nda & anda approval

12

Obtaining Approval of New DrugApplications and AbbreviatedNew Drug Applications froma Chemistry, Manufacturing,

and Controls Perspective

DHIREN N. SHAH

Aventis Pharmaceuticals

Kansas City, Missouri, U.S.A.

1. INTRODUCTION

Chemistry, Manufacturing, and Controls (CMC) is a relativelysmall section (approximately 15–20%) of a typical New DrugApplication (NDA), but it often becomes a reason for delay inthe approval of NDA/Biologics Licensing Applications (BLAs).For Abbreviated New Drug Applications (ANDAs), however,

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Copyright © 2005 by Marcel Dekker

the CMC section is significant (around 80–90%). This sectionalso becomes quite important in the postapproval life-cyclemanagement of the products. It should be noted that theCMC section is made up of three distinctly different but over-lapping disciplines/sciences: synthetic/fermentation chemistry,analytical chemistry, and formulation chemistry. Also, the CMCsection continuously changes with clinical phases. Typicallyduring clinical phase 1 trials, the CMC section is quite smalland contains laboratory-scale manufacturing experience forthe drug substance and the drug products with quite simpleanalytical methodologies. During clinical phase 2 trials, theCMC section evolves to pilot-scale manufacturing of the drugsubstance and the drug products, and the specifications andanalytical methodologies become more sophisticated. End ofphase 2 (EOP2) usually becomes a pivotal point in the drugdevelopment since at this point decisions and major commit-ments are made to as to whether to go forward with the phase 3clinical development and marketing authorization applica-tion (NDA/BLA). EOP2 means for the CMC section a majorshift in planning and execution. The drug substance anddrug product manufacture typically need to be moved to com-mercial site at a commercial scale, and the specifications andthe analytical methodologies need to be upgraded and finalized.So, one can see that the CMC section is a ‘‘moving target.’’After the completion of clinical phase 3 studies, an NDA/BLA issubmitted to the U.S. Food and Drug Administration (FDA) forreview and approval. The CMC section of an NDA/BLA shouldcontain all the relevant developmental information that bridgesphase 1 through 3 leading up to the NDA/BLA submission.

This chapter will systematically analyze and describe theFDA organization, its various regulations and guidances,the industry process by which CMC information is generatedand submitted, and various ways to compress timelines andsecure timely approvals of NDA/BLAs and ANDAs. As thischapter is being written, it is expected that the CMC reviewand approval process for new chemical entities and possiblybiotechnologically produced drugs and generic drugs at theFDA may undergo a paradigm change. However, the basicprinciples behind obtaining approval of NDAs/BLAs/ANDAs

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in a timely manner remain the same. It is anticipated thatICH Q8 (Development Pharmaceutics) and ICH Q9 (RiskAssessments) will reflect the paradigm shift at the agency.

2. CURRENT U.S. FDA ORGANIZATION

The U.S. Food and Drug Administration is one of the mostimportant customers for pharmaceutical companies. In orderto understand the review and approval process for the CMCsection of NDAs and ANDAs, one should be familiar with theregulatory authority and the process in the United States.The U.S. FDA is an agency within the Department of Healthand Human Services, and it regulates biologics, drugs, food,devices, and veterinary products. It is made up of eight cen-ters/offices. The biologics such as vaccines and blood productsare regulated by the Center for Biologics Evaluation andResearch (CBER). The Center for Drug Evaluation andResearch (CDER), which is the largest of the five centers inthe FDA, regulates drugs that include NDAs and ANDAs. Thedevices are regulated by the Center for Device and RadiologicalHealth (CDRH). Animal products are regulated by the Centerfor Veterinary Medicines (CVM). The Center for Food Safetyand Applied Nutrition (CFSAN) regulates foods and nutritionalproducts. The National Center for Toxicological Research(NCTR) regulates all types of toxicological research. The Officeof the Commissioner (OC) and the Office of Regulatory Affairs(ORA) provide administrative and management support.

