Quality overall summary (QOS) template for CEP applications

Quality overall summary (QOS) template for CEP applications, Certificate of Suitability (CEP), Monographs, European Pharmacopoeia.

Quality overall summary (QOS) template serves as a starting point for summarizing the dossier content supporting an initial Certificate of Suitability (CEP) request. Adapt and adjust it to fit the specific details of your substance and application.

Quality overall summary (QOS) template for Certificate of Suitability (CEP) applications

Purpose:

The QOS provides a concise overview of the overall control strategy for the substance’s quality and demonstrates how regulatory requirements are met. It serves as a crucial document for CEP reviewers to quickly grasp the key information regarding the substance’s quality and rationale behind the control strategy.

Structure:

The QOS should include relevant information from each Module 3 section, maintaining consistency between the QOS and Module 3 content. Focus on core information about the substance’s quality and scientific justifications supporting the control strategy. This is not a place for verbatim repetition of Module 3 details.

Content:

Answer the yes/no questions and fill-in tables as needed, tailoring the template to provide clarity and completeness. You may amend the template if necessary to effectively present the information. Remember, not all data tables from Module 3 will be directly applicable to the QOS’s level of summarization. Additionally, separating the QOS into open and restricted sections is discouraged.

Key sections:

• General Information: Introduce the substance, its intended use, and any relevant quality standards.
• Manufacturing Process: Briefly describe the manufacturing process steps and critical quality attributes (CQAs).
• Control of Starting Materials and Reagents: Outline the quality controls for starting materials and reagents.
• In-Process Controls: Summarize the in-process controls implemented to monitor and ensure process consistency.
• Finished Product Specifications: Specify the acceptance criteria for the final product based on relevant parameters.
• Analytical Methods: Briefly describe the analytical methods used for testing and their validation status.
• Stability Studies: Summarize the stability studies conducted and their conclusions regarding product shelf life.
• Impurities: Identify and characterize potential impurities, outlining their control strategies.
• Packaging and Labeling: Describe the packaging and labeling specifications for the substance.
• Regulatory Considerations: Address any relevant regulatory requirements and how they are met.

Remember:

• The QOS should be concise and easily understandable, avoiding excessive technical jargon.
• Focus on clarity and completeness, providing enough information for reviewers to grasp the essential aspects of the control strategy.
• Maintain consistency between the QOS and Module 3 content while tailoring the QOS to its specific purpose.

Quality overall summary (QOS) template for CEP applications

2.3.S Drug SUBSTANCE

2.3.S.1 General Information

• Maximum daily dose (MDD)
• Route of administration
• Duration of treatment (at least indicate an applicable range: < 1 month, >1 – 12 months, >1 – 10 years, or >10 years to lifetime), used for the development of the control strategy and specifications presented (Indicate the source of this information)

2.3.S.1.3 General Properties

Briefly information of physico-chemical properties (e.g. polymorphic form).

2.3.S.2 Manufacturer

2.3.S.2.1 Manufacturer(s) and sites involved in the entire process

Site	Role of the site :
Name and address only, no other contact information or coordinates	List all manufacturers involved in manufacturing operations after the introduction of starting materials, including contractors, intermediate manufacturers and other proposed production sites or facilities, quality control / in process testing sites, milling, micronisation and sterilisation sites in case a corresponding grade is claimed.

2.3.S.2.2 Description of Manufacturing Process and Process Controls
(a) Process outline:
Give a brief narrative step-by-step description of the manufacturing process from the starting materials to the final substance.
The chemical reactions and at least critical purifications procedures should be mentioned, the in-process controls as well as identification of steps, intermediates, reagents and solvents used should be indicated. Do not include the detailed description from dossier in Module 3, hence amounts of materials or details of process operative parameters do not need to be reported here.
Indicate the maximum batch size (or range) for the final substance.

