INTERNATIONAL PHARMACEUTICAL QUALITYInside The Global Regulatory Dialogue

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MONTHLY UPDATE–AUGUST 2010UNITED STATES

CMC/REVIEW

• Biosimilar/Biobetter Pathways on Merck Radar . . . . .2

• CDER on Biotech IND Communications:

Early CMC/Clinical Dialogue Avoids Problems . . .3

Phase II/III Change Transparency Urged . . . . . . . .5

• CMC Filing Variations Cause Approval Delays . . . . .7

GMP/INSPECTION

• Approval Withholds Explained by NJ District . . . . . .8

• Biologics Inspection Guide Released by CBER . . . . . .9

• FDA Recall & Suppy Chain Authorities:

FDA Releases Q&A on Recalls . . . . . . . . . . . . . . . . .10

Recall Mandate for FDA Proposed by Congress . .11

Senate Bill Focuses on Recalls and Supply Chain . . .12

• J&J/McNeil Update:

Quarterly Results Show Recall/GMP Impact . . . . .13

Complaint Handling Cited at Third Plant . . . . . . . .14

• Part 11 Inspection Initiative Announced by CDER . . . . .15

• Vaccine Plants Continue to Draw FDA Attention . . .17

EUROPE

CMC/REVIEW

• Biosimilar Product Interactions Increasing at EMA . . .19

• EMA Challenges Require Dialogue, Purves Stresses . .20

• PAT Team Restructured to Aid Communications . . .24

GMP/INSPECTION

• MHRA Pursuing New Sanctions for Non-compliance . .25

INTERNATIONAL

CMC/REVIEW

• ICH Quality Initiatives:

Q4B Annexes 13 and 14 Out for Comment . . . . . . .27

Q11 Structure and Content Taking Shape . . . . . . .28

Starting Materials at Issue in Q11 . . . . . . . . . . . . . .30

GMP/INSPECTION

• GMP Regulation in India:

Auditing Shows GMP Trouble Spots for API Firms . .31

Industry Growth Prompting Regulatory Upgrades . .32

• International Joint Inspection Programs:

EMA/FDA Pilot Seeks Participants . . . . . . . . . . . . .33

International API Pilot Gaining Traction . . . . . . . .34

• WHO Issues Draft Micro Lab Guide, Revising Others . .36

EDITOR’s NOTE: Welcome to the second issue of IPQ’s “Monthly Update” on keyCMC/GMP developments in the US, Europe, and internationally. The IPQ family ofpublications has been expanded to include breaking stories “In the News” on ourweb site, “Weekly News Alerts” sent via e-mail, and the “Monthly Update.” Thesenow accompany our in-depth “Special Reports” on emerging areas of concern drawingparticular attention from industry and regulators. IPQ’s new offerings bolster ourmission of helping readers understand, engage in and respond to the dialogue and

developments around evolving and harmonizing the regulation of pharmaceutical and biologic quality and manufacturing. Subscribers and license holders to IPQ have access to all of these sources of cutting-edge newsand in-depth analysis as well as to the full IPQ archives. Visit IPQpubs.com for further information.

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Success for both biotech innovator companies and biosimi-lar manufacturers under the new health care legislation willrequire working with FDA to optimize the regulatoryapproval pathways and understanding the key differencesbetween biosimilars and biobetters, a Merck executive main-tained in a recent interview.

Merck Bioventures President and Biologics/Vaccines SeniorVP Michael Kamarck commented in a BioPharm Internationalpodcast in early July that the new health care legislation “real-ly hits the sweet spot” both for companies that are developinginnovative products and for those producing biosimilars.

Benefiting innovator companies in the legislation is a 12-year exclusivity period. For biosimilar manufacturers,Kamarck pointed out, there are clinical pathways that aresomewhat abbreviated and that would allow a reduction inthe time and some of the costs as compared to the require-ments for an innovator product.

Every company will develop its own strategy for filing“based on what it feels the risks are,” commented the MerckVP – some may choose abbreviated pathways for biosimi-lars, while others may choose to file traditional biologiclicense applications (BLAs).

The earlier users of the regulatory pathway, includingMerck, will have the opportunity to work with FDA to opti-mize the pathway and make it efficient. “In doing that, Ithink we will make the pathway hugely valuable” in thefuture, Kamarck commented.

The Merck exec discussed the potential the new leg-islation provides for the interchangeability ofbiosimilars, through which a biosimilar drug coulddirectly substitute for the reference innovator drug.

Merck does not view this interchangeability provision asviable at this time. “We think these products need to gothrough rigorous clinical testing and that interchangeabilityis something that is in the far future for biosimilars,” heexplained. “We think the standard of interchangeabilityneeds to be very, very high before we put the decision-mak-ing on which of the compounds to use in the hands of thepharmacists as opposed to the physicians.”

Even without interchangeability, the Merck official positsthat developing biosimilars is still a “robust business modeland business opportunity for the right companies.”

Different Approach Needed for Biobetters vs. Biosimilars

Kamarck turned his attention to the so-called “biobetters” –molecules that are similar to marketed products but aremore efficacious, require a lower dosing frequency orreduce the risk of immunogenicity.

He commented on the hurdles to producing biobetters, point-ing to a couple of recent examples that have shown that thedevelopment of biobetters is really not straightforward – thatit is not always possible to predict that the changes made toa molecule are going to make it any better.

Understanding Biosimilar/Biobetter Approval Pathways and DifferencesKey to Success, Merck Exec Says

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Merck is approaching biobetters as if they were new drugs –with similar risks, similar investments in clinical trials and asimilar probability of success. Biosimilars, on the otherhand, are seen as a separate category where the probabilityof success is much higher, but with development costs thatwill be lower than for innovative/biobetter compounds.

With biosimilars, it is “important to work through the newregulatory pathways to assure that in fact there is someabbreviated version of the trials that will allow us to dothem more quickly and at less cost,” Kamarck emphasized.

At Merck, innovator and biobetter drug develop-ment are being handled by the R&D group, andbiosimilars by Kamarck’s Merck Bioventuresgroup.

Reviewing one of the biobetter technologies that Merck hasbeen exploring, Kamarck expressed his view that anadvancing technology allowing control of glycoforms onmolecules, particularly on antibodies that are glycosolatedproducts, will be instrumental in producing biobetters.

Typically mammalian cells produce heterogeneous proteinproducts, whereas the “GlycoFi” technology now beingdeployed by Merck allows rigorous control that can producea single molecule with a single carbohydrate conformation.

Kamarck reported that initial calculations suggest that thistechnology will be price-competitive with using CHO cells.

He pointed out that other large pharma companiesare also looking at developing both innovator andbiosimilar products – a turn from the traditionalmodel where companies focused either on innova-tive or generic products, but generally not both. Hedoes not see this as a conflict, but as a necessity.

“There is another emerging part of the pharmaceutical busi-ness, Kamarck explained, "and that is making sure that therest of the world other than the US and Europe have accessto these wonderful medicines in these regions that we referto as the emerging markets.” Even in the US many of theinnovator biotech products are considered prohibitivelyexpensive by some individuals or insurance companies.

“I think we are finding that balance between…an innovativecompany and a company that is also dedicated to…makingthese products accessible more broadly to a larger part of theworld’s population,” Kamarck emphasized.

FDA's Center for Drug Evaluation and Research (CDER) isstressing that communication problems between the CMC andclinical groups working in Phase I can result in important risksnot being identified and can impede IND/Phase I progress.

Discussing CMC issues that can cause problems during theIND development and marketing application submissionphases, CDER Biology Team Leader Chana Fuchs noted atthe AAPS National Biotech Conference in San Francisco inmid-May that “speed bumps“ causing delays in Phase I aredivided into two general categories: • not identifying a sig-nificant and unreasonable risk, and • submitting insufficientinformation to FDA to assess the risk to the subjects.

Significant and unreasonable risks include unacceptablespecifications, product contamination, mislabeled productand the use of penicillin either in the medium or in the facil-ity. While not common, the penicillin issue is still seen onoccasion. “Sometimes for early phase products the less-experienced sponsors would not necessarily realize that thisis so critical,” Fuchs commented.

The CDER official noted that “unreasonable risksnot identified” can arise due to communicationproblems between the CMC and clinical groupsworking together in Phase I.

IPQ MONTHLY UPDATE–AUGUST 2010

Communication Between CMC and Clinical Groups is Key in IND Phase,FDA says

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• BioPharm Podcast

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Unacceptable specifications – for example, endotoxin limitsthat would result in the use of a product over a safety limit –should not appear in a Phase I application. “The communica-tion between your clinical and CMC groups needs to be rathertight to assure we do not have these conflicts,” she noted.

Fuchs commented that insufficient information for risk assess-ment is a more common problem in clinical applications.

Examples cited include: • inadequate information describ-ing the manufacture, certification, or verification of the drugsubstance and drug product • inadequate release specifica-tions • inadequate or lack of stability data • product used inclinical and toxicology studies are not the same • lack of cellbank testing for endogenous or adventitious agents, and •no information on the country of origin of ruminant orhuman-derived material used in manufacturing or whetherit was used.

Fuchs cited virus removal as a specific case. If the manufactur-ing scheme claims to remove retroviruses, for example, theremust be enough data “for the reviewer to assess the appropri-ateness of the scaled-down model.” If you are claiming gener-ic or modular clearance for a platform then detailed informa-tion on the product, process, and the ranges for which themodel was validated are required for the reviewer “to assesswhether you are within that platform or not.”

There are also important considerations for endogenousproteins and monoclonal antibodies, she noted.Immunogenicity assays for endogenous protein counter-parts “should be in place by Phase I, and testing patientsamples should start with the Phase I trials. For monoclon-al antibodies, if you do not have a qualified assay earlyon…you can collect the samples to run adequately and pro-ceed to testing a little bit later. It is not absolutely necessaryfor most monoclonal antibodies to start [this testing] at thePhase I study. It is a risk-based approach that we are talk-ing” about.

The CDER official noted that drug development “is a longpath of choices that you make.” She provided insights from“my own experience, things that I have seen” that can helpbiotech product applicants navigate through the CMCimplications and requirements in the various stages ofbiotech product development and submission.

Fuchs stressed that the choice of appropriatebioassays during the selection of a drug candidateis an important factor in its later success.

Efforts “up front” in the drug discovery candidate selectionprocess “can really pay dividends later” in development.

Fuchs noted that bioassays for potency are widely-used asselection tests and are used to understand the molecules thatare chosen. For that reason, the firm “really needs to rely ona…well-characterized assay based on the mechanism ofaction at the beginning as well as other suitable assays thatare vital at this stage.”

One issue seen during candidate selection is failure to con-sider characteristics required for a successful product,including considerations of product profile, stability, PK,and immunogenicity.

The CDER biochemist cited a case in which there was areduced analytical characterization in research, which led tothe selection of a potent product that “had many product-related substances along with it and inherent instability.”Ultimately there were substantial delays in developmentdue to processing issues, and a second-generation productwas based on another clone. “That could have probablybeen dealt with early on,” she commented.

In another case, a PK assay not relevant to the mechanism ofaction was selected. The product exhibited suitable PK inserum but did not get to the site of action effectively, and sopre-clinical dose ranging studies had to be redone. TheCDER team leader noted that this occurred “very early on indrug discovery candidate selection and development” andcould likely have been avoided.

Need for CMC/Clinical Coordination ExtendsThrough Phase II/III

In Phase II the primary objective is to help assure that thescientific evaluation of the drug is adequate to review thedrug’s effectiveness and safety, the reviewing official noted.At this point in development, “you really need to startincreasing your product characterization and your assaysshould be well-qualified. You need to start understandingand controlling things at a much higher level.”

The communication channels between the CMCand clinical development personnel involved inthe submission remain important in Phases II andIII, Fuchs emphasized.

“CMC development should really parallel your clinicaldevelopment,” she said. “When you modify or add a clini-cal protocol to your IND you need to remember to submit

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the corresponding CMC information. For example, if youdecide to put in a placebo controlled trial, or if you decide touse this product in conjunction with another product…youreally need to submit the CMC data appropriate for theplacebo,” or the second product. “Keep in contact with yourclinical counterparts and be sure CMC and clinical areaware of what each other is doing.”

Timing of the FDA interaction is also critical during thisphase, Fuchs stressed. “If you do not start early enough toassess the comparability and you do not submit the data tothe FDA early enough to allow us to review that compara-bility and be able to assess it and get back to you should wefind any issues, or get back to you to say ‘this is fine, goahead,’ then you end up bumping into really tight timelinesthat you may not be able to meet within your clinical trial.”

One common problem noted during Phases II andIII is the lack of available product for testing oradministration.

Firms need to have “sufficient ‘process one’ materials ormanufacturing capabilities to make more of it so that youcan continue your comparability studies – either the non-clinical or clinical bridging studies if necessary – and contin-ue your clinical trial,” the CDER team leader emphasized.“We have encountered many times where sponsors just donot have any more. They cannot do any more. They arestuck. They have to stop their clinical trial because they donot have enough material.”

[Editor’s Note: See the companion story below for Fuchs’advice on facilitating Phase III and BLA submissions.]

IPQ MONTHLY UPDATE–AUGUST 2010

Comparability studies for changes that inevitably occur during Phases II and III for biotech products must beplanned for by the firms conducting them, FDA is stressing.

The agency is also cautioning that communication with FDAduring the end-of-Phase-II and pre-biologic licenseApplication (BLA) meetings and through the submissionand preapproval inspection process is important to under-stand common expectations and make it easier to workthrough issues that will arise due to these changes.

Center for Drug Evaluation and Research (CDER) BiologyTeam Leader Chana Fuchs noted at the AAPS NationalBiotech Conference in San Francisco in mid-May that in thebiotech context change is expected. “I have not seen an INDwhere change did not happen. So comparability is needed.”

The CDER official cited case studies in whichchanges made during Phases II and III resulted invarious issues and delays.

In one case, Phase III manufacturing changes in a monoclon-al antibody “resulted in a different product, literally.”Although the resulting product had similar characterizationprofiles, it did not meet the same specifications as the originalmolecule. A clinical trial could not confirm that the materialswere indistinguishable, and a human PK study showed that

there were significant PK differences. “So they needed to doanother clinical trial,” Fuchs commented, “which is the onlyway to kind of resolve differences at that point.”

Another example cited involved a human IgG2 monoclonalantibody that was produced in Chinese hamster ovary(CHO) cells. “Prior to Phase II, which is pretty early,” Fuchsexplained, “there were multiple manufacturing changesmade between cell lines, bioreactors, scale-up, manufactur-ing site, the process, and downstream.” In the submissioncomparability plan no data were presented, and “the plandid not provide sufficient detail, did not provide acceptancecriteria, and did not address viral safety risks.”

The CDER official commented that “the feedback that thecompany wanted and needed to have by a certain time sothey could start their studies was not going to be there. Thatis a time delay.”

Another important problem the agency has beenseeing involves sponsors not having sufficientproduct or lots retained to support comparabilitystudies.

