website.
USP is making the proposed chapters available for down-load and comment earlier than in the past “in order to solic-it the widest possible stakeholder input.” The public com-ment period ends October 15th, 2010. Comments andinquiries regarding these chapters should be directed toTina Morris, at [email protected].
USP is holding its third annual bioassay workshop onAugust 11-12 at its headquarters in Rockville, MD focusedon bioassay development, guidance, changes and case stud-ies to help advance its compendial initiative.
Bioassays Important in Comparability
The importance of good bioassays and their uses and limita-tions was highlighted at the AAPS National Biotech Conferencein San Francisco in May by CDER Office of BiotechnologyProducts (OBP) Biochemistry Lab Chief Emily Shacter.
Speaking on the role of bioassays in comparability studies ofbiologics, Shacter emphasized that “bioassays are very impor-tant. You can inject a protein into the body, but is it active ornot, or to what degree is it active? This is very important forknowing that you have the correct dosing of a protein.”
USP Upgrading Bioassay Coverage; FDA Weighs In on Bioassays at AAPS’ National Biotech Meeting
UNITED STATES
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She pointed out that the situation is different for small mole-cule products, most of which do not have a bonafide potencyassay that is used for their release or characterization, becausethe molecule itself can be much more highly characterized.
Stressing the importance of understanding higher-orderstructure of protein molecules, the FDA biochemist notedthe key questions that get raised in this context: “How doyou know when you have the correct structure? How doyou know when you have a structural variant present?How do you know if the structure has changed significant-ly, meaning that there would be a clinical difference? Andconsequently how do you know that change is important?And to what extent can we answer these questions using thevarious physicochemical tests that we have available?” Oneof the important tools in determining the correct structurefor a protein is the bioassay, she emphasized.
While an important weapon in the arsenal,Shacter also pointed out that bioassays have theirlimitations.
“While important, bioassays do not reveal some very impor-tant aspects of clinical activity, like biodistribution. So whenyou are doing an in vitro assay for biological activity, thatdoes not tell you anything about how much the protein isgoing to get around to where it is going to go or how long itis going to stay in the body, and consequently how long andwhere it will be active.”
In addition, bioassays “do not reveal much” about the phys-iological modulators, whether there are low-level variantspresent, or the potential for immunogenicity.
“While tests for higher-order structure cannot replace bioassays,bioassays also cannot really fully replace higher-order structure[characterization] which is really what the body sees,” Shacter
pointed out, adding that both are needed “in order to reducethe risk that we have from a change in manufacture.”
The challenges and advancing science aroundbioassays are drawing considerable attention atbiotech-related forums, and conferences are beingset up to focus on the issues involved.
The biotech analysis society CASSS put together a compre-hensive bioassay conference held on the NIH campus inBethesda, MD in November 2009. The meeting wasdesigned to foster interactions between sponsors and regu-lators regarding expectations for these assays, and includedpresentations and workshops by key players in industryand FDA. The conference focused on bioassay: • scientificapproaches & regulatory strategies • use throughout theproduct lifecycle • development and selection • postapproval management • statistical analysis, and • valida-tion and design for lot release and stability testing.
A second in what CASSS projects will be an annual meetingis scheduled for November 8-9.
The Biopharmaceutical Emerging Best Practices Association(BEBPA) will hold a conference in Barcelona, Spain onSeptember 29 to October 1 also focused exclusively on bioas-says. Included will be a pre-conference workshop on theUSP chapter revisions.
FDA speakers at recent conferences have been open abouttheir inability to discuss biosimilar issues at this time, whilethey digest the implications of the recently-passed PatientProtection and Affordable Care Act (PPACA).
At the AAPS National Biotechnology Conference in SanFrancisco in May, CDER’s Office of Biotechnology ProductsLaboratory of Biochemistry Chief Emily Shacter explainedto the audience that the focus of her talk changed from
biosimilars to the role of stability in comparability assess-ments to accommodate this hiatus.
The PPACA, which was signed into law on March23, is the health care law in which was embeddeda pathway for regulation and approval of biosim-ilars. “I have talked about biosimilars for years,but now that we actually have a law it is muchmore complicated,” Shacter noted.
IPQ MONTHLY UPDATE–JULY 2010
FDA Tabling Public Biosimilar Discussions While Digesting Complexities of New Legislation
Downloads from the story:
• USP <1032> Design and Development of Biological Assays
The FDA biotech official explained that biosimilarityinvolves comparing products from different processes madeby different manufacturers, whereas comparability involvescomparing a protein made by the same manufacturer afterprocess or formulation changes to determine if the protein iscomparable to the product manufactured before the change.
“When you think about it,” she noted, “you can use yourimaginations to extrapolate” the principles of comparability“to try to see what kinds of science and approaches will beused for biomilars. The science is not going to change, butthe regulatory pathways and some fundamental differenceswill exist.”
Under the recently enacted PPACA, FDA was given theauthority and responsibility to regulate biosimilar products,which are now a newly-defined class of medical products.FDA is “carefully evaluating” the newly enacted biosimilarsprovisions that are in the health care law “in order to bestdetermine how to implement” them, Shacter explained.
She told the audience that there is a cross-center workinggroup that has the responsibility for establishing policies
and procedures for implementation of the provisions “in themanner that works in the best service of the public health.”This group is being led by CDER Director Janet Woodcockand the acting head of the Center for Biologics, KarenMidthun.
Shacter explained that FDA is in the process ofdeveloping their implementation policies, andwhile those are ongoing “the agency does notwant to give any false messages, misleading mes-sages, or wrong messages. Quite frankly we arejust not talking right now, because we do notwant to create any more confusion.”
Noting that the law is complicated and “it needs to be gonethrough very carefully,” Shacter emphasized that FDA’sgoal is to “come up with policies that actually work" andaccomplish the bill's objectives.
FDA has been indicating that it prefers to delay meetingswith potential biosimilar sponsors until completion of thislegislative review phase.
A new draft guidance from FDA specifies 40 types of low-risk manufacturing changes that will now qualify for annu-al report filing and represents a significant step in theagency’s effort to reduce the number of supplements thathave to funnel through the Center for Drug Evaluation andResearch (CDER) clearance process.
Following a discussion of the agency’s basic approach toregulating manufacturing changes and its goal to reduce thefiling burden, the draft “guidance for industry” on “CMCPostapproval Manufacturing Changes Reportable in AnnualReports” provides the list of changes qualifying for annualreporting in an appendix.
The 40 types of changes are divided into six cate-gories: • components and composition • manufac-turing sites • manufacturing process • specifica-tions • container/closure system, and • miscella-neous changes.
Examples from the list of qualifying changes include: a newsupplier of inactive ingredients; addition of barriers in a fill-ing or compounding area; certain minor manufacturing
process changes made under conditions as prescribed; somechanges to a drug substance or drug product to comply withthe official compendia; some changes in container/closuresystems for nonsterile drug substances; and reduction ofexpiration dating for a drug product for reasons other thanstability failures.
The guidance is applicable to both new and abbreviatednew drug applications (NDAs/ANDAs). A backgroundsection describes the categories of changes in FDA’s three-tiered classification system (major, moderate, and minor)and the regulatory filing requirements for each.
A “discussion” section notes that the number of CMC man-ufacturing supplements for NDAs and ANDAs has contin-ued to increase over the last several years. FDA explainsthat, in connection with its Pharmaceutical Product QualityInitiative and risk-based approach to CMC review, it hasevaluated the types of changes that have been submitted assupplements and determined that many of these “presentvery low risk to the quality of the product and do not needto be submitted in supplements.”
New FDA Draft Guidance Reduces Reporting Burden for CMC Postapproval Changes
INSIDE THE GLOBAL REGULATORY DIALOGUETM
JULY 2010 | 5
The guidance clarifies that the list of changes provided is to beused in the context of specific products and circumstances todetermine whether the proposed change has the potential toadversely impact that product. Based on that analysis, the“NDA or ANDA holder may decide that a change describedin Appendix A would more appropriately be submitted as asupplement rather than in an annual report. We, therefore,consider this guidance to provide recommendations” asopposed to requirements for annual reporting.
The guidance includes a description of the requirements foran annual report and the governing regulations.
FDA is asking that public comments and suggestionsregarding its new draft guidance be submitted within 90days of its June 25 publication date in the Federal Register.For questions regarding the document contact CDER Officeof Pharmaceutical Sciences Associate Director for Policy JonClark at 301-796-2400.
Change Flexibility Also in Focus in EU
Reduction of the reporting burden for postapproval manu-facturing changes has been a target for some time in both theUS and the EU, with each moving in the same direction, butat different paces.
The effort is intimately linked to the fostering of the ICH’sQbD/Q8-10 paradigm and the concerted push by regulators in the ICH regions to encourage the flow ofchanges that are needed throughout the product lifecycle tosupport a continuous improvement framework.
Industry and regulators have been debating how to reducethe constraints created by their marketing applications onthe one side and the GMP process validation and changecontrol requirements on the other as part of the effort tounleash the power of science and technology to improveproducts and processes (IPQ, May 2010, pp. 24-25).
Speaking at an IFPAC workshop in February, Center for DrugEvaluation and Research (CDER) Office of New Drug QualityAssessment (ONDQA) Director Moheb Nasr previewed thenow-released guidance and shared his vision for the future.
Nasr suggested that “sometime in the future rather thanhaving three categories of supplements, you may have onlytwo – changes that are low risk that could be reported inannual reports and the high risk changes that will still needto be submitted to the agency for approval.”
Manufacturers who have a good understanding of their prod-ucts and processes and a robust quality system “may not needto have this CBE 0 category, and some of these changes wouldbe moved to annual report,” the ONDQA director said.
In Europe, the encumbrances of its multi-state sys-tem have resulted in its lagging behind the US ininstituting more progressive policies. However,the EU has been actively working to update itsrules and guidance in this area, and in Januaryreleased a pair of guidances spelling out revisedvariation filing expectations and procedures.
At the February IFPAC workshop, EMA ScientificAdministrator Evdokia Korakianiti stressed the importancethat the improved flexibility in the revisions provide.“Postapproval regulatory flexibility was not possible untilthe end of 2009,” she stated. “We are quite happy to say thatnow this has been taken care of.”
IPQ MONTHLY UPDATE–JULY 2010
Downloads from the story:
• CMC Postapproval Manufacturing Changes Reportable in Annual Reports
• EC Post-authorization Procedural Advice: Human Medicinal Products
• EC Q/A List for Submission of Variations
The US Pharmacopeia (USP) is seeking help from drug man-ufacturers in its effort to update monographs for small mol-ecules and excipients that use outdated technology, havesafety/environmental concerns, or are missing key aspects.
The focus for “modernization” of excipient monographswill be to replace relatively non-specific identification proce-dures with more specific tests such as infrared spectroscopy.
USP announced on May 28 that it is seeking proposals toreplace or add procedures for the 200 small molecule mono-graphs and 96 excipient monographs it has prioritized asmost in need of updating.
USP emphasized that “in order to maintain consistency withFDA-approved control strategies, it prefers to receive sub-missions from manufacturers of FDA-approved prod-
USP Seeks Help from Industry for its Monograph Modernization Effort
ucts…or manufacturers intending to seek FDA approval.”Submissions from other sources will be considered on acase-by-case basis and should follow ICH Q3 guidelines.
The announcement follows a resolution that wasadopted at the 2010 USP convention in late Aprilcalling for the pharmacopeia to “strengthen its focuson core compendia activities,” including updatingmonographs, during the next five year cycle.
USP CEO Roger Williams noted at the April meeting that“we have monograph backlogs in all our compendia includ-ing USP-NF – both missing monographs and monographsthat need updating. USP is working diligently to solve thischallenge.”
Speaking at the same meeting, FDA CommissionerMargaret Hamburg underscored the importance of updat-ing USP monographs, calling it “one of the most pressingtasks before us.”
In an effort to focus the modernization effort, USP has devel-oped a spreadsheet containing an initial list of the mono-graphs for which it is seeking input, and intends to addmore as the work progresses. The spreadsheet will beupdated and posted on the USP website on the last Friday ofeach month.
Guidelines for submission of revisions and reference stan-dard materials were included in the announcement.
Downloads from the story:
• May 28 USP press release
• Monograph modernization spreadsheet
• USP submission checklist
• USP guideline for suppliers of reference standard materials
• USP convention resolutions
The rapidly expanding use of nanotechnology in therapeu-tic formulations is driving FDA to better define the regula-tory and analytical framework needed to assess and addressthe potential concerns involved.
At the AAPS National Biotech meeting in San Francisco onMay 19, FDA Center for Drug Evaluation and Research(CDER) research chemist Katherine Tyner elucidated someof the reasons for regulator caution regarding nanoparticles.“Nanoparticles have access to parts of the body other com-pounds do not,” she emphasized. In addition, as particlesget smaller their “surface properties dominate over bulkproperties,” and surface reactivity increases.
Addressing emerging regulatory considerationsfor nanoparticle-containing therapeutics at another recent conference, CDER Office ofPharmaceutical Science Research Policy AssociateDirector Nakissa Sadrieh pointed to the analyticaluncertainties on the horizon. Sadrieh is chair ofCDER’s Nanotechnology Working Group that isexploring what further guidance and policy maybe needed in the area.
“What I guess we don’t know right now is for the type ofnanoparticle that we may be looking at,” for example, a den-
drimer or nanotube, “what are going to be the importantproperties that we need to know [and] what is the best wayfor us to be able to evaluate those properties?” she said. “Ifsomebody could actually generate a table with the particle,the property and the methods that one would use to actual-ly evaluate or characterize, that would be a great help to beable to adequately review these products and to knowwhether there are issues that we need to look at or not.”
Another area of concern, she added, is that the properties ofnanoparticles may be “quite different from the normal prop-erties that we look at right now for small molecules, [e.g.]electron microscopy methods. These are not methods thathave been used in the past in manufacturing. So we need tofind ways of being able to identify methods that are going tobe adaptable to be able to actually develop drugs.”
Sadrieh explained that there is an agency-wide guidancethat is being developed to cover the use of nanoscale mate-rials in FDA-regulated products.
[Editor’s note: The opportunities and challenges aroundnanotechnology development and regulation, includingSadrieh’s extended analysis, are explored in the May 2010issue of IPQ as part of an in-depth report on the changingCMC landscape.]
Make Plans Now to Attend Upcoming USP EventsFeatured Event
Third Annual Bioassay Workshop August 11–12, 2010 • Rockville, Maryland
This scientific forum is your opportunity to engage with colleagues and discuss bioassay development, guidance, changes, and case studies as USP’s Bioassay Chapter Suite moves forward. For additional information and registration details visit www.usp.org/meetings/workshops/2010Bioassay.html.
4 5th Annual Global Conference on Pharmaceutical Microbiology Advances in Microbial Control and Product Quality • Co-sponsored by PDA and USP • October 25–27 •Capital Hilton, Washington, DC
4 Impurities, Adulteration, and the Changing Role of the USP in Global Drug Quality • November 13–14 • New Orleans, LA
For details and registration information, visit www.usp.org/meetings/workshops.
Meet with USP Representatives at Industry Conferences & Exhibitions
4 IFT 10 Annual Meeting and Food Expo • July 17–20 • Chicago, IL (Booth 3373), www.am-fe.ift.org
4 2010 PSWC/AAPS • November 14–18 • New Orleans, LA (Booth 1319), www.pswc2010.org
4 EAS 2010 • November 15–17 • Somerset, NJ (Booths 100–101), www.eas.org
INSIDE THE GLOBAL REGULATORY DIALOGUETM
JULY 2010 | 7
The development of measurement standards for visible andsub-visible particles in parenteral products is drawing atten-tion from regulators and industry at biotech conferences.
At the AAPS National Biotech meeting in San Francisco onMay 18, FDA Office of Biological Products Division ofTherapeutic Proteins Deputy Director Barry Cherney under-scored the need for particle standards.
Noting the lack of standards for protein particles, Cherneypointed out that an effort is taking shape in which FDA, TheNational Institute of Standards and Technology (NIST), andindustry will partner to develop these much-needed stan-dards. A proposal by NIST to assist on this front drew dis-cussion at CASSS’ annual WCBP conference in January.
At the AAPS San Francisco meeting, FDA Center for DrugEvaluation and Research (CDER) Principal Investigator andSenior Regulatory Research Officer, Jack Ragheb, comment-ed on why FDA is concerned about particles. He cited thepotential for immunogenicity, and added that the level ofparticles in an injectable product also serves as “a sentinel ofproduct quality.”
[Editor’s note: The opportunities and challenges aroundstandards development for biotech product particulates andNIST’s potential role are explored in the May 2010 issue ofIPQ as part of its analysis of the changing CMC landscape.]
IPQ MONTHLY UPDATE–JULY 2010
Particulates in Biotech Products: Standard Setting Effort Gaining Traction
FDA investigators will be looking for more transparencybetween a sponsor and its contract sites regarding the spon-sor’s drug application commitments and the contractor'splant-wide GMP status, FDA Cincinnati DistrictInvestigator and Preapproval Manager Kathleen Culveremphasized at a Global Outsourcing Conference at XavierUniversity on June 14.
Drug firms that outsource manufacturing and testing activ-ities should share the appropriate sections of their drugapplications with the contract firms to avoid misunder-standings, facilitate site compliance with the commitmentsin the application and aid review and pre-approval inspec-tions, Culver emphasized. “I am looking for this when I dothe pre-approval inspection to assure there are no misunder-standings and that we will not end up with adulterated ormisbranded drug product,” she explained.