(b) Synthesis scheme / or diagram for non-synthetic process
Provide the synthetic process scheme, from the starting materials to the final substance including the structural formula for the starting materials and all intermediates (indicate when intermediates are not isolated). Mention all solvents, reagents, catalysts and process-aids used in the process.
Include names or numbering of all steps. In case a convergent synthesis is followed the scheme should reflect all the synthetic branches. For starting materials and intermediates include chemical name and in-house code names if any (in particular in case different code names linked to different manufacturers or sites are used in the dossier, Module 3). Mass / MW values do not have to be reported here.

If possible, yet depending on the complexity of the process, consider if the scheme/diagram could be presented in a condensed way (e.g. within a single page).

(c) Alternative processes, if applicable: explain the differences from the main process

(d) Blending: explain conditions, if performed.

(e) Recovery of materials: comment shortly on the conditions of recovery and their controls, identify steps recovered from and where re-introduced.

(f) Reprocessing: briefly describe the reprocessing procedures, and identify the corresponding trigger quality attributes.

2.3.S.2.3 Control of Materials
(I) Starting material(s)
For each starting material include a short justification for the selection of the material as per ICH Q11 and respective ICH Q11 Q&A.
Complete sections (a) to (d).
(a) Chemical name, in-house name.
(b) List all manufacturers

Manufacturers name and address

(c) Provide a flow-diagram of the starting materials synthesis including mention of solvents,
reagents and catalysts used.
(d) Specifications:

Test	Acceptance criteria	Analytical method

(II) Other materials

• Quality of water: specify the quality grade of water when used in the last steps of process.

2.3.S.2.4 Controls of Critical Steps and Intermediates
(a) Indicate critical steps if any, and in-process controls which are performed

Test	Acceptance criteria	Analytical method

(b) Control of intermediates:
List the controls performed

Test	Acceptance criteria	Analytical method

2.3.S.2.5 Process Validation and/or Evaluation
(a) For aseptic processing and sterilization only: shortly report process validation and/or evaluation studies outcomes.
(b) In case the Ph. Eur. monograph does present a Production section: explain shortly how compliance is ensured.

(c) In case the substance is manufactured by an enhanced approach, Quality by Design, continuous manufacturing or process analytical technology concepts derived from ICH Q8 – Q11: summaries relevant process validation activities.

2.3.S.3 Characterisation

2.3.S.3.1 Elucidation of structure and other characteristics
List studies performed for elucidation of the structure, as relevant.
In case a specific grade is claimed indicate briefly the available evidence data for the specific physical characteristic (examples: polymorphism or information on particle size distribution).

2.3.S.3.2 Impurities
This section should make clear which control strategy is applied.
(I) Related substances
Identify all the potential and actual impurities, their origin and fate in the process, and briefly justify the specification applied or the absence of control.

Impurity	Origin	Company acceptance criteria	Ph. Eur. acceptance criteria	Test results at release	Test results at in stability studies	Analytical method
Impurity X
Unspecified impurities
Total

In addition for impurities not listed in the Ph. Eur. monograph and present above the reporting threshold /disregard limit, shortly discuss on the ability of the method(s) of the monograph to control them, if relevant briefly report on the corresponding retention time, and limits of detection/quantification.

Mutagenic impurities:
(a) Summarise the specific discussion on potential mutagenic impurities arising from the synthesis of the final substance, its starting materials and degradation products, with reference to ICH M7 guideline or the applicable guideline in veterinary products. Briefly justify each impurity classification as per ICH M7 guideline section 6 i.e. class 1 to 5 and, as applicable, the applied control strategy i.e. identify and justify the control approach option according to ICH M7 section .

8.1. Justification should be supported by carryover data as needed

Impurity	Origin	Class	Control option justification, acceptance criteria

(b) Report a brief summary and conclusions of the risk assessment addressing the possible formation of N-nitrosamine impurities and, as relevant, describe the control strategy applied.

(II) Other impurities
(a) Briefly report on the need for control of other impurities e.g. residues of reagents.