If adequate original material is not available, product that iswell-characterized and comparable to the product used in thepreviously-conducted Phase I GMP studies must be used in

Preparing for and Communicating Manufacturing Changes During LateStage Development Smooths Biotech Clearance Process with FDA

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Phase III, and all CMC issues that directly relate to the char-acterization of the new product lots must be resolved.

“That really impacts your clinical agreements with the clin-ical division, so you need to assure that these are straight-ened out and resolved in a timely fashion, and know how itis going to come out,” Fuchs pointed out.

End-of-Phase II and Pre-BLA Meetings Key to Success

The FDA team leader stressed the importance of end-of-Phase-II and pre-BLA meetings as “real keys to success.Missing out on them or not utilizing them to your best benefiteven for CMC is a real shame.” She further commented thatCMC development plans and submission plans “should real-ly be discussed in these meetings to assure that expectationsfrom both sides and requirements are clear to both of us.”

Once the BLA is filed, a review takes place to assure that allinformation required is present in the BLA. This review doesnot check the quality of the information, only that all the infor-mation the agency needs is present. “You will hear if it is not– if we find things that are missing,” Fuchs explained.

Information that the agency has found missing during thisinitial review includes: • complete process validation •manufacturing not taking place during the time of theinspection • process validation data for a formula not in the“to-be-marketed format,” and • no fact sheets ready forinspection at the time of submission.

During the BLA review, comparability studiesremain “one of the big hoops [because] many spon-sors find that they need to make post-Phase IIImanufacturing changes. That is a high-risk activi-ty,” Fuchs stressed. Although the risk of makingchanges would be lower earlier in the process, “weunderstand it is not always possible.”

Examples of post-Phase III changes the reviewer has seen asproblematic are a changed source of polyethylene glycol(PEG) that changed the PK and differences in the PK whereadditional safety or efficacy data was required. The regula-tor cautioned that “maybe you want to plan PK studies asearly as you can to understand that you will not have anyproblems once you submit a BLA, or if you do you willknow what you need to develop in order to further yourapproval.”

Issues surfacing in CDER reviews that are not related to com-parability include: • omission of key data from the BLA •drug substance stability studies conducted in containers thatwere not representative of drug substance container materi-al • drug product long-term stability data from pilot scalenot fully representative of the full scale, and • a request todrop specific release tests for the to-be-approved productthat was not supported by sufficient information in the BLA.

“I think you can discuss some of these things in your pre-BLA meetings. Earlier than the BLA, you may know whatto expect in a better way,” Fuchs commented.

After the BLA is submitted, a pre-approval inspection willbe conducted to check the commitments in the BLA againstactual practices in the manufacturing facility, with a focuson bioburden, fermentation and manufacturing process con-trols. A successful inspection is required for licenseapproval.

Fuchs concluded her presentation with a fewhelpful hints on facilitating communication dur-ing the review process.

When submitting applications or communicating with theagency regarding a product, it is important to “know youraudience…and identify your needs,” she noted. For exam-ple, “when you submit an IND or an amendment to an IND,the cover letter is really important.”

The appropriate clinical division needs to be identified, as dif-ferent areas review different types of molecules. “Is it abiotech product? Is it a small drug molecule? Is it a combina-tion product? Is it an antibody-drug conjugate – which willneed two different CMC reviewers from two different divi-sions to partake in the review?” Fuchs stressed that getting theinformation to the correct place will help avoid delays.

In addition, the CDER official recommended thata firm identifies what it is submitting and itsneeds.

Questions firms should answer are: • “Do you require fullresponses versus partial responses to clinical holds? • Whatis a realistic date by which you need feedback on compara-bility data? • [For] meeting requests, who will need to bethere, who will you need [from the agency] for the meetingand what topics do you want to discuss?”

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IPQ MONTHLY UPDATE–AUGUST 2010

Manufacturing information that is inaccurate, incomplete,inconsistent, or in the wrong section in new and abbreviat-ed new drug applications (NDAs/ANDAs) as well as facili-ties not being ready for an inspection continue to be prob-lem areas causing delays in application approvals, Centerfor Drug Evaluation and Research (CDER) officials arereporting.

Speaking at DIA’s Annual Meeting in mid-June, CDEROffice of New Drug Quality Assessment (ONDQA)Associate Director for Regulatory Affairs Michael Folkendtnoted that his office has seen “wide variation on where andhow the manufacturing information is submitted in thedrug application, which results sometimes in a delay in ini-tiating the inspection process or not finding a facility untillate in the review cycle.”

The CDER review official outlined deficiencieshis office has noted that resulted in approvaldelays and provided suggestions on how andwhere to present the requested information tosmooth the approval process.

Noting that some information is redundant between theModule 3 sections of the NDA and the FDA form 356H,Folkendt highlighted the importance of putting that infor-mation in both places.

“I want to emphasize that in addition to each of the relevantModule 3 sections, we ask that you list all of the manufactur-ing facilities in the application as an attachment to FDAform 356H.” He added, “if you are submitting an electron-ic submission, which is absolutely fantastic for us, put it inModule 1 right behind the 356H form.”

Folkendt requested that applicants “put this information insome sort of tabular format.” Noting that there is no tem-plate or required way to submit the data, he suggested to“sort it by sites in order of manufacturing process – thathelps us keep track and see that all the manufacturing infor-mation is there.”

Also important is that the information is listed in the appro-priate sections and that what is in the modules and the 356Hform match. When manufacturing sites are either notincluded or listed in the wrong section, delays result.

More “troublesome” is having a given site listed in both the356H form as well as in Module 3, but site information isinconsistent – for example, different addresses or contactinformation.

“What that will do is immediately prompt us to call theapplicant and ask for clarifications” Folkendt explained. “Ifthere is enough information [missing] we will ask for themto submit an amendment to correct that information. Wecannot [request] an inspection without a complete set of information.”

The CDER official turned his attention from loca-tion and consistency of the content in the applica-tion to the content itself.

One problem seen in applications that is “not infrequent” isinclusion of the mailing address or the address of the corpo-rate headquarters for the firm rather than the address wherethe manufacturing process actually takes place. “We do notinspect post office boxes,” Folkendt quipped.

He stated that “luckily we know some of those administrativeheadquarters and we know to call up and find out where themanufacturing process is actually being performed.” If theapplication is from a firm the agency is not as familiar with,the inspector could show up and discover that the manufac-turing actually occurs at a different location.

“This may not be a problem if it is the building next door or abuilding the next block over, but it does become a problem ifit is the next town over. If they cannot get to that second site,that could result in a delay in approval of the application.”

It is also important to let the agency know if the site has beeninspected before because “we have to do a few extra steps inorder to initiate the inspection of a facility we have neverbeen to before,” the CDER official pointed out.

Other information required regarding the manufacturing facili-ty includes previously assigned registration numbers: theFacility Establishment Identifiers (FEI), the Central FileNumbers (CFN), the DMF numbers associated with theprocess, and if applicable, the Data Universal NumberingSystem (DUNS) number once it is assigned. “Give us all ofthem that facility has,” Folkendt noted. “If you try to hunt andpeck, it may not match what we have in our various databases.”

FDA Seeing Wide Variation in Drug Application ManufacturingSubmissions, Causing Approval Delays

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All activities performed at the manufacturing site must alsobe included in the summary sheet, he advised, including: • “the production stage – that is, whether it is a drug sub-stance or a drug product manufacturer, or an intermediate,[etc.] • and then within that production stage the produc-tion process that they are actually performing – [for exam-ple] a labeler, a manufacturer, a micronizer, a packager. Tellus whether it is a primary or a secondary packager.” If test-ing is performed, it is important to include the type of test-ing being done to “help us get the right inspector out to thefacility and get the most efficient inspection done.”

The application must also include a statement thatall facilities are ready for inspection. If they arenot, it could become a refuse-to-file issue.

“Under the PDUFA and the 21st Century review paradigm,[NDAs are] expected to be complete at the time of submis-sion, and completeness includes the ability for us to go outto that site at any time and inspect it,” Folkendt stressed.

To schedule an inspection, the name, title, phone number,fax number, and e-mail address of an authorized point-of-contact person is required.

It should be someone who is “authorized to actually sched-ule that inspection at that facility,” the review official noted,adding that e-mail is the preferred method of communica-tion. Submitting incorrect information or the name of a per-

son who is not authorized to schedule the inspection couldhave serious consequences.

Folkendt noted instances where the agency scheduler con-tacted the facility and the response was “we do not do thatprocess” or “no we cannot schedule an inspection” for somereason. The agency “will make up to two, three or fourattempts at dates for an inspection, but if none of them aresuccessful for whatever reason, they will issue a withholdrecommendation and that will close that review cycle forthat facility,” he explained. “We cannot approve any appli-cation if there is a withhold recommendation.”

For domestic facilities that FDA decides to inspect, it takes113-136 days from the time the application is received untilthe inspection is completed and a recommendation given tothe review division. For foreign facilities, it takes about 200days – including a mandatory 60-75 day notification to theState Department before the inspector can leave the US to goto the foreign site and sometimes even longer, the CDERofficial noted.

The dramatic increase in the number of ANDA applicationsbeing submitted by companies located abroad and the extratime and resources needed to review those applications hascontributed significantly to a growing backlog problemfaced by CDER’s Office of Generic Drugs (IPQ May 2010Report, pp. 17 – 20).

Facility listing errors on the application and a lack of availabili-ty of development data source documents during pre-approvalinspections are causing the New Jersey District to recommendwithholding drug approvals, its investigations branch directorMyriam Sosa told DIA’s June Annual Meeting.

In 2009, fourteen withhold recommendations were issued inthe New Jersey district: • three because the facility waswithdrawn • six due to no testing performed at the site, and• five for lack of development data.

Sosa explained that a “facility withdrawn” withhold recom-mendation is made if a firm or testing laboratory is listed as partof an application but the sponsor decided it would not be used

to support the application and did not update the application onfile. This category has also been used when the inspection teamdiscovered an outside facility listed had no contract with thedrug manufacturer.

A withhold recommendation for “no testing performed atthe site” is given when the inspection team goes to a contracttesting facility, for example, and discovers that the lab is notaware that it has been listed on the drug application.

The third category of NJ withhold recommendations stemfrom source documents for data cited in the application notbeing readily available for the inspection team to checkagainst the application.

Facility Listing Errors and Missing Development Data Draw WithholdRecommendations From FDA’s NJ District

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The FDA field official provided other situations in which awithhold recommendation could be made:

• Firm not ready: the firm submitted an application involv-ing a manufacturing site but the site was not ready forinspection – sometimes related to a site transfer or analytical method transfer.

• Inadequate response: an initial withhold recommenda-tion was discussed but the FDA’s concerns were not ade-quately addressed in the response.

• API quality: ill-defined particle size that may affect disso-lution and has the potential to cause potency failures.

• Lack of qualified processing equipment: no assurancethat consistent results may be achieved, for example a vialfilling operation for an injectable product.

• Inadequate manufacturing environment: for example,humidity monitoring in a manufacturing area where ahygroscopic product is produced.

• Manufacturing and laboratory OOS and deviationinvestigations inadequate.

• Laboratory data: documentation and accuracy of the data– for example, lack of bound notebooks and controlledanalytical worksheets.

Sosa noted that in 2009, 42 pre-approval siteinspections were conducted in the New Jersey dis-trict, with several involving multiple productapplications.

A total of 55 product applications were covered as part ofthe 42 site inspections, which included contract testing sitesand other facilities. Of the 55 applications, 31 were for oralsolid dose products, 22 were for control testing labs, andtwo were for active pharmaceutical ingredient (API) manu-facturers. Ten of the applications were NDAs and 45ANDAs.

Common 483 observations during these inspections includ-ed: • no raw data or missing data to support the application• no investigation of batch failures or OOS results, or inves-tigations not complete •lack of qualification of essentialequipment, and •lack of validated analytical methods.

IPQ MONTHLY UPDATE–AUGUST 2010

The Center for Biologics Evaluation and Research (CBER)released in June a revised version of its Compliance ProgramGuidance (CPG) 7345.848, “Inspection of Biological DrugProducts,” which combines and replaces previous versions ofCPGs covering related biological products and providesinspectional guidance to investigators for conducting biennialor for-cause inspections across the biologics spectrum.

The new umbrella CPG, which became effective on January1, 2010, supersedes the CPGs for licensed allergenics(7345.001), licensed vaccines (7345.002), plasma derivatives(7342.006) and therapeutic drugs (7341.001).

The new compliance program clarifies that the firms it cov-ers include:

• all licensed manufacturers of vaccines and related prod-ucts, including source material manufacturers andlicensed bulk manufacturers

• all licensed manufacturers of allergenic products (allergenic patch test manufacturers are not included)

• unlicensed source material suppliers• all licensed manufacturers of fractionated products• certain recombinant products, and certain human cell, tis-

sue, and cellular and tissue-based products (HCT/Ps) reg-ulated as drugs, and/or biological products.

A list of the 21 CFR regulations applicable to the productsthese firms manufacture is included.

The CPG provides inspectional guidance to investigatorsassigned to perform biennial or for-cause inspections of the manufacturers covered and provides administra-tive/regulatory guidance for compliance officers andinvestigators.

General inspection information not new to this revised ver-sion is included – for example, regarding systems-based

CBER Releases Updated Compliance Program Guide on Inspection ofBiological Drug Products

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IPQ MONTHLY UPDATE–AUGUST 2010

AUGUST 2010 | 10

inspections and what key elements should be covered ineach of the six systems when evaluating overall compliance.

Part V, “Regulatory/Administrative Strategy,” covers thedecision-making process for recommendation of regulatoryactions against noncompliant firms and factors that areunique to biologics to take into consideration.

This section of the document states that “because the num-ber of manufacturers of biological drug products (vaccines,allergens, etc.) is often small, medical need and relativeavailability of the product(s), as well as the potential adverse

effect of the CGMP deficiencies on the finished product(s)should be considered when determining the appropriateadvisory, administrative or judicial action.” It further listsvarious types of deficiencies and the recommended result-ing regulatory actions that should follow, ranging from awarning letter to license revocation or suspension, seizure,injunction, and prosecution.

Download from the story:

• CPG 7345.848 Inspection of Biological Drug Products

FDA provided on its website in early August a Q&A givingadditional guidance on human drug recalls – their purpose,FDA’s authority to mandate them, over-the-counter (OTC)drug versus prescription drug recalls, and related investiga-tions.

The Q&A was posted in the context of the recent debate and proposed legislation around FDA’s recall authority (seefollowing story) and the issues raised by what was referredto in the Congressional inquiry as the “phantom recall” byJ&J (IPQ Monthly Update July 2010, p. 16). Links are pro-vided in the Q&A to the specific guidance documents rele-vant to the issues addressed.

The Q&A document addresses the following six questions:• What is a recall? • Can FDA mandate a recall of humandrugs? • Are OTC drugs subject to the same recall provi-sions as prescription drugs? • Do manufacturers of OTCproducts have to report quality defects? • Does FDA expectfirms to investigate both released and rejected lots for poten-tial recalls? • What happens if a firm does not voluntarilyrecall a defective product?

