Quality Overall Summary Reviewers Guide

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Quality Overall Summary Reviewers Guide

Questions to be completed by Sponsors for the preparation of a Quality Overall Summary

“The Quality Overall Summary (QOS) is a good place to explain the things that are missing, likely not necessary and why certain guidelines were not followed.”

“The value of the QOS should be to point reviewers at the most important information to support the quality of the drug in the most transparent presentation possible.”

As those involved with the process know, preparing content for regulatory submissions can be repetitious and time consuming. The preparation of CMC documentation faces distinctive challenges not usually found in nonclinical and clinical content creation. Contract medical writers and regulatory guidance are readily available for clinical study reports and clinical protocols, yet experienced technical writers and consistent interpretation of guidance are not as obtainable or complete for most types of CMC documents.

The Quality Overall Summary (QOS) section promotes the quality-based review functionality to create submission content. It can be tailored during any stage of drug development, so this allows for the natural growth of the CTD and in particular the Quality sections of the IND/IMPD throughout development.

There is no need to submit irrelevant, redundant, or unorganized data. Health Agencies are looking for practical scientific knowledge and understanding of product and process achieved. One challenge that arises is that there are a substantial number of new guidelines and regulations that define the format and approach for regulatory submissions, yet, most require further clarifications or interpretation before a sponsor can put them into practice.

A critical component in defining an organization’s proficiency to CMC regulatory content creation is the development of guidance interpretation that contains the organization’s development and submission strategy and details the relevant standards of practice that support the creation of compliant submissions. The QOS can provide a blueprint.

A further challenge is the fact that the preparation of CMC documentation is often done across multiple departments, within the company, as well as outsourced to contract manufacturing and analytical testing labs. Inconsistent information and format between source reports and submission components can create problems for the regulatory reviewer.

For those who know and understand this potential issue well and can create technically sound and consistent CMC regulatory submission content. Congratulations! For the others, Due to the lack of appropriate specific regulatory guidance around the art of technical writing, it is imperative that each company develop and document the information to support their product development and eventual registration.

In response to these issues I focus on the Quality Module, to enable sponsors to quickly locate critical guidance information, derived from 32 different guidance documents. Design to facilitate communication of risk assessment and strategy throughout a research and development organization and provide an easier means to generate submission ready regulatory content.

Promote improved consistency within and across departments, which will lead to improved submission content quality and clarity where guidance’s are not detailed or specific enough. Provide a common foundation for understanding the “indefinable gray areas,” where most guidance’s lack clarity.

The blog was developed for the biotech industry by experienced  experts and is based on their insights and practical understanding, which spans the document development and submission lifecycle.

Questions to be completed by Sponsors for the preparation of a Quality Overall Summary

  • Product Quality: Question-based Review

2.3.S DRUG SUBSTANCE

2.3.S.1 General Information

  1. What is the nomenclature, molecular structure, molecular formula, and molecular weight?
  2. What are the physicochemical properties including physical description, pKa, polymorphism, aqueous solubility (as function of pH), hygroscopicity, melting points, and partition coefficient?

2.3.S.2 Manufacture

  1. Who manufactures the drug substance?
  2. How do the manufacturing processes and controls ensure consistent production of drug substance?

2.3.S.3 Characterization 

  1. How was the drug substance structure elucidated and characterized?
  2. How were potential impurities identified and characterized?

2.3.S.4 Control of Drug Substance

  1. What is the drug substance specification? Does it include all the critical drug substance attributes that affect the manufacturing and quality of the drug product?
  2. For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?

2.3.S.5 Reference Standards

  1. How were the primary reference standards certified?

2.3.S.6 Container Closure System

  1. What container closure system is used for packaging and storage of the drug substance?

2.3.S.7 Stability

  1. What drug substance stability studies support the retest or expiration date and storage conditions for the drug substance?

2.3.P DRUG PRODUCT

2.3.P.1 Description and Composition 

  1. What are the components and composition of the final product? What is the function(s) of each excipient?
  2. Does any excipient exceed the IIG limit for this route of administration?
  3. Do the differences between this formulation and the RLD present potential concerns with respect to therapeutic equivalence?

2.3.P.2 Pharmaceutical Development

2.3.P.2.1 Components of the Product

2.3.P.2.1.1 Drug Substance
  1. Which properties or physical chemical characteristics of the drug substance affect drug product development, manufacture, or performance?
2.3.P.2.1.2 Excipients
  1. What evidence supports compatibility between the excipients and the drug substance?

2.3.P.2.2 Drug Product

  1. What attributes should the drug product possess?
  2. How was the drug product designed to have these attributes?
  3. Were alternative formulations or mechanisms investigated?
  4. How were the excipients and their grades selected?
  5. How was the final formulation optimized?

2.3.P.2.3 Manufacturing Process Development 

  1. This section is optional for a non-critical dose drug formulated in a solution or an immediate release dosage form
  2. Why was the manufacturing process described in 2.3.P.3 selected for this drug product?
  3. How are the manufacturing steps (unit operations) related to the drug product quality?
  4. How were the critical process parameters identified, monitored, and/or controlled?
  5. What is the scale-up experience with the unit operations in this process?

2.3.P.2.4 Container Closure System

  1. What specific container closure attributes are necessary to ensure product performance?

2.3.P.3 Manufacture

For All Products

  1. Who manufactures the drug product?  
  2. What are the unit operations in the drug product manufacturing process?
  3. What is the reconciliation of the exhibit batch?
  4. Does the batch formula accurately reflect the drug product composition?  If not, what are the differences and the justifications?
  5. What are the in-process tests and controls that ensure each step is successful? 

If Product is Not a Solution

  1. What is the difference in size between commercial scale and exhibit batch? Does the equipment use the same design and operating principles? 
  2. If the Product is a NTI Drug or a Non-Simple Dosage Form
  3. In the proposed scale-up plan what operating parameters will be adjusted to ensure the product meets all in-process and final product specifications? 
  4. What evidence supports the plan to scale up the process to commercial scale? 

2.3.P.4 Control of Excipients

  1. What are the specifications for the inactive ingredients and are they suitable for their intended function?

2.3.P.5 Control of Drug Product

  1. What is the drug product specification? Does it include all the critical drug product attributes?
  2. For each test in the specification, is the analytical method(s) suitable for its intended use and, if necessary, validated? What is the justification for the acceptance criterion?

2.3.P.6 Reference Standards and Materials

  1. How were the primary reference standards certified?

2.3.P.7 Container Closure System

  1. What container closure system(s) is proposed for packaging and storage of the drug product? Has the container closure system been qualified as safe for use with this dosage form?

2.3.P.8 Stability

  1. What are the specifications for stability studies, including justification of acceptance criteria that differ from the drug product release specification?
  2. What drug product stability studies support the proposed shelf life and storage conditions?
  3. What is the post-approval stability protocol?

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