(b) Any material derived from a human /animal source is used during the manufacture (Yes/ No).
If yes, identify the origin/use and, in case of an animal origin susceptible to TSE contamination, indicate where information regarding compliance with Ph. Eur. General Monograph 1483 is placed.

(III). Residual solvents
(a) List all solvents used in the process and the relevant control strategy:

Solvent	Used in step x/y	ICH solvent classification and limit	Proposed limit	Test results	LOD /LOQ of the method (ppm)

(b) Briefly report how the risk for class 1 solvents as potential contaminant in relevant process solvents is taken into consideration.

(IV) Elemental impurities
(a) Comment briefly on identified risks, on intentionally introduced elements and, if relevant, on their control.

Element intentionally introduced	Used in step x/y	limit in the final substance	Analysis results	Analytical method, LOD (ppm)

(b) A risk assessment on elemental impurities has been performed according to ICH Q3D and the EDQM Implementation guideline PA/PH/CEP (16) 23 (Yes/ No).

2.3.S.4 Control of the Substance

2.3.S.4.1 Specification / 2.3.S.4.2 Analytical Procedures
List the specifications based on Ph. Eur. monograph and any additional ones

Test	Acceptance criteria	Analytical method
Description
Identification
Related substances
…

2.3.S.4.3 Validation of Analytical Procedures
(a) For non-Ph. Eur. test methods briefly report on the analytical validation performed (tabular summary).
(b) For a method used as alternative in place of the relevant Ph. Eur. monograph method: indicate how study demonstrates equivalence between the in-house and the monograph’s method i.e. cross-validation.

2.3.S.4.4 Batch Analyses
Summarise batch data provided in Module 3, as relevant, supporting different grades of the substance and demonstrating equivalence for multiple sites or alternative routes of manufacture

Test	Acceptance criteria	Results of Batch Number Batch size Manufacturing date Production site(s)	Results of Batch Number Batch size Manufacturing date Production site(s)	Results of Batch Number Batch size Manufacturing date Production site(s)
Appearance
Identification
Related substances
…
…

2.3.S.4.5 Justification of Specification
(a) Shortly comment on the specification compared to the requirements of the Ph. Eur. monograph, especially on additional impurities that cannot be controlled by the tests of the monograph.

(b) If a test of the Ph. Eur. monograph for a specific impurity is not performed because the impurity is not possible to be formed or introduced according to the described manufacturing process, briefly present the scientific rationale.

2.3.S.5 Reference Standards or Materials

Confirm whether the primary reference standards used are the Ph. Eur. CRS. and mention any other standards employed.

2.3.S.6 Container Closure System

(a) Describe the packaging including alternative options. If relevant indicate composition of multilayer components, colour /opacity of plastic containers or glass, addition of inert gas, oxygen scavenger or desiccant:

	Composition / nature of the material(s) :
Primary
Secondary
Tertiary

(b) For primary packaging materials list the current EU regulations/directives and appropriate Ph. Eur. monographs which are declared to be complied with.

2.3.S.7 Stability

A re-test period is requested (Yes/ No), if yes, indicate the duration and any specific storage conditions.

2.3.S.7.1 Stability Summary and Conclusions
Indicate the stability testing studies performed:

Study conditions	Accelerated conditions	Long-term conditions	Intermediate conditions (if any)
	e.g. 40°C±2°C, 75% ± 5% RH	e.g. 25°C± 2°C, 60% ± 5% RH	—
Data available	x months, number of batches	x months, number of batches	x months, number of batches
Batch size
Manufacturing date
Packaging	Indicate if it is the same as for commercial purpose

Additional summary tables may be needed to cover different container closure systems or climatic zones.

• Briefly report on control parameters excluded from stability studies compared to those at
  release.
• Any significant change has been observed in the parameters tested (Yes/ No), briefly comment
  on the available study results in support of the requested re-test period.

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