A recall is defined as actions taken by a firm to remove fromthe market any product that is in violation of laws adminis-tered by FDA. Recalls of a drug may be conducted on afirm’s own initiative or by agency request.

The Q&A explains that although FDA does not have author-ity to mandate a recall of a human drug, it can take otherlegal actions such as seizure or injunction against manufac-turers “that persist in marketing a defective product” ormarket a product that is “defective or flawed [and] could behazardous to health” if the firm does not perform a request-ed voluntary recall. These provisions apply to OTC as wellas prescription drugs.

OTC product manufacturers’ responsibilities for reportingquality defects are clarified, with differences noted regard-ing OTC monograph drugs, for which quality defect report-ing to FDA is not required, and those that were approved byan NDA where reporting is required.

Also discussed are agency expectations regarding recall-related investigations.

FDA Releases Q&A on Recalls, Holding and Distribution of Human Drugs

Download from the story:

• FDA Recall Q&A

INSIDE THE GLOBAL REGULATORY DIALOGUETM

AUGUST 2010 | 11

IPQ MONTHLY UPDATE–AUGUST 2010

Download from the story:

• H.R. 5740

Chairman Edolphus Towns (D-NY) announced that he hasintroduced H.R. 5740, “a bill to provide for the mandatoryrecall of adulterated or misbranded drugs,” that wouldamend the Federal Food, Drug and Cosmetic Act (FD&CAct), to provide new recall authority to FDA.

Towns had stated his intention to introduce a mandatoryrecall bill during a committee hearing in May that examinedJohnson & Johnson’s recall of children’s medicines (IPQMonthly Update July 2010, p. 16).

Under the bill, any individual or firm in the US licensed toproduce drugs must inform FDA of the identity and loca-tion of one of its drugs if there is reason to believe that theproduct is “adulterated or misbranded” and there is “rea-sonable probability that the use or consumption of, or expo-sure to the drug…will cause a threat of serious adversehealth consequences or death to humans or animals.” Itstates that the notification process will be the subject of laterregulation or guidance.

The provisions of the bill allow FDA to request avoluntary recall or order a mandatory recall whenit has reason to believe a drug is “adulterated,misbranded, or otherwise in violation of this Act.”

The bill also outlines appeal processes for the manufactur-ing firm to follow if it disagrees with the action, and pro-vides the ability for FDA to amend or vacate the order afterthe appeal.

H.R. 5740 has been referred to the House Committee onEnergy and Commerce.

Legislation Introduced to Provide FDA Mandatory Recall Authority forHuman and Animal Drugs

A bill introduced in the Senate in early August wouldamend the Food, Drug and Cosmetic (FD&C) Act to provideFDA with new monetary penalty and recall tools andrequire drug firms to audit and document the steps in theirproduct ingredient supply chains.

The Drug Safety and Accountability Act of 2010 was intro-duced in the Senate in early August by Michael Bennet (D-CO), and has the same title as the 2008 bill (S.3409) spon-sored by the late Edward Kennedy (D-MA), which did notmove beyond the committee stage.

The provisions in the new bill use somewhat different language but are directed at a similarrange of objectives to those in the Kennedy bill.

Spurred by a recent voluminous recall by J&J of children’sproducts, which was the subject of Congressional hearingsin May (IPQ Monthly Update July 2010, p. 16), deaths from

tainted heparin in 2007 and 2008, which also drewCongressional hearings (IPQ May/June 2008 Report), andconcerns that “up to 80%” of active pharmaceutical ingredi-ents (API) are manufactured in countries where regulatoryoversight does not meet US standards, the bill seeks to tight-en oversight and accountability to help safeguard thedomestic drug supply.

Major provisions of the bill include:

• a requirement for drug firms to have a “quality management plan” covering detailed documentation of materials and API supply chains

• FDA establishment of a tracking system listing all plants supplying API or drug products to the US

• FDA pursuit of cooperative and mutual recognition agreements with overseas regulatory agencies

• a new focus on over-the-counter (OTC) products • mandatory recall authority for FDA

New Senate Bill Proposes Supply Chain Requirements for Drug Firms,Mandatory Recall Authority for FDA

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IPQ MONTHLY UPDATE–AUGUST 2010

AUGUST 2010 | 12

• FDA subpoena power during investigations • civil penalties for failure to comply with the new

provisions, and • whistleblower protection.

Under the bill, drug firms would be required todefine and document responsibilities and communication processes for all contract firms intheir drug and raw material supply chains in“quality management plans.” The concept ofthese plans represents a new feature in the Bennetbill which was not included in the earlierKennedy version.

Also required by the proposed legislation would be assess-ments by drug firms of the “suitability and competence” ofa contract firm to carry out its specified activities prior to thefirm doing business with the contractor through audits,material evaluations, or qualification, and periodic on-siteaudits after business commences.

The information required for “each producer, manufacturer,distributor and shipper” involved in the production andtransport of drugs and APIs would include the names,addresses, phone numbers, and Global Positioning System(GPS) coordinates of those firms.

Under the bill, FDA would develop and implement infor-mation systems to track “every establishment” listed above,and ensure that the information systems work properly andcommunicate appropriately with each other within one yearafter passage of the bill. Each facility would have to have aData Universal Numbering System (DUNS) number, whichwould be used by FDA to identify it in the agency’s electron-ic systems.

Also within one year, FDA would have to issue a report thatdescribes agency progress on implementing cooperativearrangements and mutual recognition agreements with for-eign regulatory authorities relating to the regulation ofdrugs and GMPs. Guidelines on what information may bedisclosed and exchanged are included.

OTC products, typically considered by FDA as lower-riskthan prescription drugs for inspection classification purpos-es, would now be classified similarly to prescription drugs,according to the bill.

The new legislation provides a process for FDA tofollow if it finds “reasonable probability” that ahuman drug would cause serious health conse-quences.

The first step in the process would be to notify the manufac-turers, importers, distributors or retailers to cease distribu-tion, and then to hold an informal hearing. After the hear-ing, the agency could issue a mandatory recall if deemednecessary.

FDA would have the power to “administer oaths and affir-mations, subpoena witnesses, compel the attendance of suchwitnesses, take evidence, and require the production of anybooks, papers, documents, or other materials that are rele-vant to the investigation.”

The agency would also be granted authority to impose civilpenalties on firms that violate the provisions of the new leg-islation.

Included in the bill is a lengthy section providing protectionto so-called “whistleblowers,” defined as employees of adrug firm who “refuse to violate or who disclose violations”of the FD&C Act.

Adding authority into the FD&C Act for FDA to mandaterecalls was also the focus of a bill (H.R. 5740) introduced inthe House in mid-July by Chairman Edolphus Towns (D-NY). (See previous story).

Download from the story:

• Drug Safety and Accountability Act of 2010

To register for this meeting, please go to: www.signmeup.com/71247

For Additional Information, please contact the Rx-360 Secretariat: Kim.rouse@dbr.com +1 202-230-5608

Rx-360 Open Meeting

Current Members/

Observers: Biopharmaceutical Manufacturers:

Abbott Laboratories

Alcon Laboratories

Amgen Amylin

AstraZeneca

Baxter

Biogen Idec

Boehringer Ingelheim

Bristol-Myers Squibb

Cephalon

Eli Lilly

GlaxoSmithKline Hospira

Johnson & Johnson

Merck & Co., Inc.

Novartis

Pfizer

sanofi-aventis

Takeda

Watson

Suppliers: Archimica

BASF

Fagron

Freight Watch

GE Healthcare

Hovione

Labochim

LifeConEx

Mallinckrodt Baker Merck KGaA

Reliable Biopharmaceutical

Sigma Aldrich/SAFC

Spectrum Chemical & Laboratory Products

Temptime

VWR

West Pharmaceutical Services

Observers:

Active Pharmaceutical Ingredients Committee

Council for Responsible Nutrition

European Generic Medicines Association

European Fine Chemicals Group

International Pharmaceutical Excipients

Council

Parenteral Drug Association

Pharmaceutical Quality Group

Pharmaceutical Services Corporation Regulatory Compliance Associates

RMC Pharmaceutical Solutions Incorporated

SQA Services, Inc.

Safis Solutions, LLC

The Weaver Group, Inc.

The RxThe RxThe RxThe Rx----360 Board of Directors invites you to attend an 360 Board of Directors invites you to attend an 360 Board of Directors invites you to attend an 360 Board of Directors invites you to attend an Open Meeting on Thursday, 16 September 2010Open Meeting on Thursday, 16 September 2010Open Meeting on Thursday, 16 September 2010Open Meeting on Thursday, 16 September 2010

9:30 9:30 9:30 9:30 –––– 17.00 CET 17.00 CET 17.00 CET 17.00 CET Hosted by Merck KGaAHosted by Merck KGaAHosted by Merck KGaAHosted by Merck KGaA Frankfurter Str. 250Frankfurter Str. 250Frankfurter Str. 250Frankfurter Str. 250

64293 Darmstadt, Germany64293 Darmstadt, Germany64293 Darmstadt, Germany64293 Darmstadt, Germany This Open Meeting is an opportunity for non-members to learn more about

Rx-360’s strategic goals/objectives, progress and plans, including:

• RxRxRxRx----360 Year360 Year360 Year360 Year----inininin----Review Review Review Review – learn about Rx-360’s activities in 2010 and

near-term plans.

• Legal Considerations Legal Considerations Legal Considerations Legal Considerations – governance, membership, antitrust compliance.

Meet with Rx-360 Board members and the Secretariat to answer any

questions your company may have regarding membership in Rx-360. • Working Group presentations and informational sessions Working Group presentations and informational sessions Working Group presentations and informational sessions Working Group presentations and informational sessions on shared

audits, third party (joint) audits, audit standards, and other Rx-360 activities – meet with Rx-360 leaders to discuss the progress of the

organization’s working groups. • Several regulators have been invited to attend and present on the

latest regulatory trends in the US and EU.

NOTE: There is no charge for this Open Meeting, but you must register by 3 September 2010 in order to attend.

The members of Rx-360 would like to thank Merck KGaA for hosting the Open Meeting and appreciate their time and commitment to this event.

Visit www.rx-360.org for updates and more information

Rx-360 Mission: Create a global quality system that meets the expectations of industry and regulators and helps ensure patient safety by enhancing product quality and authenticity throughout the supply chain.

Hotel Information: A block of rooms have been reserved at NH Hirschberg

Heidelberg (Brandenburger Strasse 30, D-69493) until August 18. You must reference Booking Code: Merck 45619. http://www.nh-hoteles.pt/nh/pt/hotels/alemanha/hirschberg/nh-hirschberg-heidelberg.html

SAVE THE DATE !

SPREAD THE WORD !

INSIDE THE GLOBAL REGULATORY DIALOGUETM

AUGUST 2010 | 13

IPQ MONTHLY UPDATE–AUGUST 2010

During a July 20 J&J investor’s conference call covering thecompany’s second quarter results, Investor Relations VPLouise Mehrotra provided an update on J&J/McNeil’s cur-rent compliance situation and the significant financial andoperational impact of the firm’s compliance and recall prob-lems (IPQ Monthly Update July 2010, p. 15).

Mehrotra explained that McNeil’s Las Piedras facility, whereproduction had been impacted by recall problems and an FDAwarning letter, is now operating at normal production levels.Restocking commenced in the second quarter and will contin-ue to ramp up during the third quarter, she said.

Operations at the Fort Washington facility remain suspend-ed in connection with the recall of children's liquid OTCproducts manufactured there and an FDA inspection inApril which prompted the voluntary shutdown.

Noting that the suspension of manufacturing also impactedadult OTC products manufactured at that facility, includingTylenol, Motrin, and Zyrtech, Mehrotra commented that “aswas previously announced, we do not anticipate havingalternate sources of supply before the end of 2010 for mostof the products that were produced at this site. Alternatesupply of the remainder of these products is projected tostart in the first quarter of 2011 and continue to expandthroughout the year.”

McNeil submitted a remediation plan to FDA onJuly 15th.

“The plan is comprehensive and encompasses among otheritems, training, resources and capital investments in quality

and manufacturing systems across the McNeil organiza-tion,” the J&J exec said.

Mehrotra also commented on the ongoing legal ramifica-tions: “There are a variety of ongoing legal actions in con-nection with the recall including the initiation of lossesagainst McNeil and the ongoing governmental investigationinto circumstances regarding the recall. We continue coop-erating with the government's investigation and request forinformation, including the receipt of a grand jury subpoenafrom the US Attorney's office for the Eastern District ofPennsylvania.”

Another J&J official, Dominic Caruso, providedadditional insight during the conference call intothe financial impact of the company’s complianceproblems.

While the majority of McNeil’s US OTC business has notbeen impacted by the recalls or suspension of manufactur-ing at the Fort Washington facility, Caruso reported that thenegative effect on the firm’s annual sales from not shippingproducts produced at this facility is estimated at approxi-mately $600 million.

For the first quarter of 2010, U.S. sales of OTC pharmaceuti-cals and nutritionals were down 27% – attributable almostentirely to the McNeil recall and compliance problems.

[See following story for FDA findings at an inspection con-cluded in July at McNeil’s Lancaster, PA facility.]

J&J Tallies Up the Impact of its Compliance and Recall Problems inQuarterly Investor Update

WWW.IPQPUBS.COM

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AUGUST 2010 | 14

McNeil’s complaint handling – a problem area cited inFDA’s January warning letter to parent company J&Jregarding its Las Piedras, Puerto Rico plant and in an Aprilinspection at the OTC drug manufacturer’s FortWashington facility (IPQ Monthly Update July 2010, p. 15)– was also of concern to agency investigators in an inspec-tion completed July 9 at McNeil’s plant in Lancaster, PA.

FDA’s two-week inspection at the Lancaster, PA plant, joint-ly owned by Merck as indicated on the 483, was conductedby Sharon Thoma, who also inspected McNeil’s FortWashington plant in April, and Anita Michael. The prod-ucts manufactured at the plant include Imodium Pluscaplets, Pepcid Complete chewable tablets, and Mylanta.

The 12-page FDA form 483 issued following theinspection contains twelve observations coveringfour quality systems: quality (5), laboratory (4),production (1), and facilities and equipment (2).

Among the quality system problems cited was a failure to“thoroughly review any unexplained discrepancy whetheror not the batch has been already distributed.” When dis-crepancies were reviewed, the 483 asserts, the reports didnot always include appropriate conclusions and follow-up.

One example referenced was a lack of follow-up concerning“multiple and repeated product mix-up complaint investiga-tions to determine the causes for the repeated mix-up oftablets.” FDA noted that the investigation was incomplete asthe firm did not review repeated previous complaints observedfor the same product line and a similar mix-up of tablets.

Similar observations regarding McNeil’s handling of com-plaints were cited in the January warning letter and theApril 483 issued at Fort Washington (the July Lancaster 483did not reference the earlier citations).