The CDER organization consists of therapeutic area–based review divisions. Each review division has the primaryresponsibility of reviewing submissions and provides an actionthat could involve approval, approvable, nonapproval, requestfor more information, etc. The review divisions are staffedby the division director, medical reviewers, pharmacologists,chemists, bio-statisticians, bio-pharm reviewers, project man-ager staff, etc. The chemistry and bio-pharm reviewers reportto the Office of Pharmaceutical Sciences (OPS). The Office ofGeneric Drugs (OGD) also reports to OPS. The OGD has two

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divisions of chemistry, each made up of five teams. This divisionof OGD is based on major therapeutic classes. As this chapter isbeing written, by the middle of 2005 the chemists from reviewdivisions will be combined into one new drug chemistry groupunder the Office of New Drug Chemistry. The objective behindthis change is consistency in reviews and better time manage-ment. This step is a predecessor to other CMC review andapproval practices changes being planned at the agency.

Various regulations as published in the 21 Code of FederalRegulations (CFR), guidances and points to consider (PTC)published by FDA, the Manual of Practices and Procedures(MaPP) published by FDA, and guidelines published by theInternational Committee on Harmonization (ICH) are impor-tant documents that become the foundation of scientificallyand regulatorily sound CMC submission documents.

3. FDA AND ICH CMC/QUALITYREGULATIONS AND GUIDANCES

FDA regulates new drugs as well as generic drugs under theFederal Food, Drug, and Cosmetic Act enacted by the U.S.Congress. The law, among other things, ensures that drugsand devices are safe and effective for their intended uses andall labeling used is truthful, accurate, informative, and notdeceptive. Chapter five and specifically subchapter A of the Actprovides for Drugs and Devices. The interpretation of the Actis provided in the Code of Federal Regulations (CFR), which ispublished annually. There are 50 titles/sections in CFR, andtitle 21 specifically provides interpretation of the Federal Food,Drug, and Cosmetic Act. Typically the regulations are brief andoften difficult to fully interpret for actual implementation. FDAissues guidances and PTCs, which provide further interpreta-tion of the regulations. FDA also publishes MaPPs, whichare approved detailed instructions to FDA reviewers in orderto standardize reviews of submissions.

The reader is encouraged to make use of all FDA guid-ances and manuals. If properly used, they will ensure the

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quality of CMC submission, which should result in approvalby FDA.

4. FDA’S QUALITY BY DESIGN (QbD) ANDPAT INITIATIVE AS PART OF CENTURYGOOD MANUFACTURING PRACTICES

FDA, in its latest initiative for the Twenty-First Century GoodManufacturing Practices has, among other things, two initia-tives named Quality-by-Design (QbD) and Process AnalyticalTechnologies (PAT). PAT should not be considered as ‘‘infinitetesting,’’ but it is a part of the QbD. Both of these initiativesgo to the basics of product development, whether it is for a newdrug or a generic product. By employing basic principles ofscience-based drug substance and drug product development,one can achieve QbD. The whole idea behind QbD and PAT isto build quality into the drug product from the very beginningof the manufacturing process so that testing for quality at theend may not be that critical. For example, a thorough physical,chemical, and biological (as necessary) understanding of all thecomponents of the dosage form and a complete analysis andknowledge of all the critical manufacturing processes shouldresult in a product in which the quality is built in and theremay be limited need for final testing for quality. Properly selec-ted in-process testing and controls should provide the basis forQbD. Process analytical technologies embrace the principlesof QbD and include at-line, on-line, off-line, and in-line testingof in-process materials at critical stages of manufacturing. PATprovides for continuous manufacturing and real-time releaseof the product and the possibility of replacing the conventionalvalidation batches. The reader is encouraged to read and followFDA’s draft guidance on PAT. One of the ways to success-fully obtain approval of NDAs is to ‘‘retro-engineer’’ the drugsubstance and drug product. Once the sponsor identifiesthe final characteristics of the drug product to be marketed(dose, dosage type, shape, color, marking, packaging, etc.),a development and regulatory plan should be generated that



will determine what kind of CMC information needs to begenerated—and when—to secure an approval by the agency.Figure 1 summarizes the QbD and PAT intiatives. Aspects ofQbD and PAT will be discussed later in this chapter.

