Manufacturing Process Development as per ICH -Q11
The approaches to developing and understanding the manufacturing process of the drug substance, and provides guidance on what information should be provided in Module 3 of the Common Technical Document (CTD) Sections 3.2.S.2.2 –3.2.S.2.6 (ICH M4Q).
All the aspects of development and manufacture that pertain to drug substance, including the presence of steps designed to reduce impurities.
and also ICH Q11 clarify the principles and concepts that the development and manufacture of drug substance discribe in ICH Guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality System (Q10).
As per dis guideline the company can choose to follow different approaches in developing a drug substance. One is the terms “traditional” and “enhanced” are used to differentiate two possible approaches.
Second the traditional approach, set points and operating ranges for process parameters are defined and the drug substance control strategy is typically based on demonstration of process reproducibility and testing to
meet established acceptance criteria.
Enhanced approach consider the risk management and scientific knowledge that are used more extensively to identify and understand process parameters and unit operations that impact critical quality attributes (CQAs) and develop appropriate control strategies applicable over the life cycle of the drug substance which may include the establishment of design space(s).
A company can use either a traditional approach or an enhanced approach to drug substance development,
or a combination of both.
Manufacturing Process Development
The goal of manufacturing process development for the drug substance is to establish a commercial manufacturing process capable of consistently producing drug substance of the intended quality.
Drug Substance Quality Link to Drug Product
The required quality of the drug substance should be determined through consideration of its use in the drug product as well as from knowledge and understanding of its physical, chemical, biological, and microbiological properties or characteristics, which can influence the development of the drug product (e.g., the solubility of the drug
substance can affect the choice of dosage form).
Process Development Tools
Quality Risk Management (QRM as per ICH Q9) can be used to assessing for the design of the manufacturing process,quality attributes ,manufacturing process parameters, and increasing the assurance of routinely producing batches of the intended quality. QRM can be carried out during the development process and repeated as greater knowledge and understanding.
Approaches to Development
As per ICH Q8 the “Strategies for product development vary from company to company and from product to product. The approach to, and extent of, development can also vary and should be outlined in the submission.”
These concepts apply equally to the development of the drug substance manufacturing process. An applicant can choose either a traditional approach or an enhanced approach or a combination of both.
Manufacturing process development should include, at a minimum, the following elements:
• Identifying potential CQAs associated with the drug substance so that those characteristics having an impact on drug product quality can be studied and controlled;
• Defining an appropriate manufacturing process;
• Defining a control strategy to ensure process performance and drug substance quality.
An enhanced approach to manufacturing process development would additionally include the following elements:
1.A systematic approach to evaluating, understanding and refining the manufacturing process, including;
- Identifying, through e.g., prior knowledge, experimentation and risk assessment, the material attributes (e.g., of raw materials, starting materials, reagents, solvents, process aids, intermediates) and process parameters that can have an effect on drug substance CQAs;
- Determining the functional relationships that link material attributes and process parameters to drug substance CQAs;
2.Using the enhanced approach in combination with QRM to establish an appropriate control strategy which can, for example, include a proposal for a design space(s).
Drug Substance Critical Quality Attributes
A Critical Quality Attributes is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
Critical Quality Attributes of Drug substance typically include those properties or characteristics that affect identity, purity, biological activity and stability of drug substance.
Impurities are an important class of potential drug substance CQAs because of their potential impact on drug product safety. For chemical entities, impurities can include organic impurities (including potentially mutagenic impurities), inorganic impurities e.g., metal residues, and residual solvents.
Biotechnological/biological products, for example, typically possess such a large number of quality attributes that it might not be possible to fully evaluate the impact on safety and efficacy of each one. Risk assessments can be performed to rank or prioritize quality attributes.
Prior knowledge can be used at the beginning of development and assessments can be continously updated with development data (including data from nonclinical and clinical studies) during the life-cycle.
Linking Material Attributes and Process Parameters to Drug Substance CQAs
During manufacturing process development should be identify the material attributes (e.g. of raw materials, starting materials, reagents, solvents, process aids,intermediates) and process parameters should be controlled and we can be used Risk assessment to identify the material attributes and process parameters that having potential effect on drug substance CQAs.