With reference to consumer complaints of an uncharacteris-tic odor in the firm’s OTC products – ultimately found tostem from a preservative in wood pallets – FDA maintainedin the January warning letter concerning the Las Piedrasfacility that: “We are aware of the complaint informationavailable to your company, the sequence of events, and theextent of your firm's follow-up measures during this period.We have concluded that your company did not conduct atimely, comprehensive investigation.”

The 483 issued in April at Fort Washington referred toMcNeil’s large-scale recall of children’s products, whichwere the subject of approximately 46 complaints by con-sumers over the previous year, primarily for black specksand particles in the products. According to the FDA 483, thefirm did not initiate a CAPA for these complaints asrequired by company procedure.

Also of primary concern during the July inspection in thequality systems area were issues with documentation,including the investigators having to ask for particular doc-uments multiple times and significant delays in producingthe requested documents. For example, the report statesthat “organizational charts were requested on 06/23/10 andrequested approximately 10 times before receiving fullinformation on the structure/organization on 07/01/10.”Some of the documents, when produced, were found to beinaccurate.

Along with the handling of written and oral complaints anddocumentation, other quality system concerns included alack of sufficient detail in equipment cleaning and mainte-nance procedures.

The laboratory system’s four observations involved: • a lackof “establishment of scientifically sound and appropriatetest procedures” • lab deviations • standardization of refer-ence standards/reagents, and • issues with sample labelingand identification. Similar laboratory issues regarding labcontrols and sample identification were cited on the AprilFort Washington 483.

The investigators at Lancaster took issue with a lack ofdetermination of microbial flora in the production facility,routine inspection and maintenance of electrical andmechanical equipment, and personnel not following clean-ing and maintenance procedures.

Downloads from the story:

• McNeil July 483

• McNeil April 483

• J&J January warning letter

FDA Concern with McNeil’s Complaint Handling Extends to Lancaster, PA Facility

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INSIDE THE GLOBAL REGULATORY DIALOGUETM

AUGUST 2010 | 15

IPQ MONTHLY UPDATE–AUGUST 2010

FDA’s Center for Drug Evaluation and Research (CDER)will be conducting a series of inspections of drug manufac-turers that will evaluate the industry’s understanding of andcompliance with the Part 11 regulations. The inspectionfindings will be used to assess whether or not the agency'srelated regulations and guidance need to be adjusted.

CDER announced that it will begin the inspections at manu-facturing and clinical investigation sites both in the US andabroad in the near future. The agency will not disclose howthe sites will be selected for inspection nor provide advancenotifications of inspection to those sites.

In a mid-July press release, CDER pointed out that concernswith the 1997 regulation were addressed in its August 2003“Scope and Application” guidance, which limited the wayPart 11 would be enforced during inspections and provideddiscretion in interpreting compliance. The press releaseexplains that CDER “intends to take appropriate action toenforce Part 11 requirements for issues raised during theinspections that do not fall under the enforcement discretiondiscussed in the guidance.”

In the wake of this announcement, ISPE held awebinar on the new inspection initiative.Conformity Director Sion Wyn and CDER Officeof Compliance (OC) Project Management OfficerGeorge Smith provided background and detailson the upcoming effort. Wyn is an advisor to FDAon Part 1; Smith is co-chair of the FDA Part 11working group.

Wyn began with an overview of the regulatory expectationsregarding Part 11 and the Scope and Application guidance. Theoverall expectation, he said, is that a manufacturing company orclinical investigator site have adequate controls in place toensure that the regulated electronic records are trustworthy,reliable and generally equivalent to their written counterparts.

The electronic records must also preserve the content andmeaning of the records “so that the regulated company couldthen consistently use those records to fulfill regulatory dutyand that they would be available for inspection by the agency.”

Noting that computerized systems are becomingincreasingly “fundamental” to all business andmanufacturing processes, Wyn highlighted twopotential and related problem areas in particular:record lifecycle and system interfaces.

“A particular electronic record may have quite a complexlifecycle, being passed along between many various sys-tems, all of which need to be in a state of control and in com-pliance,” he stressed.

The Part 11 expert predicted that there will be less focus onindividual systems in inspections and more scrutiny of theinterfaces between the various interconnected systems.“How they effectively communicate with each other acrossthe infrastructure will become more and more important,”he emphasized.

Building on the background provided by Wyn,CDER’s Smith discussed the current state of Part 11compliance and the center’s upcoming plans for ini-tiating inspections focusing on those regulations.

Since the Scope and Application guidance was published in2003, FDA has been “in a reevaluation phase,” he explained.The agency has been monitoring Part 11 compliance and is“looking to put in place whatever is needed to move forwardand make sure that the Part 11 requirements are enforced.”

Smith emphasized that Part 11 “did not go away” and thatFDA continues to enforce it, though much of the enforce-ment “is not obvious” as the citations are generally to thepredicate rules and do not reference Part 11 directly.

CDER’s Office of Regulatory Affairs (ORA) willbegin inspection assignments focused on Part 11requirements as per the enforcement discretiondescribed in the scope and application guidance“very soon,” Smith explained. “We hope toimplement and complete it within 2010.However, it might be expanded or might be short-ened. It all depends on what we find.”

The initial focus will be on human drug clinical investiga-tors and manufacturers. The initiative will include both sur-veillance and for cause inspections with a particular focuson “areas of high risk to find out if the appropriate controlsare or are not in place,” the OC official stressed. “

Where industry may not be compliant or understand theenforcement, we will enforce it as described” in the 2003guidance .CDER intends to use the inspections to determinethe current level of compliance in the industry and to “gath-er information to help us determine the path forward withregards to Part 11 reevaluation,” Smith said.

CDER Will Focus on Part 11 Compliance in Upcoming Inspections

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IPQ MONTHLY UPDATE–AUGUST 2010

AUGUST 2010 | 16

Possible outcomes of the reevaluation, he explained,include: • no changes to existing guidance • publishingadditional guidance to clarify issues found in the inspec-tions • amending Part 11 or its preamble • updating exist-ing compliance policy manuals that “might contain outdat-ed interpretations of Part 11,” and • a complete rewrite ofPart 11.

Global and Legacy Systems Among IssuesAddressed in Q&A Session

The implications for global computer systems and legacysystems were among the issues addressed by Wyn andSmith in the Q&A that followed.

Wyn responded to a question regarding how to define aprocess owner for a system that traverses multiple coun-tries. He referred to ISPE’s current Good AutomatedManufacturing Practice guide (GAMP 5) and the associatedgood practice guide on global information systems as refer-ences to help companies “think about their specific casesand come up with answers,” including which decisionsshould be made at global, regional and local levels.

“I do not think it is a case that there is one person or a hand-ful of people who have to make all decisions,” Wyn com-mented. “Based on risk assessment, different people willprobably need to get involved in different decisions and itwill probably be a cascade or hierarchy to a certain extent,with certain decisions being escalated.” System owners, henoted, should generally be the process owners as opposed totechnical or compliance personnel.

Legacy systems have been of particular concern at drugmanufacturers, many of which have data in older systems.“We are not going to enforce that [systems in place before1997] be Part 11 compliant,” Smith emphasized. Wyn addedthat “there is no reason why a system that has been in placeand operating successfully for many years…should nothave an acceptable level of record integrity.”

The length of the upcoming inspections, what toexpect, and training of the investigators conduct-ing them were other focuses in the Q&A.

Smith stressed that “there is no such thing as a Part 11inspection.” The inspections will be “normal” inspections,with requests to the investigators regarding which systemsand controls CDER wants them to look at. The investigatorswill not receive specific training on what to look for, but willbe briefed “on what we want to look at for that particularinspection.”

Responding to a question regarding what the investigatorswill be looking for, the OC official indicated that the agency“will not be giving specifics with regard to what we will belooking for because that is going to change over timedepending on what we find.” He added that previous cita-tions and warning letters covering Part 11 violations “mightbe one place we start, but we are not going to be boxed inwith specifics on this.”

An important focus of Part 11 is record integrity,and the so-called “preserved record.” Smith clari-fied the meaning of this term and Wyn comment-ed on its import.

According to Smith, the FDA perspective is that a preservedrecord is one that is retained for the period of time specifiedin the regulation and is complete, containing the informa-tion required by the associated predicate rule.

“It is not so much about the meaning of the preservedrecord, as preserving the meaning of the record,” Wyn com-mented. It is important to “understand what is the realpractical value now and in the future of that record, andhow you can preserve the meaning and the value of thatrecord.”

Wyn will conduct an ISPE-sponsored two-day training ses-sion on Part 11 December 6 – 7 in Philadelphia.

Downloads from the story:

• CDER Part 11 Inspection Press Release

• FDA 2003 Scope and Application Guidance

• ISPE Part 11 training by Sion Wyn

INSIDE THE GLOBAL REGULATORY DIALOGUETM

AUGUST 2010 | 17

IPQ MONTHLY UPDATE–AUGUST 2010

Complaint and deviation handling/reporting and contami-nation control – concerns that have been in the forefront ofFDA attention during vaccine manufacturing inspections –were again focal points at a March/April inspection ofSanofi Pasteur’s vaccine plant in Marcy l’Etoile, France thatresulted in an “untitled letter” from the agency on July 22.

FDA’s focus on vaccine production has escalated in recentyears as this product segment has expanded.

This focus was reflected in warning letters during 2008 to twomajor vaccine manufacturers, Merck and Novartis (IPQMay/June 2009 Report), citing some of the same concernsfound at Sanofi. The three letters are as much indicative of thecomplexity of the operations involved as the level of GMPnon-compliance.

The untitled letter to Sanofi maintains that inspectors found“significant deviations” from CGMP requirements in thefirm’s manufacture of both licensed biological products andbulk drug substances. The warning letters to Merck andNovartis also referenced both bulk and dosage productionfacets.

Vaccines involved in the Sanofi inspection included therabies vaccines Imovax and Imogam, Act-HIB(Haemophilus influenzae), Ipol (polio), and Typhim Vi(typhoid). A rabies vaccine was also among the productsimplicated at Merck and a hemophilia vaccine at Novartis.

In the Sanofi letter, FDA acknowledged receipt ofthe firm’s written responses to the 483 inspectionobservations, dated April 21, May 17 and June 11.However, the agency requested further responseto specific items and a commitment that theresponses will be addressed globally.

Focusing first on the product side, the letter cites the findingthat Sanofi had “failed to thoroughly investigate any unex-plained discrepancy or the failure of a batch or any of itscomponents to meet any of its specifications, and failed toextend the investigation to other batches of the same drugproduct and other drug products that may have been asso-ciated with the specific failure or discrepancy.”

Giving examples, the letter notes that Sanofi’s investigationsinto recurring Typhim Vi out-of-specification (OOS) results

had identified pyrogenicity of a component used in thepyrogen testing and in the manufacture of Typhim as a“probable root cause” but did not evaluate incoming rawmaterials that may also have contributed to the problem.

In Merck’s case, FDA’s focus was on the handling of OOSresults in its stability program, which the firm concludedwere due to ingress into the vial headspace during ship-ment. At Novartis, investigators cited the incomplete inves-tigation of batches that failed viable rabies virus testing aftervirus inactivation, claiming that Novartis had not identifiedthe root cause.

Regarding complaint handling, FDA maintained thatSanofi’s investigations of complaints of difficulty in with-drawing product into syringes received between February2008 and February 2009 were inadequate in that they did notinclude an evaluation of the “reconstitution of retain sam-ples with the 0.4% NaCl diluent used in the marketed prod-uct.”

At Merck, FDA expressed concern that the firm’s investigationof pressurization problems did not include all potentially-impacted finished batches or investigation of the possibilitythat the pressurization issues seen by its customers might bedue to the packaging materials not functioning as validated.

Also highlighted in the Sanofi letter was the fail-ure to submit Biological Product DeviationReports (BPDRs) for lots of bulk and finisheddosage form product that had failed stability atvarious time points.

Biological product deviation reporting is frequently raisedas an issue during biologic inspections. Late reporting hasbeen a particular problem for vaccine manufacturers.

Where 96% of the 169 BPDRs submitted in FY 2008 for aller-genic products were within the requested 45 day reportingtime, only 60% of the 97 vaccine reports during the yearmade that deadline. In vitro diagnostics were in the middlerange with 77% of 78 IVD reports made within 45 days (IPQMay/June 2009 Report).

BPDR issues cited in the Merck warning letter involved alack of thoroughness of the investigations and considerationof all potential factors in root cause investigations.

Complaint and Deviation Handling, Contamination Control Continue toDraw FDA Attention at Vaccine Plants

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Another problem noted at Sanofi was not informing FDAabout changes in the production process involving pyrogentesting from the license application. Sanofi committed tosubmitting a supplement to cover the manufacturingchanges that were previously unreported, according to theletter.

In the section of the Sanofi letter addressing bulk drug pro-duction, FDA stated that trend reports on clean area envi-ronmental monitoring were frequently approved late, andthat controls to prevent contamination and mix-ups wereinadequate.

The Novartis warning letter cited issues with microbial con-tamination found in two lots of rabies vaccine after inactiva-tion and how the firm responded. At Merck, FDA focusedon the failure to assess the impact of recent changes to asteam-in-place (SIP) system that may have been involvedwith sterility failures.

All three of the letters remind the firms of theimportance of correcting the referenced problemson a global basis.

The Sanofi letter requests that the firm’s response include adiscussion of “implementation of global Quality Assuranceoversight to ensure that adequate steps are taken for theevaluation of product impact, deviation investigations, andadequate and effective corrective and preventive actions.”

Sanofi is requested to submit a response, but the letter doesnot specify a timeframe as is common in warning letters.

Also notably absent in the Sanofi untitled letter is the stan-dard warning letter statement that further regulatory actionmay be taken on the part of the agency. According to FDA,untitled letters are initial correspondence that “cite viola-tions that do not meet the threshold” for issuing a more seri-ous warning letter.

[Editor’s note: The IPQ May/June 2009 Report contains anextended analysis of FDA concerns in vaccine manufacturing.]

Downloads from the story:

• Sanofi Pasteur Untitled Letter July 2010

• Novartis Warning Letter January 2008

• Merck Warning Letter April 2008

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IPQ MONTHLY UPDATE–AUGUST 2010

Biosimilar Products, Guidelines and Requests for Scientific AdviceContinue to Increase in EU

EUROPE

The European Medicines Agency (EMA) portfolio ofapproved biosimilar products and guidelines and the relat-ed requests for scientific advice continue to expand, withinterest increasing in particular in monoclonal antibodies.

The EMA is in the process of adding four more biosimilarproduct-specific guidelines: A new guideline on recombi-nant erythropoietins (EPO) was cleared in March to becomeeffective in October, and new guidelines are under develop-ment on monoclonal antibodies, follitropin alpha (recombi-nant follicle stimulation hormone) and interferon beta.

Concept papers on the latter three have gone out for com-ment. The monoclonal antibody comment period ended inJanuary and the period for follitropin alpha and IFN-betaclosed in June. These four will accompany the agency’sexisting guides on recombinant human insulin, somatropin,granulocyte-colony stimulating factor (GCSF), low molecu-lar weight heparin, and interferon-alpha.