5. SPONSOR COMPANY AND AGENCYPROCESSES TO SUCCESSFULLY DEVELOPTHE CMC SECTION OF NDAs ANDANDAs BASED ON QbD AND ICH/FDAREGULATIONS

The activities at the sponsor company in regards to CMC devel-opment from pre-IND through various phases of INDs leadingup to the NDA and, in the case of generic drugs, the processleading up to ANDA determine one’s success or failure. Theproduct one delivers to FDA is the CMC submission, andits scientific quality determines its successful approval by theagency.

Figure 1 Quality-by-Design and Process Analytical Technologiesinitiatives.

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5.1. Pre-IND Phase

In this very early phase of drug development some basic workis performed. Preliminary solubility in various solvents, stabil-ity, and other important structural elucidations and charac-terizations are typically determined, which become the basisfor future development of the new molecular entity. Of course,limited work is done at this stage, since the failure rate for newmolecular entities (NMEs) is quite high. The CMC informationfrom this stage typically becomes the basis for developmentpharmaceutics, and as the drug development progresses,additional tests and information are carried out.

5.2. IND Phase 1

This phase is still an early phase of product development anda limited and necessary effort is typically made. Since CMC isa multi-functional section, it will be highly beneficial to puttogether multi-functional teams consisting of scientists fromdrug substance synthesis, formulation, analytical, regulatory,writing group, etc. This team of people becomes responsibleand accountable for putting together the CMC section of theIND and following the new drug’s progress through phases 2and 3 and making sure an NDA is filed on a quality submission.In some instances, a sponsor may want to request a pre-IND meeting, which could be in the form of a teleconference,with the agency to seek advice and/or clarification. The agencyrequires that a briefing document be submitted by the spon-sor at least 4–6 weeks prior to the meeting. The briefingdocument should contain relevant information on the drugsubstance and drug product and concise questions about whichthe sponsor seeks advice from the agency. FDA requires limitedCMC information in a phase 1 IND. The main emphasis is onthe safety of the volunteers and patients, and hence the spon-sor is required to make a connection between preclinical mate-rial and the proposed clinical material from impurity andbioavailability points of view. (It is conceivable that the mate-rial used in the preclinical safety studies was not as bioavail-able as the clinical material posing a safety risk to thepatients.) Also, if the clinical material has any impurity with



safety implications, the agency will want to know more aboutit. At the time of submitting an original IND, very limited stabil-ity information is required. A commitment to generate con-current stability data during the course of a clinical trial andreporting the data in most cases should suffice. It is the spon-sor’s responsibility to make sure that the NME is stable in thedosage form when given to patients. During this early phaseof clinical development, the analytical methods should be capa-ble of determining the assay, impurities, etc., with specifi-city, accuracy, and precision. A formal validation of methodstypically is not required at this early stage of development.Of course, as the drug development progresses, the analyticalmethods should be progressively validated so that they ensurestrength, identity, purity, potency, and quality (SIPPQ) of theproduct. The sponsor must wait for a period of 30 days beforeinitiating studies on human volunteers and patients. Duringthis period the agency determines whether the sponsor couldproceed with proposed studies, and if it has any objection it willinstruct the sponsor not to initiate the study (known as clinicalhold) until the deficiencies are satisfactorily addressed. Theagency has issued a guidance as to the format and the contentof the CMC section of IND, and the reader is encouraged toread and apply it to fullest extent as possible.

