Overcoming Challenges In Preparing CMC Dossiers — Tips For Success

By Albert Yehaskel, President and CEO, Refuah Global Pharmaceutical Development

Preparing a chemistry, manufacturing, and control (CMC) dossier can be a daunting task.  It is a detail-oriented undertaking, and as the saying goes, the devil is in the details.  Whether you are assembling the CMC dossier for an Investigational New Drug (IND) application, New Drug Application (NDA), Drug Master File (DMF), Biologics License Application (BLA), or Abbreviated New Drug Application (ANDA), organization of your information and data is paramount. Assembling a CMC dossier is information- and document-based. There are four main questions that need to be addressed for getting it right the first time:

1. Do you have all the information required to assemble a high quality and complete dossier?  More often than not, the answer is “no.” “I have information that is missing” or “I have all the information but I cannot locate it” are typical answers.
2. Do you have the manpower to start and finish the job?  This includes personnel who are well-versed and experienced in assembling an electronic Common Technical Document (eCTD), who know and understand the data and can be critical about what will go in the dossier and what will not.
3. Do you have project management capabilities within your firm? Related to the previous question, is someone on your team well-organized and capable of dealing with the day-to-day details of a myriad of information, who can create a timeline and ensure that the timeline is followed?
4. What is your submission target date? Everyone will need to be coordinated and focused on meeting this date. Project management will create a timeline of all the CMC pieces to ensure that the timeline is met.

Staying the course towards your ultimate goal will be your challenge.  You will be pulled in many directions during this endeavor, and you will be faced with many speed bumps … and some brick walls. As part of project management, you will need to identify the risks as they arise and mitigate them as quickly as possible to ensure you meet your goal.

Organization
Organizing what needs to be done, at the outset, will go a long way toward helping you achieve your goals. First, identify your CMC dossier team.  What are the responsibilities of each member?  You will need to assign specific tasks and completion dates for each deliverable. You should also consider cross-fertilizing your team — that is, in the event a team member(s) is not available, someone on the team can take over his or her responsibility to ensure no slippage in the timeline.

Establish dates by which Modules 1, 2, and 3 of the Common Technical Document (CTD) will be completed, and try to stick to those dates.  Slippage will occur — it’s part of drug development — but by staying organized, you can reduce and minimize its impact.  Plan to meet as often as necessary to discuss progress.  This could be once a week, twice a month, or on an ad hoc basis, depending on many factors.  Create a tracking chart in either Microsoft Excel or Word to keep track of what is completed and what remains outstanding.  This tracking chart should capture who will complete certain sections, the dates of completion, and comments on specific issues as they arise and critical areas that need attention.

It is imperative that a gap analysis is conducted at the outset. The best way to achieve this is to use the CTD outline (or table of contents) to see what is available and what is missing. Once the gap analysis is completed, you will know exactly what you have and what you need.

The Quality Modules
One of the biggest challenges in assembling the CTD will be obtaining specific information from your vendors.  For example, stability reports, validation reports, and tooling for your clinical trial material (CTM) and/or final product are areas that are commonly subject to delays.  Ensure that your contract research organization (CRO), contract manufacturing organization (CMO), and other vendors are carefully managed and not the other way around … you do not want them managing your timeline.

As previously stated, there are three modules in the CTD that you will need to focus on for any CMC dossier you plan to assemble: Module 1 – administrative information, Module 2 – quality overall summary (QOS), and Module 3 – the CMC quality data and information. In the following sections, we will review each of these modules.

Module 1 – Administrative Information

The following information is required for Module 1:

• Form FDA 356h
• Field copy certification
• Patent certifications
• Exclusivity claim
• Letters of authorization (reference to DMFs)
• Environmental assessment
• Labeling

Form FDA 356h

Form FDA 356h serves as the cover sheet to an NDA, BLA, or ANDA application. Instructions for filling this form completely can be found on the FDA website and are very straightforward.

There are some key points in Form FDA 356h that are important and sometimes overlooked.  Section 29 of the form addresses establishment information.  You will need to gather the establishment name and address, and for that establishment you will also need a registration / Facility Establishment Identifier (FEI) number, a Master File (MF) number, and its unique, nine-digit D-U-N-S number (from Dun & Bradstreet).  Establishment contact information such as name, address, telephone number, fax number, and email address is also required.

Another key aspect in Section 29 is a question that FDA expects you to address in Form FDA 356h: Is the site ready for inspection (and if not, then when)?  It is incumbent upon the applicant to ensure that the site is ready for inspection before submitting an NDA/ANDA.  This can be accomplished by way of a mock FDA inspection and is highly recommended and encouraged.  You must evaluate the facilities to ensure that the company is capable of manufacturing product pursuant to the information in the application and in accordance with cGMP regulations. By doing so, you will determine if adequate controls are in place to manufacture the product consistently, and an internal inspection will assure that the facilities listed in the application are in compliance with cGMPs (i.e., manufacturing, adequate analytical controls, process development, and packaging).  Furthermore, you must verify the authenticity and accuracy of the data submitted in the application.