In turn, where the contract firm manufactures formultiple clients, it is important that the sponsorhave access to other client’s audit findings andrecords that shed light on the contractor’s overallquality system, Culver stressed.
“How can you really thoroughly audit a GMP system whenyou cannot review all the deviations, investigations or data gen-erated in that system?” the FDA investigator asked. Shestressed the importance of performing thorough audits of thequality systems during the contract manufacturer selectionprocess.
Application Commitments Should be Shared with Contractors
“Transparency between the sponsor and the contract siteregarding drug application commitments is crucial,” Culveremphasized. She pointed out that “sometimes this trans-parency about these commitments in the drug application ismissing. I think this really needs to change if the contract-ing industry is going to thrive and continue.”
The field official called on industry to “reconsider the cur-rent practice of not providing copies of the drug applicationto your contract site, or at least the sections of the drugapplication that apply to what that contract site will bedoing for you.” She reminded the attendees that the com-mitments in the drug application are legally binding andmust be met once the application is approved.
Culver pointed to the FDA investigator concernwhen inspecting a contract site with the findingthat the contractor had not been supplied with theCMC section of the application, or at least theparts applicable to the work being done at the site.
“This lack of full disclosure between the sponsor and thecontract site can impede my pre-approval inspectionbecause from the get-go I do not have that assurance thatthis contract site knows what the commitments are in thedrug application,” she explained. “I have to figure that outbefore I can start evaluating GMPs.”
FDA Wants to See More Transparency Between Drug Companies and Contractors on Sponsor’s Application and Contractor’s GMP Status
“It is becoming a big red flag for me,” Culver said. “Howcan the contract site assure they are meeting the drug appli-cation commitments if they do not have a copy of these com-mitments? What if the NDA/ANDA sponsor fails to dis-close critical drug application information to the contractsite? We see this happen.”
Culver pointed out that the only party ever likely to discov-er that the sponsor has omitted critical information to thecontract site is an FDA investigator when auditing againstthe application.
When a contract site does not have a copy of the drug appli-cation commitments applicable to their contracted responsi-bilities, FDA must conduct the GMP audit and also audit theintegrity of the information transfer process between thesponsor and the contract site. “Is it really FDA’s job to man-age the disclosure process of critical information to yourcontract site?” she asked, replying “I do not think it is.”
Culver stressed that transparency over the applica-tion commitments is important to the compliancestatus of both the sponsors and the contract sites.
“I would like to suggest to you all today that it is time to re-examine this business practice that some of you might haveof not providing the drug application information directlyto the contract site in light of your collective responsibility toassure that the commitments in that drug application aremet,” she proposed. “The transparency it adds to the drugapproval inspection and review process for contract sitesand for FDA is tremendous when all parties are workingfrom that same document, that key legally-binding docu-ment, the filed drug application.”
Confidentiality Agreements Can Create GMP Blind Spots
Culver noted that sponsors performing audits at contractmanufacturing or testing sites are at a disadvantage whenthey cannot review all the records because of confidentialityagreements with other clients.
The FDA field preapproval manager is “startingto be concerned there is a huge blind spot possi-bly being created…. What if there is evidence ofa serious GMP system failure in client A’s records,but client B cannot review those records?”
Culver cited an example of a recent inspection of the rawmaterials system at a contract manufacturing site in which
she found a deviation regarding the use of an excipient froman unapproved supplier. Although the deviation wasapproved and the product released, no root cause was iden-tified.
The question became, she noted, “are the raw material con-trols in the SOPs inadequate to prevent this from happeningagain? Or are the raw material controls written in the SOPsreally adequate but people are not actually followingthem?”
Culver’s investigation revealed that the excipient was notavailable from the approved supplier, so the contactorsourced it from an unapproved supplier to allow manufac-turing to continue in violation of the firm’s SOPs. “If youjust sat down and read all the SOPs that said anything abouta raw material control, you would be misled into believingeverything was fine,” the investigator pointed out.
She noted that the major incident involving melamine in petfood a few years ago was analogous, also stemming fromthe use of an unapproved supplier.
In the end, she told the drug sponsors in the audience, “it isyour product. Your name is on the label. You are liable.You are responsible. You have to make sure your audits ofthese contract firms are robust enough and rigorous enoughto find these serious system deficiencies if they exist despiteall the confidentiality agreements.”
Selecting Contract Sites on Cost Could be Costly
Culver shared her concern about the practice of selectingcontract sites on the basis of cost alone, emphasizing theimportance of rigorous GMP system inspections in the con-tract site selection process.
“Some sponsors I hear select their contract sitesbased on unit dose cost alone. I do not think thatthis is a good idea.” She provided a mock exam-ple to illustrate the point.
In setting up the example, the FDA inspector explained thatthe agency’s Compliance Policy Guide on drug manufactur-ing inspections (CPG 7356.002) lays out the FDA roadmapfor conducting routine GMP inspections of drug firms, andalso prescribes how to classify the inspection after it is com-pleted. According to the CPG, when performing a systemsinspection, if one system is found to be out of control, thefacility as a whole is deemed to be out of control.
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Culver then walked the audience through the exampleinvolving a routine inspection at the “Lowest-Cost TabletManufacturer” (LCTM) in Cincinnati, Ohio. “We go out anddo this inspection, we cover the quality system and at leastone other system, and we find serious deficiencies in thequality system, and a 483 is issued.”
The investigations branch classifies this routine inspectionas Official Action Indicated (OAI), and a warning letter isrecommended. In FDA’s Field Accomplishment andCompliance Tracking System (FACTS) on the company’sprofile screen, “everything is unacceptable because we did asystem inspection,” Culver explained. Next the supervisorconfirms on that screen in FACTS that those profiles areunacceptable.
A compliance officer then reviews the report and all therecords and drafts the warning letter and forwards this caseto CDER’s Office of Compliance in Washington for finalreview and approval. That compliance officer also goes intothat profile screen for this company in the FACTS systemand again confirms all product lines are unacceptable.
The warning letter is then approved and issued. The pro-files remain unacceptable until corrections are made andverified by FDA.
“Meanwhile,” Culver explained, “up in CDER, a drug appli-cation is being reviewed for a tablet. The sponsor of thedrug application contracted out the manufacturing toLCTM. The sponsor selected [this manufacturer] about twoyears ago based on unit dose cost alone. Of course it takessome time to negotiate the contract, make the submissionlots, do the stability testing, assemble the application andsend it in. Months or maybe a couple of years have gone bysince they selected them,” she said.
As CDER begins to process this ANDA or NDA, one of thethings they have to do is look at the GMP status of everycompany that is associated with making or testing the prod-uct, Culver explained. For this application, there is a GMPstatus enquiry for LCTM which goes to the CDER Office ofCompliance. OC forwards it to the Cincinnati district office,which recommends withholding approval for this drugapplication and for any new products at this facility until thecorrections are made and the profiles are acceptable.
“What is the cost impact of selecting LCTM to make yourdrug product now?” Culver queried. “What does a onemonth, two month, six month, twelve month or eighteenmonth delay in approval of your application cost?”
She acknowledged that cost is always a factor inany business dealing, but “if it is the only thingyou are looking at, you are going to get burned bythe systems inspection eventually if that contractsite goes out of compliance.”
“Some people might say that FDA is being unreasonable toautomatically recommend withhold for this application justbecause that contract site messed up on somebody else’sproducts,” Culver noted. However, using a systems inspec-tion approach, “what we know is that it does not make anysense to give approval for another application at this con-tract manufacturing site that is out of control.”
“They have shown us that their systems are out of controland potentially or definitely are producing adulterated ormisbranded drug products. Our thinking is that if we addanother new product into that mix and they go through thatdysfunctional system, we are going to get adulterated ormisbranded drug product…. They need to fix their systemsfirst and then they can add new products into that systemonce it is under control.”
The field official offered a list of questions forsponsor firms to consider when selecting a contract site:
• “Does this site have a really good GMP track record forconsecutive inspections? Do they stay in compliance?If they stay in compliance that means they must havegood systems that are under control.
• If they have those robust GMP systems, those six sys-tems, do they have good quality assurance oversight ofthe operations and the products?
• Do they have a well-controlled raw materials system?
• Do they have a production system that is under tightcontrol?
• Is the facility and the equipment well-maintained?
• Is the lab capable of generating scientific and sound testdata?
• Are the packaging and labeling systems well-definedand controlled?”
Culver commented that “once you know the answers tothose questions and you have answers you are comfortable
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with – that these systems meet GMPs – then cost is obvious-ly a factor.” However, she cautioned, “it is important thatyou evaluate GMP systems and not just cost when you areselecting your contract sites.”
Sponsors and Contract Firms Share in Results
Noting the intimate relationship between sponsors and con-tract sites, Culver cautioned that under FDA’s enhancedenforcement approach, contractor compliance problemsmay lead to investigations of sponsors.
“Many times there are very good partnerships betweensponsors and contract sites and they make very high quali-ty drug products. Of course that is what we all want,”Culver affirmed.
However, she commented, “I do have to start wondering howFDA is going to manage this or react when we have a commer-cial drug product produced at a contract firm under the spon-sor’s oversight and it is found to be non-compliant – it is adul-terated or misbranded. Aren’t both parties really responsible?”
Pointing to the joint responsibility the two partieshave for assuring the drug product meets the filedspecifications, Culver said she is starting to won-der “if the contract site gets a warning letterbecause the drug product that they made for thatsponsor is adulterated or misbranded, then maybeshouldn’t we also go after the sponsor?”
On the clinical side this focus of attention on the sponsor isalready taking place. A recent FDA Bioresearch MonitoringProgram inspection resulted in a warning letter issued toPfizer in April for “failure to ensure proper monitoring ofthe investigation” at a contract clinical investigation site.Johnson and Johnson Pharmaceutical Research andDevelopment received a similar letter as a study sponsor inAugust of last year.
Culver noted that the FDA deputy chief counsel for litiga-tion has been warning industry about increasing misde-meanor prosecutions against responsible corporate execu-tives under the FD&C Act.
“I do not think they have him out here giving those speech-es for no good reason, folks,” she emphasized. “That iswhat I am assimilating down here on the front lines – that Ineed to pay more attention to who is making the decisionsat the contract sites, and possibly at the sponsor. Don’t youthink responsible executives could be found both at thesponsor and the contract site? I am starting to think yes.”
Downloads from the story:
• Kathleen Culver’s presentation at Xavier University
• Pfizer April 2010 BIMO warning letter
• J&J August 2009 BIMO Warning letter
FDA sent a letter to medical companies expressing concernabout the increase in cargo thefts of FDA-regulated drugproducts and clarifying its expectations from companies andthe agency’s role when thefts occur.
In the letter, Acting Assistant Commissioner forRegulatory Affairs Michael Chappell urged stake-holders to “immediately” review securitythroughout their supply chains from manufactur-ing through distribution to the point of sale, stat-ing they should be “one step ahead of thieves” insecuring warehouses and transportation.
Chappell emphasized that drug manufacturers and othersin the pharmaceutical supply chain “have a fundamentalresponsibility to continuously review their warehouse phys-
ical security and security practices and procedures for trans-porting products to ensure that measures are in place tominimize the risk of warehouse and cargo theft.”
The letter directs firms to contact FDA’s Office of CriminalInvestigation when a theft occurs, and provides contactinformation and a list of questions an FDA district officemay ask about the incident. It notes that prompt public noti-fication of a theft is a critical step in protecting public health,and strongly encourages companies to issue press releasesas soon as possible after such an incident.
FDA Shares Concerns, Expectations Regarding Pharma Cargo Thefts
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Heightened scrutiny of drug manufacturers by FDA has ledto an increase in warning letters, injunctions and importalerts, and in turn has significantly increased the demandfor consulting services, Lachman Consultants’ PresidentRoy Sturgeon told the participants in an investor “confer-ence call” sponsored by New York-based Lazard CapitalMarkets (LCM) on June 22.
“We are in an unprecedented era in drug enforcement,”Sturgeon explained. “We have 300-400 active clients –everything from one-person entrepreneurial firms all theway up to the largest pharma companies. Nobody is beingspared the scrutiny of FDA.”
LCM billed the conference call as designed to inform itsclients about how FDA enforcement actions against drugmanufacturers could “become a major point of consterna-tion for investors” in the immediate future. The financialcompany’s focus on FDA enforcement speaks to theagency’s success in raising the importance of manufacturingcompliance to the executive community.
Sturgeon highlighted the impact that increased enforcementhas had on his firm. “I would say our volume of inquiriesand work has more than doubled in the last year,” he noted,adding that Lachman consultants are spending considerabletime with firms who have received 483s as well as warningletters.
The Lachman president emphasized that once acompany receives a warning letter, it is in its bestinterest to be proactive in following up with FDA.
The agency will “issue the warning letter, then they kind ofgo away for a long time,” he commented. “There is nothingin the regulations that requires FDA to act in a particulartime. So the companies have to request meetings with FDA”to get a re-inspection. Because it is now “out of sequence orout of the queue in their biannual inspections,” the firmneeds to stay in touch with the agency to ensure that the fol-low-up inspection occurs, the consultant advised.
“It is public knowledge that we are currently working onfour consent decrees,” and possibly a fifth, Sturgeoninformed the audience. Lachman also knows of “severalcompanies that are on the cusp of negotiating with the FDA”regarding consent decrees.
In addition to consent decrees, Sturgeon noted that FDA hasbeen talking about other penalties targeting individuals atnon-compliant firms.
FDA’s Deputy Chief Counsel for Litigation Eric Blumbergtold the FDLI Annual Meeting in April that FDA will con-sider bringing criminal charges against both corporate offi-cials and individuals at plant sites for violations of theFD&C Act. Sturgeon suggested that the agency is “going tomake some poster children soon by pursuing that, and [wewill] actually see some misdemeanor or felony chargesagainst folks for violation of GMPs and other regulations.”
In addressing the changing inspection landscape,the Lachman official noted that companies arereceiving more 483 observations than in the past,and many that thought they were compliant arebeing caught off-guard by the inspection results.
“A lot of companies have said, ‘we have been inspected fivetimes in the last six years and we have only had one or twoobservations. Now all of a sudden we get 31 observations,and we thought we were ok,’” Sturgeon noted.
“If FDA goes to inspect a facility, I would say probably 60%of the facilities two years ago” would have received a 483,the consultant said. “Today I think it is close to 100%. I donot think we have had a client in the past year that has hadan inspection that has not received 483 observations.”
Foreign Firms May Not Understand FDA’s Approach
Sturgeon believes the majority of companies both in the USand overseas understand FDA regulations and what agencyinvestigators expect to see, although he has seen some dis-parity, particularly in the foreign context.
“I would say about 95% of the firms on US soil understandthe rules and regulations, and they are usually pretty goodabout reacting,” Sturgeon commented. By comparison,“about 75% of the firms on foreign soil kind of understandand have the right quality systems in place.”
The consultant estimated that the remaining 25% of over-seas firms “just do not understand – they try and justify themeans versus the journey of how they got there.” FDA is
Consulting Firms Are Busy in Wake of Stronger FDA Enforcement, Lachman’s Sturgeon Reports
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interested in the systems and controls in place, whereasthese firms focus only on the final product.
Sturgeon commented further on this disconnect: “Most [ofthese] firms will say ‘my product is perfect so what are youworried about?’ Of course you can have a perfect productand something as simple as missing a second signature on abatch record can render it adulterated under the Food, Drugand Cosmetic Act. It is very difficult to get [some] foreignfirms to understand that.”
He postulated that the firms “probably most at risk” ofreceiving regulatory action “are newer start-up companiesthat do not have the US-based experience – who want to getinto the US market and do not understand the rules and reg-ulations.” He also noted that while most companies collecta lot of manufacturing information and data, the failure totrend and act on the trends is a significant deficiency acrossthe board.
Sturgeon referenced an FDA announcement thatindicated it plans to increase foreign inspectionsthree or four-fold this year. The agency now has“the appropriations [and the staff to do it],” hepointed out.
FDA recently opened offices in India and China, allowingmore scrutiny and faster response times when issues occur
abroad. Sturgeon pointed out that there are 11 or 12 FDApersonnel on staff in Mumbai, India, and 14 on staff inChina. These are “huge areas of the world to regulate, butat least they have boots on the ground,” and the ability tobring in additional resources from the US if needed, he said.
To exemplify the impact of these new foreign offices,Sturgeon noted they “had a client in India who had a signif-icant product issue,” and although it was at a “very lowlevel – one in one million – FDA saw that and showed uptwo days later.” The investigators “were two senior peoplewho came out of CDER and CBER who are staffing thatoffice in Mumbai.”
The Lachman exec believes it will take some timefor the industry to adjust and respond to the newlevel of FDA scrutiny. The process is alreadybeginning, he said, but “some firms still have theattitude ‘we will just wait until we get hammered’[while] other firms are being very proactive.”
Sturgeon’s view is that “companies are getting the message thatit is easier and cheaper to stay out of trouble than to get out oftrouble.” He has seen an increased focus by companies to “edu-cate people at all levels in their organization about what GMPsare…. They are looking at better ways to educate the entirework force from senior executives down to the shop floor,and looking at how to make sure that training is effective."
Genzyme’s consent decree for GMP violations at its Allston,Massachusetts plant will require it to pay a $175 million“disgorgement fee” and bring the plant back into compli-ance with applicable regulations within a specified timeframe, during which time shortages of several of its drugswill continue.
The consent decree was filed in the U.S. District Court forthe District of Massachusetts on May 24, 2010, and is subjectto court approval.