5.3. IND Phases 2 and 3

IND phases 2 and 3 are pivotal and become the basis forsuccessfully obtaining approval of NDAs, because under thesephases critical CMC information that supports SIPPQ is gen-erated, drug substance and drug product manufacturing areoptimized, bioavailability of the drug product is established,and primary stability data for the drug substance and the drugproduct are generated. The multifunctional team plays a criti-cal role in advancing the NME through phases 2 and 3 leadingup to NDA submission. Based on input from the clinical stud-ies through phase 2, the safe and effective dose of the drug ischosen and various QbD parameters for the drug substanceand drug product are introduced in the product development.The agency requires that during phases 2 and 3 the sponsor

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inform the agency of any new patient safety–related informa-tion in the form of IND amendments. These amendments tothe IND typically do not require a waiting period; however, ifthe new information is significantly different from the originaland if it affects the safety of the patients in the clinical trials,then the agency may advise the sponsor not to implementthe change. The usual changes to the CMC, such as optimiza-tion to synthesis/manufacture of the drug substance, analyticalmethods, the drug product, new stability data, etc., could besubmitted in IND annual reports to the agency. The sponsorcould take advantage of the IND amendments to update theagency on the progress in the CMC and identification of criti-cal issues and proposed/planned solutions to the issues. Duringphase 2, typically the drug substance and the drug product areproduced in a large laboratory to pilot scale. At this phase, thedrug substance synthesis/manufacturing, drug product formu-lation/process, analytical test methods, etc. are fine-tunedand the principles of QbD and PAT may be introduced andimplemented. The end of phase 2 or the beginning of phase 3becomes a pivotal point in the overall drug developmentprocess. At this point the NME has shown a certain thresholdfor safety and desired efficacy and the drug development picksup the speed with which confirmation of clinical results fromphases 1 and 2 are reached in a larger patient populationin phase 3. The CMC has to match the increased clinicalactivity of phase 3 by gearing up all three disciplines: drugsubstance synthesis and manufacturing, drug product formula-tion and manufacturing, and analytical testing. Typicallyphase 3 clinical trials are conducted on many hundreds tothousands of patients, leading to marketing application. Inthis phase the CMC section has to match the expanded clinicaltrials leading towards commercial distribution. In phase 3, theCMC section should focus on two important aspects of devel-opment: combining information and data from all three phasesand bridging those with the future commercial product. FDAhas issued a guidance for CMC information requirements forphases 2 and 3. The bridging study will be discussed in thenext section.



5.4. Successful Bridging of Pre-IND, Phase 1,Phase 2, and Phase 3 with Commercial Product

One of the secrets of obtaining approval of NDAs and BLAsfrom a CMC perspective is successfully bridging the CMC infor-mation and data from preclinical through the three phases ofIND and the commercial product. Bridging of critical informa-tion on strength, identity, purity, potency, and quality startingfrom the preclinical phase leading up to commercial product isof utmost importance. Some important characteristics of thedrug substance and the drug product are as follows:

Drug substance

Structural elucidationImpurity/Related substances

SolubilityCritical relevant characteristicsCritical manufacturing informationStability (RT and accelerated)

Drug productDescriptionDegradation productsDissolution

All relevant drug substance and drug product character-ization information from all phases of development should bebridged to come up with a complete picture of strengths andweaknesses of the drug substance and the drug product. Keycharacteristics such as impurity profile, solubility of thedrug substance, dissolution-friability balance (DFB) for SODF,accelerated/forced degradation to understand the mechanis-tic aspects of degradation, design of experiments, etc., shouldbe bridged to get a complete picture of the drug product.The aforementioned information on the drug substance andthe drug product from investigational phases is bridged tothe planned commercial drug product. All of this bridginginformation, along with design of experimental data in whichthe boundaries of success and failures of all critical param-eters (drug substance manufacturing processing parameters,formulation components, composition, processing equipment

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and parameters, in-process controls, specifications, etc.) aredetermined, become part of developmental pharmaceutics andshould be included in a New Drug Application. It should beemphasized that bridging in the form of evolution of analyticalprocedures starting from preclinical phase to phase 3 andcommercial product testing should be thoroughly discussed indevelopmental pharmaceutics.