These product class-specific guidelines address clinical,non-clinical and bioassay issues and fall under EMA’s over-arching “Guideline on Similar Biological MedicinalProducts,” released in late 2005. The umbrella guideline isaccompanied by separate guidelines addressing quality andclinical/non-clinical issues for biosimilars, respectively,which were both released in mid-2006.

The number of biosimilar marketing authoriza-tion applications (MAAs) evaluated by EMA hasreached 18. Of these, 14 have been approved, oneturned down and three withdrawn.

The approvals have come in clusters for particular productclasses:

• The first biosimilar authorizations in the EU were somat-ropin products from Sandoz and Biopartners, beginningwith Sandoz’ Omnitrope in April 2006.

• EMA’s Committee for Medicinal Products for Human Use(CHMP) turned down the authorization of Biopartners’interferon alfa application filed in June 2006, which thecompany has indicated it intends to refile.

• In the 2007 timeframe, epoetin alfa authorizations wereapproved for Sandoz, Hexal, Medice, Stada and Hospira.

• In late 2007, Marvel Life Sciences withdrew its applica-tions for short, intermediate and long-acting forms ofrecombinant human insulin.

• A series of filgrastim approvals in the EU began with aRatiopharm product in February 2008. Biosimilars of theneutropenia therapy have subsequently been cleared forCT Arzneimittel, Teva, Hexal, Sandoz, and most recentlyfor a Hospira filgrastim biosimilar in June.

The requests to the EMA from companies for sci-entific advice on biosimilars have been steadilyrising as well. Advice was provided related to 13applications in 2009, up from 2 in 2003.

The requests indicate an increasing interest in monoclonalsin particular. Reflecting this interest, EMA held a well-attended workshop in July 2009 to focus on the issues inbiosimilar monoclonal development.

Addressing biosimilars as part of a presentation on EU reg-ulatory challenges over the coming decade at a CASSS CMCStrategy Forum in Vienna in late May, retiring EMA Qualityof Medicines Head John Purves highlighted the growing EUexperience as an “important reference for other regions inthe world as well.”

Purves commented that “it will be interesting to see how theglobal development of biosimilars occurs in the future.”

[Editor’s Note: See the following story for further insightsfrom Purves at the Vienna forum on the challenges the EMAfaces in regulating biosimilars, advanced therapies, person-alized medicines, variations and QbD, and the need forincreased industry/regulator dialogue to help address them.]

The biopharmaceutical regulatory challenges confrontingthe EMA over the next decade – from biosimilars, advancedtherapies, personalized medicine and transgenics to varia-tions and quality by design – will require closeindustry/regulator dialogue and new communication chan-nels, recently retired EMA Quality of Medicines Head JohnPurves stressed at CASSS’ European CMC Strategy Forumin Vienna in late May.

The criticality of open scientific dialogue and informationsharing to shaping viable regulatory policies and guidanceand steering the complex new products through their devel-opment, review and manufacturing stages was a centraltheme in Purves’ assessment of the EMA landscape.

Focused on the challenges facing biopharmaceuticaldevelopment in the next decade, the Viennaforum provided the European regulator a chanceto take a broad view of how the EMA will need toevolve to address them.

Purves left the UK’s MCA 14 years ago to join the newlyformed EMEA, where he played a key role in advancing itsquality regulatory effort and policies. He retired from theagency at the end of April.

The quality regulator pointed out that the importance of dia-logue was inherent in EMA’s mission when it was founded 15years ago to “foster scientific excellence in the evaluation andsupervision of medicines, for the benefit of public and animalhealth.” The mission, he stressed, includes communication andcoordination across the EU network as well as stimulating inno-vation and research “through the tradition of scientific advice.”

Purves noted that over the last few decades, “there havebeen significant changes in the science, there have beendevelopments in the legislation, and also developments inthe way in which the regulators have reviewed dossiers.”With the increasing complexity of the agency’s core tasks,the scientific communication channels need to be furtherdeepened if the EMA is to fulfill its mission, he maintained.

Scientific Dialogue Central To EMA Roadmap

EMA’s facilitation role is underscored in the agency’s “RoadMap to 2015,” in which EMA sets out its vision of how itshould develop as a public health agency.

The comment period on the EMA 2015 roadmap ended on April30. The roadmap will be supported by a companion document,“From Vision to Reality,” and its various objectives incorporatedin the agency’s work plans for the 2011-2015 period.

In general, the EMA roadmap points the way to a harmo-nized approach to the challenges of regulating innovativetherapies, personalized medicines and drug/device combi-nation products. It calls for strengthened measures toincrease transparency and communication and to combatcounterfeits and monitor GMP/GCP compliance.

The roadmap has four sections focused on: • further improv-ing the quality, regulatory/scientific consistency and efficien-cy of the core review process • facilitating access to medicines• addressing public health needs, and • optimizing the use ofmedicines.

Purves stressed that the EMA’s role of facilitatingaccess to medicines rests on scientific dialoguethrough the drug development process.

Industry and regulators meeting together to discuss the sci-ence, he pointed out to the Vienna CMC forum attendees,“is helpful to the regulators because they can identify ifthere are guidelines that need to be developed, and it ishelpful to the industry because it allows you to identify ifthere are any hurdles that need to be addressed in a differ-ent way.”

The risk/benefit assessments and communication become“a lot more important now,” Purves affirmed, given theneed to interact with the Health Technology Assessment(HTA) bodies throughout the product lifecycle. HTAs arenational bodies that interface with the EMA like the UK’sNational Institute for Health and Clinical Excellence. NICEmakes recommendations on existing medicines/treatments,sets quality standards, offers scientific advice to industry,and manages a national database.

In turn, the roadmap calls for the EMA to address publichealth needs by helping fill the gaps in drug developmentand the emerging science. The regulator support will be“very important” both for advanced therapies and biosimi-lars, Purves commented, pointing to the response to theinfluenza pandemic as an example of this regulatory sup-port process successfully at work.

Increased EMA/Industry Dialogue Needed to Address UpcomingBiopharm Regulatory Challenges, Retiring Quality Director Purves Says

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Quality By Design And Personalized MedicineWill Require Collaboration

In his presentation at the Vienna forum, the recently retiredquality director explored the challenges the EMA will befacing in addressing biosimilars, quality by design, and per-sonalized medicine, in particular. [Editor’s Note: The EMAbiosimilar developments addressed by Purves are covered inthe previous story.]

For QbD, Purves views as key challenges the levelof information that needs to be included in anapplication and the related issue of how to enhancecollaboration between assessors and inspectorsacross the QbD/quality system continuum.

This nexus of issues has been receiving particular attentionin the European discussions on advancing the ICHQbD/Q8-10 paradigm (IPQ May 2010 Report) and werecentral to the discussions at the ICH implementation work-shop in Tallinn Estonia in early June (IPQ Monthly Update– July 2010, p. 32).

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 US and the disconnectsof the multistate system come into play.

Purves commented in Vienna that making sure there is suf-ficient training and dialogue between industry and regula-tors in this area is critical in introducing “successfully thequality by design concept and practices. So the scientificdialogue between industry and regulators prior to and dur-ing submission is encouraged.”

EMA will also “need to address the new chal-lenges on the horizon relating to nanotechnology,synthetic biology and regenerative and personal-ized medicine.”

In the personalized medicine arena, the agency will need tobuild on the current experience with advanced therapies, hesaid, adding that some centrally authorized productsalready have personalized indications in the approvedproduct information.

Purves stressed that the scientific/technical and regulatorychallenges for these novel approaches “will be quite differ-ent.” In order to address them, the agency will need to poolits specialized expertise to adapt the regulatory framework.

The area of advanced therapies “is going to bevery interesting” over the next decade, Purves pre-dicts, drawing a parallel with “where we werewith rDNA products at the beginning of the1980s.” The workload will increase slowly, butthere will be “a very progressive and positiveincrease in the activities between the regulatorsand the industry.”

Recognizing that the review of advanced therapies would requirepulling together expertise in various diverse areas such as sur-gery and medical devices, EMA created a new “Committee forAdvanced Therapy Products” (CAT) in January 2009.

There has been a limited amount of activity to date in mar-keting applications. TiGenix’ ChondroCelect (characterizedviable autologous cartilage cells expanded ex vivo express-ing specific marker proteins) was authorized in October2009. Ark Therapeutics’ Cerepro (stimagene ceradenovec –adenoviral vector-mediated herpes simplex virus-thymi-dine kinase gene used with subsequent administration ofganciclovir) received a negative opinion in December 2009and the company is now looking at further Phase III trailsand co-partnering arrangements. The product was grantedorphan drug status in both the US and EU.

As of January 2010, 22 products had been classified asadvanced therapy medicinal products (ATMP) based on thescientific recommendation of the CAT, and one product wasunder review for the ATMP designation.

Addressing the guidance needs for the new biologi-cals, Purves noted that a guideline on the require-ments for quality documentation concerning investi-gational medicinal products is under development.

EMA is also in the process of revising its guidelines on trans-genic animals and plants, which were developed back in1995. The agency did publish a guideline on the quality ofbiological active substances produced by stable transgeneexpression in higher plants in 2008.

EMA approved GTC Biotherapeutics’ antithrombine alfa prod-uct ATryn produced in transgenic goats in mid-2006, whichwas also approved in the US in early 2009. The company islocated in Framingham, Massachusetts. A recombinant C1inhibitor from transgenic rabbits, Rhucin, from Netherlands-based Pharming Group, received a negative EMA opinion inMarch 2008, and a resubmission is currently under evaluation.Applications have not yet been submitted to the agency usingtransgenic plants.

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Purves emphasized the enhanced role EMA should take inhelping facilitate new approaches to medicinal productdevelopment and the need for applying “a more proactiveapproach to public health threats where medicines areimplicated,” building on the positive experience gained inthe influenza pandemic response.

Along with the new technology products, globaliza-tion is another force challenging EMA to evolve itsregulatory strategies and broaden cooperation andcommunication pathways, Purves stressed.

Manufacturing and clinical research is moving away fromthe classical sites in the EU and US, and “the world isbecoming very much a ‘supermarket’ in pharmaceuticals.So we need to look at things in a globalized manner. Thereare changes to the role of regulators, and I think there needsto be a lot more discussion, as there has been over recentyears, amongst the regulators – a call for more internationalharmonization and cooperation.” Counterfeiting is also adriver for cooperation, Purves added.

The EMA strategy includes further increasing the interactionswith international regulatory partners such as with FDA on“clusters” like vaccines and advanced therapies and on QbD,which, in turn, “stimulates the global approach,” Purves com-mented. The work with ICH and WHO “is also going to furtherstrengthen the globalization of the regulatory approach. So weneed to strengthen the partnerships using these tools.”

Echoing a recurrent theme among the FDA hierarchy on theglobal challenges, the former EMA regulator also stressedthe importance of recognizing and enhancing “the ability torely on local regulators to assure the equivalent approach tomanufacturing and control of medicines and authorizationand supervision of clinical trials” as well as pharmacovigi-lance. The focus needs to be on “where products are beingproduced and tested,” he said, and support provided fortraining and capacity building in those regions.

Forum Participants Weigh In.During the discussion period that followed Purves’ presen-tation at the European forum, participants drilled down fur-ther on the need for open scientific dialogue to advance theregulatory process and how the need can be addressed.

Abbott Laboratories’ Brian Withers, who is the ExpertWorking Group (EWG) “rapporteur” for the developmentof the drug substance guideline Q11 (see story on p. 28),pointed out that “the word ‘dialogue’ – scientific dialogue

and dialogue throughout the development cycle” – came up“a lot of times” during Purves’ “really interesting” presenta-tion. “Does the EMA have a thought about what that wouldlook like?” Withers asked him.

Withers added that the EMA’s procedure for “’scientificadvice’ is okay if you have specific questions, but the abilityto have a dialogue throughout development, particularly onquality-by-design issues,” is something industry has beeninterested in. “Does the EMA have a view on that now?”

Purves responded by sharing his experience onthe important role that scientific dialogue hasplayed in allowing the regulatory process to keeppace with new technologies.

While at UK’s Medicines Control Agency (now MHRA), his“initial experience regarding dialogue was back in the 1980swhen we had the first rDNA application for humansequence insulin in the UK. At that stage, I think the indus-try and the regulators were both wondering how do we takethings forward. And what we did at that stage was sitaround the table and actually talk about the scientific issues,and we came to an agreement on what would be a reason-able submission from the regulators’ point of view andbased on the science that the company had provided.”

Subsequent to that, Purves continued, “the experience in thelate 80s and the early 90s showed quite clearly that repeatedscientific advice was helpful in identifying potential hurdlesbefore the submission of applications.”

Turning to the current dialogue around QbD andthe changing variations regulations, Purves notedthat this is a new area for both the regulators andthe industry, potentially requiring new communi-cation channels.

“The regulators are probably more curious about the compa-ny’s strategy for taking the product forward. What do youwant to do? I think if a request was put forward to the agencyto have that dialogue before some of the variations were sub-mitted in relationship to, say, quality by design, I am sure thatthat would be agreed to. The mechanism of how that is goingto be done, I think, needs a little bit more thought.”

Recognizing Withers’ comment on the limited scope of thecurrent scientific advice procedure, Purves added that “thereis also the opportunity for the industry going to the agency todiscuss some new issues…. If the industry takes that initiativeand puts in requests, I am sure they are going to be honored in

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some way. But probably one needs to think of a more formalway of doing it. That will come out from the initial discus-sions between the industry and the regulators.”

Sharing Science Drives Toward Harmonization

The participants in the dialogue at the Vienna CMC forumpointed to the power that the sharing of science has in driv-ing toward harmonization.

Purves reflected that in the mid-80s when the 12 EU mem-ber states began to come together to review dossiers throughthe consultation procedure, their reports “were really quitedisparate with respect to comments.” However, as scientif-ic information was shared and guideline discussions pur-sued, the member states began aligning. The internationaldiscussions in the ICH and WHO contexts fostered furtherconsensus building.

Advance therapies present a ripe area for regulators andindustry to dialogue as “was quite evident” at the workshopEMA held in May on stem cells, Purves maintained. While itis early in the regulatory curve and there are many openquestions, “the debate that was had at that meeting helpedtake things forward.”

In general, in approaching new technology areas such asadvanced therapies and biosimilars, Europe needs to take amore holistic view, he asserted, with the national competentauthorities, the EMA and the HTA bodies and the otherstakeholders working together to share the information onsafety, efficacy and quality as early as possible.

Former FDA biotech regulator Kenneth Seamon, currently aprofessor at the University of Cambridge, commented onthe need for post-marketing feedback from physicians andpractitioners to help fill in the gaps left by the small patientpopulation studies conducted for approval. “I think that isan area where we would benefit from further world align-ment,” he said. Seamon was cofacilitator of the influential A-MAb case study illustrating a biotech QbD developmentprocess (IPQ May 2010 Report).

The question was posed whether industry’s ulti-mate goal of a single global application and clear-ance process was achievable.