Issues at the Allston plant surfaced in October 2008, whenan agency inspection led to issuance of an FDA form 483,followed by a Warning Letter in February 2009.
The letter delineated issues involving both drug products(Fabrazyme, Cerezyme and Myozyme) and bulk substances
and components. The drug product discussion focused onthe firm’s microbiological contamination control procedures– in particular its air flow studies.
At issue in the bulk substance area was bioburden monitor-ing after hold times of intermediates or pooled buffers dur-ing purification of Fabrazyme, Myozyme and Cerezyme.The letter also maintains that Genzyme’s current procedur-al and automated in-process controls for formulating pooledbuffers did not assure that the pooled buffers would meettheir specifications.
FDA asserted that the firm’s follow up to these “documenteddeviations did not include training of operators or thosesupervising formulation operations.” Genzyme’s mainte-nance of certain bulk process equipment and computer sys-tems in a validated state was also cited (IPQ, May/June 2009).
Genzyme Consent Decree Results in $175 Million Fine; Drug Shortages Will Continue
The plant’s problems expanded in June 2009 when a virusthat impairs cell growth was detected in one of six bioreac-tors. Genzyme decided to interrupt bulk production at theplant for six weeks to sanitize the facility, leading to short-ages of the drugs produced there.
At a follow-up inspection at the Allston plant lastFall, FDA continued to find significant problemsin the firm’s systems and issued a 49-item 483.
FDA National Expert Investigator Thomas Arista and histeam identified a broad range of deficiencies during theNovember 2009 inspection.
Foremost among these was a concern with StandardOperating Procedures (SOPs) regarding deviations. Theteam found, “no established standard operating procedureto describe the periodic review and the contents of thereview of deviations and investigations performed by theQuality Unit.”
Also at issue were investigations of failed batches and com-ponents. According to the 483, investigations into metalparticle contamination in finished drug product byGenzyme showed the equipment used in the aseptic fillprocess had shed metal particulates into vials before thedrug product was filled. FDA maintained the firm’s followup to this conclusion was inadequate in failing “to addressprevention contamination before long term correctiveactions are implemented in 2010 and 2011.”
The issue of metal particle contamination continued as atheme in observations related to other manufacturing equip-ment. For example, the pans used in the depyrogenationprocess for drug product vials were identified by the firm asa source of metal particle contamination in finished drugproduct due to metal-on-metal contact with the trays andother prep components. The investigator’s findings indicat-ed the problem was compounded in that 100% visualinspection on finished drug product was unable to reliablydetect and reject vials containing metal or other foreign par-ticles.
On the same day in November that the 483 wasissued, FDA sent a letter warning to healthcareprofessionals about the potential for foreign par-ticle contamination of several products manufac-tured by Genzyme.
The letter stated that “foreign particles, believed to be foundin less than 1% of products based on product lots assessed to
date, include stainless steel fragments, non-latex rubberfrom the vial stopper, and fiber-like material from the man-ufacturing process and could potentially cause seriousadverse events in patients.”
In the letter, FDA explained its rationale for not requestinga recall of the tainted products, stating that it was “acutelyaware of the critical need for patients to have continuedaccess” to these important products, and citing the lack oftherapeutic alternatives for Cerezyme, Fabrazyme,Myozyme, and Aldurazyme. FDA decided to allow theproducts to remain on the market and made suggestions inthe letter regarding their use that it said “would help reducethe incidence of serious adverse events.”
Six months later, in May of this year, FDA andGenzyme entered into the consent decree, whichimpacts the manufacture of products at that facilityand sets forth specific remediation requirements.
Genzyme has agreed to a work plan for making facilityimprovements. The plan begins with selecting, within 10days of entry of the decree by the court, an independentexpert who will inspect the plant and issue recommenda-tions. Genzyme will use the expert’s recommendations tocreate a work plan, subject to FDA approval, that requiresspecific steps for bringing its Allston plant into compliancewithin given dates. Genzyme has also agreed to transferfill/finish operations from the Allston plant to other facili-ties in a specified time frame.
Genzyme is a sole supplier of several enzyme replacementdrugs for injection that are used to treat rare genetic disor-ders, including Cerezyme, Fabrazyme, Myozyme, andThyrogen. The products undergo all or some stage of man-ufacture at the Allston plant.
FDA is working with Genzyme during the company’s reme-diation to ensure availability of the medically necessarydrugs it produces, and has communicated with health careproviders regarding its plan to limit distribution of certaindrugs to those who need them most until the shortages areresolved.
In a June 29 update, Genzyme clarified its currentproduction status and the impact remediationefforts are having on its ability to release productand supply the market.
The firm stated on its newly-created “Genzyme supplyupdate” website that the Allston plant has “resumed normal
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operations.” However, the supply of Cerezyme andFabrazyme in the coming months “could particularly beaffected by two factors: the impact of the production disrup-tions originally reported in April and the effects of prepar-ing to implement the FDA Consent Decree.” The firmexplained that the conditions of the consent decree have cre-ated extra steps in the manufacturing processes that “haveaffected the pace of manufacturing and product release.”
Genzyme also notes that a third factor impacting Fabrazymeproduction is the introduction of a new working cell bankthat has “not reached the targeted levels of productivity andoutput.”
Downloads from the story:
• Genzyme February 2009 Warning Letter
• Genzyme June 2009 Statement on Bioreactor Contamination
• Genzyme November 2009 Form 483
• FDA Letter to Health Care Providers November 2009
• Genzyme May 2010 Consent Decree
• FDA Consent Decree Press Release
• Genzyme Supply Update Website
FDA’s mandate to protect the public health requires makingdecisions in situations where there is no law explicitlyempowering it to act, FDA Chief Counsel Ralph Tylerstressed at the Food and Drug Law Institute (FDLI) AnnualMeeting in late April.
In turn, Tyler explained that a key role for FDA lawyers is tobe advocates for the agency in helping it reach its policy andenforcement goals in situations where waiting for approvalfrom Congress does not allow a timely enough decision.
There are times when the agency is seeking to answer prob-lems “which, if you asked the question, ‘did Congress havethis in mind when they wrote this law?,’ the honest answerwould be no,” explained Tyler, adding “that kind of ques-tion arises with some frequency.”
Like every client, he said, FDA “is entitled to alawyer who is its advocate. Responsible advocacydoes not mean advising that because Congress hasnot said, in just so many words,” what theagency’s power is that it should not take action.
The Chief Counsel cited a recent decision regarding the vac-cine Rotarix. This vaccine was found to contain an extrane-ous but apparently harmless virus, and after consultationwith agency lawyers the commissioner asked the nation’s
pediatricians to discontinue its use or use an alternate vac-cine in its place until scientists could more thoroughly inves-tigate the matter. Tyler characterized this decision as “emi-nently reasonable, measured, and appropriately cautious.”
However, others outside the agency were critical of thisdecision, saying there are no statutes or agency rules allow-ing the commissioner to make such a request since theagency does not regulate the practice of medicine. Tylercharacterized this view as “breathtakingly incorrect.”
He noted that the commissioner’s explicit statutory authori-ty includes conducting educational and public informationprograms relating to the responsibilities of the FDA. Inaddition, “she of course has both the right and the obligationto speak out on matters of public health concern within theFDA’s jurisdiction,” the chief counsel explained, includingmaking physicians aware of an unexplained substance in avaccine currently in use. “How would it be in the interest ofpublic health to say that the law compels the commissionerto stand mute?” he questioned.
Tyler emphasized that these are questions that arise daily atFDA, and the agency and its lawyers will continue to findcreative and lawful ways to help the agency reach its policyand enforcement goals in cases where no explicit law orauthority exists.
Protecting the Public Health Trumps Explicit Legislative Mandate, FDA’s Chief Counsel Tells FDLI
On April 30, McNeil Consumer Healthcare, the OTC divi-sion of Johnson & Johnson (J&J), announced a recall of about1,500 lots of liquid infant’s and children’s Tylenol, Motrin,Zyrtec and Benadryl, and voluntarily shut down the plantwhere they were manufactured at the end of a two-weekFDA inspection at their Fort Washington, PA facility.
The inspection followed on the heels of a January warningletter to a McNeil plant in Las Piedras, Puerto Rico and aFebruary meeting between FDA and McNeil, where FDAexpressed concerns that issues at that plant might be presentat other facilities.
The January warning letter cited concerns with Correctiveand Preventive Action (CAPA) for customer complaints. Itwas issued soon after a recall initiated by McNeil inDecember 2009 and expanded in January for Tylenol ArthritisPain Caplets after consumer complaints of a foul odor and“temporary and non-serious gastrointestinal events.”
The products recalled in April were the subject ofapproximately 46 complaints by consumers overthe previous year, primarily for black specks andparticles in the final product.
According to the FDA 483 issued April 30, the firm did notinitiate a CAPA for any of these complaints, as required bycompany procedure – the same concern cited in the Januarywarning letter. Other deficiencies identified during the FortWashington inspection include a lack of validation for theprocess used to manufacture one of the recalled products,failure to assure uniformity and homogeneity, use of excip-ients that were known to be contaminated, and lack of ade-quate GMP training for manufacturing personnel.
On May 1, FDA issued a statement on the recall, advisingconsumers to use generic versions of the drugs. In thenotice, FDA commented that, “while the potential for seri-ous medical events is remote, FDA advises consumers whohave purchased these recalled products to discontinue use.”
FDA held a press conference on May 4 to brief themedia on the McNeil inspection and recall.
Commissioner Margaret Hamburg addressed the attendees,stating that FDA had posted the 483 inspection finding doc-ument on their web site, and members of the press hadaccess to it prior to the briefing.
“We thought it would be important to put those findings ina proper perspective,” said Hamburg, “so we arranged thiscall in order to give reporters access to some of the senioragency leaders who can help explain more about the inspec-tion findings at the McNeil plant and any other informationthat you might be interested in.”
FDA announced it will review the final report fromthe inspectors once it is completed and decidewhether further regulatory actions will be taken.
On May 5, leaders of the House Committee on Oversightand Government Reform, Reps. Edolphus Towns (D-N.Y.)and Darrell Issa (R-Calif.), issued a joint statement express-ing their concern about the McNeil recall and indicated theywould be “asking tough questions about the conditions ofthe manufacturing plant and controls put in place by thedrug company’s management, and about whether FDA’sinspection and recall procedures were sufficient.” A hear-ing is expected in the coming weeks.
McNeil Voluntary Plant Shutdown, Product Recalls Follow FDA Inspection
Downloads from the story:
• McNeil April 30 2010 Recall
• McNeil January Warning Letter
• December 2009 Recall
• January recall expansion
• FDA statement on April 2010 recall
• McNeil 483 April 2010
• House Committee on Oversight and Government Reform Statement
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Process Validation Regulatory Submissions Quality Assurance
The House Committee on Oversight and GovernmentReform brought Johnson & Johnson (J&J) and FDA to thetable on May 27 to take a hard look at J&J’s recent recall andGMP compliance problems.
In focus at the Congressional hearing were J&J’s actions –including what was referred to by the committee as a “phan-tom recall” – FDA inspection findings, and possible furtherGMP and criminal investigations.
Committee chair Edolphus Towns (D-NY) opened the hear-ing by noting the concerns and questions that have resultedfrom the recall by McNeil, a division of J&J, of 136 millionbottles of over-the-counter children’s products due to cus-tomer complaints and manufacturing issues at their FortWashington, Pennsylvania plant. One of these questionshad to do with J&J recall procedures.
Towns pointed to “disturbing information” that the com-mittee obtained from FDA regarding how J&J addressedproblems with one of its Motrin products in 2008. Ratherthan issue a recall, the document which FDA provided thecommittee suggests, Towns said, that McNeil “sent contrac-tors out to stores to buy the product back and told the stores,‘not to mention’ a recall,” and only announced a recall of theaffected product when confronted by FDA about this. “Isthis a standard operating procedure for McNeil?” he ques-tioned.
Regarding the manufacturing and quality issues, the chair-man emphasized that the committee needs “to knowwhether this is an isolated issue or part of a widespreadproblem” at McNeil. He said that the committee will alsoinvestigate what J&J is doing to resolve the issues andwhether FDA needs additional resources or authority toensure the safety of children’s medicines.
FDA Deputy Principal Commissioner JoshuaSharfstein represented the agency at the hearing,accompanied by CDER Office of ComplianceDirector Deborah Autor and AssociateCommissioner for Regulatory Affairs MichaelChappell.
Sharfstein informed the committee that FDA has had “grow-ing concerns about the quality of the company’s manufactur-ing process” due to a number of unsatisfactory inspections,
beginning prior to 2009 and extending through 2009 and2010. He provided a chronology of events to illustrate whathad occurred during that time frame.
The deputy commissioner reported that in the Spring of2009, FDA identified several “serious” cGMP violations atMcNeil, including use of a partial lot of the ingredientmicrocrystalline cellulose in manufacturing a product whenthe master lot it came from had tested positive for gram neg-ative bacteria, in contradiction to the company’s standardfor the material.
Although all drums actually used tested negative for thebacteria, and both the firm and the agency agreed that thethreat to public health was small, it still represented a cGMPviolation, he noted, and resulted in a recall of almost eightmillion bottles of finished product in August 2009.
In the Fall of 2009, FDA became aware of customer com-plaints of a “musty odor” in some McNeil products, whichthe company began receiving one year earlier, “despite therequirement that such reports be referred to the agencywithin three days,” Sharfstein emphasized.
FDA inspectors urged McNeil to conduct a “complete inves-tigation,” which resulted in the firm discovering that 2,4,6-Tribromoanisole, a pesticide used to treat the wooden pal-lets used for storage of empty medication bottles, was leach-ing into the bottles and subsequently the medication theycontained. The small quantities making their way into themedicines was not thought to pose a significant health risk,FDA concluded.
In January 2010, FDA issued a warning letter toMcNeil, Sharfstein noted, expressing “serious con-cerns about the company’s control over the qualityof its drugs and the company’s failure to aggres-sively investigate and correct quality problems.”
The warning letter was followed by “an extraordinary meet-ing” in February 2010 with senior officials at Johnson &Johnson in which FDA put the firm “on notice” regardingthe agency’s increasing concerns about whether the “corpo-rate culture supported a robust quality system” as evi-denced by the recent product recall and warning letterdevelopments.
House Committee Hears from J&J and FDA on McNeil’s Recall and Compliance Problems
INSIDE THE GLOBAL REGULATORY DIALOGUETM
JULY 2010 | 17
Of particular note, said the deputy commissioner, wasFDA’s concern that there was a pattern of conduct including“failure to report material information to FDA in a timelymanner, miscalculating and/or misstating risks and benefitsof their products, and reactive vs. proactive approaches toproduct quality problems.” The agency told the J&J officialsat that February meeting that significant, immediate stepswere needed to be taken in these areas.
In April 2010, FDA inspectors returned to McNeil’s FortWashington facility – sooner than originally scheduled dueto the recent compliance issues – and discovered that thefirm had ceased operations at the plant just days before dueto manufacturing issues, including particle contamination inoral products. FDA inspectors cited a wide range of viola-tions, including the company’s failure to meet its own spec-ifications.
Agency scientists concluded that the potential for health riskfrom these violations was remote. However, they represent-ed GMP failures and were “unacceptable,” commentedSharfstein. He added that FDA will continue to work withMcNeil to help ensure its Fort Washington plant will makeacceptable products when it reopens, according to a planagreed to by both the firm and the agency.
The J&J experience, Sharfstein stressed, underscores theimportance of using what is learned at one facility to guideinspections of other facilities owned by the same parentcompany, adding that the agency is developing new proce-dures to aid in this task. He further noted that FDA willwork with Congress “to secure additional authorities thatcould assist us in assuring product quality and acting morequickly” when quality problems occur.
Sharfstein also emphasized FDA’s desire to keepthe public informed in a more timely mannerregarding inspections of drug manufacturers.
“As part of our transparency [initiative] we have proposedmaking public every inspection – when it is happening andwhat the outcome of that inspection is,” he told the committee.Public comment is being sought on that initiative, he noted.
During the question-and-answer period, committee chairTowns asked the deputy commissioner if he could providean assurance “with complete certainty” that no childrenwere harmed from the tainted products that were on themarket prior to the recall. Sharfstein responded he couldnot, but said that from what the agency knows at this timethere is no evidence of children who had “serious prob-
lems.” The recall was initiated, he indicated, because therewere “remote risks.”
The chair also questioned Sharfstein regardingthe “phantom recall” performed by McNeil.
“I am not sure we know the complete story, but it began”the FDA topsider responded, with a dissolution problem forcertain presentations of Motrin tablets. The company noti-fied the agency that it would be evaluating whether therewas product on the shelves that should be recalled,Sharfstein explained. Thereafter, the agency was “alerted byone of the state boards of pharmacy that, instead of justlooking to see whether or not there was medication to recall,the company had a contractor that was going out and tryingto buy up all the medicine when they went into the store.”
A document the agency obtained and shared with the com-mittee, as referenced by chairman Towns, appeared toinstruct the contractor to act “like a regular customer” whenmaking the purchases, stating that “there must be no men-tion of this being a recall,” Sharfstein noted. “It was trou-bling to us…and when FDA found out about this we insist-ed that an actual recall occur,” he explained, adding that “itreflected poorly on the company.”
Towns asked Sharfstein what new regulations he believesneed to be enacted to help prevent a similar occurrence inthe future.
The deputy commissioner responded that FDA is givingconsideration to some items similar to those contained in thepending food safety legislation, including mandatory recallauthority, easier access to records, and civil money penal-ties. In view of delays in initiating the J&J recall, Sharfsteinsuggested that FDA’s need for mandatory recall authority“is a fair question to ask.”