5.5. Developmental Pharmaceutics andIts Importance to CMC

As discussed above, Design of Experiments, Quality-by-Design,Process Analytical Technologies, bridging of all the phases ofINDs, technology transfer, etc., become the basis for develop-mental pharmaceutics, which becomes the foundation of a goodCMC section of NDAs and ANDAs. It provides an overview ofthe thoughts and rationale behind the product development andcommercial product to the CMC reviewing staff at the agencyand becomes an important tool in the review and approvalprocess. The ICH CTD format also provides for a sectionfor Development Pharmaceutics. ICH Q8 is on developmentalpharmaceutics, and once this guidance (which is at early stagesof its development at this time) is finalized, it should provideappropriate guidance to the industry.

5.6. Technology Transfer to Manufacturing

It is obvious that at the end of phase 3 clinical trials, the mostcritical and important step is to make sure that the drugproduct is ‘‘manufacturable,’’ because without it the new drugcould not be commercialized. Over the past 30 years, majorpharmaceutical and generic companies have often failed toproduce commercial products immediately upon approval ofNDAs/ANDAs because companies failed to perform timelytechnology transfer. Technology transfer involves transferringof information and experience from lab and pilot scales toa commercial level for the drug substance, drug product, andassociated analytical testing procedures. All these become thebasis for seamless and sound manufacturing of the new drugon a commercial scale.



5.7. Quality-by-Design and Process AnalyticalTechnologies

As this chapter is being written, the Office of PharmaceuticalSciences (OPS) under CDER is in the process of redesigningand introducing a paradigm shift in the CMC reviews and com-pliance investigations. It is expected that by the end of 2005the Agency would have implemented the planned changes inCMC reviews and compliance investigations. The ICH throughinitiation of Q8 (Pharmaceutical Development) and Q9 (RiskAssessment) is also gearing up towards the same goal of OPS.Both ICH Q8 and Q9 will involve the concept of QbD. Quality-by-Design, which encompasses Process Analytical Technologiesand embraces building quality in the process and productthroughout the manufacturing process, may be summarizedas follows:

QbD ¼ Preprocess controls ðPPCsÞ

þ in-process controls ðIPCsÞ

þ Postprocess controls ðPOPCsÞ

PPCs: Preprocess controls (throughout the preclinical,the three phases of INDs, and for commercial produc-tion) such as thorough physical-chemical-biologicalcharacterization of the (a) drug substance and allits manufacturing/synthesis components and (b) exci-pients. The drug substance starting materials, itsother components (catalysts, solvents, etc.), key andpivotal intermediates, etc., should be thoroughlycharacterized. The pharmacopoeias provide fairlygood chemical characterization, but do not providethorough functional physical characterization, and it isup to the sponsor to develop that characterization. Thedrug substance physical and chemical characteriza-tion is of critical importance to successful Quality-by-Design. Some examples of PPCs are chemicalpurity of starting materials and intermediates, purifica-tion steps, drug substance particle size and specific

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surface area, density, excipient particle size and shape,density, etc.

IPCs: In-process controls is the heart of process analyt-ical technologies. IPCs such as assay, purity, residualsolvents, particle size, specific surface area, polymor-phism, etc., are critical in the manufacturing of drugsubstance. For drug products, in-process controlssuch as granulation endpoints, moisture level, contentuniformity, etc., are critical. Process analytical technol-ogies could involve off-line, at-line, in-line, on-linetesting of in-process parameters for drug substanceand drug product. Carefully and strategically chosenin-process controls, if done in-line or on-line, mayobviate final testing because of the large sample size.

PoPCs: Postprocess controls play an important role inQbD. Testing of final drug product per specifications,storage conditions, long-term and accelerated stabilitystudies are components of PoPCs.

5.8. Sponsor-FDA Meetings

FDA allows several kinds of meetings with sponsors in orderto assist and gather information. Meetings such as pre-INDtypically are clinical oriented. For CMC section, end-of phase 2and pre-NDA meetings are important for the CMC section ofNDAs and BLAs. (FDA has issued a guidance on sponsor-FDAmeetings.) The sponsor should submit a briefing document tothe agency at least 6 weeks prior to the requested meeting, andthe briefing document should contain relevant backgroundinformation and questions on which the sponsor is seekingadvice. The briefing document should not be voluminous. Itshould be a focused document that contains specific questions/issues. The sponsor can easily enhance its NDA/BLA/ANDAsubmissions by taking advantage of these meetings.