CDER Office of Biotechnology Products (OBP) DirectorSteven Kozlowski commented that “it is a long path to trustcompletely the review of an application by another group,”and a complicated one both scientifically and politically.

“On the other hand,” Kozlowski said, “I think the more thescience is transparent and shared, the more the requirementsbecome the same. As John [Purves] said, when groups talktogether, usually we end up coming to the same conclusion.So I think the more we share the science…the more therequirements will tend to harmonize of themselves.

“Trusting another group to do an inspection for you, to actu-ally review all of the data, I think those are challenges.”However, the CDER official maintained, “if you can come toagreement that the science principles are the same, you areat least a large step in that direction and save industry a lotof effort too, even if they need multiple applications.

“So I think that over time, we move closer together. Whenthere will be a global marketing application reviewed byone local regional group – that is an attractive idea, but a lit-tle bit off in the future.”

Seamon commented that “mutual recognition is a holy grail,but it is still going to be…many years.”

The former FDAer emphasized the importance of sharingongoing post-approval inspectional data as well as thedevelopment science, questioning whether “there are strongenough opportunities for transparent discussions” on thepost-approval side.

Kozlowski concluded the session discussions onthe benefits of scientific information sharing toevolving the regulatory process by pointing to theneed for industry to understand that these bene-fits far outweigh the risks.

The regulatory agencies, the OBP official said, can establishbilateral sharing agreements, but sharing more broadlybecomes an industry decision. “We can’t force you to share datayou don’t want to share…. It needs to be industry viewing thatthe value of sharing is greater than the risk of sharing.”

He pointed to treating biotech science as proprietary out ofconcern for biosimilars as a case in point. “The way technol-ogy advances, your lawyers may worry about protectingsome piece of data or some analytical test [but] that willprobably be irrelevant by the time that product is chal-lenged.”

Kozlowski urged the industry participants to “think longterm – that sharing the science is much less risky than youthink…. It is worth thinking about the true risk and value ofsharing a lot of this information.”

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The EMA is restructuring its PAT Team to advance theteam’s role in facilitating the communication within theagency and with industry needed to further the ICH Q8-10/QbD objectives.

The restructuring will involve a shift in both the team’smandate and membership over the next year – a moveaimed at helping integrate the disparate elements in thecurrent EMA quality regulatory structure, AFSSAPSreviewer and PAT team member Kowid Ho told a CMCstrategy forum on implementing quality by design cospon-sored by the biotech science society CASSS and FDA inmid-July.

The biotech CMC strategy forums are held semiannually inthe U.S. and once a year in Europe. They are designed tobring industry and regulators together to drill down onspecific quality topic areas deemed important in progress-ing biotech product regulation.

July’s meeting, held at the National Institutes of Health(NIH) in Bethesda, Md., was the third of the CMC strategyforums that has been focused on implementing QbD in thebiotech context. [Editor’s Note: The dialogue at the firsttwo QbD forums is analyzed in the Sept./Oct. 2007 andSept./Oct. 2008 IPQ reports, respectively.]

Recognizing the relative unfamiliarity of the USaudience with the complexities of EU regulationand regulatory structures, Ho provided the histo-ry leading to the current situation, an explanationof how the system works, and the resulting needfor changes to the PAT team to help support QbDimplementation.

The AFFSAPS official explained that the EuropeanCommission (EC) promulgates rules for the EU, and underthe commission is the EMA, responsible for the review ofmedicines.

The EMA structure includes a number of scientific commit-tees, each of which includes representatives from all 27member states along with observers. The opinions that are drafted in these committees must be agreed to by allrepresentatives.

The EMA’s Committee for Human Medicines and Productsfor Human Use (CHMP) oversees a number of “workingparties” related to pharmaceutical and biotech regulation.

The communication becomes “tricky,” Ho emphasized,when issues span several working parties. For example, aQbD application for a biologic requires input from the GMPInspection Working Party, the Biologics Working Party(BWP), and possibly the Quality and the Scientific AdviceWorking Parties. Each group submits their input to theCHMP, whose recommendation is needed for the applica-tion process to proceed.

The PAT team member commented that currently “veryoften” when companies ask the team where to go for adviceor, for example, information on a pilot program, theresponse is not always clear. The team can provide advice,but only on an informal basis, he explained. The BWP isresponsible for the actual submission for a biologic and willgive a final opinion to the CHMP, while scientific advicecomes from a different group.

Frequently the PAT team is not involved when it may havebeen advantageous to have had them in the discussions. “Sothe system is not working perfectly at the current time,” Hocommented.

The AFFSAPS official explained that the team’sstructure and mandate is currently being revisedto help address these communication issues.

“By next year there will probably be a completely differentgroup with a different mandate, which most probably willbe more focused on the advice to companies and the peerreview of all [QbD] applications,” he said.

The PAT team was started in 2004 and initially includedquality assessors appointed by the Quality Working Partyand inspectors appointed by the inspectorates. Today, itincludes representatives and the chairs from the EMA’squality, biotechnology and inspectorate working parties,five quality assessors, four GMP inspectors, plus an observ-er from EDQM.

“All this is being reorganized,” the APSSAPS revieweremphasized. The latest plan calls for the team to have equal

EU Restructuring PAT Team to Help Address Communication Challengesof the New Quality Paradigm

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numbers of quality assessors and biological assessors – like-ly five or six from each working party. The ratio of inspec-tors to assessors will also change. “This is ongoing, and thiswill most probably be applicable and implemented by2011,” he noted.

Speaking at the PDA/EMA conference last October, LinaErtle, who also represents the French agency AFSSAPS on

the PAT team, foreshadowed the coming changes to theteam, noting that the long-term EMA vision is to institution-alize QbD concepts and practices.

[Editor’s Note: For a discussion by Ertle and other EU offi-cials of the PAT Team’s role in advancing ICH’s vision forQbD, see the IPQ May 2010 Report, pp. 19 – 21]

IPQ MONTHLY UPDATE–AUGUST 2010

The UK’s Medicines and Healthcare products RegulatoryAgency (MHRA) is actively exploring the addition to itsenforcement toolbox of a range of monetary and statutorysanctions for use against non-compliant drug manufactur-ers, similar to those available to FDA.

In a recently-released “Enforcement Strategy” documentdescribing the additional sanctions sought, MHRA explainsthat “in most cases compliance is achieved without the needto resort to enforcement action or the need to apply sanc-tions.” However, the agency noted, when penalties areneeded, the range of sanctions available to regulators is“limited.”

Part of the UK’s “Better Government Initiative,” the newenforcement strategy report provides an overview of theMHRA, the laws it enforces, its jurisdiction, and theagency’s current enforcement paradigm and tools.Appendix B titled “Macrory Sanctions” – the last four pagesin the 33-page document – addresses the new tools beingconsidered for dealing with non-compliant firms.

The appendix proposal, which would provide theMHRA with enforcement powers reflective ofthose FDA invokes in a consent decree, representsthe culmination of a broader effort begun almostfive years ago.

In September 2005, attorney and environmental law professorRichard Macrory was commissioned by the UK to examinecompliance by regulated businesses in the country, with a par-ticular focus on the use of sanctions and their effectiveness.Macrory considered the work of “56 national regulators and 468local authorities,” publishing his findings, analysis and recom-mendations in a 131-page report in November 2006.

In 2008, the UK government agreed to implement nine of therecommendations from the report in whole or in part underits Regulatory Enforcement and Sanctions Act. MHRAbelieves that implementing a subset of these sanctions forthe industries it regulates would result in a “substantial ben-efit to public health.”

Financial and Criminal Penalties and ConsentDecree-Like Agreements On the Table

The agency is exploring the use of the following approachesas outlined in Appendix B of the enforcement strategyreport: • fixed and monetary administrative penalties • statutory notices • enforceable undertakings • “under-takings plus,” and • restorative justice.

Monetary administrative penalties are fines applied directlyby a regulator, with an administrative appeals process avail-able through the regulatory agency. They may be either fixedor variable – fixed fines would be applied to “low-level, minoror high-volume instances of noncompliance,” with theamounts to be determined by legislation, whereas variablefines would be for much higher amounts as determined by theregulator according to a yet-to-be published table.

In some instances of regulatory non-compliance, under theproposed rules, regulators will have the option of issuing a“statutory notice,” which requires the recipient to performor refrain from a particular behavior and specifies the stepsthe firm must take and the timetable required for regulatorycompliance. The statutory notice may also include remedi-ation provisions the firm must follow to amend for the dam-ages caused by non-compliance. If the behavior is deemedto be intentional, criminal prosecution may result.

MHRA Pursuing New Monetary and Statutory Sanctions for Non-compliance

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IPQ MONTHLY UPDATE–AUGUST 2010

AUGUST 2010 | 26

If regulators believe that financial or criminal penaltieswould be “absorbed by the business with a limited impacton the culture or the management,” an “enforceable under-taking” agreement may be in order. This would be a legal-ly binding agreement between the firm and the regulatorunder which the firm would agree to carry out specific activ-ities to rectify its non-compliance. The “undertakings plus”provision in the appendix would add a monetary penaltynegotiated between the regulator and the firm.

If the above provisions are adopted, the philosophyof “restorative justice” may come into play – aconcept similar to disgorgement in a US consentdecree.

The report explains this as a “holistic process that addressesthe repercussions and obligations created by harm with aview to putting things right.” The Macrory report suggests

that the approach would represent a shift in thinking versusthe current models of punishment and recommends usingpilot test cases in addressing regulatory compliance.

Regarding the proposed sanctions, Macrory stated that theuse of this toolkit will “also impose some burdens on regu-lators in order to ensure sanctions are used responsibly,safeguard the rights of the regulated communities andmaintain public confidence in the regulated system.”

In the introduction to its new enforcement strategy MHRAindicates it is “actively exploring options to consult on theproposed use of [the Appendix B] sanctions in more detail.”

Downloads from the story:

• MHRA Enforcement Strategy

• Macrory Report

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For subscription and sponsorship information visit IPQpubs.comor contact Rich Messmer — messmer@IPQpubs.com, Tel: 540-246-3923.

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IPQ MONTHLY UPDATE–AUGUST 2010

FDA has made available for comment the Step 2 drafts ofICH Q4B Annex 13 covering the bulk density and tappeddensity of powders and Annex 14 on bacterial endotoxintesting. The drafts were cleared for release by the ICHSteering Committee meeting in June.

Annex 13 recognizes the interchangeability in the bulk den-sity pharmacopeial chapters that have been developed forimplementation in the three ICH regions, subject to specificconditions noted in the annex for three of the methodsincluded in the chapters involving bulk density, tappeddensity and powder compressibility.

The effective dates of the compendial texts on bulk and tappeddensity that will be granted interchangeable status by Annex13 are: • July 2010 for the European Pharmacopeia (Ph. Eur.2.9.34) • October 2010 for USP’s General Chapter <616> and • March 2011 for the Japanese Pharmacopeia (JP 3.01).

The new JP text is provided in its English version as an appen-dix to the Annex 13 draft. The annex indicates that the intro-ductory paragraph in the JP version is not fully harmonized.

The Annex 14 Step 2 draft provides that the chapters on bac-terial endotoxin testing procedures contained in the threepharmacopeias are interchangeable subject to a restrictionon which assay must be used to make a final determinationin case of differing results among the approved methods.The draft also states that the pharmacopeial proceduresshould be calibrated to the WHO international standard forendotoxins.

The effective dates of the interchangeable pharmacopeialtexts on bacterial endotoxin testing are: • January 2010 forthe EP (Ph. Eur. 2.6.14) • October 2010 for USP’s GeneralChapter <85> and • March 2011 for the JP (4.01).

As with Annex 13, the English version of the new JP text isappended to Annex 14. The draft indicates that the full JPtext is harmonized.

Two other Q4B annexes – Annex 11 on capillaryelectrophoresis and Annex 12 on analytical sieving– reached Step 4 (ready for regional adoption) atICH’s Estonia meeting.

Q4B is the umbrella guideline covering the “Evaluation andRecommendation of Pharmacopeial Text for Use in the ICHRegions.” The clearance process for the annexes basicallyinvolves the Q4B EWG working through the PharmacopeialDiscussion Group (PDG) to assess the general method chap-ters in the regional pharmacopeias, outline issues that needconsideration and address them.

The respective Q4B annex is then developed, which recog-nizes the analytical procedures as interchangeable, subjectto the particular conditions outlined. The annexes also con-tain a section on “considerations for implementation” thataddresses the impact of the different regulatory mechanismsin the U.S., EU and Japan.

As such, the ICH process is helpful not only in reducing test-ing complexity and redundancy through general chapterharmonization and the allowance for interchangeability, butin clarifying how the testing requirements and their enforce-ment vary in the three regions.

In addition to the progress on the Q4B annexes,ICH also advanced its quality initiatives on heavymetals (Q3D) and drug substances (Q11) at itsJune meeting (see following story).

The decision to add Q3D to the Q3 impurities guidelineseries reflected the concerns of the regulatory communityregarding heavy metals and the desirability of a harmonizedapproach to the criteria and methodologies needed to con-trol them (IPQ Nov./Dec. 2008 Report, pp. 37-39).

Endorsed by the ICH Steering Committee at its meeting inSt. Louis in October 2009, the Q3D EWG met for the firsttime in Tallinn to begin work on the guideline. Q3D willprovide qualitative and quantitative limits on metal impuri-ties in drug products and ingredients.

[Editor’s Note: An analysis of the ongoing ICH quality ini-tiatives is included in the IPQ May 2010 Report.]

ICH Q4B Annex 13 on Powder Density and Annex 14 on BacterialEndotoxin Testing Out for Comment

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IPQ MONTHLY UPDATE–AUGUST 2010

AUGUST 2010 | 28

The structure and content of ICH Q11 on drug substancedevelopment and manufacturing is taking shape as theExpert Working Group (EWG) resolves the challenging issuesaround the guideline’s breadth and depth and its relationshipto the other guidelines in the ICH quality family.

Under the current structure emerging out of the EWG dis-cussions at its June meeting in Tallinn, Estonia, the guidelinewill contain sections on: • manufacturing process develop-ment • description of the manufacturing process • startingmaterials • control strategy • process validation/evaluation• process lifecycle management, and • location of informa-tion in the CTD.

Each of the sections includes discussion of the applicableprinciples, identification of molecule-specific information(small vs. large, etc.) that may be needed, and what informa-tion should be provided to the regulator in filings relevantto the section topic.

At DIA’s annual meeting in Washington, D.C. inmid-June, ICH Q11 rapporteur Brian Withers(Abbott U.K.) provided an update on the discus-sions at the Tallinn EWG meeting the weekbefore and the current status of the guideline’sstructure and content.

Withers stressed the general importance of Q11 “both frommaking some of the principles in Q8 real for biotech” and inextending them from development into manufacturing.

Q11 is intended to be a high-level guidance clarifying andharmonizing the regulatory expectations relevant to manu-facture as well as design and development. “That is impor-tant,” Withers commented, “because Q8 did not get into themanufacturing” of the drug product, whereas with Q11, “weare moving into that area. And that has its own set of issues.”