Committee ranking member Darrell Issa (R-CA) questionedCDER’s Deborah Autor on whether there is “a potential forcriminal liability for some of the acts” that the agency hasuncovered. Autor replied that CDER has “referred this toFDA’s criminal investigative unit, and they have to judgewhere to go from there.” Issa responded that that in itselfshould be a “fair warning to people watching this hearing.”
After a recess, the second panel convened withJ&J Consumer Group Worldwide ChairmanColleen Goggins presenting the company’s viewof the recall, the issues leading up to it, and itsremediation plans.
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Goggins stated that J&J and its McNeil subsidiary realizesthat it has a responsibility to provide consumers with thehighest quality products possible, and in this instance, “wehave not lived up to that responsibility, and the recall istherefore a disappointment.”
The quality and process issues at McNeil which led to therecall, “are unacceptable,” she emphasized, apologizing “tothe mothers, fathers, and caregivers for the concern andinconvenience caused by the recall.”
The J&J official stated, however, that she believes there hasbeen some confusion in the media with respect to this recall. Reading from her prepared statement she stressed fourpoints: “(1) As the FDA noted last month, the health risks toconsumers from the recalled products were remote; (2)McNeil has no indication of a serious adverse medical eventcaused by any of the issues referenced in the recallannouncement; (3) no raw materials that tested positive forobjectionable bacteria were ever used in the manufacture ofMcNeil’s pediatric products; and (4) McNeil rejected theproducts that it found had excess active ingredient.”
Goggins stressed that McNeil has made “significant organi-zational changes in order to augment the quality and opera-tions leadership on the management team and in all McNeilfacilities,” including a new VP of quality assurance, a newVP of operations, a new plant manager and a new head ofquality for the Fort Washington plant.
McNeil and its outside consultants are in theprocess of developing a comprehensive actionplan on quality improvements, which the compa-ny will share with the agency by July 15, the J&Jofficial told the committee.
The basic elements of the plan include “Governance andManagement Controls,” “Training and Culture ofCompliance,” “Full Assessment and Improvements,” and“Communication with FDA and Interim Actions.”
During Q&A for the second panel, Committee chair Townscommented that information found during the investigation“raises questions about the integrity of the company” –painting a picture of a company that is “deceptive, dishon-est, and has risked the health of many of our children.”
In his first question, the chairman asked about McNeil’s pro-duction of products with excess amount of active ingredient.Goggins responded that they “were found but neverreached the market.”
Discussion followed regarding the so-called“phantom recall.”
Goggins explained that a dissolution issue with Motrintablets in packages distributed in gasoline stations led todiscussions with FDA’s San Juan district. Part of those dis-cussions included J&J hiring a third-party contractor toascertain the “depth of the distribution” of these productsand create an inventory of what products were in the retailmarketplaces.
“I cannot tell you about the behavior of thosecontractors…or what they did say or did not say or howthey acted,” she explained, but she stressed that there wasno attempt to “mislead or hide” what they were doing, andthat FDA was aware of their actions at the time. Committeechair Towns requested documentation of this action, includ-ing confirmation that FDA in San Juan was aware of whatwas happening at the time.
Committee member Dennis Kucinich (D-OH) raised a ques-tion regarding Goggins’ statement that “no raw materialsthat tested positive for objectionable bacteria were ever usedin the manufacture of McNeil’s pediatric products.” Hecited FDA’s indication that the firm “knowingly proceededto partially release some of the remaining raw material” anduse it in manufacturing after finding bacterial contamina-tion in the master lot of that raw material.
Goggins emphasized that this issue “has been in the mediaand is simply incorrect.” She admitted that the firm tested alot of microcrystalline cellulose, which tested positive for anobjectionable bacteria, but said it was rejected. “We havenever used a product that tests positive for objectionablebacteria in our manufacturing process,” she asserted, notingthat all final products are also tested for objectionable bacte-ria, and many contain preservative systems that would“preclude the growth of the bacteria.”
A follow-up line of questioning focused on con-sumer reports of a “musty odor” in some of itsproducts and McNeil’s failure to notify the FDAin a timely manner.
Goggins explained that early reports were investigated aspotential microbiological contamination and were inconclu-sive. Complaints ceased for six months, and the firmbelieved the problem had “gone away.”
In April 2009, more complaints surfaced, she explained, stat-ing the investigation at that time involved an outside con-
INSIDE THE GLOBAL REGULATORY DIALOGUETM
JULY 2010 | 19
sultant who discovered the source of the odor to be comingfrom a rare contaminant that is difficult to identify. Onlytwo laboratories in the world have had experience with it,Goggins pointed out, adding that there were no seriousadverse events due to “trace levels” of this contaminant.
In response to a question regarding why the firm did notnotify FDA about the potential microbial contaminationwithin three days “as required by regulation” the J&J exec-utive replied that she was not aware of the exact chronolo-gy, but emphasized that McNeil did undertake an investiga-tion of the product in question “and it was found not to havemicro contamination.”
Committee chair Towns closed the meeting by indicatingthat “what we have heard today is not reassuring” and thereare still unanswered questions. He added that he intends tointroduce legislation to give FDA mandatory recall authori-ty and the power to “order a halt in drug production.”
IPQ MONTHLY UPDATE–JULY 2010
Downloads from the story:
• Chairman Towns’ opening statement
• Prepared testimony of FDA’s Sharfstein
• Prepared testimony of J&J’s Goggins
• FDA presentation on McNeil phantom recall
• Motrin phantom recall instructions
• Closing statement by Chairman Towns
House Committee on Oversight and Government ReformChair Edolphus Towns (D-NY) has sent a letter to Johnson& Johnson (J&J) CEO William Weldon requesting addition-al specific information on a market action taken regardingone of its Motrin products last year.
Information requested on what Towns terms a “phantomrecall” includes the names of J&J employees who wereinvolved in making the decision to pursue this action,names of the contractors involved, and all records related tothe action.
The letter, dated May 28 and publicly released onJune 2, follows a Congressional hearing the daybefore that brought J&J and FDA to the table to takea hard look at J&J’s recent recall and GMP compli-ance problems (see companion story on p. 16).
Specifically Towns was following up on allegations made inthat hearing that J&J hired contractors to purchase suspect-ed defective products from retail outlets rather than initiat-ing a recall, performing a so-called “phantom recall.” It wasnot until this activity was discovered by FDA that J&Jannounced a recall of the affected medication.
In the letter, Towns says these allegations raise a question of“whether Johnson & Johnson placed a higher priority onpreserving the reputation of its Motrin brand than it did onconsumer protection.”
To assist the committee in its investigation, Towns requested• copies of all records relating to or referring to this action •names of all outside contractors and subcontractors engagedfor this purpose with full contact information • copies of allcontracts and agreements related to this action • names of allJ&J employees who were involved in the decision to pursuethis action, and • a copy of the entire document entitled"CSCS Motrin Purchase Project (June 12, 2009)".
Towns also questioned whether J&J has ever used outsidecontractors or employees in other instances to purchase J&Jproducts from retail outlets, and if so, to provide a detaileddescription and documentation of each instance.
The letter requests that the documents be supplied by June 7.
House Committee Chair Towns Asks J&J’s CEO for Detailed Information on McNeil Recall Actions
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Contract firms identified as helping Johnson & Johnson withwhat House Oversight committee chair Edolphus Towns(D-NY) has referred to as a “phantom recall” received lettersfrom the committee asking them to detail their roles in theaction.
Information requested includes the names of all J&J andMcNeil employees who engaged the firms, details on theservices provided including all related documentation, andwhether the firms have contracted in the past to do similarwork for J&J or are currently engaged in similar activities.
The letters, dated June 3, follow a similar letter sentto J&J’s CEO William Weldon on May 28. The let-ters result from a Congressional hearing on May 27that brought J&J and FDA to the table to take ahard look at the company’s recent recall and GMPcompliance (see companion stories on pp. 16 & 19).
According to information obtained by the committee, WIS ofSan Diego, California was recruited by Carolina SupplyChain Services (CSCS, now a division of Inmar) "on behalfof Johnson & Johnson" to purchase the affected Motrin.Both firms received letters.
In the letter to David Mounts, CEO of Inmar, a Winston-Salem, North Carolina firm, Towns asked specificallywhether CSCS was “engaged by J&J and/or McNeil, or their
agents, to recover suspect Motrin?” If so, the chairmanrequested names and contact information of all J&J andMcNeil employees who engaged CSCS. In addition, docu-mentation on all past and current work for those firms wasalso requested.
Sean Davoren, President and CEO of WIS, also received aletter asking for specific information regarding the workperformed for McNeil. Towns asked WIS to provide a copyof the entire document entitled, “CSCS Motrin PurchaseProject (June 12, 2009)” – the committee had received one page of that document in preparation for the May 27hearing.
In addition to all records pertaining to the work the firm hasor is currently performing for CSCS on behalf of J&J, the let-ter asked the WIS CEO: “How many packages of the sus-pect Motrin did WIS purchase and what was done withthem?”
The letter requests that both firms supply all documents byJune 11.
Congressional Investigation into J&J Recall Actions Widens to Include Contractors
Downloads from the story:
• House Committee Press Release June 3
• Letter to CSCS
• Letter to WIS
FDA has updated its pre-approval inspection (PAI) compli-ance program guidance (CPG 7346.832) to better reflect theagency’s 21st century quality initiative and the new ICH Q8-10/QbD regulatory paradigm.
The new PAI CPG represents a significant overhaul of theprogram guidance to reflect current agency risk-basedthinking and objectives, and is the first major revision sinceits original release in 1994. FDA has been working on revis-ing the program for some time and has issued interim revi-sions with more minor changes in the past few years.
The reach of the new version is extended to encompass largemolecules, and it includes new sections to adapt the preap-proval program procedures to the evolving quality regula-tory approaches. For example, there is a new section on howthe agency wants its internal “knowledge transfer program”to flow between reviewers and inspectors.
“CDER's pre-market assignments and communications willnow effectively transfer product and manufacturing knowl-edge from CDER to ORA inspections,” the new PAI guid-ance states. “Specifically, CDER staff will alert the inspec-tion team to manufacturing and laboratory issues foundduring the pre-market application review.”
FDA Adjusts Its Pre-approval Inspection Guide To Reflect ICH Q8-10 Paradigm
The agency has also recently released an internaldirective as part of CDER’s "manual of policiesand procedures" (MAPP 4730.3) that focuses onclarifying reviewer and inspector roles andresponsibilities reflective of a more lifecycle-oriented regulatory approach (IPQ, May 2010).
The MAPP specifically breaks down the responsibilities forevaluating biotech applications between CDER’s Office ofCompliance Division of Manufacturing and Product Quality(DMPQ) and the Office of Biotechnology Products (OBP).The MAPP reflects the need for the application review and
GMP compliance groups to work more closely together inadvancing the ICH Q8-10/QbD objectives.
[Editor’s Note: The May issue of IPQ includes an in-depthanalysis of how the quality-by-design objectives areimpacting knowledge management and transfer and thereviewer/inspector relationship within FDA and EMA.]
IPQ MONTHLY UPDATE–JULY 2010
Downloads from the story:
• FDA PAI Compliance Program Guidance, CPG 7346.832
• CDER MAPP 4730.3
European manufacturer Fresnius is stepping in to help fillthe US shortage in the injectible anaesthetic propofol causedby GMP problems at Teva and Hospira that resulted inwarning letters and recalls.
FDA's lengthy warning letter to TEVA in December, postedin April, focused on the manufacture of their generic versionof propofol, and primarily related to microbial contamina-tion and testing, including endotoxin in distributed product.In July 2009, during the course of the inspection cited in thewarning letter, Teva issued a recall for propofol.
A few months after the Teva warning letterHospira also received a warning letter for propo-fol citing particulates in finished batches of thedrug, following a November recall.
The combined propofol recalls led to a shortage in the USmarket, causing FDA to take the unusual step of allowing asimilar drug approved in other countries, but not in the US,Fresenius' Propoven, to be imported and sold in the US untilthe approved US propofol manufacturers are in a positionagain to supply the market.
Propofol Shortage Follows Teva and Hospira Warning Letters and Recalls
In the wake of GMP concerns resulting in an FDA warningletter and recall, and a clinical practice-related lawsuit ver-dict involving heavy punitive damages, Teva announced onMay 28 that it will discontinue manufacturing its genericinjectable emulsion version of the sedative propofol.
In July 2009, Teva issued a nationwide recall of some lots of itsinjectable propofol because of elevated endotoxin levels after atleast 40 people became ill following use of the product.
In December, FDA issued a warning letter to Teva citing theproblems in controlling microbial contamination and endo-toxin in final product. Hospira also issued a propofol recalldue to quality problems in November. The Teva and
Hospira recalls led to a US shortage of the drug beginning inthe Fall of 2009 (See companion story above).
In announcing that it will discontinue propofol manufactur-ing, Teva did not comment on the motivation for its deci-sion. The firm said it will continue marketing doses thathave already been made. FDA confirmed there remains ashortage of propofol in the market.
In early May, Teva was found liable in a lawsuit inLas Vegas district court, and ordered to pay $356million in damages to a plaintiff who claimed hecontracted hepatitis C when one of Teva's propofolvials was used by more than one patient.
Teva Discontinues Propofol in the Wake of FDA GMP Concerns and Lawsuit Verdict
Downloads from the story:
• Teva Warning Letter
• Hospira Warning Letter
• Announcement by FDA regarding shortages of propofol.
The jury also awarded $144 million in punitive damagesagainst Baxter International Inc., which distributed theproduct. Both firms plan to appeal the verdict. In additionto the punitive damages, the plaintiff was awarded $5.1 mil-lion in compensatory damages.
The plaintiffs, Henry Chanin and Lorraine Chanin, suedTeva and Baxter for negligence and product liability claim-ing that Mr. Chanin contracted hepatitis C as a result ofproduct misuse related to unsafe clinical practices. The alle-gation was that syringes were reused on multiple patients orthat vials labeled for single use were reused multiple timeson multiple patients.
Chanin, age 62, was the headmaster of a private school inLas Vegas when he was diagnosed with hepatitis C in 2006after he had undergone an endoscopic procedure at a localclinic. The Chanins sued the endoscopy clinic, the healthcare practitioners and the drug manufacturers. The healthcare defendants settled before trial.
The plaintiffs alleged that Teva stopped making 10 milliliter sin-gle-use vials of propofol and switched to 50-milliliter single-usevials, while only 10 milliliters of propofol are needed for theaverage colonoscopy. By putting five times the needed amountin a “single use” vial, Teva encouraged health care practitionersto use propofol left over in the larger vials for multiple patients– a practice that causes contamination, they asserted.
The plaintiffs said the defendants should have noticed aproblem after nearly 150 incidences of infection associatedwith the larger vials were reported.
Teva and Baxter argued that the 50-milliliter vialwas plainly labeled for single use only.
Teva said it continues to believe that the evidence shows itacted responsibly and that the jury was not allowed to hearevidence that the propofol was “blatantly misused” by theclinic. Teva and Baxter claim the health care practitioners inChanin’s case not only reused the propofol vial among sev-eral patients but reused a single syringe on multiple vials toinject several patients, causing the cross-contamination.
The Southern Nevada Health District traced the outbreak ofhepatitis C to unsafe injection practices at outpatient surgi-cal centers according to a 2008 report. The agency advisedabout 50,000 patients who received endoscopy proceduresat the clinics to get tested. The 2008 notification promptedwidespread concern and led to numerous lawsuits.
Propofol, a generic version of AstraZeneca’s Diprivan, is ashort-acting anesthesia medication which is used for seda-tion during medical procedures, such as colonoscopy andendoscopy, as well as in dental surgery. Teva, Hospira, andEisai of Japan have been authorized to sell generic versionsof the drug.
Downloads from the story:
• Teva Warning Letter
• Hospira Warning Letter
• Announcement by FDA regarding shortages of propofol.
FDA is developing national procedures for engaging stateagencies in the follow-up to recalls and moving toward part-nerships with state agencies to allow the use of state data tosupport other regulatory actions.
Part of FDA’s obligation is to make sure recalled productsare removed from the market promptly. Doing that is “anenormous job,” FDA Office of Regulatory Affairs ActingAssociate Commissioner Michael Chappell stressed at theFDLI Annual Conference in late April.
FDA has “spent an incredible amount” of its valuableresources on product recalls, Chappell noted, and theagency is looking for other partners and other processes toensure that products are removed in a more timely mannerwith fewer resources devoted to the effort.
In addition, FDA is modifying its regulatory pro-cedures manual to specifically permit the use ofstate data for compliance actions such as warningletters and untitled letters.
“What is important about that,” Chappell emphasized, isthat the evaluation of the state data to support those actionswill “follow the same process as if it was FDA data.”
In the past, the FDA official admitted, there has been somereluctance to use state data to support FDA’s enforcementactions. “I think this is the first in what will probably becontinued efforts to better integrate states and FDA as welook at trying to regulate both the domestic and to someextent the international environment.”
FDA to Partner with State Agencies on Recalls and Regulatory Actions
The consortium creates a win-win approach for all interested parties.
Patients benefit due to the enhanced security of the supply chain and improved product quality.
Regulatory bodies benefit from the improved security and quality, which will allow them to focus their limited resources on other areas that create public health risks.
