Regulatory Submission and DMF

What does ICH stand for? What is it?

-international council for harmonization
-it is a unique harmonization project involving the regulators and research-based industries of US, EU and Japan

What are the objectives of the ICH?

-to improve efficiency of new drug development and registration process
-promote public health and prevent duplication of clinical trials in humans and minimize the use of animal testing without compromising safety and efficacy

What are the four topic codes of ICH guidelines? What is an example of each?

-quality: impurity limits
-efficacy:conduct of safety
-safety:genotoxicity
-multidisciplinary:medical terminology

What are some characteristics about ICH?

-there are working groups that help to develop guidelines
-there are pharmacopeias for the 3 regions
-there is a 5 step process for guideline development

What is a Common Technical Document (CTD)? What are examples?

-an internationally agreed format for the preparation of marketing applications to regulatory authorities for new medicines approval
-IND, NDA, BLA, ANDA, Type III DMF

What is the main goal of the CTD?

-it eliminates the need to reformat the information for submission to the different ICH regulatory authorities

What are the five different modules for a CTD?

-1: administrative information and prescribing information
2: CTD summaries (quality, safety and efficacy)
3: quality
4:nonclinical study reports
5: clinical study reports

What information is submitted in eCTD Module 3?

-CMC information

To manufacture a DS or DP, what do you need to have?

-chemistry: composition of the DS or DP
-manufacturing: process
-controls: quality control testing

Why must CMC activities be defined?

-to ensure the DS/DP is safe, effective and consistent between batches

What is the chemistry information in the CMC?

-drug substance description, nomenclature, structure, physicochemical properties, impurities, structure determination, container closure, description of drug product and excipients

What is manufacturing information in the CMC?

-manufacturing process for intermediates and drug product, manufacturing sites, equipment, how excipients/raw materials are combined, r&d development, scale-up, commercial manufacturing process

What is the control information in the CMC?

-control of critical steps and process parameters, critical quality attributes (CQA), analytical method description and validation, reference standards, batch analysis, stability data, expiry dating, in-use period, manufacturing and environmental controls, packaging controls

What is the module 3- quality CTD format?

3.1 table of contents
3.2 body of data
3.2.S drug substance
3.2.P drug product
3.2.A Appendices
3.2.A.1 Facilities and Equipment (biotech)
3.2.A.2 Adventitious agents safety evaluation
3.2.A.3 Novel Excipients
3.2.R Regional Information
3.3 Literature References

What are the 7 subsections of 3.2.S?

1.general information
2.manufacture
3.characterization
4.control of DS
5.reference standard
6.container closure
7.stability

What are the 8 subsections of 3.2.P?

1.description and composition
2.pharmaceutical dev’t
3.manufacture
4.control of excipients
5.control of drug product
6.reference standard
7.container closure system
8.stability

What are the different documents included in the IND/NDA?

-preformulation report- API
-pharmaceutical development report
-analytical methods development report- API, impurities, residual solvents, drug product
-process optimization and scaleup
-stability reports- API and drug product

What are the materials (chemistry) information included for CMC of small molecules vs biologic?

-small: chemical compounds
-biologic: cells, DNA/RNA, tissues

What is the manufacturing information included in the CMC of small molecules vs biologics?

small: chemical synthesis and simple purification
biologic: preparation of cells, complex manufacturing process, complex purification

What is the characterization (control) information included in the CMC of small molecules vs biologic?

small: chromatography, spectoscopy, impurites, water content, microbial limits
biologic: chromatography, spectoscopy, peptide mapping, SDS-PAGE, antibody binding, sequencing, cell viability, host cell protein, adventitious agent testing

What is the difference between 351a vs 351k?

-351a establishes safety and effectiveness of a new product while 351k demonstrates biosimilarity

What is needed in 351a vs 351k?

-a: clinical S&E (phase 1-3), clinical pharmacology, nonclinical, analytical
-k: analytical (the foundation), nonclinical, clinical pharmacology, additional clinical studies

Who is the review meeting during new drug of biologic development between?

-sponsor and CDER/CBER staff

What are the three types of review meetings?

-type A meetings:clinical holds-30 days
-type B meetings: pre-IND meeting, end of phase 2 meeting, pre-BLA or NDA meeting-60 days
-type C meetings:complete response letters, after review questions-75 days

When are meeting packages sent to the FDA?

-2 weeks before the meeting date

What are the three components of the NDA that need to be clear in order to be approved?

1.quality: drug synthesis and drug product development
2.efficacy: clinical/medical/statistics
3.safety:pharmacology/toxicity/adverse events

Explain the sample “program” review timeline?

-when a NDA is submitted, it takes 60 days for the FDA to perform filing checks and accept the application to start their review
-they then recieve a PDUFA date and it will take around 10 months for the FDA to review the application
-it takes 12 total months for the standard application to be reviewed

What may the FDA use in its evaluation of the NDA?

-an advisory committee

The FDA may not refer to Ad Comm if…..

-clinical trials are similar to existing approved products and/or no safety or efficacy issues or no significant public health questions

What do advisory committees provide?

-a wide range of expertise and can often provide useful recommendations

Does the FDA have to agree with the final recommendations of the advisory committee?

-no, they are not obligated to agree

Who is responsible for reviewing the company’s data and proposed labeling?

-a team of CDER/CBER physicians, statisticians, chemists, pharmacologists and other scientists

Upon completion of the review period the FDA will…

-approve! (first cycle approval) or
-send a complete response letter (CRL) for the NDA or BLA

After the review is completed the sponsor recieves…

-final approval letter for marketing approval with or without phase 4 commitments OR
-complete response letter

What does the CRL reflect?

-the FDA’s complete review of the original data and identifies deficiencies in the application

What does a CRL mean?

-the application is not approvable in the current form

What are the reasons the CRL could contain for the denial?

-description of specific deficiencies, clinical, labeling
-inadequate data submitted to support approval
-bioavailability or BE data required, patent certification
-safety requirements- (new) active ingredients, impurities
-GMP status of the manufacturing facilities for the DS or DP
-FDA might recommend actions for approval!

What does a Drug Master File (DMF) contain?

-confidential detailed information about facilities, processes, articles used in the manufacturing, processing, packaging, and storing of one or more human drugs

Is a DMF required by law or FDA regulation?

-no, a DMF is submitted solely at the discretion of the holder (voluntary)

What is issued upon submission of a eCTD DMF?

-a DMF number

What is information in a DMF used to support?

-IND, NDA or ANDA

What are some other characteristics regarding a DMF?

-a DMF is not a substitute for an IND, NDA or ANDA as it does not have any clinical data and the DMF holder updates their information annually
-DMF is not approved or disapproved but reviewed with a referenced application

What are the five types of DMF?

1: no longer applicable
2:drug substance and drug products
3.packaging material such as bottles and caps
4:excipients, colorants, hard capsules
5:discouraged

NDA/ANDA/BLA applicants do not have to submit….

-manufacturing information for packaging or excipients used, ONLY LoA

What is a letter of authorization (LoA)?

-authorizes the NDA sponsor to reference the DMF and must be included in the NDA/BLA/ANDA