By being inspection-ready, you ensure that all necessary documentation — e.g. batch records, validation reports, and standard operating procedures (SOPs) — is available on site.  You should also have on-hand a brief description of the specific manufacturing steps and/or type of testing conducted at the site, such as final dosage form, stability testing, and assays.

Section 31 of Form FDA 356h addresses some chemistry requirements.  At some point after the application is submitted, you will be asked to submit samples (21 CFR 314.50 (e)(1) and 21 CFR 601.2 (a) — submit only upon FDA’s request) and the methods validation package (21 CFR 314.50(e)(2)(i) and 21 CFR 601.2).  Prior to submitting your application, prepare a list of the samples (lot numbers, date of manufacture) and identify their location for ease of access.

Field Copy Certification

A field copy certification (21 CFR 314.50 (1)(3)) should be included with the submission in section 1.3.2 of the eCTD. Sponsors and applicants should notify the district office by letter that their eCTD submission will be submitted to FDA, and because the field offices have access to the complete submission on the FDA network, an individual field copy is no longer required. The letter should indicate the drug and application number and the FDA center and division.

A copy of the letter should be placed in eCTD section 1.3.2.   A letter certifying that the electronic quality section has been submitted should also be provided to the appropriate Office of Regulatory Affairs district office.

The field copy should be a separately bound copy of the quality section (Module 3) for the NDA and ANDA. You should send this copy directly to the appropriate field office. A field copy is not required for the BLA.

Labeling

Labeling pieces consist of the following documents: draft labeling, draft carton and container labels, annotated draft labeling text, proposed structured product labeling (SPL), core data sheet, and target product profile.  The salient information found in these labeling pieces includes the following:

• Name of the medicinal product
• Qualitative and quantitative composition
• Pharmaceutical form
• Pharmaceutical particulars
  • List of excipients 
  • Incompatibilities
  • Shelf life
  • Special precautions for storage
  • Nature and content of container
  • Instructions for use and handling and disposal

 

Module 2 – Quality Overall Summary (QOS)

The QOS is a summary that follows the scope and the outline of the body of data in Module 3. The QOS should only reference information, data, or justification that was already included in Module 3 or in other parts of the CTD. The QOS should include sufficient information from each section to provide the quality reviewer with an overview of Module 3 for both the drug substance and the drug product. The QOS should also emphasize critical key parameters of the product and provide, for instance, justification in cases where guidelines were not followed. The QOS should include a discussion of key issues that integrates information from sections in the quality module and supporting information from other modules (e.g., qualification of impurities via toxicological studies discussed under the CTD-S module).

Question-Based Review (QbR)

The FDA has issued the Manual of Policies and Procedures (MAPP) 5015.10, which clarifies how drug substance and drug product reviewers in the Office of Pharmaceutical Science (OPS) should assess NDAs.

The QOS is assembled via question-based review (QbR), a general framework for a science and risk-based assessment of product quality that incorporates important scientific and regulatory review questions.  The quality reviewers evaluate the responses and body of data in Module 3 supporting the applicant’s answers.

The QbR model is not intended to replace the detailed supportive information in Module 3 (found in section 3.2 of ICH M4Q). The QbR model only provides a format that helps applicants convey aspects of the application (e.g., development history, risk management, control strategy, and scale-up plans) in the QOS in Module 2.

Companion documents are available to help the reviewers clarify the information that should be provided by applicants in QbR submissions. There are essentially two companion documents, one for the drug substance and one for the drug product. For every question found in these companion documents, a response must be provided.

Module 3 – Body of Information

Below is a chart outlining the contents for Module 3.  It is beyond the scope of this article to cover each of these items in detail.  The reader is strongly encouraged to review the guidance documents provided in the Reference section, which discuss in detail the exact information and data needed to populate each of these modules.