5.9. NDA Submissions

NDA submission on a new drug should follow the FDA andICH guidance. From a technical regulatory perspective, if all



the work is done properly as described in sections a through h,the NDA submission should become fairly easy and result inapproval in a timely manner. The submission should follow theFDA and ICH guidances, and moreover it should be reviewer-friendly. The data should be presented in a clear-cut manner.One should remember that the product that the FDA seesfrom an applicant is the NDA/ANDA submission. The chem-istry reviewers have a responsibility to make sure that theproduct they approve meets the regulatory requirements asprescribed in the Code of Federal Regulations. Submissionsto the FDA should be accurate and of high quality.

All submissions to the FDA must meet four importantcriteria in order to secure approval the first time: (a) Adher-ence to Regulations and Guidances—strict adherence to FDACMC regulations and guidances for format and content, whichinclude those ICH quality guidelines that have reached step 5.It is possible to adopt an approach other than that provided bythe FDA guidances; however, it is the applicant’s responsibilityto secure approval on the alternative approach from the FDAreviewing staff (for example, at EOP2 and/or Pre-NDA meet-ing). Careful and strategic implementation of guidance shouldbe received from the reviewing staff at the FDA; (b) Introduc-tion—submissions should have an introductory section thatclearly provides the purpose, scope, and context of the submis-sion that helps the reviewing team. This introduction shouldhave a clear delineation of any agreement made prior to thesubmission. The introductory section should provide a higherlevel overview of the submission, which will lead into the nextsection, where the nuts and bolts of the submission are pro-vided. This section should end with a summary of the submis-sion; (c) Body of the submission—this part of a submission isof utmost importance since it provides the main basis forapproval. The chemistry review staff has to provide a rationalefor their action (approval, nonapproval, approvable, etc.) anda good introduction and summary aids them in making theirdecision. The information provided in submissions must befocused, relevant, precise, accurate, complete, and of quality.When it comes to quality of the submission, one should adoptthe philosophy of ‘‘quality always.’’ In this main body of the

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submission, one should pay special attention not to provideredundant and unrelated information, because it takes awayfrom the reviewers’ attention and wastes their precious time.The submission should have a logical flow of informationand justified decisions based on scientific rationales. The logi-cal flow of information and justified decisions along with clearobjectives and findings that lead to clear conclusions provide acoherent submission. The main body of the submission shouldfollow the time-tested organizational characteristics of a soundbeginning, experimental details, organized results, discussionof results, and conclusions. Information should be providedwith an appropriate combination of text, figures, tables,etc., which will provide a clear picture of the submission. Theinformation should convey a clear message and conclusion andshould follow the usual standards of quality (free of typo-graphical and grammatical errors, clear legends, footnotes asnecessary for clarity, etc.); (d) A summary and conclusionsection should be provided, including any short- or long-termcommitments (such as placing batch(es) of drug product onlong-term stability and reporting the data to the agency at alater date, etc.).

5.10. ANDA (505b2) Submissions

The ANDA submission on a generic drug should follow the FDAguidance. FDA has provided a clear-cut format and contentguidance on the organization of an ANDA. Section VII of theguidance provides for detailed CMC requirements. The appli-cant should provide a statement on the components andcomposition of the product. This should be followed by infor-mation on raw materials (active ingredient and inactive ingre-dients), description of manufacturing facility, information onthe outside/contract firms, manufacturing process and packag-ing instructions, in-process information, packaging materialcontrols, controls for finished dosage form, analytical methodsfor the drug substance and drug product, stability of finisheddosage form, and availability of samples. If the generic productis a parenteral product, the applicant must provide steriliza-tion assurance information and data package. The above CMC



section is somewhat similar to the NDA requirements, and ifit follows the above recommendations, obtaining approval foran ANDA should be easy. The CMC section should be precededby information on the bioavailability/bioequivlaence of thedosage form in relation to the reference listed drug.

