ICH Q11 Slide Summary

This summarizes the ICH Q11 and covers the major topics of this guideline. For brief overview please go through the actual guideline present on ICH website.

1. ICH Q11 DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES (SUMMARY) Dr. Dilawar Hussain Pharm.D, MPhil Scholar Hamdard University (Faculty of Pharmacy)

2. Introduction, Scope and Target Harmonization of scientific and technical principles relevant to the design, development & manufacture of drug substances as part of a total control strategy designed to ensure product quality & consistency. Provide guidance on the information to be provided in CTD Sections 3.2.S.2.2 – 3.2.S.2.6 Provide further clarification on principles & concepts described in ICH guidelines Q6,Q8, Q9 & Q10 as they pertain to the specification, development and manufacture of drug substance. To establish a commercial manufacturing process capable of consistently producing drug substance of the intended quality.

3. Manufacturing Process Development General principles Drug substance quality link to drug product Process development tools Approaches to development Drug substance critical quality attributes (CQAs) Linking material attributes & process parameters to drug substance CQAs Design space Submission of information Overall process development summary Drug substance CQAs Manufacturing process history Manufacturing developmental studies

4. Process Development Tools Quality Risk Management (as described in ICH Q9) Assessing quality attributes & manufacturing process parameters. Increasing assurance of routine achievement of acceptable results. Risk assessment can be carried out early in the development and shall be repeated as knowledge & understanding increases on the process. Knowledge Management (as described in ICH Q10) Prior knowledge & development studies which include chemical, engineering principles and applied manufacturing experience.

5. Approaches to Development Approaches of development vary from company to company & product to product. Traditional Approach: Identifying potential CQAs having impact on product quality. Defining appropriate manufacturing process. Defining a control strategy to ensure process performance & quality. Enhanced Approach: Prior knowledge, experimentation and risk assessment. Determining linkage between material attributes & process parameters to CQAs. Using enhanced approach in combination with Quality Risk Management to establish appropriate control strategy. Traditional & Enhanced approaches are not mutually exclusive.

6. Drug substance Critical Quality Attributes (CQAs) CQA is a physical / chemical / biological / microbiological property that should be within an acceptance criteria to ensure the desired product quality. CQAs are used to guide process development. CQAs can be modified as the knowledge & process understanding increases. CQAs include the properties that can affect identity, purity, biological activity and stability. Impurities are important aspect of drug substance CQAs due to their potential impact on drug product safety.

7. Example: Linking Material Attributes and Process Parameters to Drug Substance CQAs - Chemical Entity Process design : Constant concentration of intermediate F Constant temperature during reflux Hydrolysis impurity NMT 0.30% Possible source of water during reflux: Water content of intermediate E

8. Based on risk assessment, parameters affecting hydrolysis : Time of reflux & Water content of intermediate E The reaction was expected to follow second-order kinetics according to the equation below: Where F refers to the concentration of intermediate F

9. Graphical presentation for linking the extent of hydrolysis to reflux time & water content of intermediate E :

10. Control strategy by Traditional approach : Dry intermediate E to a maximum water content of 1.0% Target -reflux time to 1.5 hours & maximum of 4 hours Control strategy by Enhanced approach : 2nd order rate equation can be integrated (Chemical Reaction Engineering, Levenspiel 2nd Edition, 1972)

11. Solving this equation for time (t) gives maximum allowable reflux time for any combination of water content & target level for hydrolysis impurity (Initial concentration of intermediate F in reflux mixture will be essentially constant

12. Description of manufacturing process and process controls Manufacturing process should be provided as follows, Process flow diagram, Sequential procedural narrative, In-process controls to be indicated in the process description, Scaling factors, if the process is scale dependant, Should include design space (if any).

13. Selection of starting materials and source materials General principles Selection of starting materials for synthetic drug substances Selection of starting materials for semi-synthetic drug substances Selection of source materials for Biotechnological / Biological products Submission of information Justification of starting materials selection for synthetic drug substances Justification of starting materials selection for semi-synthetic drug Substances Qualification of source materials for Biotechnological / Biological products

14. Control Strategy Control strategy is a planned set of controls, derived from product and process understanding, that assures process performance & quality. It include,  Control on material attributes  Controls implicit in the design of manufacturing process  In-process controls  Controls on drug substance

15. Process Validation / Evaluation Process validation involves the collection and evaluation of data, from the process design stage throughout production, that establish scientific evidence that a process is capable of consistently delivering a quality drug substance.  Process should be validated (ICH Q7) before commercial distribution.  Number of batches to be considered for validation depends on  The complexity of process,  Level of process variability,  Amount of experimental data / process knowledge available on specific process.  For non-sterile drug substances, results of process validation are not normally included in the dossier.

16. SUBMISSION OF MANUFACTURING PROCESS DEVELOPMENT & RELATED INFORMATION IN CTD FORMAT  Quality risk management and process development in 3.2.S.2.6.  Critical Quality Attributes in 3.2.S.2.6 & 3.2.S.3.1, 3.2.S.4.1 & 3.2.S.7 (if relevant).  Design space in 3.2.S.2.2, 3.2.S.2.4, 3.2.S.2.6, 3.2.S.4.5 (wherever the relevant justification is applicable).  Control strategy in 3.2.S.4.5 and can also be in 3.2.S.2.2, 3.2.S.2.4, 3.2.S.2.6, 3.2.S.4.1.

17. Life Cycle Management  Product & process knowledge should be managed from development through the commercial life of the product up to discontinuation.  Process performance, control strategy & suitability of design spaces should be periodically evaluated through out the life cycle and can be done as a part of Product Quality Review (ICH Q7).  It includes process development, technology transfer, process validation and change management activities.  Any changes within the design space (if submitted in DMF) does not require any approval by regional regulatory authorities.  There should be a systematic managing knowledge related to both drug substance & manufacturing process throughout the life cycle.