The scope of Q11 stretches across small and large moleculedrug substances as defined in Q6A and Q6B, which hasinvolved the EWG in identifying the similarities and differ-ences and how they should be addressed from a guidancepoint of view, the rapporteur explained.

In developing a structure for the guideline, the EWG decidedthat Q11 would reach beyond “just telling people what to sub-mit” under the M4Q/CTD format to addressing “enhancedand systematic approaches” and science-based concepts forprocess development, manufacturing and validation.

Filing on Non-critical Parameters Among Issues for EWG

In his presentation, Withers went through each of the desig-nated chapters of the evolving guideline, highlighting theissues that have generated the most discussion and how theEWG is proceeding to address them.

The discussion on manufacturing process devel-opment in the current draft closely reflects theprinciples and approaches outlined in Q8(R), withsome interpretation in the drug substance context,he said.

Some language has been included on development tools,quality risk management and prior knowledge. Platformmanufacturing is addressed in particular, reflecting its rela-tive importance in the biotech context.

The Q8(R) definition of critical quality attributes (CQAs)was considered broad enough to be easily applicable to drugsubstances and has been retained, and impurities are used toexemplify this application in view of their importance indrug substance development and manufacture.

The rapporteur reported that the current version contains adetailed section “relative to the rest of the guide” addressingthe submission of process development information. Itrequests a summary to be provided to give the regulator anoverview. The summary should list the CQAs that havebeen defined and brief descriptions of the stages of evolu-tion of the process and control strategy, a linkage to theidentification of material attributes and process parametersthat have an impact on the CQAs, and the development ofany design space.

Along with the listing of CQAs, the guideline will ask thatmore detail be provided on the rationale for identifying par-ticular attributes as critical. Regarding the manufacturingprocess history, the information of interest includes whatversions there were during development and how those linkto what went into clinical studies.

A subsection on manufacturing development studies in thedraft gives information about what to provide on riskassessments – “the basis for your experimentation, what youwere trying to achieve,” Withers explained. The associateddata should be presented “at a level that the regulator comesto the same conclusion that you did from the studies.”

ICH Q11 Guideline Structure and Content Taking Shape

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The section on the description of the manufactur-ing process is currently very short, Withers report-ed – basically cross-referencing M4Q on wherethe information goes in the CTD structure anddiscussing elements of the design space.

Generating EWG debate has been the issue of how to addressnon-critical parameters – an issue that drew considerableattention among participants at the Q8-10 implementationworkshop in Tallinn (IPQ Monthly Update July 2010, p. 36).

Pointing out that whether to file information on non-criticalparameters or put numerical ranges around them continuedto generate considerable discussion at a DIA session earlierin the day on biotech QbD, Withers noted that at one stagethe EWG had put a statement in the guideline saying thatthe range was all that was needed to be provided for criticalprocess parameters. However, the concept was not general-ly accepted by regulators and was removed.

“There is still a sense that somewhere the different parame-ters should be treated in a different way,” he said, addinghis view that “we have to think about ways of doing that inthe guidance.”

The elements that the guideline will defineregarding the control strategy represent the appli-cant’s commitment for controlling quality andinclude input material, attribute control, proce-dural control and the drug substance specificationitself.

The EWG has made the distinction between a traditional andQbD control strategy, the rapporteur said. “There is a discus-sion on what needs to be done if you wish to move controlsupstream in a process. It allows for a combination ofapproaches. So it recognizes that not all molecules will be con-trolled in the same way in all places or for all unit operations.”

In addressing manufacturing and validation, theQ11 EWG has affirmed that it would be mindfulof not creating redundancy to the ICH drug sub-stance GMP guideline Q7 (IPQ May 2010 Report,p. 5), and the discussion of validation in the drafthas been kept at a high level. It is only about apage and a half compared to FDA’s 25 page draftguideline on the subject, Withers pointed out.

The section is one where balancing the needs for small andlarge molecules comes into play, he explained.

“Small molecules don’t need to submit any validation apartfrom sterile products at the time of submission. Large mole-cules need to submit validation information at the time ofsubmission.” Also, “validation has a slightly different mean-ing in biotech in terms of what it includes. So there are ele-ments of, for example, column lifecycle, column cleaning…considered to be validation that are included within the sub-mission, where small molecule is very much focused ondemonstrating the ability to manufacture the product by theprocess.”

In terms of principles, Q11 will incorporate the Q7 definitionof validation as “documented evidence that the process canperform effectively,” and will recognize both the traditionalapproach and continuous process verification as defined inQ8. “We have tried to put some color on what that means fordrug substance,” Withers said.

Some biotech-specific validation issues are addressed in theemerging draft. These include laboratory studies to supportthe validation of column lifecycles and emphasis on theremoval of impurities and reference to viral clearance stud-ies. Also addressed is the use of platform or prior knowl-edge vs. the product-specific validation information needed.

In the biotech context, the issue of pooling and splittingcomes into play, Withers noted. “Actually it becomes verydifficult to understand what a batch is from a validationpoint of view, so there is some clarity there.”

The Q11 rapporteur described the section onproduct lifecycle management as “a work inprogress. We are not quite sure what to includeon this.”

Monitoring of process performance and its link to the ele-ments in Q10 is among the issues being considered – also theinternal evaluation of post-approval changes.

Pointing out that “there are different regulatory processesavailable in the different regions that can help and hinderthis section,” Withers commented that “there is still a gooddeal of work to do in this section before we have a consen-sus view.”

In addressing the last section on the location ofinformation, the EWG has focused on the submis-sion of items not specifically covered by the exist-ing M4Q guideline.

IPQ MONTHLY UPDATE–AUGUST 2010

The ICH Q11 Expert Working Group (EWG) has beenwrestling with balancing regulatory transparency withindustry flexibility in defining the starting material as itmoves forward in drafting the guideline on drug substancedevelopment and manufacturing.

Reporting on the discussions that took place theprevious week at the EWG’s meeting in Tallinn,Estonia (see previous story), Q11 rapporteur BrianWithers (Abbott, U.K.) pointed out at DIA’sAnnual Meeting in Washington, D.C. in mid-Junethat the starting material guidance was among thechallenges drawing his group’s attention.

With the application of the Q7 drug substance GMPs atissue, Withers explained, the later the starting material isdesignated in the process, “the more flexibility there is forindustry [but] the less visibility there is to the regulator,either in a submission or via review of the quality system. Sothe challenge for the expert working group has been how toget that balance between transparency and flexibility interms of the two approaches.”

Industry has also had to think about this balance in terms ofhow much value to place on predictability. If industry want-ed predictability, the guidance could have been written eas-ily to delineate the starting material as a specific number ofsteps, say five or six, from the last step in the synthesis,Withers stressed.

“That would have been, I think, acceptable to all the agen-cies, and it would have given predictability to industry. Butit wouldn’t necessarily give the flexibility for industry topropose alternatives when it is linked to the overall controlstrategy for the drug substance. That has proved difficult –again, how to build in a risk-based approach to the designa-tion of the starting material.”

EWG Addresses Starting Material Risksand Justification

The current draft’s discussion of starting materials includesa set of principles that relates risk and distance from the endof manufacturing.

“The further away you are from the end, the more chance”to address impurities, for example, in the intervening steps,Withers explained. In turn, physical properties only general-ly become significant for a small molecule toward the endstages.

A new concept is being applied here by the EWG, the rap-porteur commented: “What we are saying is regulatorsassess the suitability of the starting material and the adequa-cy of the control over the starting material. What is incum-bent on industry to do then is to provide sufficient descrip-tion to the regulator so that they can understand the impu-rity formation and clearance within a particular molecule.”

Regulatory Transparency vs. Industry Flexibility at Issue for StartingMaterials in ICH Q11

WWW.IPQPUBS.COM

IPQ MONTHLY UPDATE–AUGUST 2010

AUGUST 2010 | 30

The EWG’s current thinking is to place:

• for CQAs – the list and rationale in S.2.6• for design space – the description in S.2.2, the supporting

studies in S.2.6, and the relationship to the overall controlstrategy in the S.4.5 as per Q8(R)

• and for the control strategy – the summary in S.4.5, therelated details in S.2.2, 2.3 and 2.4, and the evolution ofthe strategy during development in S.2.6.

In reviewing the progress of the EWG on Q11,Withers stressed the importance of industry’sinvolvement during the current stage in theguideline’s development process.

He urged the industry DIA meeting participants to take theopportunity to provide input “early and often” on Q11 andother guidelines before a Step 2 draft is settled on. “Once theexpert working groups have made their mind up, it is goingto be very difficult to change that at a later stage. And so theguideline is better if you comment earlier.”

The EWG rapporteur projects that the Q11 guideline will notreach Step 2 until sometime after the November ICH meet-ing in Japan.

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AUGUST 2010 | 31

IPQ MONTHLY UPDATE–AUGUST 2010

In line with Q7, the EWG defines a starting material as a sig-nificant structural element or one that can be isolated as anintermediate. Q7 states that its GMP guidance does notapply to steps prior to the introduction of the defined “APIstarting material.”

In the biotech context, the starting material is clearly the cellbank. Since there are other ICH guidances that deal with thecontrol of cell banks, Q11 does not need to focus on theissue, Whithers indicated. For semisynthetic materials, thecell line could be defined as the starting material, but flexi-bility will be allowed where they are well defined, he said.

In terms of the justification, the approach beingconsidered is that the applicant will need to sayhow the material proposed as the starting materi-al complies with the general principles that theguideline has laid out.

“This can include a discussion on the specifications, thecapability of the analytical methods, the fate of impurities,and I guess most important, the link to the overall controlstrategy,” Withers said. “How does this control and thisdesignation of this starting material link to the assurancethat the drug substance will be of appropriate quality?”

Allowance will be provided for commercially availablematerial. “Material that has a non-pharmaceutical market

and is commercially available can be designated as a start-ing material without justification,” Withers explained.However, he clarified, this “does not mean that you do nothave to justify the specification associated with that materi-al. It is just that you can say, ‘I can designate that as a start-ing material.’”

The application to materials that are commercially availableand have a wide pharmaceutical use in more than one mol-ecule has raised industry questions, the Q11 rapporteurnoted. “That has been a difficult item to deal with,” he said,“because how do you separate that from custom synthesis,which is not part of the process of designation of startingmaterials? I think there is still some debate to be had there.”

While debating the issues involved, the EWG hasalso wrestled with where to include the discus-sion of starting materials in the guideline.

Noting that the initial placement was in the control strategyand then it was moved into the description of the manufac-turing process, Withers commented that “it seemed to get inthe way of the guideline wherever we put it.”

While a “very important section” for small molecules, “largemolecule people have absolutely no interest in this whatso-ever.” The decision, accordingly, he explained, was to havea separate chapter dedicated to the issue.

Potential GMP concerns among India’s expanding numberof API suppliers include equipment handling, CAPA, docu-mentation and training, Semler Research CenterCOO/Director Gurudatta Gayatri reported at the DIAAnnual Meeting in June.

Gayatri highlighted the rapid growth of the Indian APIindustry as a supplier to the US and Europe, the areas of rel-ative weaknesses he has seen among the Indian API manu-facturers he has audited on the part of interested US and EUcompanies, and the initiatives underway in India to central-ize and strengthen its regulatory oversight.

During the numerous audits Gayatri has conduct-ed of Indian API facilities, the most commonGMP weaknesses he has seen are in the areas of:• cleaning validation • qualification of equip-ment • documentation • analytical method trans-fer • CAPA, and • training of temporary staff.

There is a lack of general understanding regarding cleaning val-idation in “many companies,” he said. Firms may focus only onvalidating cleaning for the product being manufactured andmiss the requirement to validate the removal of a different APImanufactured beforehand on the same equipment.

Potential GMP Trouble Spots at India’s API Firms Include EquipmentHandling, CAPA, Documentation, and Training, India Auditing Expert Finds

WWW.IPQPUBS.COM

IPQ MONTHLY UPDATE–AUGUST 2010

AUGUST 2010 | 32

Gayatri explained that the concept and practice of requalifi-cation of equipment may also be poorly understood.“People have been using equipment for five years or tenyears [and] there is no checking on the wear and tear of theequipment,” although periodic requalification is expected.The ISO standard 14644.3 has only been recently recognizedas important guidance in the qualification of air handlingunits, he said.

Gayatri further finds that quality management system doc-umentation is frequently lacking, specifically for changecontrols and deviations. In particular, there is often not agood justification section with adequate science contained inboth types of documents.

Analytical method transfer is of particular concern in thelaboratories. Methods are generally developed in corporatelabs and how well they will transfer to the manufacturinglabs “is not considered,” Gayatri commented.

His experience over many audits also shows that the needfor corrective and preventive actions (CAPAs) is not well-understood and that many times they are not conductedwhen they should be.

The last common deficiency that the Semler Research Centerofficial highlighted was training of temporary staff membersworking in API facilities.

In general, the number of temporary staff members outnum-bers the number of permanent staff, and their training shouldbe equivalent but generally is not. “Whereas the trainingrecords for all the permanent staff will be fantastic, there isabsolutely a lack of training of temporary staff,” he said.

Although FDA has issued relatively few warningletters to firms in India, a pair of letters issued toRanbaxy in 2008 indicate that the agency is spot-ting the same problem areas identified by Gayatri.

FDA concerns addressed at Ranbaxy included: • CAPA(inadequate failure investigations) • cleaning validation(inaccurate records of cleaning equipment and use) • docu-mentation (incomplete batch production and control records),and • qualification of air handling units (inadequate beta-lac-tam containment program) (IPQ May/June 2009 Report)

Downloads from the story:

• Ranbaxy Dewas 2008 Warning Letter

• Ranbaxy Poanta Sahib 2008 Warning Letter

India is working to strengthen its central drug regulatoryauthority and related laws and regulations in response to itsrapidly expanding domestic industry and the need for moreinteraction with foreign regulatory counterparts.

The growth of the Indian drug industry and the regulatoryresponse underway was highlighted by Semler ResearchCenter (SRC) Director Gurudatta Gayatri at DIA’s AnnualMeeting in June.

The Indian government and its DirectorateGeneral of Health Services’ Central DrugsStandard Control Organization (CDSCO), has rec-ognized the need for more stringent regulatoryoversight of drug manufacturing in India and hasbeen implementing a plan to improve the relatedlaws and regulations, the SRC official commented.

The current CDSCO plan, which covers the five year periodfrom 2008 – 2012, Gayatri explains, includes initiatives in tenareas: • a common technical format following the ICH CTDmodel • clinical trials • medical devices • pharmacovigi-lance • interaction with national and international regulato-ry bodies • overseas inspector training • inspections byCDSCO of foreign firms • transparency and accountability• electronic submissions and records, and • creation of anFDA-like “Central Drugs Authority" (CDA).

Gayatri noted that a more autonomous CDA with a mandateto upgrade the national regulatory system would provide anunderpinning for the other initiatives and is the focus of a billnow under consideration in the Indian parliament.