3.2.S Drug Substance

3.2.S.1 General Information

3.2.S.1.1 Nomenclature

3.2.S.1.2 Structure

3.2.S.1.3 General Properties

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturers

3.2.S.2.2 Description of Manufacturing Process and Process Controls

3.2.S.2.3 Control of Materials

3.2.S.2.4 Controls of Critical Steps and Intermediates

3.2.S.2.5 Process Validation and/or Evaluation

3.2.S.2.6 Manufacturing Process Development

3.2.S.3 Characterization

3.2.S.3.1 Elucidation of Structure and other Characteristics

3.2.S.3.2 Impurities

3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specification

3.2.S.4.2 Analytical Procedures

3.2.S.4.3 Validation of Analytical Procedures

3.2.S.4.4 Batch Analyses

3.2.S.4.5 Justification of Specification

3.2.S.5 Reference Standards or Materials

3.2.S.6 Container Closure System

3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusions

3.2.S.7.2 Postapproval Stability Protocol and Stability Commitment

3.2.S.7.3 Stability Data

3.2.P Drug Product

3.2.P.1 Description And Composition of the Drug Product

3.2.P.2 Pharmaceutical Development

3.2.P.2.1 Components of The Drug Product

3.2.P.2.2 Drug Product

3.2.P.2.3 Manufacturing Process Development

3.2.P.2.4 Container Closure System

3.2.P.2.5 Microbiological Attributes

3.2.P.2.6 Compatibility

3.2.P.3 Manufacture

3.2.P.3.1 Manufacturers

3.2.P.3.2 Batch Formula

3.2.P.3.3 Description of Manufacturing Process And Process Controls

3.2.P.3.4 Controls of Critical Steps and Intermediates

3.2.P.3.5 Process Validation and/or Evaluation

3.2.P.4 Control of Excipients

3.2.P.4.1 Specifications

3.2.P.4.2 Analytical Procedures

3.2.P.4.3 Validation of Analytical Procedures

3.2.P.4.4 Justification of Specifications

3.2.P.4.5 Excipients of Human or Animal Origin

3.2.P.4.6 Novel Excipients

3.2.P.5 Control of Drug Product

3.2.P.5.1 Specifications

3.2.P.5.2 Analytical Procedures

3.2.P.5.3 Validation of Analytical Procedures

3.2.P.5.4 Batch Analyses

3.2.P.5.5 Characterization of Impurities

3.2.P.5.6 Justification of Specifications

3.2.P.6 Reference Standards or Materials

3.2.P.7 Container Closure System

3.2.P.8 Stability

3.2.P.8.1 Stability Summary And Conclusion

3.2.P.8.2 Postapproval Stability Protocol and Stability Commitment

3.2.P.8.3 Stability Data

3.2.A Appendices

3.2.A.1 Facilities And Equipment

3.2.A.2 Adventitious Agents Safety Evaluation

3.2.A.3 Novel Excipients

3.2.Regional Information

3.2.R.1 Executed Batch Records

3.2.R.2 Method Validation Package

3.2.R.3 Comparability Protocols

3.3 Literature References

 

Finalizing the CMC Dossier

After months of organization and writing, your submission is almost ready. You will need to ensure that all the CMC documents have gone through a thorough peer review, external review, or both.  Allow time to review comments, make changes, and finalize the document as a group.  Once all changes and QA/QC have been completed, label the document as “FINAL” with a date. If this will be an eCTD submission (which is highly recommended), convert the document to PDF and ensure bookmarks are operable.  For hyperlinking, make sure that any links appear in blue font color.  Once the CMC section is published, all bookmarks and hyperlinks should be checked, one by one.

Your submission is now ready for filing.

References:

1. MAPP 5015.10 – Chemistry Review of Question-based Review (QbR) Submissions
2. M4 – Organization of the eCTD
3. Guidance for Industry – Providing Regulatory Submissions in Electronic Format
4. Q1A(R2) – Stability Testing of New Drug Substances and Products
5. Q1C – Stability Testing for New Dosage Forms
6. Q2(R1) – Validation of Analytical Procedures: Text and Methodologies
7. Q3A – Impurities in New Drug Substances
8. Q3B(R2) – Impurities in New Drug Products
9. Q3C(R5) – Impurities: Guideline for Residual Solvents
10. Q3D – Elemental Impurities
11. Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products
12. Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological
13. Products
14. Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
15. Q8(R2) – Pharmaceutical Development
16. Q9 – Quality Risk Management
17. Q10 – Pharmaceutical Quality System
18. Q11 – Development and Manufacture of Drug Substances

About The Author

Albert Yehaskel is president and CEO of the consulting firm Refuah Global Pharmaceutical Development. He has been in the pharmaceutical industry for over 40 years, working for companies including Schering-Plough, Lederle Laboratories (part of American Cyanamid, now known as Wyeth), Block Drug, Sanofi, Purdue Pharma, Daiichi-Sankyo, Shionogi USA, and Indigo Pharmaceuticals. Over 25 years of his career has been devoted to regulatory affairs, managing and directing domestic and international regulatory submissions, orchestrating key FDA meetings, and conducting pharmaceutical research and development. He has two master’s degrees — an MBA in economics and finance from Fairleigh Dickinson University and an M.S. in organic chemistry from Queens College, City University of New York — as well as a B.S. in chemistry from the Polytechnic Institute of Brooklyn.