Pharmaceutical and biotech product manufacturers benefit by protecting and improving the quality of raw materials, components, excipients and active pharmaceutical ingredients; by reducing rejects, investigations and audit burden; by improving cycle times; and by allowing internal resources to be redeployed to other quality efforts, such as working with their suppliers.
Suppliers benefit from clear and consistent auditing standards, the reduced number of individual customer audits and the reduced administrative burden of audits.
Third party auditor firms benefit from a more standardized audit approach, high-quality training, and a potentially increased customer base.
Professional and trade organizations benefit from the opportunity to contribute and from access to comprehensive standards and training materials that they can use to benefit their members.
NEED FOR INDUSTRY ACTION As regulators, pharmaceutical executives, supplier executives and members of professional organizations, our ultimate mission is to serve patients. In order to achieve this mission, we require secure and reliable supply chains that deliver quality materials so that medicines can be trusted by health care practitioners and patients. Legislators, regulators, and other organizations around the world are developing and implementing measures to curtail activities that undermine product quality or mitigate their impact. Rx-360, as a global consortium, complements these efforts and offers a level of consistency and scope world-wide that local measures cannot achieve.
R x - 3 6 0 i s a n i n t e r n a t i o n a l consortium of pharmaceutical and biotech companies and suppliers to the industry, incorporated in 2009, that aims to develop and implement a global quality system to help members ensure product quality and authenticity throughout their supply chain to enhance patient safety.
FDA is fast-tracking a set of changes to 21 CFR Part 211 tar-geting control of raw materials, excipients and componentsused in pharmaceutical manufacturing.
Also being completed are changes impacting managementresponsibilities, self-inspections, defect investigations,change control, training documentation, and use of purifiedwater in manufacturing.
A GMP guidance detailing expectations for qualityagreements is in the works as well, and the regula-tions may be further upgraded to support the guidance in this area.
Recent contamination and adulteration events in the US andaround the world, including the tragic heparin and diethyl-ene glycol contaminations (IPQ May/June 2008 andNov./Dec. 2008), have prompted FDA to “fast-track”changes to the regulations governing supply chain andingredient control.
Announcing the forthcoming GMP proposals at a GlobalOutsourcing Conference at Xavier University on June 14,Center for Drug Evaluation and Research (CDER) Office ofCompliance Team Leader Brian Hasselbalch stressed thatthese adulteration issues “represent credible threats to ourmarketplace” and that “raw material controls have to beimproved.”
Hasselbalch explained that once the agency has completedthe drafting process, the proposed regs will follow FDA’sstandard review and comment process, with either three orsix months to provide comments.
The ORA Guidance and Policy Team leader reported thatthe changes will primarily involve 21 CFR 211 sections 80 –96. They will require drug producers to know who the orig-inal manufacturer is for all excipients and active ingredients,and any subsequent repackers and relabelers – “that youknow who they are, who handles [the material] in the sup-ply chain,” similarly to the EMA proposed pedigree,Hasselbalch said.
The US effort to strengthen its supply chain rulesparallels a similar move underway in the EUwhich was also discussed at the Xavier conference(see companion story on page 30).
In addition, there will be an expectation for manufacturersto audit their suppliers, although FDA is still workingthrough the details of those requirements.
“We will not demand that you individually audit,” the com-pliance official commented. “We acknowledge and recog-nize a surrogate or a third party audit arrangement. It maybe more efficient and more effective, quite honestly.” Athird party audit, he said, would have to be performed by “acredible auditing arm [with] certain characteristics thatassure the integrity and the quality of the audits.”
The new regs will also require tamper-evident packaging orother security features applied by the original manufactureror by a subsequent repacker, and use of only components“recognized as safe for their intended use.” Hasselbalchcited BSE materials as an example, and said that the regula-tion will reference CFR section 300.100 on banned compo-nents as well as the inactive ingredient list.
The last proposal in this set of changes will require manufac-turers to notify FDA of any lots of components or excipientswith “serious defects.” The idea is that FDA can then notifyother users of the material and allow them to more quicklyrecover the material from the market. Hasselbalch notedthat “you might not see it for whatever reason, but if some-body else does you will learn about it and that will be toyour benefit.”
The second set of changes being made to the reg-ulations represents phase two of an effort FDAhas been working on for several years to enhanceexisting regulations and propose additions. Thefirst phase was finalized last year (IPQ Jul./Aug.2008, pp. 33 – 40).
The phase two changes include: • establishment of manage-ment responsibilities • requirements for self-inspection,change control, and documentation of training and its effec-tiveness • enhancing existing regulations regarding defectand problem response • requirements for purified andpotable water, and • withdrawal of the expiration datingexemption for over-the-counter (OTC) products.
The regulation will contain more detail about corporateresponsibility and executive responsibility/accountability,consistent with current guidance such as ICH Q10. The
FDA Fast-Tracking Supply Chain cGMP Upgrades; Other GMP Changes,Quality Agreement Guidance Taking Shape
pattern for the GMP development would thus reflect thatprojected in the quality agreement case – “a guidance first toget you used to it, then the regulation,” Hasselbalch noted.
The FDA official said that most companies already have aself-audit program, and the agency believes it should berequired. He assured the audience that FDA’s policy of notlooking at the self-inspection reports except in highlyunusual circumstances will not change.
Explicit requirements will be added for change control sys-tems, including the requirement for firms to have a changecontrol procedure.
Regarding GMP training, the new regulations will requirethat the training be performed and documented. It is a “lit-tle known fact,” that the regulations do not require thistraining, Hasselbalch noted, calling it an “oversight.” Inaddition, some measure of training effectiveness will berequired, though how that will be done will not be specified,he explained, adding that FDA will be “open-ended andopen-minded.”
FDA will also be enhancing two particular regulations:211.192 and 211.180(e). The changes, Hasselbalch explained,will “clarify more about what a defect investigation shoulddo and the nature of the follow-up,” including more deliber-ate analysis, documentation, and timeliness. “We are notgoing to set timeframes on it – we do not like to do that – butwe are going to insist that it be more timely.”
Section 211.180(e) requires an annual review, and FDAwants to specify that this assessment process be more fre-quent. The review is the “key feedback mechanism in theregulations, to teach you what you did not know about yourprocess and product quality,” Hasselbalch commented.
In the proposed regulation, purified water will become the de facto quality of water for drug manufacturing, and explicitinstructions for testing of potable water will also be included.
The last proposed change will be to withdraw the expirationdating exemption for OTC drugs. Currently if the OTC drugis stable for at least three years and there is no daily doselimitation, (e.g., sun screens), there is no requirement forexpiration date labeling. Under the new regulations, anexpiry date will be required. The reasoning behind this stip-ulation will be included in the preamble, Hasselbalch com-mented.
Also in the works at FDA is a GMP guidance thatwill provide the elements FDA expects to see in aquality agreement, which may be called a “techni-cal agreement” or simply a “contract.” The guid-ance will explain the expectation that the agree-ment be in writing and specify clearly what eachparty commits to do.
Other expectations discussed in the guidance will include: • identification of the contract site address, building, andequipment/line, and services/materials to be provided • description of the drug, its intended use, and all specifica-tions • provision for periodic audits to CGMP and contractspecifics • a commitment to share regulatory inspectionfindings • procedures for change control related to newequipment, facility modifications, change in key personnel,change in SOPs and test methods, and • full disclosure of allerrors, deviations, changes, OOS results, and investigations,as well as adverse events that did or might impact the drug.
Hasselbalch also noted that FDA is beginning work onPhase 3 regulation changes, which may include qualityagreement requirements to support the guidance and “fac-tors that disfavor quality.”
Download from the story:
• Hasselbalch’s slide presentation at Xavier University’s Global Outsourcing Conference
An FDA task force released on May 19 a set of transparencyprinciples for public comment which propose to changewhat GMP and CMC documents and information are avail-able to the public and with what timing.
The proposals include making more information availablemore rapidly regarding GMP inspections, enforcementactivities, and investigational, marketing and supplementalfilings.
The “Transparency Task Force” launched Phase II of itsthree-phase initiative by releasing a report containing 21draft proposals for expanding the disclosure of informationby FDA while maintaining confidentiality for trade secretsand individually identifiable patient information. FDA isaccepting public comment on the content of the proposals,as well as on which draft proposals should be given priori-ty, on the FDA website’s task force page until July 20, 2010.
The transparency initiative, which began in June 2009, isdivided into three phases: Phase I, “FDA Basics,” wasannounced in January and is intended to provide the publicwith basic information about how FDA works, primarilythrough the web page “FDA Basics.” Phase II is titled“Public Disclosure;” Phase III, “Transparency to RegulatedIndustry,” is set to begin in the Summer of 2010.
The agency notes that not all the proposals will necessarilybe implemented, as some may require changes in law or reg-ulation and some may require substantial amounts ofresources.
The proposals are divided into eight categories,with varying numbers in each category: AdverseEvent Reports (1), Docket Management Process(1), Enforcement Priorities and Actions (2), ImportProcedures (1), Inspections (2), ProductApplications (10), Recalls (3), and Warning andUntitled Letters (1).
Explaining the transparency thrust in the enforcement con-text, FDA noted that each year its Office of RegulatoryAffairs (ORA) issues a workplan that provides estimatedresource allocations and information regarding inspections.
In the past, this workplan has not been available to the public, as the element of surprise can be important for
inspections. The task force is recommending workplansolder than five years be posted for public view, beginningwith 2001.
In addition, it proposes to indicate in FDA’s weekly“Enforcement Report” when the U.S. Department of Justicefiles a case seeking enforcement action on FDA’s behalf in acourt of law and the final determination of that case, ifknown.
Pointing to the proposal for expanding information onagency inspections, FDA Principle Deputy CommissionerJoshua Sharfstein commented at a Congressional hearing onthe Johnson & Johnson recalls last week that “as part of ourtransparency we have proposed making public everyinspection – when it is happening and what the outcome ofthat inspection is” (see companion story on page 17).
Currently, information related to inspections of pharmaceu-tical manufacturing facilities becomes available throughFreedom of Information after a period of time – a time lagthat grew substantially during the years of the Bush admin-istration, when simple requests for FD-483s could gounfilled for several years.
Proposed by the task force are the followingchanges, which if adopted, would make theinspections and their final classification knownimmediately:
(1) “FDA should disclose the name and address of the enti-ty inspected, the date(s) of inspection, type(s) of FDA-regu-lated product involved, and the final inspectional classifica-tion – Official Action Indicated (OAI), Voluntary ActionIndicated (VAI), or No Action Indicated (NAI) – for inspec-tions conducted of clinical trial investigators, InstitutionalReview Boards (IRB), and facilities that manufacture,process, pack, or hold an FDA-regulated product that is cur-rently marketed. The disclosure of this information shouldbe timed so as not to interfere with planned enforcementactions.”
(2) “FDA should generate, and share with the public, infor-mation about the most common inspectional observations ofobjectionable conditions or practices that are made duringinspections of FDA-regulated establishments and post thatinformation online on a regular basis.”
FDA Proposing More Transparency on Inspection Findings, Recalls, and Drug Filings
WWW.IPQPUBS.COM
IPQ MONTHLY UPDATE–JULY 2010
JULY 2010 | 26
There are ten proposals under the “ProductApplications” section, relating to various types offilings.
Currently FDA generally does not disclose any informationabout the existence, status, or contents of an application sub-mitted to the agency until the product/application has beenapproved, licensed, or cleared.
These proposals would make basic information about appli-cations available – for example: the existence of the applica-tion; whether an investigational new drug (IND) applica-tion has been placed on hold, terminated, or withdrawn;whether various types of applications or supplements havebeen submitted, resubmitted, or withdrawn; and whether arefuse-to-file or complete response letter has been sent to theapplicant.
Regarding drug recalls it is recommended that the public benotified when FDA determines a recall has been terminated.Another proposal relates to recall information that may berequired in the future: “When a system is set up that pro-
vides FDA with authority to require companies to submitcertain information to the agency when they initiate anaction to recover or correct a product that is in the chain ofdistribution, FDA should disclose this information as soonas practicable after receiving this information from thefirm.”
Regarding warning letters and untitled letters, the task forceproposed to publicly post untitled letters in much the sameway that warning letters are now posted. An untitled letteris "initial correspondence . . . that cites violations that do notmeet the threshold" for issuing a more serious "warning let-ter," per FDA Regulatory Procedures Manual, Ch. 4,Advisory Actions 4-27 (2006).
Downloads from the story:
• FDA Phase II transparency proposal
• FDA’s comment page for the proposal
• FDA Regulatory Procedures Manual
• FDA Basics web page
IPQ wishes to thank the following sponsors
WestNovaPure.com
David Begg AssociatesAn NSF International Company
For subscription and sponsorship information visit IPQpubs.comor contact Rich Messmer — [email protected], Tel: 540-246-3923.
The European Commission has published a revised draft ofVolume 4, Annex 2, “Manufacture of Biological MedicinalSubstances and Products for Human Use.”
This revision is taking place due in part to the need to includean increased range and complexity of biological products, andnew products such as advanced therapy medicinal products.This guidance is required for these new products to meet therequirements of Article 5 of Regulation 1394/2007 and to alignwith details in Directive 2009/120/EC.
Many final biological products are actually active substances.However, Directive 2004/23/EC on Human Tissue and Cellscovers only the donation, procurement and testing of the tis-sues and cells, which become the “biological active substances”for many biological medicinal products. This guidance seeksto clarify further requirements, and takes into account that bio-logical processes are inherently less predictable and more vari-able than chemical manufacturing processes.
Up until now, pharmaceuticals have been classi-fied for regulatory purposes by their method ofmanufacture. The Annex along with companionguidelines will now give further guidance on themanufacturing of biologics by defining two dif-ferent aspects, as noted in the draft:
a) Stage of manufacture – for biological active substances tothe point immediately prior to their being rendered sterile,the primary guidance source is Part II. Guidance for the sub-sequent manufacturing steps of biological products are cov-ered in Part I. For some types of product (e.g. cell-based
products) all manufacturing steps need to be conductedaseptically.
b) Type of product – this annex provides guidance on thefull range of medicinal substances and products defined asbiological.
These two aspects are shown in a table giving examples tohelp manufacturers define what is needed for their specificproducts. The draft guidance notes that “the level of GMPincreases in detail from early to later steps in the manufactureof biological substances but GMP principles should always beadhered to. The inclusion of some early steps of manufacturewithin the scope of the annex does not imply that those stepswill be routinely subject to inspection by the authorities.”
The annex is divided into two main parts: • Part A containssupplementary guidance on the manufacture of biologicalmedicinal substances and products – from control over seedlots and cell banks through to finishing activities, and test-ing • Part B contains further guidance on selected types ofbiological medicinal substances and products.
The initial concept paper for this draft was released in May2005, and the first public consultation took place beginningin March 2008. Significant changes have been made as aresult of this consultation. Public consultation on this revi-sion will take place until July 15, 2010.
Draft Revision of EU Annex 2 For Biologicals Out For CommentEUROPE
Download from the story:
• Manufacture of Biological Medicinal Substancesand Products for Human Use
The EU and Cambodia have recently taken additional stepsin the fight against counterfeit drugs: the Council of Europe(EC) updated the EU draft guidance on “falsified medi-cines,” and Cambodia initiated a crackdown on illegal phar-macies operating in their country.
In late April, the EC published a set of draftamendments to EU Directive 2001/83/EC aimed atpreventing “the entry into the legal supply chainof medicinal products which are falsified.”
The draft defines a medicine as “falsified” if any aspect of itscomposition, manufacture, origin, or history is misrepre-sented, including records relating to its distribution.
Falsified active pharmaceutical ingredients (APIs) are alsoaddressed, with a recommendation that competent authori-ties need to inspect both manufacturers and distributors ofAPIs used as starting materials.
EU and Cambodia Take Steps to Fight Counterfeit Drugs
The EC draft explains that safety features are still underdebate. Discussions among committee members regardingwhat types of products should be subject to safety featuresindicate that “most delegations” are in favor of creating pro-visions that allow that certain nonprescription drugs at highrisk of being counterfeited could be subject to compulsorysafety features, the document reports. It also notes that a“large number” of delegations believe that it should be pos-sible to exclude certain categories of prescription-only med-icines at low risk of falsification from such requirements.
Other provisions introduced include: • a requirement to usegood manufacturing practices for excipients, “albeit in amore lenient form than for active pharmaceutical ingredi-ents”• clarifications regarding responsibilities of manufac-turing authorization holders that re-label or repackage • arequirement on authorized distributors to keep records ofbatch numbers of medicinal products • clarification of theprocess to identify third countries that have an adequateregulatory framework to ensure safety of APIs, and • drop-ping the requirement that safety features must have trace-ability.
In Cambodia, illegal pharmacies have been iden-tified as a primary source of substandard andcounterfeit medicines, and the government alongwith a consortium of non-governmental organiza-tions have succeeded in shutting down 65% ofthese stores between November of 2009 andMarch of 2010.
Led by the country’s Inter-Ministerial Committee to FightAgainst Counterfeit & Substandard Medicines, the shopswere targeted because of evidence that they were among theprimary sources of substandard and counterfeit medicinesin Cambodia.
In a press release in late April, the US Pharmacopeia (USP)announced the success of this effort, helped in part by theidentification of the illegitimate pharmacies through thecombined efforts of: the U.S. Agency for InternationalDevelopment (USAID)-funded Promoting the Quality ofMedicines Program, implemented by the USP; the GlobalFund to Fight AIDS, Tuberculosis, and Malaria; and theWorld Health Organization.
USAID Office of Health, Infectious Diseases and NutritionDirector Richard Greene commented that “the resolution insuch a short period of time is a major accomplishment on thepart of the Cambodian government – and a significant stepforward in assuring the quality of life-saving medicines forpatients in the country.”