The risk assessment can help to define the elements of the control strategy that pertain to materials upstream from the drug substance that include an assessment of manufacturing process capability, attribute detectability, and severity of impact as they relate to drug substance quality.
when assessing the link between an impurity in a raw material or intermediate and drug substance CQAs, the ability of the drug substance manufacturing process to remove that impurity or its derivatives should be considered in the assessment. The risk related to impurities can usually be controlled by specifications for raw material/intermediates and/or robust purification capability in downstream steps.
The risk assessment can also identify CQAs for which there are inherent limitations in detectability in the drug substance (e.g., viral safety).In these cases, such CQAs should be controlled at an appropriate point upstream in the process.
For chemical entity development, a major focus is knowledge and control of impurities.It is important to understand the formation, fate (whether the impurity reacts and changes its chemical structure), and purge (whether the impurity is removed via crystallisation, extraction, etc.) as well as their relationship to the resulting impurities that end up in the drug substance as CQAs. The process should be evaluated to establish appropriate controls for impurities as they progress through multiple process operations.
In a traditional approach, material specifications and process parameter ranges can be based primarily on batch process history and univariate experiments.
In a enhanced approach can lead to a more thorough understanding of the relationship of material attributes and process parameters to CQAs and the effect of interactions.
Risk assessment can be used during development to identify those parts of the manufacturing process likely to impact potential CQAs. Further risk assessments can be used to focus development work in areas where better understanding of the link between process and quality is needed. Using an enhanced approach, the determination of
appropriate material specifications and process parameter ranges could follow a sequence such as the one shown below:
• Identify potential sources of process variability;
• Identify the material attributes and process parameters likely to have the greatest impact on drug substance quality. This can be based on prior knowledge and risk assessment tools
• Design and conduct studies (e.g., mechanistic and/or kinetic evaluations,multivariate design of experiments, simulations, modelling) to identify and confirm the links and relationships of material attributes and process parameters to drug substance CQAs;
• Analyse and assess the data to establish appropriate ranges, including Small-scale models can be developed and used to support process development studies.
The development of a model should account for scale effects and be representative of the proposed commercial process. A scientifically justified model can enable a prediction of quality, and can be used to support the extrapolation of operating conditions across multiple scales and equipment
Design space is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by
the applicant and is subject to regulatory assessment and approval (ICH Q8).
The considerations for design space for an enhanced approach to the development of the drug product are applicable to drug substance. The ability to accurately assess the significance and effect of the variability of material attributes and process parameters on drug substance CQAs, and hence the limits of a design space,depends on the extent of process and product understanding.
Design space can be developed based on a combination of prior knowledge, first principles, and/or empirical understanding of the process. Models (e.g., qualitative,quantitative) can be used to support design spaces across multiple scales and equipment.
A design space might be determined per unit operation (e.g., reaction, crystallisation,distillation, purification), or a combination of selected unit operations. The unit operations included in such a design space should generally be selected based on their impact on CQAs and do not necessarily need to be sequential.
The linkages between process steps should be evaluated so that, for example, the cumulative generation and
removal of impurities is controlled. A design space that spans multiple unit operations can provide more operational flexibility.
The development and approval of a design space for some biotechnology/biological drug substances can be challenging due to factors including process variability and drug substance complexity (e.g., post-translational modifications). These factors can affect residual risk (e.g., potential for unexpected changes to CQAs based on uncertainties related to scale sensitivity) which remains after approval of the design space.
Depending on the level of residual risk, it may be appropriate for an applicant to provide proposals on how movements within a design space will be managed post approval. These proposals should indicate how process knowledge, control strategy and characterization methods can be deployed to assess product quality following movement within the approved design space.