5.11. Quick and Complete Response (QCR)Team Approach to FDA Questions/Comments

Once an NDA or ANDA has been submitted by an applicantand filed (meaning accepted) by FDA, during and/or after thecompletion of the review, FDA might have questions/commentson the submission. The questions/comments may come verballyor in writing. In either case it is very important for the appli-cant to respond to the questions/comments in a timely,thorough, and accurate fashion. Often applicants form a team(such as QCR) that develops complete and timely responsesthat aide the agency’s review process. The QCR team, if prop-erly organized, could play an important role in obtaining theapproval of NDAs in a timely manner.

6. UNDERSTANDING THE CMC REVIEWPROCESS

The CMC review process at FDA is quite transparent. Theagency publishes its most current ONDC organization chartand several MaPPs. The primary CMC review chemistsreview the submissions and share their reviews with thechemistry team leaders. Based on their reviews, they mayissue information request letters. Alternatively, CMC reviewsare further reviewed by CMC division directors and then ulti-mately by the director of ONDC. Once the reviews are finalizedby the CMC reviewers and ONDC management, the reviewdivision director will issue appropriate letters (approval, non-approvals, approvable, etc.). The CMC reviewers issue a reviewreport, which includes their assessment and reasons for theirrecommendations. As stated earlier, the overall CMC reviewand approval processes may change in 2005 as a result of

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ICH Q8 and Q9. However, it should be remembered thatthe basics and fundamentals of CMC reviews (and complianceinspections) will focus on strength, identity, purity, potency, andquality, which are surrogates of safety and efficacy of drugs.The OGD follows a similar review process. Of course, forANDAs the final reviews stop at the OGD head level. The CMCreviewers have a legal responsibility to review and assess CMCsubmissions and to make sure that the submissions meet thelaw and regulations and the product meets the strength, iden-tity, purity, potency, and quality requirements. If for somereason a product is recalled because of SIPPQ, then the review-ing staff that approved the product is in part responsible. Thus,understanding the review process and the responsibility of thereviewing staff is important in obtaining approval of NDAs/BLAs.

As this chapter is being written, the Office of Pharmaceu-tical Sciences is planning for a paradigm change in the CMCreviews and compliance. The ICH through Q8 (PharmaceuticalDevelopment) and Q9 (Risk Assessment) is also gearing uptowards the same goal of OPS.

7. PROBLEMS AND CHALLENGES INVOLVEDIN SECURING TIMELY APPROVALS ANDPOTENTIAL SOLUTIONS

Most delayed approvals are due to poor science contained in thesubmission and poor submission strategy. The poor sciencemay be reflected in instability of the product or unacceptablelevels of impurities or poor product bioavailability as measuredby tablet dissolution, etc. A good product developmentplan based on the principles of QbD (see above) should resultin an approvable submission. Judicial use of contacts with theagency and maximizing various FDA-sponsor meetings shouldavoid delays in the approvals of applications. Agency reviewersare available to assist the industry as long as it is done ina professional manner. The Agency is pushing for science-based regulations and review practices. Applicants should take



advantage of this new paradigm to secure approvals in a timelymanner. As described in Sec. 5.9, the quality of submissionis critical in securing approval of applications in a timelymanner.

8. SUMMARY AND CONCLUSIONS

This chapter has offered some practical ways to develop ascience-based, regulatory-friendly application that should beapproved at first submission. By focusing on the fundamentalscientific principles and FDA and ICH guidances, it is quitefeasible to obtain approval of NDAs and ANDAs. In orderto obtain approval of NDAs/ANDAs in a timely manner, oneshould focus on four pillars: (a) development of CMC basedon QbD/PAT, (b) application of FDA and ICH CMC regulationsand guidances, (c) bridging of phases 1 through 3 to a success-ful NDA, and (d) preparing sound CMC scientific and regula-tory submissions.

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21. FDA, Center for Drug Evaluation and Research, ‘‘BACPAC I:Intermediates in Drug Substance Synthesis: Bulk Actives Post-approval Changes: Chemistry, Manufacturing, and ControlsDocumentation,’’ Guidance Document, (February 2001).