As part of this effort, Cambodia also banned sales of prod-ucts from five manufacturers in the country.
Downloads from the story:
• EC draft document on falsified medicines
• Cambodian initiative
Two trade associations in Europe, through separate butrelated efforts, are advancing the dialogue on preventingcounterfeit medicines from entering the legitimate drugsupply chain: one by publishing a set of guiding principlesto call attention to the issue; the other by successfully exe-cuting a pilot program on security of drug products in thesupply chain.
In May, the International Federation ofPharmaceutical Manufacturers and Associations(IFPMA) published a document titled “Ten Principles on Counterfeit Medicines” to “re-focus attention on this issue and underline theR&D-based pharmaceutical industry’s stance inthe global fight against counterfeit medicines.”
According to IFPMA, this document was written in part due
to the continued rise in the incidence of counterfeit medi-cines and the resulting public health concerns.
The document emphasizes the trade association’s belief thatthere is a lack of awareness among policy makers and thegeneral public about the “real consequences of this criminalactivity and the scope of action that is needed.” It notes thatdeveloping countries are particularly at risk, in part due tolimited resources for detection and enforcement.
Eduardo Pisani, Director General of the IFPMA, comment-ed: “We hope that the Ten Principles will highlight the fullscope of the problem and demonstrate that the fight againstcounterfeit medicines is simply about protecting patients’health.” Although this document may serve to frame andadvance the dialogue on this topic, it does not propose anyspecific actions or solutions.
European Trade Associations Step Up to the Plate on Drug Counterfeiting
The European Medicines Agency (EMA) has updated itsGMP facility inspection procedures to align with recent revi-sions to its EU GMP Guide reflective of ICH Q8-10 principles.
In the revised document, wording has been added to recom-mend the use of risk-based planning for inspections and toclarify the scope and application of inspections of importers.In addition, the EMA has added an annex on conductinginspections of active substance manufacturers.
The new version of this guidance is more comprehensiveand prescriptive than the 2006 version, suggesting specificdocuments and procedures for GMP inspectors to evaluate,and providing recommendations on how to conduct thewrap-up meeting.
The new drug substance inspection annex isintended to “harmonize inspection procedures,frequency of inspections and follow-up proce-dures, thus ensuring a consistent approach toassessment and decision-making by CompetentAuthorities” in line with current EC Directives.
The annex advises member states to establish the legal andadministrative framework needed for identification of
facilities, access to facilities and data, and GMP inspectionsof active substance manufacturers and importers, includingsites which only repackage or re-label active substances.
Detailed procedures using a quality systems approachwhich are consistent with EU-level documents need to beestablished by member states to ensure site compliance withGMPs and with European Pharmacopia monographs whereapplicable. Sufficient resources should also be available andtrained to conduct the inspections, according to the annex.
The sterilization and aseptic processing of sterile active sub-stances are not covered in this annex. Whole blood andplasma are also excluded. However, active substances thatare produced using blood or plasma as raw materials areincluded.
FDA has also been updating its inspection guidance, includ-ing the compliance program guide for pre-approval inspec-tions, to reflect a more risk-based, ICH Q8-10 approach (seerelated story on page 20).
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JULY 2010 | 29
Protecting patient health was also the focus of arecent pilot program carried out in Swedenbetween September 2009 and January 2010 by theEuropean Federation of Pharmaceutical Industriesand Associations (EFPIA).
The pilot involved creation and use of a system for tracingand verification of drugs in the legitimate supply chain frommanufacturers and wholesalers through pharmacy retailers.EFPIA released an analysis and final report on the pilot inApril.
EFPIA worked with the pharmacy chain Apoteket AB andthe wholesalers Tamro and KD Pharma using a 2D matrixcoding system on over 95,000 drug packages from 14 manu-facturers distributed through 25 pharmacies in Sweden, ver-ifying each product at the point it was dispensed.
The pilot involved introducing packs of products designat-ed as expired, under recall, and “unknown” into the supplychain – the unknown packs were not listed in the systemand were used to represent counterfeits. The system correct-ly identified each of 250 products under recall, 250 productsthat had expired and 250 products that were “unknown” tothe system.
EFPIA stressed an important feature of the pilot programwas the active participation of all the various stakeholdersas well as their “willingness and ability to cooperate.” Allparties involved indicated that the pilot was a success andcould serve as a model for other European countries.
IPQ MONTHLY UPDATE–JULY 2010
Download from the story:
• EMA revised inspections document
Downloads from the story:
• IFPMA Ten Principles
• EFPIA pilot report
EMA Updates Facility Inspection Procedures to Align with EU GMP Guide Revisions
MHRA is requesting that all manufacturing sites inspectedafter April 1, 2009 under its risk-based inspection (RBI)approach submit interim updates to communicate signifi-cant changes between inspections.
MHRA put its RBI effort in place following public consulta-tion that began in late 2007 (IPQ, Jul./Aug. 2008).
The guidance, instructions, updated report on the RBI effort,and form which must be filled out for the interim updateswere published as part of the announcement. Affected sitesare those UK sites that hold a manufacturing authorizationfor finished products and investigational medicinal products, and third-country sites that are named on a UKmarketing authorization or where UK has been the referencemember state on a decentralized procedure.
Sites will be required to complete a “compliance report” inadvance of being inspected – this will be prompted by theinspector. Additional information is available on the MHRA
site. The compliance report should be returned to theinspector that last inspected the site prior to the inspection.
The inspection process will be largely indistinguishablefrom the one that operated in recent years and will concludeas usual with a closing meeting where findings are verballyreported to site contacts. Inspectors will discuss the submit-ted compliance report at the opening meeting as they wouldhave done previously with changes advised.
MHRA is Requiring Interim Update Reports for Risk-Based Inspections
Downloads from the story:
• MHRA Guidance for completing API interim reports
• API Interim Report Form
• Guidance for completing site compliance and interim reports
• Site compliance and interim report form
• MHRA report on progress on the initiative, April 2010
• Example forms and additional information on the MHRA web site
Changes to the EU regulations that govern technical agree-ments, outsourced activities, active pharmaceutical ingredi-ent (API) supply chains, and the storage and transit of med-icines are in progress and expected to be released soon forpublic consultation.
The changes to the EU regulations “will significantly affectanybody who wants to supply to Europe," MHRA GMPInspector Rachel Carmichael emphasized at a GlobalOutsourcing Conference at Xavier University on June 14.
The EU effort to strengthen its supply chain rulesparallels a similar move underway in the US,which was also discussed at the Xavier conference(see companion story on page 23).
Over the past few years, MHRA and EU inspectors havenoted deficiencies in technical agreements that govern howfirms outsourcing activities and their contractors perform-ing the tasks work together. Deficiencies cited include nothaving an agreement or a requirement for one in place, doc-
uments not routinely reviewed, and lack of detail regardingtechnical and GMP responsibilities.
“Our general stance is if you do not have a signed technicalagreement in place you ought not to be doing any work,”Carmichael emphasized, noting that “if you have notdefined what your expectations are you cannot really be thatsurprised if they do not deliver on them.” The fact that acompany has outsourced activities to a professional organi-zation does not mean that it fully understands the details ofwhat is expected, she noted.
Carmichael’s understanding is that the title ofChapter 7 will change from “ContractManufacture and Analysis” to “OutsourcingActivities” to reflecting the scope of the revisionsit will contain.
Chapter 7 will encompass “any outsourced activity, which ifit were performed on site would normally be subject toinspection,” Carmichael explained. She added that some
EU Moving to Tighten GMP Requirements on Outsourcing and Supply Chain Control
form of risk-based language in line with the ICH guidelineswill be used.
Items being considered for addition to the revised EU out-sourcing chapter include: • qualification and validationwork for new premises • maintenance and calibration ofequipment and premises • storage and distribution • art-work generation and print ready material, and • assessmentand sourcing of starting and packaging materials.
An initial draft of the revision is expected to be released laterthis month, with public consultation anticipated to start inSeptember and guidance finalization a year later.
A separate EU proposal also in the works willrequire a detailed “pedigree” of the API supplychain and the creation of a list of all suppliers ofcritical raw materials and intermediates.
“We are talking about everybody here, up to the finalrelease of the final API being identified, being named in apedigree that the company holds,” explained the MHRAinspector, including “the suppliers and the sites from thepoint of release of the API to the point of receipt by the fin-ished product manufacturing site.”
Updates will be made to several regulations to implementthe supply chain pedigree requirement. These includechanges to Chapter 1 (Quality Management), which willrequire product quality reviews to cover the supply chain inaddition to starting materials. Chapter 5 (Production) willrequire that verification on receipt that the materialsreceived have come via the expected supply chain.
The EU is also working on a template for the QualifiedPerson (QP) declaration, planned to go out for consultationby the end of this year.
MHRA and EU inspectors have noted numerous deficien-cies in the last few years regarding control of transportation
conditions for drugs, including: • no temperature dataavailable during transit • no review of the temperature dataconducted prior to QP certification • variations in the num-ber of data loggers between shipments, driven by whatmanufacturer has available • lack of awareness of the distri-bution chain, and • use of unapproved transport hubs enroute to the product’s final destination.
These deficiencies and a major recall of 111 prod-uct lines last year in the United Kingdom due toextreme temperature, humidity, and storage con-dition deviations are prompting the EU to proposea series of other changes to the regulations to clar-ify expectations for shipping and storage of drugs.
EU Commission-level documents will be changed, alongwith Chapters 5, 6, and 7 and Annexes 15 and 16 of the EUGMP Guide. A new “frequently asked questions” section onthis topic will also be added.
Carmichael said she expects to see a concept paper on theshipping and storage rules soon as well and an initial draftout for consultation in November.
Other changes in the works in the EU, the MHRA officialnoted, include: • the tightening of requirements for beingnamed as the “responsible person” on a drug wholesalerlicense • bringing “free trade zones” under regulatory juris-diction, and • applying some degree of control over unap-proved “transit hubs.”
Carmichael advised the industry attendees to perform risk-assessments on their supply chains and attempt to shortenthem to improve their security.
IPQ MONTHLY UPDATE–JULY 2010
Download from the story:
• Rachael Carmichael’s slide presentation at Xavier conference
The ICH Q8-10 Implementation Working Group (IWG) hasconcluded, based on its industry/regulator workshop inTallinn, Estonia in early June and the IWG’s internal meet-ing the following week, that refinement of the trainingmodel used in the workshop, additional Q&As, and furtherevaluation of the other ICH quality guidelines for inclusionof Q8-10 principles are needed.
Future areas of focus for the IWG will include examining theremaining technical and regulatory gaps to determine theneed for development of further training – potentiallyincluding non-ICH regions – and how to proceed withassessment of the other ICH quality guidelines for consis-tency with quality-by-design principles.
The IWG workshop, co-sponsored by PDA andISPE, was attended by 240 participants from 34countries, with 100 assessors and inspectors from32 different health authorities and 140 industryexperts representing 45 companies. The ratio ofassessors to inspectors among the regulators wasabout three-to-one.
The workshop began with four plenary presentations on thedevelopment, assessment, manufacturing, and inspectioncomponents of Q8-10 implementation. A mock case studywas developed for the workshop to elucidate the applicationof QbD in these phases of the product lifecycle.
With the case study as an anchor for the discussions, break-out sessions followed on design space, control strategy,quality risk management, and pharmaceutical quality sys-tems through which the participants rotated.
In the breakout sessions, the IWG solicited input from the par-ticipants on three primary questions related to the ICH Q8-10guidances: • Are we clear with the key messages? • Are therepractical concerns on implementation? • Where is more clar-ification required for practical harmonized implementation?
The case study followed the application of QbDfor both the API and drug product.
The API for the product was a single neutral polymorphwith low solubility and high permeability, or Class II under
the Biopharmaceutical Classification System (BCS). The sol-ubility (dissolution) was affected by particle size, and theAPI degraded by a hydrolytic mechanism.
The drug product was an oral immediate-release tablet pro-duced by a direct compression manufacturing process. An invitro/in vivo correlation (IVIVC) had been established allowingdissolution to be used as a surrogate for clinical performance.The blending process control options in conventional versusreal-time release testing were explored at the workshop.
The second and third of the IWG “integrated implementa-tion training workshops” will be held in Washington, DC,October 6-8, and in Japan preceding the scheduled ICHmeeting there in November.
At DIA’s annual meeting in Washington, DC inmid-June, Center for Drug Evaluation andResearch (CDER) Office of New Drug QualityAssessment (ONDQA) Deputy Director ElaineMorefield reported on the Tallinn workshop andsubsequent IWG discussions.
Morefield explained that based on the discussions, develop-ment of “optimized plenary and breakout presentations”and an “improved structure” for the breakouts is planned,although there will be no changes in speakers or topic leadsfor the Fall sessions “so that we can keep consistency.”
In addition to assessment of the Tallinn workshops, at itsfollow-up meeting the IWG focused on determining theneed for harmonization across all the ICH quality guidelinesand the best way to use the feedback and learning obtainedfrom the three training workshops.
The initial finding of the IWG “is that there is not a need todirectly revise existing guidelines” to include ICH Q8-10principles but “there are gaps that we should address,” IWGmember Morefield noted. The group plans to further eval-uate these gaps after the completion of the three workshops,combining feedback from those sessions with its own analy-sis to chart the course forward.
Although the Tallinn workshop was billed as“integrated implementation training,” effectively
ICH Q8-10 IWG Making Adjustments Based on Estonia Workshop and Follow-up ICH Meeting
INTERNATIONAL
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it was really more oriented toward identifying gapsthan resolving issues and developing guidance.
Morefield commented that the experience level with ICHQ8-10 implementation was not as high at the workshop asmay have been anticipated. Noting the number of regula-tors in the audience in Tallinn, the FDA official pointed outthat in Europe, “they have not had as many applications, sothey have not had the experience in reviewing the applica-tions with these kinds of materials yet.” She also pointedout that the case study materials were delayed in gettingout, adding that the IWG will make an effort to get the doc-uments in the hands of the participants earlier for the nexttwo workshops.
“The work group decided that true collaboration is a little bitdifficult to accomplish in a situation like ICH IWG,”Morefield explained. Instead of trying to resolve all the guid-ance challenges in-house, the IWG is considering producing alist of topics where further publication and discussion wouldbe useful and making that list available “so that people couldpotentially publish on their own in these areas.”
At the meeting in Tallinn, Pfizer Executive Director RobertBaum noted that while the IWG will be continuing to exam-ine the existing guidances, "we probably cannot revise them,but we can at least identify those that may need some sortof revision or maybe some statements up front that alternateapproaches are available." Baum stressed, however, that theIWG will continue to address industry questions through itsQ&A mechanism.
A proposed agenda has been developed for the NovemberIWG meeting in Fukuoka, Japan and includes developmentof a training summary report, optimization of training mate-rials for future use, and evaluation of the need for trainingin non-ICH areas.
Along with the Q8-10 sessions, the ICH meetingalso advanced quality initiatives on heavy metals(Q3D), drug substances (Q11), and pharmacopeialmethods (Q4B). [Editor’s Note: An analysis of theICH objectives on these three quality topics isincluded in the May issue of IPQ, which addressesthe impact of the ICH Q8-10 paradigm on the CMCreview and inspection processes.]
Two annexes for the Q4B guideline “Evaluation andRecommendation of Pharmacopoeial Text for Use in theICH Regions”– Annex 11 on Capillary Electrophoresis andAnnex 12 on Analytical Sieving– reached Step 4 (ready forregional adoption). Another two– Annex 13 on Bulk andTapped Density and Annex 14 on Bacterial Endotoxin–reached Step 2 (regional comment phase).
In addition, two expert working groups (EWG) were estab-lished – one for a new multidisciplinary topic on genotoxicimpurities (M7), and another for a new safety topic on pho-tosafety evaluation (S10).
IPQ MONTHLY UPDATE–JULY 2010
Download from the story:
• ICH Tallinn Press Release
Regulators from all three ICH regions participating in a Q8-10 training workshop in Estonia in early June stressed theneed for pharma company senior management support toachieve the ICH quality system objectives – pointing to theimproved quality, compliance, communication and relation-ships with regulators that result from this commitment.
During a panel discussion at the workshop, ICH QualityImplementation Working Group (IWG) Rapporteur Jean-Louis Robert (EDQM) asked the panelists, “if you had to sellthe ICH principles to senior management in one slide, whatwould [you] highlight as the top five key benefits?”
Center for Drug Evaluation and Research (CDER) Office of
New Drug Quality Assessment (ONDQA) Director MohebNasr pointed to better quality and compliance as toppingthe benefit list. The ICH processes “provide manufacturingflexibility and that comes with a great opportunity as youcontinue to deal with shrinking markets and challenges inpharmaceutical development,” he stressed.
“I would like to add better communication between industryand regulators, which is a key issue,” said AFSSAPS AssistantDirector Jacques Morénas. “For me one of the top issues toraise to senior management is really facilitating communica-tion between” regulators and industry, which among otherbenefits serves to reduce “the number of inspections or depthof inspections, or the length of inspections.”
Senior Management Involvement is Critical for ICH Q8-10 Implementation Success, Regulators Affirm
Referencing large drug recalls and the May BritishPetroleum oil rig explosion in the Gulf of Mexico in particu-lar, Pfizer Executive Director Robert Baum noted that therehave been a number of very recent events that “point togood opportunities to sell quality, both in the pharmaceuti-cal industry and elsewhere.” Baum’s message to seniormanagement would be that “quality should be consideredan investment, not a cost. Quality saves money, it makes formore profit, it makes for good public relations, and it makesfor good patient relations. There is no down side.”