The bill proposes that CDA would be an autonomous organ-ization under the Ministry of Health and Family Welfare. Its

India Strengthening its Central Regulatory Authority to Keep Pace withIndustry Expansion

INSIDE THE GLOBAL REGULATORY DIALOGUETM

AUGUST 2010 | 33

mission would be to provide technical vision and policydirection, and it would phase in more centralized regulationof drug manufacturers over time. The bill calls for separateCDA divisions for the regulation of drugs, medical devices,and clinical trials.

At this time, drug regulatory responsibilities aredivided between the central government andIndia’s 35 states.

Among other scientific and administrative functions,CDSCO promulgates regulations, regulates clinicalresearch, approves licenses to manufacture certain types ofdrugs (blood banks, large volume parenterals, vaccines andsera), regulates market authorizations of new drugs andstandards for imported drugs, and performs testing in itslaboratories.]

The Indian states, on the other hand, license most drug man-ufacturing facilities and testing labs, approve drug formula-tions, conduct pre- and post-licensing inspections, and con-duct drug recalls.

Whether or in what way these responsibilities will changewill depend on the final version that is passed of the legisla-tion now being considered.

In framing the changes to the regulatory structure,Gayatri provided some current statistics that dram-atize India’s growth as a global API supplier.

India, he pointed out:

• now accounts for 8% of global pharmaceutical produc-tion, double what it was five years ago

• manufactures over 400 different APIs• was second only to the US in ANDA approvals, with 132

vs. 169 from the US• filed more US drug master files (DMFs) from 2001 to 2007

(1270) than the US (698) or China (359)• filed over 300 DMFs in 2007 compared to just 50 in 2002,

and• was second only to the US in numbers of certificates of

suitability filed in Europe between 1998 - 2007, with 312compared to 326 filed from the US.

Based on his extensive experience in auditing API manufac-turers in India, Gayatri also discussed some of the areas ofpotential GMP weakness in the Indian industry, which takeon more importance as that country increases its presence inthe global API market (see previous story).

IPQ MONTHLY UPDATE–AUGUST 2010

The EMA is continuing to seek drug manufacturers willingto participate in its joint inspection program with FDA forfinished products. In an August 11 announcement, EMAexplained that companies that have submitted two equiva-lent applications for the same product to both EMA andFDA can request to participate in the pilot.

The two agencies are conducting joint inspections to helpboth agency and industry participants save resources andavoid duplication of effort and to determine if the collabora-tion will help to more effectively deploy inspection resourcesand allow more manufacturing sites to be inspected. EMA istaking the lead in coordinating the joint inspections.

The request for participants is the latest development in thepilot, begun two years ago as one outcome of the

Transatlantic Administrative Simplification (TAS) initiative,which involved US and EU regulators and industry (IPQNov./Dec. 2008 Report).

During 2009, two joint inspections of manufacturing sites inthe EU were completed “successfully” and an “observedinspection” was carried out in the US, according to a TASreport in early 2010. The experience from these inspections“has resulted in some agreed opportunities for improve-ment which will be developed as part of the ongoing collab-orative activities,” TAS stated.

Along with joint inspections, the TAS report provided anupdate on the variety of other healthcare product regulato-ry areas targeted by the initiative for further collaborationand harmonization between the US and Europe. The TAS

FDA/EMA Joint Inspection Program for Finished Products SeekingApplicants

initiative addresses procedures, guidance, and scientificinformation sharing in areas ranging from counterfeit med-icines to biomarker development and critical path/innova-tive products.

Attached to the EMA August invitation for jointpilot participants were two related documents: •one containing advice to applicants, and • the sec-ond outlining a set of common principles.

The first document contains advice and instructions forpotential applicants and a form for applicants to use torequest a joint inspection. It states that although the pilotcovers primarily pre-approval inspections, joint routine sur-veillance inspections may also be conducted if both FDAand EMA have indicated they intend to inspect the sameproduct in a similar time-frame.

Joint inspections are voluntary and “usually occur at therequest of the applicant” but may also be initiated by theEMA or FDA. A request for a joint inspection is “no guar-antee that a joint inspection will be performed,” the EMAclarifies.

The second document outlines the principles and proce-dures the agencies will use in the inspections. Key points

include: • the need for a “contact point” for communicationwith the firm to be inspected • how communications withthe contact point and the agencies take place • how the leadinspection authority will be selected • duties of the leadinspector • how inspection findings will be communicated• the requirement for each authority to issue a separateinspection findings report in English, and • that eachinspectorate is responsible for any follow-up actions withintheir jurisdiction.

A flow chart of the inspection coordination, conduct, andfollow-up activities is included, with references back to spe-cific sections of the document.

The EU and the US are also participating along withAustralia in a broader joint inspection program focused onactive pharmaceutical ingredients that is also advancing (seefollowing story).

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Downloads from the story:

• EMA/FDA announcement

• Advice and instructions for applicants

• Joint inspection common principles

• TAS announcement January 2010

The international API pilot joint inspection program involv-ing regulatory authorities in the EU, US, and Australia isresulting in rapid sharing of inspection reports for non-com-pliant sites, follow-up inspections at other facilities ownedby the companies found to have non-compliant sites, andprompt notification of regulatory actions taken.

European Medicines Agency (EMA) Scientific AdministratorOliver Gross told the DIA Annual Meeting in June that thepilot program – now extended an additional six months to theend of 2010 – has been successful and has allowed “real collab-oration” between the participating agencies.

The EMA official cited a joint inspection of a facility in Indiaconducted by the European Directorate for the Quality ofMedicines (EDQM) and Australia’s Therapeutic GoodsAdministration (TGA) as an example of this collaborationprocess at work.

The Indian facility was found to be non-compliant. Becausethe EDQM is not a national regulatory authority, it could notissue a “non-compliance statement,” so it was issued by TGA,which has a mutual recognition agreement (MRA) with EMA.TGA then sent a copy of the report to all EU member states.

“Because one site was non-compliant, we had suspicionsthat another site may be non-compliant also,” Gross com-mented. In fact, the other site was inspected and found to bemore seriously non-compliant than the first one. Thisinspection resulted in product recalls, and the inspectionreport was shared with all of the pilot participants.

In another case, a Japanese site was inspected by the Italianauthority and found to be non-compliant. In addition, TGAfound issues with a CAPA the firm had submitted. Theresult was a joint inspection by EMA Italian inspectors andTGA in June.

International Joint API Inspection Pilot Program Sees Positive Results

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IPQ MONTHLY UPDATE–AUGUST 2010

The joint API inspection pilot was initiated inresponse to several factors: • increased demandfor international collaboration on inspections aspart of the Transatlantic Administrative Simpli-fication Action Plan (2006-7) • the heparin con-tamination situation in 2008 • concerns with glob-alization of the API supply chain, and • the lackof guidance equivalent to Q7 outside the ICHregions (IPQ Nov/Dec. 2008 Report).

The primary objectives of the program were to improve theefficiency of API inspections and the use of agency resourcesthrough collaborative inspection planning and conduct.

Data from 2005 to 2008 showed many duplicate inspectionswere being performed. Out of 85 inspections examined, 46of them were performed at the same site by two differentauthorities within 12 months, and eight of these were con-ducted during the same month.

Participants in the pilot include: the TGA; the EMA, as wellas member states France, Germany, Ireland, Italy, and theUnited Kingdom; the EDQM (targeting EuropeanPharmacopoeia specifications); and the FDA.

The key performance indicators chosen at the start of thepilot, Gross explained, were to:

• “increase the transparency and the visibility of participa-tion in inspection planning – so we are changing planningand knowing who is inspecting where

• decrease duplicate inspections, when one, two or sometimes three inspectorates from different regions inspectthe same manufacturer within months or within sixmonths…

• increase the number of inspections applied to more thanone authority, and

• have a positive assessment of the deliverables – so wewanted people participating in this pilot to be happy at theend of the pilot.”

Beginning in July 2008 through June 2010 about fifteen tele-conferences were held during which initial planning andlater information sharing took place. In the earlier sessions,the participants agreed that all would continue to plan andperform inspections outside the pilot. In the context of thepilot, Q7 was the agreed-upon standard.

The plan was to “more or less agree on common conclusionsafter the joint inspection whenever possible,” Grossexplained. Each authority would be involved with follow-

up actions in cases of non-compliance, with possible jointfollow-up actions. In addition, a confidentiality agreementwas signed between the participating authorities to allowsharing of inspection information.

To aid in planning and sharing of information, aspreadsheet referred to as the “master list” wascreated containing a table of sites to be inspectedand site actions.

“We have two parts in this master list where we have a tableof sites [providing] the most possible information on eachsite, and then we have a table of actions which summarizesactions we can do together on the different sites” – for exam-ple, exchange of inspection reports or charting the inspec-tions, the EMA official noted.

The master list includes information on approximately 1000sites – 192 from TGA, 315 from FDA, and 483 from EMA.Removing the duplicate sites provided by more than oneagency, a total of 636 different sites resulted. From these, itwas determined that 89 sites were shared by all threeregions – the sites for which joint inspections by all threeregions could be considered.

46 of these shared sites are in India, and fifteen are in China.These 61 sites supply APIs to all three regions and will beprimary considerations as joint inspection targets.

In addition to planning and conducting jointinspections, the participants share reports of inspec-tions conducted by the individual inspectorates.

So far, Europe has requested 36 inspection reports from theother regions, FDA 22 and TGA 14.

As of June 2010, six joint inspections have been conductedunder this program and four more are planned before theend of the year. For these inspections, each inspectorateproduced its own inspection report using its own format butcontaining similar content.

“When we do a joint inspection, we usually askthe inspectors to give us some feedback becausewe are interested to know how this joint inspec-tion between the regulatory authorities is going –where they are having problems, what we canimprove,” Gross explained.

The feedback has been that: • early communication andagreement of the team composition, scope and duration of the

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inspection is important • inspectors having one day beforethe inspection for preparation facilitates better inspections •inspectors are able to work well together and there have beenno major problems, and • there have been no major differ-ences in interpretation of the GMP standards notes.

Gross pointed out that there has been especially good feed-back from Europe and TGA “because the way they conductinspections is more similar.”

The EMA administrator commented that there remainsroom for improvement in the joint inspection system,

“because even after our collaboration we observed that westill do duplicate inspections and the system does not knowthat they are being done.” He predicted that “it is going bet-ter and better because the planning and exchange of plan-ning [information] has improved.”

Gross pointed out that participants are “sending the updatesmore regularly so we can really share up-to-date informa-tion.” In the future, the group plans to share a web-baseddatabase for inspection planning, perhaps similar to theEudraGMP inspection module.

WHO is expanding its guidance library to focus specificallyon GMP expectations for microbiology labs and is adjustingits existing guidelines on drafting site master files, on waterused in pharmaceutical manufacturing and on and heating,ventilation, and air-conditioning (HVAC) systems

Comments on the draft documents are due toWHO by September 1 for the site master file andwater guides, by September 9 for the HVACguideline, and by October 1 for the microbiologylab document.

The new draft guideline on microbiology lab GMPs grewout of inspector experience with the 2009 revision of WHO’s“Good Practices for Pharmaceutical Quality ControlLaboratories.”

WHO inspectors found that the QC labs they were prequal-ifying “might benefit from additional guidance, with a spe-cial focus on microbiology,” the background section of thenew document explains. Their suggestions were reviewedby the WHO Expert Committee on Specifications forPharmaceutical Preparations resulting in development ofthe micro guide.

The 27-page draft guideline contains 12 sections describingmicro lab good practices regarding: • personnel • environ-ment • validation of test methods • equipment • reagentsand culture media • reference materials and reference

cultures • sampling • sample handling and identification• disposal of contaminated waste • quality assurance ofresults/quality control of performance • testing proce-dures, and • test reports.

Also included are five appendices covering the general use ofreference cultures and examples of lab operations, includingcalibration, qualification, and maintenance of equipment.

Along with the pharmaceutical QC lab good practices, otherWHO documents applicable to microbiology labs, the newguide notes, include:

• general guidelines for the establishment, maintenanceand distribution of chemical reference substances

• the International Pharmacopoeia and first supplement(fourth edition), and

• general requirements for the competence of testing andcalibration laboratories.

In the case of its site master file (SMF) guideline,WHO is asking for public comment on how theguideline should be revised in view of a reviseddraft from the Pharmaceutical InspectionCooperation Scheme (PIC/S) and EMA of theirSMF guidance.

In November of last year in Uppsala, Sweden, the PIC/SCommittee agreed to launch a public consultation involving

WHO Proposes New Guideline for Microbiology Labs and Adjustments toSite Master File, Water and HVAC Guides

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IPQ MONTHLY UPDATE–AUGUST 2010

national and international industry and professional associ-ations on a revised draft developed in coordination withEMA of “Explanatory Notes for Industry on the Preparationof a Site Master File.”

In March, the EU Commission (EC) ended its three-month pub-lic consultation on the document, which it recommended beadded to the proposed Part III of the GMP guide. The ECexplains that Part III under the EC proposal will have “docu-ments which are not themselves GMP guidelines and have nostatutory force but which complement the GMP guidelines andrelated regulatory procedures such as, in this case, inspections.”

A final harmonized guide is expected in the near future.PIC/S has indicated that they will incorporate the EC ver-sion of the SMF guide when it is finalized with the exceptionof references to qualified persons, which are not applicableto all PIC/S countries.

The proposed redraft of the WHO guideline on“Water for Pharmaceutical Use,” also out for com-ment, is its first revision in five years and takesinto account discussions at WHO’s meeting inGeneva in May.

The changes being proposed are clearly marked in the draft.Many of the changes are editorial in nature -- for example,changing “EMEA” to “EMA,” “potable drinking water” to“drinking water” and removal of “purification” from thetitle of a section that does not discuss purification methods.

Some changes to the document reflect the new quality-by-design vernacular. For example, a sentence that originallyread, “deadlegs in the pipework installation greater than 1.5

times the branch diameter should be avoided,” was changedto read, “deadlegs in the pipework should be avoidedthrough appropriate design, and where unavoidable shouldbe no greater than 1.5 times the branch diameter.”

Other changes include recommendations on water systemcapacities, deletion of distillation as the preferred methodfor producing water for injection, and a new statementregarding water systems that “any trends frequentlyexceeding action limits should precipitate a review of thequalification status of the system.”

The draft revision of WHO’s “Good Practices forHeating, Ventilation, and Air-Conditioning(HVAC) Systems for Non-Sterile PharmaceuticalDosage Forms” contains minor revisions on twopages of the 54-page document.

Like the water draft, the HVAC revision highlights changesmade to the draft. Minor changes are proposed to align thedocument with ISPE’s Oral Solid Dosage Guideline regard-ing definitions of levels of protection, cleanroom categoriesand types of air filtration recommended by area.

Downloads from the story:

WHO Guidelines:

• Pharmaceutical Microbiology Labs

• Drafting Site Master Files

• Water for Pharmaceutical Use

• HVAC

EMA Guide:

• Revised Site Master File Draft

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