22. FDA, Center for Drug Evaluation and Research, ‘‘StatisticalApproaches to Establishing Bioequivalence,’’ Guidance Docu-ment, (February 2001).

23. FDA, Center for Drug Evaluation and Research, ‘‘Nasal Sprayand Inhalation Solution, Suspension, and Spray Drug Prod-ucts—Chemistry, Manufacturing, and Controls Documenta-tion,’’ Guidance Document, (July 2002).

24. FDA, Center for Drug Evaluation and Research, ‘‘Compar-ability Protocols—Chemistry, Manufacturing, and ControlsInformation,’’ Guidance Document, (February 2003).

25. FDA, Center for Drug Evaluation and Research, ‘‘Bioavail-ability and Bioequivalence Studies for Orally AdministeredDrug Products—General Considerations,’’ Guidance Docu-ment, (March 2003).

26. FDA, Center for Drug Evaluation and Research, ‘‘Requests forExpedited Review of NDA Chemistry Supplements,’’ Manualof Policies and Procedures MAPP 5310.3 (June 1999).

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27. FDA, Center for Drug Evaluation and Research, ‘‘DrugShortage Management,’’ Manual of Policies and ProceduresMAPP 4730.1 (November 1995).

28. Code of Federal Regulations, Title 21, Part 314.81(2). Otherpostmarketing reports—Annual Reports.

29. Code of Federal Regulations, Title 21, Part 211.180. Currentgood manufacturing practice for finished pharmaceuticals—Records and Reports—General Requirements.

30. Code of Federal Regulations, Title 21, Part 211.100. Currentgood manufacturing practice for finished pharmaceuticals—Production and Process Controls—Written procedures,deviations.

31. Code of Federal Regulations, Title 21, Part 211.160(e). Currentgood manufacturing practice for finished pharmaceuticals—Laboratory Controls—General Requirements.

32. Code of Federal Regulations, Title 21, Part 314.3(b). GeneralProvisions—Definitions.

33. FDA, Center for Drug Evaluation and Research, ‘‘Format andContent for the CMC Section of an Annual Report,’’ GuidanceDocument, (September 1994).

34. FDA, Center for Drug Evaluation and Research and Center forBiologics Evaluation and Research, ‘‘Formal Meetings withSponsors and Applicants for PDUFA Products,’’ GuidanceDocument (February 2000).

35. Code of Federal Regulations, Title 21, Part 314.50(a)5. Contentand format of an application—ccApplication form.

36. Pharmaceutical Research and Manufacturers of America, 2002Industry Profile, PhRMA, Washington, DC, 2003.

37. J.A. DiMasi, R.W. Hansen, and H.G. Grabowski, ‘‘The Priceof Innovation: New Estimates of Drug Development Costs,’’Journal of Health Economics 22 (2003): 151–185.

38. H. Grabowski, J. Vernon, and J. DiMasi, ‘‘Returns on Researchand Development for 1990s New Drug Introductions,’’Pharmacoeconomics 20 (2002): suppl. 3, 11–29.

39. FDA, Center for Drug Evaluation and Research, ‘‘A Frame-work for Innovative Pharmaceutical Manufacturing andQuality Assurance,’’ Draft Guidance Document, (August 2003).



40. ‘‘GSK Announces FDA Approval of Their First PATSubmission,’’ AAPS News Magazine (April 2004): 10.

41. FDA, Center for Drug Evaluation and Research, ‘‘M2 eCTD:Electronic Common Technical Document Specifications,’’Guidance Document, (April 2003).

42. FDA, Center for Drug Evaluation and Research, ‘‘M4 Organi-zation of the CTD,’’ Guidance Document, (August 2001).

43. FDA, Center for Drug Evaluation and Research, ‘‘M4 The CTD- Quality,’’ Guidance Document, (August 2001).

44. FDA, Center for Drug Evaluation and Research, ‘‘ProvidingRegulatory Submissions in Electronic Format—NDAs,’’Guidance Document, (January 1999).

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