Some panelists questioned whether the seniormanagement in many pharmaceutical companiesare aware of the responsibilities ICH Q10 placeson them.
Q10 contains a section specifically on “management respon-sibility,” with several subsections on: • management com-mitment • quality policy • quality planning • resourcemanagement • internal communication • managementreview • management of outsourced and purchased materi-als, and • management of change in product ownership.
Japan National Institute of Health Sciences (NIHS) Divisionof Drugs Section Chief Yukio Hiyama shared with the groupthe outcome of an informal survey he did across the presi-dents/CEOs of 65 pharmaceutical innovator companies inJapan. “Most of them are not aware of Q10. That really wor-ries me a lot,” Hiyama noted.
The discussion regarding concern with manage-ment awareness of Q10 broadened to include sen-ior management awareness of the importance ofquality in day-to-day manufacturing operations.
Addressing the issue of how to foster their understandingand support, Nasr stressed the need to get them to “realizethat manufacturing is important.” He added that “itbecomes important at times to senior management whenthere are major issues and there is considerable financialpenalty or impact on the firm.”
Japan’s Hiyama concurred, commenting that “most of thesenior management in innovator companies worry onlyabout the product pipeline and marketing strategy.”
Pfizer’s Baum noted that product quality can suffer due to alack of senior management awareness of its importance andthe financial stakes involved. “I think the problem is peoplewho work in quality are a number, and when costs have tobe cut they are just one other number across the board. Butlook at some of the recalls that we are having with some ofthe major firms. It is costing them I do not know how muchmoney.”
Pfizer Quality Strategy VP Georges France added that oftennew laws and regulations are created reactively. “I thinksenior management really should think about that.”
IWG Rapporteur Robert commented that “in our business ofquality, when everything is well-done the senior manage-ment does not even hear about us. They only know aboutquality when there is a problem.”
AFSSAPS’ Morénas suggested that the IWG may considerdeveloping training for CEOs in the pharmaceutical indus-try to create awareness and help to remedy these concerns.
The importance of pulling the generics industry more direct-ly into the QbD/ICH Q8-10 implementation process wasstressed by key regulatory and industry officials during theconcluding session at the ICH Quality ImplementationWorking Group (IWG) workshop in Tallinn, Estonia in earlyJune.
The workshop was sponsored by the associations PDA andISPE, with PDA’s European office, headed by GeorgRoessling, having primary responsibility for Tallinn.
Among the prominent voices speaking up for the impor-
tance of generics industry inclusion in QbD implementationwas MHRA Expert Inspector Ian Thrussel. Innovator firmsmay now be on the QbD bandwagon, but generics are themedicines most people take and a way needs to be found todrive the new manufacturing paradigm forward in thisindustry group, he asserted.
Thrussel pointed out that “it will be many years before thepeople in this room and their families take quality-by-design medicines…. Big pharma may well have been theinnovators, but they are not the major providers of the med-icines” taken by patients today.
Generics Industry Outreach Urged at Q8-10 Implementation Workshop in Estonia
INSIDE THE GLOBAL REGULATORY DIALOGUETM
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To date the primary focus of QbD implementation has beenwith products in development that can make use of the fullrange of QbD principles. “Perhaps it is now time to…askourselves what we can do to promote the implementation”of ICH principles for generics, the British regulator com-mented. “Perhaps there is more we can leverage out of Q9and Q10, taking of course the ideas of knowledge manage-ment and so on from Q8.”
Pfizer Quality Strategy VP Georges France emphasized thatfirms that do not develop new products can still benefitfrom ICH Q9 and Q10. Firms “are not obliged to start fromthe beginning,” he commented, and using these principles“can have some benefits in terms of efficiency and in termsof yield.”
Pharmaceutical Intellectual Resource Services CEONicholas Cappuccino, an observer to the ICH process representing the International GenericPharmaceutical Alliance (IGPA), discussed the impor-tance of ICH principles to the industry he represents.
Cappuccino commented that “it is important that the gener-ics industry have a place at the ICH discussions that occur.Even though a lot of it does not directly impact the genericsindustry, indirectly it impacts it very much….. I think thatas we go forward with trying to implement the new qualityparadigm we should look for ways to include the genericsindustry.”
The IGPA representative noted that generic drug firms donot have large research and development or marketing divi-sions, and that allows senior management to focus more onquality issues than large multi-national pharma firms thatdivide their focus between various company divisions. “Forthe generics industry, a bigger part of the business isinvolved with the quality and manufacturing than it is withthe typical innovative company,” Cappuccino pointed out.On the other hand, “having said that”, he queried, “are theyreally aware of ICH Q10? I would say not.”
“I have personally tried fairly hard to bring the genericsindustry to be more participating in some of these activitieswithout a whole lot of success,” commented Center for DrugEvaluation and Research (CDER) Office of New DrugQuality Assessment (ONDQA) Director Moheb Nasr.
Pfizer Global R&D Executive Director Robert Baum notedthat while there are benefits to be gained from pushing QbDinto the generics arena, there are also challenges involved inchanging the regulatory paradigm for generics.
“I would think from a scientific perspective you would havealmost everybody on the bandwagon,” he noted.“Unfortunately, in the US, I would say the political strugglewould…outweigh the scientific aspects of this. The ramifi-cations of the political perspective in terms of lobbyists andCongress being questioned again – more generics approvedfaster – the barriers would be enormous.”
CDER official Nasr suggested that the IWG couldpromote the ICH principles to the generics indus-try by sharing the training materials it has alreadydeveloped.
“I think sharing this training material with developingcountries, who are, for the most part, responsible for themanufacturing of generic products and active pharmaceuti-cal ingredients…would be a step in the right direction,” hecommented.
Pfizer’s France suggested that in addition to sharing trainingmaterials, the IWG could put together case studies showcas-ing the value of ICH Q9 and Q10 in manufacturing. “I amsure that if you speak about yield and avoiding out-of-specand avoiding recall, the generics industry can understandthat they have [the potential for] a major saving from that. Iam sure that there is a value for us to produce these kinds ofcases.”
FDA enforcement actions involving generic firmshave focused on the problems a lack of QbD hascreated.
Pointing to recent consent decrees for generic drug firms inthe US, CDER Office of Compliance Division ofManufacturing and Product Quality (DMPQ) Director RickFriedman noted at the Tallinn workshop that a lack of goodprocess design was integral to the regulatory actions.
In one recent case, Friedman stressed, “we had a specificprovision in the consent decree that said the company mustgo back to the process design, revisit the process design, anduntil they showed the process design was sound” the firmcould not restart manufacturing.
If firms have “inconsistent processes,” they will need to “goback to the drawing board and fix those processes and bringthem up to the right design level so that they are designedfor quality,” the FDA compliance official affirmed.
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The expectations for non-critical parameters in communicat-ing with regulators on process design, control and changemanagement drew significant attention at the ICH QualityImplementation Working Group (IWG) training workshopin Tallinn, Estonia in early June.
At the workshop, co-sponsored by PDA and ISPE, a largegroup of regulators from the ICH regions and beyond satdown with industry to explore where the gaps are in theexisting Q8-10 guidance based on their expanding imple-mentation experience.
In breakout sessions through which the attendees rotatedfocused on design space, control strategy, risk managementand quality systems, the IWG asked for input on three basicquestions: • Are the guidelines clear on the key messages? • What practical concerns are emerging with implementa-tion? and • Where is more clarification needed to assure aharmonized approach?
The implication for regulatory filings and inspections ofdecisions on the criticality of parameters – an area that drewattention during the Q8-10 development process – continuesto be of concern.
Workshop participants pointed to a lack of clarity aroundthe expectation for including information on non-criticalparameters in describing the process and design space inapplications, and in turn, the corresponding regulatoryimplications for change management.
Joining a panel of IWG members at the conclu-sion of the workshop, FDA Center for DrugEvaluation and Research (CDER) Office of NewDrug Quality Assessment (ONDQA) DirectorMoheb Nasr was prompted to comment on theconcerns raised around parameter criticality andthe implications for those judged non-critical.
The manufacturer’s goal is to understand the process andprovide what is needed for the reviewer to follow how thatgoal was reached, Nasr stressed. In this context, “it is very dif-ficult if not impossible to describe a manufacturing processbased only on one or two critical parameters. So when youput in a submission, you have to include an adequate descrip-tion of the manufacturing process. That may mean inclusionof critical and non-critical process parameters.”
Nasr pointed out further that there isn’t a regulatoryrequirement to develop a design space. “It is up to theapplicant to determine what design spaces really need to bedeveloped and the parameters that need to be included.”
However, he emphasized that the parameters includedshould not be limited only to critical parameters. “You usecritical and non-critical parameters when you develop adesign space and that would be based on the need for manu-facturing flexibility, operational flexibility, and to illustratethe degree of understanding” from the development studies.
Addressing the concern about regulatory requirements forchange management once critical and non-critical parame-ters are included, Nasr pointed out that, in any case, changeswithin the design space do not need clearance. For changesto critical parameters outside the design space, firms willneed to follow the regional filing requirements for changemanagement, he said.
Nasr framed the critical/non-critical discussion in the largercontext of looking beyond the regulatory concerns to thequality and control benefits that will flow from incorporat-ing the enhanced QbD approaches.
Having clarity on regulatory expectations is important.However, Nasr urged firms not to overlook the opportunitythe experimentation and risk management around criticali-ty determinations provides in furthering the development ofthe control strategy. “I think that is where the value in usingquality risk management experimentation and determina-tion of criticality is – it is not only for regulatory purposes,”the FDA reviewing official maintained.
Pfizer Global R&D Executive Director RobertBaum suggested that firms need to understand thecurrent phase-in stage and base criticality deci-sions “on the science right now” rather than onhow those decisions can be finessed.
“Despite some of us thinking we have been working in thisarea for a long time, we are still very early in the learningcurve,” he maintained. Providing more information “will helpall of us gain a better understanding of what we are trying toaccomplish by describing design spaces in applications.”
Taking exception to colleagues who say “we do not have to
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include non-critical parameters because they have no impacton efficacy,” Baum asserted that “we cannot prove that. Wemay not think they do, but establishing linkages betweensafety, quality and efficacy is very difficult.”
The PhRMA IWG member maintained that “the issue of post-approval changes will work itself out. I do not think by includ-ing non-critical parameters in design space we are putting anunnecessary burden on industry around post-approvalchanges. We can find a way” that accommodates the needs of“both assessors and inspector via our pharmaceutical system.”
More generally, Nasr cited the workshop presen-tations as indicating that the “IWG may need toconsider further discussion on lifecycle manage-ment of these enhanced approaches.… These arenot things that are static – they are dynamic, andthey need to be updated and evaluated andimproved…. I think we need a general discussionon it.”
More specifically for the design space, regardless of the reg-ulatory process, companies will have a responsibility tomake sure the design space remains robust to ensure “thequality of the product manufactured in their facility.”
If the design space has not been fully verified at full scale,“upon commercial manufacturing the data will need to sup-port what has been expected at smaller scale. If not, maybeadjustments need to be made to reflect full-scale manufac-turing ability using the design space.” In turn, if a model hasbeen used in developing a design space, the model mayneed to be further verified or adjustments made to it.
“Many of these activities can be done under the quality sys-tem,” Nasr stressed. “There may be some regulatoryrequirements as well,” he added, “but the focus is not onlyon what specific regulatory submission you need to do. Thefocus has to be on making sure that these design spaces, themodels, are living and they continue to be updated.”
Pfizer’s Baum commented further on the importance of tak-ing a lifecycle perspective in evaluating the design spaceand other QbD development work.
“I am in development, and we work closely with our col-leagues in manufacturing in the latter stages of develop-ment. We think that we have a pretty good handle on thedesign space at the time the application is developed, but nomatter how much development work we have, we haveactually made relatively very few batches compared to what
we are going to make in the early stages of manufacturing.The comment I get back from our manufacturing colleaguesis that they learn more… with regard to process understand-ing, process capability, in the first three months of manufac-turing than we may learn in five years of development.”
Regardless of regulatory issues, Baum stressed, “there is aneed to monitor and evaluate design space just from a scien-tific understanding perspective.”
Nasr explored further the relationship betweenthe design space and the quality system in lifecy-cle management.
“If you develop a robust design space, and that robustdesign space has been approved, you have authorization foroperational flexibility within that design space – no ques-tions.” On the other hand, the ONDQA director suggested,“if your design space is not fully developed and fully robust,then you can still...provide assurance to the regulatoryauthorities that your quality system will provide appropri-ate oversight for operation within that design space.”
Nasr clarified that he was not implying the need for exten-sive quality system information in the submission.
“What I am saying now is the following: If you have a fullydeveloped robust design space, you are fine. If you do nothave a fully robust design space you may get an approveddesign space with the flexibility you would get for a robustdesign space if you have a robust quality system. So havingthese going hand in hand will provide the flexibility and theassurance of the quality that we as regulators expect.” Afully-developed quality system will “provide us with addi-tional assurance in case there is something in the designspace that you provided at the time of marketing authoriza-tion that is insufficient or incomplete.”
Regulators Cite Need for TighteningAssessor/Inspector Linkage
Nasr’s remarks opened the door more generally to a discus-sion of the relationship between the QbD-based applicationand the GMP/inspection process, and the need for moreintensive communication between those performing the tworegulatory functions.
The issues of how much information should be included inapplications regarding quality control systems and wherethe review responsibilities should reside were focal points ofattention at the Tallinn workshop.
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Brought into relief were the challenges of theinterrelationships between the design/develop-ment work, the control strategy, the quality sys-tem, and lifecycle validation and change manage-ment approaches within the new Q8-10 paradigmon the one hand, and the regulatory structuresneeded to accommodate them on the other.
While there has been collaboration in the past betweenassessors and inspectors, Nasr suggested that “it is clear aswe implement Q8, 9, and 10, that we need to enhance thatcollaboration to a great extent.” He added that joint inspec-tions may help bring about this enhanced communication.
The challenge of enhancing the assessor/inspector commu-nication process is even more pronounced in the Europeancontext, where the preapproval inspection process has notbeen as fully implemented as in the U.S. and the disconnectsof the multistate system come into play.
The timing and location of the inspection is a key issue inbridging this gap, AFFSAPS Assistant Director JacquesMorenas stressed, noting that a preapproval inspection hasdifferent requirements. The IWG and the EMA’s PAT teamhave insisted “on the need to have a closer working relation-ship between assessors and inspectors” to define the scopeof the inspection and the questions that need to beanswered, the EMA IWG representative said.
In turn, Morenas recognized that joint inspections on the FDApre-approval inspection model involving both assessors andinspectors may be needed. “Keep in mind also that with thisnew paradigm, we are in a learning process – you industrybut also regulators. So we need to have, not a new approach,but a better approach between inspectors and assessors.”
Regarding post-approval routine inspections, Morenas clar-ified that if a manufacturing site is delivering a pharmaceu-tical product which is meeting its specifications, whether aQbD or a traditional product, “the way to inspect” wouldremain the same with “no difference.”
At another juncture in the discussions, the AFFSAPS officialalso pointed to the problem of integrating the handling of sus-pect quality defects into the regulatory equation in Europe.“In many agencies,” he noted, “we have independent depart-ments dealing with handling” of suspected quality defects.For defects related to products incorporating QbD and designspace, “it is very important to be able to feed back this infor-mation to assessors and inspectors in a good way because thiswill have a legal impact also,” he noted.
While issues remain, Pfizer’s Baum sees progressin moving from a “checkbox culture” in terms ofdossier filings to the more flexible and meaning-ful QbD approach where science is the guide.
“There has been a lot of frustration over the past few yearsat various meetings where, when we have breakouts likethis or a panel, the questions we would usually get are ‘howmuch of this kind of information needs to go into thedossier? How many design of experiments is enough to jus-tify a design space?’ Now I think we are moving to the point,all of you, where you can see that… we need to do enoughso we can justify to ourselves we have done things scientifi-cally correctly. And if you have done that yourself, thenyou can probably [make that case] to those who inspect yourprocesses.”
“I think it is moving to this new culture, and if you can helpus spread that word it will be of tremendous benefit to all ofus,” the IWG member told the Tallinn workshop participants.
Echoing Baum on the input and support neededby the IWG in making further progress, AFFS-APS’ Morenas added an historical perspectivebased on his 30-year involvement with the regula-tory inspection process.
When Morenas started as an inspector, discussion withindustry was seen as a conflict of interest. By contrast, hesaid, “for seven years now I have been involved in this ICHprocess and I can see how we are moving from this old wayto a new way in which we are discussing and cooperatingfor elaborating these new concepts. And I am verypleased…to be part of this evolution of relationship betweeninspectors and assessors, and also between regulators andindustry. I think we need to keep that in mind because it isvery important for the future.”
To the concern that using the new concepts will result inmore inspections, Morenas emphasized that the inspectorsinvolved see the goal as “really the opposite.”
He also responded to another concern he heard during theworkshop sessions about inconsistencies between inspec-tion systems in the US, EU and Japan and within the EUitself. Morenas urged attendees that have concrete casesinvolving non-consistencies between inspectors to use asso-ciations such as PDA, DIA and ISPE to direct these problemsto the regulators and “we will look at them altogether to seewhere we need to train our inspectors” or where furtherexplanations may be needed.
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“Really I think we need to make progress all together,”Morenas stressed.