Submission of Manufacturing Process Development Information
The information provided on the development of the drug substance manufacturing process (primarily in Section 3.2.S.2.6 of the application) should identify significant changes during process development, link relevant drug substance batches with the developmental stage of the manufacturing process used to prepare them, and explain
how prior knowledge, risk assessments, and other studies (e.g., experimental, modelling, simulations) were used to establish important aspects of the manufacturing process and control strategy. Process development information should be logically organised and easy to understand. Manufacturers can present process development information in a number of different ways, but some specific recommendations are provided below for consideration.
Overall Process Development Summary
It is recommended that the manufacturing process development section begin with a narrative summary that describes important milestones in the development of the process and explains how they are linked to assuring that the intended quality of the drug substance is achieved. The following should be included in the summary:
• List of drug substance CQAs;
• Brief description of the stages in the evolution of the manufacturing process and relevant changes to the control strategy;
• Brief description of the material attributes and process parameters identified as impacting drug substance CQAs;
• Brief description of the development of any design spaces.
Following the overall process development summary, the manufacturing process development section should include more comprehensive information, as recommended below.
Drug Substance CQAs
The CQAs of the drug substance should be listed, and the rationale for designating these properties or characteristics as CQAs should be provided.In some cases,can be justified by appropriately explains why other properties or characteristics that might be considered potential CQAs are not included in the list of CQAs.
Links or references should be provided to information submitted elsewhere in the submission (e.g., 3.2.S.3.1,Elucidation of Structure and other Characteristics) that supports the designation of these properties or characteristics as CQAs.
Manufacturing Process History
A brife description should be provided of significant changes made to the manufacturing process or site of manufacture of drug substance batches used in support of the marketing application (e.g., those used in nonclinical or clinical studies or stability studies in support of a marketing authorisation) and, if available, production-scale
The description should usually follow a chronological sequence ending with the proposed commercial process. Batch information (batch size or scale, site and date of manufacture, route and process used, and intended purpose [e.g., in a specified toxicology or clinical study]) and supporting data from comparative analytical testing on relevant drug substance batches should be provided or referenced.
For biotechnological/biological drug substances, the reason for each significant change should be explained, together with an assessment of its potential to impact the quality of the drug substance (and/or intermediate, if appropriate).
The manufacturing process history section should include a discussion of comparability during development as
described in ICH Q5E. A discussion of the data, including a justification for selection of the tests and assessment of results, should be included.
Testing used to assess the impact of manufacturing changes on the drug substance and the corresponding drug product can also include nonclinical and clinical studies. Cross-reference to the location of these studies in other modules of the submission should be included
Manufacturing Development Studies
The studies and risk assessments used to establish important aspects of the commercial manufacturing process and control strategy cited in the application should be listed (e.g.,in tabular form). The purpose or end use of each cited study or risk assessment should be provided.
Each cited study or risk assessment should be summarised with a level of detail sufficient to convey an understanding of the purpose of the study, the data collected, how it was analysed, the conclusions reached, and the impact of the study on the manufacturing process or further development of the manufacturing process. The
particular parameters and ranges studied should be described and discussed in relation to the proposed operating conditions or design space for the commercial manufacturing process.
The risk assessment tools and study results on which a design space is based should be adequately described.
Where development refers to specific prior knowledge, the relevant information and data should be provided and, where appropriate, the relevance to the particular drug substance should be justified.
Small-scale models used to support development of the commercial manufacturing process should be described.
Description of Manufacturing Process and Process Controls
The description of the drug substance manufacturing process represents the applicant’s commitment for the manufacture of the drug substance. Information should be provided to adequately describe the manufacturing process and process controls.
The description of the manufacturing process should be provided in the form of a flow diagram and sequential procedural narrative. The in-process controls for each step or stage of the process should be indicated in the description.
Scaling factors should be included for manufacturing steps intended to span multiple operational scales when the process step is scale dependent. Any design spaces in the manufacturing process should be included as part of the manufacturing process description.
Many biotechnological/biological products have complex upstream processes and use splitting and pooling to create a drug substance batch. An explanation of how batches of drug substance are defined by the manufacturer (e.g., splitting and pooling of harvests or intermediates) should be provided. Details of batch size or scale and batch numbering should be included.