The IWG will be holding two additional “integrated imple-
mentation training workshops” – in Washington DC,October 6-8, also co-sponsored by PDA and ISPE, and inJapan preceding the scheduled ICH meeting there inNovember.
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Novo Nordisk’s broad-reaching quality-by-design (QbD)initiative for protein development is gaining traction fasterthan the company had anticipated, fueled by buy-in fromtop management and the production department.
Discussing the steps his company has taken to implementQbD across its protein product and process developmentoperations at ISPE’s Washington Conference in early June,Novo Nordisk (NN) Senior QbD Manager MichaelSchousboe noted the enthusiastic uptake the program hasgotten. “It has really spread a lot faster than we originallyanticipated” and now has “very high management buy in,”he reported at the ISPE conference’s Product QualityLifecycle Implementation (PQLI) track.
NN has developed a workable model for implementingQbD as a “strategic initiative” encompassing its quality,CMC and production departments, Schousboe said, and theeffort has been “ramped up” based on the positive experi-ence gained. He highlighted the strong “push” coming fromthe production unit, in particular, as the impact on processefficiency and capability becomes clearer.
The “picture from an implementation project point of viewis sort of ideal,” the QbD project manager noted – “having alot of customers screaming for what you are trying to sell.”
Novo Nordisk is now implementing a “QbD strat-egy” during the CMC phase for each of its devel-opment projects. “That has been made mandatorythrough QbD being recognized by managementas a very important tool to achieve what we wantto achieve,” Schousboe said.
“Basically every development project in the CMC phase hasbeen asked to create an overview of…what we have done so farthat matches this concept,” and with the current level of knowl-edge that NN has in the project, which of “the pallet of differentQbD tools” would it make sense to use and “how do we do thatin the best way” that is most beneficial to the company.
“We are not going to be able to force every developmentproject to use every tool all over the place,” Schousboe com-
mented, and the degree of implementation will vary.Projects may be too far into the CMC phase to start over,given the “fundamentally different mindset” involved in theQbD development approach. “Creation of the strategies” inturn, he stressed, “is really important in changing that mind-set and also forcing the project to really think about wherethey can find benefits in this.”
Given the paradigm shift involved, NN is taking a“small steps approach,” Schousboe said: “slowlybut steadily trying to change people’s attitudetoward things, creating awareness around all ofthis – getting them to work with it and through thattry to show examples and benefits that this actual-ly works, thus creating a pull effect in what we aredoing.” The QbD manager cited two rather dramatic examples of this approach in practice.
In the first case, Novo Nordisk used process understandingand redesign to virtually eliminate the significant unit-to-unit variation and increase in pressure needed over time toperform the process function.
A first step was the analysis of the “abundance of data” NNalready had in hand “to really dig into what was impor-tant.” Screening designs were done to filter out the mostimportant factors. The team “ended up with basically whatwe would call a full design space – actually a statisticalmodel explaining what we perceived was going on to findout exactly how we could influence the critical qualityattribute for that specific process.”
With the process understanding and design spacein hand, the team set out to implement a newmanufacturing line.
The usual thing to do when buying a production line is todictate to the vendor what the equipment should look like.“In contrast,” Schousboe said, “what we did here was tobasically tell them ‘this is the process that we want to run,these are the attributes that we want to have, this is the waythat we want to control it, now build us a line that can dothat.’ After some discussion they actually went out and did
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that, and the really cool thing was that when it came in thedoor, it actually ran [in tight control] from day one. Wehave never seen a line running like that before. This meantthat it had been built to take care of that process in the bestpossible way.”
He cited this as “a very good example of how you can real-ly utilize the knowledge that you have in the entire design –both in the process, but especially also in the equipment.”
In a second example cited by Schousboe, NN developed anactivation step for a Factor VII analogue using a mechanisticmodel and PAT. The firm’s sensitivity analysis showed thatpH was the only significant parameter, and significantimprovements were realized with better measurement andtighter control of pH.
Noting that QbD “is a very big concept,”Schousboe commented that Novo Nordisk hasdeveloped a viable model on how to do it: “Weknow which elements we want to put into qualityby design. We even know how to apply the differ-ent tools together. We can start a more focusedimplementation, really pushing this into thedevelopment projects.”
The firms QbD effort has three tracks covering CMC imple-mentation, education and the quality management system.
The effort is getting a “very high focus” in the CMC area,Schousboe stressed – “pushing the concepts into the workthat is being done in basically all our development projectsin different ways.” The education track involves “buildingwhat we call a ‘QbD Academy’ to get the right competenciesin place – building on those that we already have, but obvi-ously expanding on that.” Standard operating procedures(SOPs) are also being added to the quality management sys-tem to reflect the goals of the model.
The model in turn, Schousboe explained, basically works onfour levels – extending from patients or customers at thetop, through the product, process and facility.
The goal is “to make sure we get the connection between theselevels and really can explain what is going on here” in terms ofthe cause-and-effect relationship combined with the risk assess-ments – “to make sure in the end that we deal with every pos-sible risk to the patient through the control strategies.”
Early in the development process, Novo Nordisk’s objectiveis to have a “first run” view of all four levels and to start
establishing the cause and effect relationships. However,understanding that “some of the projects will be killed off,”NN will not “throw everything at it at this point.” On theother hand, Schousboe pointed out, “for the platform proj-ects, we can get a lot further in this first iteration.” The objec-tive is have a “proof of concept” to work with in the nextdevelopment phases, and then using the knowledge of therelationships to effect continuous improvement after theproduct is launched.
Novo Nordisk intends to take the QbD effort “very muchbeyond the CMC phase,” the project manager added. “Wewant to go into our production units making sure that theycan actually take over the information that comes out of theCMC area – that they can use this in their facility design andthat they can use it on existing products as well.”
During the Q&A period that followedSchousboe’s presentation, a revealing exchangeoccurred encompassing the message coming fromkey regulatory officials in the U.S. and Europeinvolved in advancing QbD that industry shouldfocus first on the manufacturing and quality ben-efits rather than the regulatory payoffs which mayensue (IPQ, May 2010).
Commending the Novo Nordisk initiative for translating“these interesting and novel concepts into actual practicalreality on the ground,” a PQLI workshop participant askedSchousboe if his company was concerned about how regula-tors outside of ICH who were not up to speed wouldrespond to a QbD-oriented application.
Schousboe explained that fear was initially expressed at NNaround the “whole regulatory submission part.” However, ingetting started, the company “simply wanted to take that fearaway, because otherwise we would not be able to talk aboutthe concept and how we wanted to use this. So we startedlooking at what are some of the actual benefits of doing this.”
As initial experience was gained, it become “very clear” thatthere were significant monetary benefits to be derived fromQbD implementation and that regulatory flexibility is “byfar the lowest benefit,” Schousboe emphasized.
“The real big benefit is in the fact that you know more aboutyour process, that you are able to control it, that you reducethe variation that you see within that process from thebeginning. So you get a number of benefits with the speedand low variation. That to any company, I would say, is thebusiness case for doing QbD – not the regulatory part of it.
The NN official downplayed the regulatory con-cerns, noting that the stronger scientific underpin-ning and quality assurance involved in the QbDdevelopment approach should only enhance theapplication clearance process.
“If you can explain the full story – ‘listen guys, we are incontrol because we have a full understanding of this, andthis is the data to support it. This is the way that we want tocontrol it in the end, the control strategy. We are producing
good products. Do you want them on the market?’ – if wecan present a file that does that, I am quite sure that no mat-ter what country you ask, they will accept it.”
Schousboe added, on the other hand, that how much of theQbD information package will be included in applicationsfor certain countries “is a totally different question.”
[Editor’s Note: Novo’s findings on the positive impact QbDhas had on its operations complement those provided byPfizer at a DIA conference a week later. See companionstory below]
Pfizer’s assessment of its data on the impact of implement-ing quality by design indicates that QbD is “a very largevalue proposition,” Global Manufacturing NetworkPerformance Senior VP Gerald Migliaccio reported at DIA’sAnnual Meeting in Washington, DC on June 16.
The “real benefits” seen by Pfizer, Migliaccio stressed, haveincluded enhanced process understanding, higher processcapability, better product quality, and increased flexibilityto implement continuous improvement changes with lessregulatory encumbrance.
“We have found that as you get more mature in quality bydesign and you get more mature in your risk assessments,you are doing a lot more work around what is critical, but alot less non-value-added work around what is not critical,”he said. QbD and the risk assessments associated with it“really allow you to focus on what is important.”
Pfizer has found that, while there is some incremental costduring the development phase, the value proposition is sig-nificant when looked at across the development/manufac-turing spectrum. “You have to look at this of course acrossthe enterprise,” Migliaccio pointed out. “The investmentoccurs in research and development, and those of us on thecommercial side get the payback. So we have to play nicewith each other.”
Pfizer Data Show QbD Process Enhancement
Pfizer has compared the results of an analysis of previouslydeveloped processes with those developed recently employ-ing the enhanced QbD approaches. The data demonstrates
QbD’s impact on the robustness of processes and the abilityto improve them.
The process capability was measured based on the weakestlink in the process. “So you could have had great processcapability over nine of ten key quality attributes for a givenprocess, but one was 0.8 and that is the process-basedprocess capability,” Migliaccio explained.
In 2007, Pfizer assessed the data for about 150 differentprocesses, with about 1800 key product attributes includedin the measurement. For 81% of the processes studied, thecapability was found to be greater than 1, which is aboutthree sigma. The other roughly 20% “needed a little helpbased on the weakest link,” Migliaccio explained.
By contrast, analysis of a half dozen QbD developed prod-ucts, for which 125 key quality attributes were identified,showed a significant increase in “highly capable” processesto 92%, with that percentage on the increase through contin-ual improvement. The additional process understandingmakes the QbD-developed processes easier to improve, witha 100% goal achievable “pretty quickly,” Migliaccio com-mented.
The Pfizer official explored in more detail the caseof its first QbD product, which was entered into theFDA small molecule pilot, to show how QbD spursa process up the sigma ladder. He focused on onekey quality measurement for the process – the assay.
The capability at launch was about 1.2, or about 3.5 sigma,which “is not bad based on the normal 2 to 3 sigma that we
Pfizer Finds QbD a “Large Value Proposition,” VP Migliaccio Tells DIA Annual Meeting
had seen for a lot of our traditionally developed products.But within six months, because of the process understand-ing that we have and the continual improvement efforts wewere able to make, we got it up to 1.8, which is about 5.5sigma. So this is the advantage of having the process under-standing that the design space gives you. And this is thedata that supports it.”
Stessing that “higher process capability obviously shouldlead to better quality,” Migliaccio pointed out that continu-al improvement of the traditional fixed process can onlyachieve about a 3 sigma result in terms of the firm’s internalquality measurement. However, with QbD-developedprocesses, 6 sigma becomes targetable.
The Pfizer official noted that “there are a lot of ways tomeasure process quality. Those of us in quality like to meas-ure it using deviations, because deviations are all about vari-ability. And of course with process capability, the higher weget, the lower variability we have – the fewer deviations.”
To demonstrate the impact of QbD, Pfizer ana-lyzed the 2007 deviation rates for three tabletproducts manufactured in the same facility.
There were two strengths of product A and B included inthe assessment. The two products were launched in theearly 1990s. The third product, developed with QbD, waslaunched in early 2007.
During 2007, 4-8% of product A batches were found to havesome form of deviation that needed to be investigated, withproduct B having up to 1.5% needing investigation. By con-trast, the QbD product was at 0.7%, with that number “com-ing down rapidly since we launched it,” Migliaccioexplained. “Again it is all about process capability leading tobetter product quality.”
Noting that he was head of quality for 11 years at Pfizer,Migliaccio asked his colleagues in the audience in quality to“think about how many resources in manufacturing andquality you have to do investigations. Just think about tak-ing all of those resources and putting them on continualimprovement. This sells me.”
In support of the power of QbD to impact processrobustness, the Pfizer official shared with theaudience a case-in-point that an Abbott officialhad brought to his attention. The case involvedone of Abbott’s first QbD products, for which alot of learning had taken place regarding a key
raw material and its variability and a flexibledesign space had been established.
Abbott built in off-line NIR and on-line PAT to understandthe variability of the material and to be able to adjust theextrusion process accordingly. Along with the adjustableprocess, the design-of-experiments allowed cycle time to beextended continuously up to seven days.
The results have been “amazing,” Migliaccio noted: “1800batches without a deviation. Zero failures. It is reallyunheard of in our business. So that is another case of thequality of the products that have been developed throughquality by design. “
The global manufacturing VP cited another examplefrom Pfizer’s experience demonstrating the increasedflexibility that a QbD foundation provides.
“We had a very robust design space. We launched the productand the initial demand was four times what was forecast. Weneeded to ramp up production very quickly. Unfortunatelywe only had one facility where we were geared up to makethis product. We were able to ramp up production within thefirst few months 66% just by optimizing our conditions with-in our design space. We had enough knowledge of where theoptimal points were. Obviously when we launched the prod-uct, we were in what we considered the most robust range.But as we started making product and understanding theprocess further at full scale, we learned that within the designspace we could adjust certain parameters, and we ramped upproduct 66% with no regulatory filing required.”
Pfizer needed to expand production more than that as thedemand rose, which was done through the appropriate reg-ulatory submissions, but the 66% production ramp-upbought some valuable time to do so.
“It is all about how you design that design space, how youcommunicate that design space in your application,”Migliaccio stressed. “We were able to have that level of flex-ibility to achieve that increase in productivity [with] no cap-ital investment, no additional human resources – simplyadjusting the parameters within the design space.”
QbD’s Value in Process Design, Robustness, and Control
“So there is a value proposition here,” the Pfizer official sum-marized. “We feel strongly about that.” The value extendsthrough product and process design, robustness and control.
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“As you are developing this, you are obviously focusing onwhat is critical and you are getting rid of a lot of non-valueadded activities. So you are lean by design, and that is costsavings –certainly on the production side.”
The increased process robustness involves reduceddefects, rejections and investigations. “Just thinkabout all of those resources that you can redeployonto improvement – onto doing things that youreally want to do,” Migliaccio commented.
The process control part of the value proposition includesthe potential for reduced testing. Pfizer has been conserva-tive and is a “little behind some companies in real timerelease” but is “getting there,” he said. “Trust me, quality bydesign just opens the door to it.”
Also flowing from better process control, he pointed out, arereduced inventory costs, “which are more and more of anissue for us these days,” improved yields because of loweredrejections and defects, and, “of course,” lower costs of goods.On the cost-of-goods savings, Migliaccio commented that hewas not going to “try to talk about how much. It is hard to
put it together on a product-by-product business case, if youwill. I am not sure if any other company has done it…. Butthe bottom line is that there are savings.”
Addressing the issue of regulatory flexibility, the Pfizer offi-cial commented that “to me it is all about continuousimprovement within your design space and making sureyou have built that design space well.”
The story of quality by design from the “shop floor level,”Migliaccio summarized, is that “it works, and the data sup-ports it. “ Noting that the DIA meeting session was alsofocused on the potential for QbD to build better bridgesbetween quality and the clinical arena, he commented that“hopefully, in the not too distant future, we will have simi-lar results.”
[Editor’s Note: Pfizer’s findings on the positive impactQbD has had on its operations complement those providedby Novo Nordisk at an ISPE conference a week earlier. Seethe companion story on page 39.]
The World Health Organization (WHO) is updating itsAnnex 4 “Good Manufacturing Practices for SterilePharmaceutical Products,” replacing its 1999 version of thatdocument to align with more recent guidance issued by thethree ICH regions.
The proposal for revision is being made to bring the WHOGMP into line with ISO 14644-1 and the current guidelinesfrom the US, Japan and EU (FDA’s 2004 guidance on steriledrug products, PMA’s 2005 aseptic processing guidance,EU’s 2008 revision of Chapter 4 Annex 1), and from thePharmaceutical Inspection Co-operation Scheme (PIC/S).
The announcement follows the forty-fourth meeting of theWHO Expert Committee on Specifications for PharmaceuticalPreparations in Geneva in October 2009. The committee meetsannually and their Technical Report Series (TRS), which includesdiscussion from the meeting and all adopted guidelines in theform of annexes, is published some months later. The 2010 doc-ument is titled TRS 957 and includes the updated Annex 4.
Key changes proposed to be made to Annex 4 include thefollowing:
• New chapters on isolator and blow/fill/seal technolo-gies have been added to the document.
• The chapter on finishing of sterile products has beenamended with additional provisions for capping of vials.
• The chapter “Manufacture of Sterile Preparations” hasbeen amended and includes provisions for clean roomand clean-air device monitoring.
WHO notes that implementation of these new practices“may need to be undertaken for certain parts using a step-wise approach, especially the part relating to the provisionfor capping in a clean or sterile environment, as this is cur-rently not implemented in most industries.”
The issue of vial capping and the statements on specific condi-tions and vial constraints around stoppering and stopper over-sealing have generated concern in industry’s review of the EUAnnex 1 revision. Underlying that concern is the tensionbetween prescriptive regulatory guidance and a more scienceand risk-based regulatory paradigm (IPQ, Jan./Feb. 2009).
WHO Updating Sterile Processing Guide to Align with US, EU, and Japan
Downloads from the story:
• WHO Annex 4, Good Manufacturing Practicesfor Sterile Pharmaceutical Products
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About Bill Paulson, Editor-in-ChiefBefore launching IPQ in September2007, Bill served for over two decades asthe primary author of “The Gold Sheet.”During his career tracking the drug andbiotech quality regulatory process, Bill'sidentification of key issues and problemareas and emerging solutions has been
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