1. What is the Normal Operating Range (NOR), and how should it be presented in marketing authorization application documents?

Answer: NOR is not a defined ICH term.NOR describes a region around the target operating conditions that encompasses normal operational variability (i.e., variability that cannot always be controlled). Multiple process parameters of the same process step can set a Normal Operating Range (NOR), but it is essential to understand the following two points:(1) NOR does not represent an active adjustment of the process;(2) The range of parameters covered by NOR must not affect the quality of the process output. Otherwise, a validated acceptable range (PAR) or multivariate design space should be established.

The purpose of using the Normal Operating Range (NORs) alone is not to introduce flexibility into production conditions, but rather to more accurately quantify the actual uncontrollable operational variability. Therefore, in marketing authorization application documents,NORs should be presented based on actual production data to reflect the controllable range of process parameters accurately.

2. What is a validated acceptable range (PAR)? How should PAR be justified and presented in marketing authorization documents?

Answer:PAR is defined as the characterization range of process parameters, within which operation, while keeping other parameters constant, will result in production that meets relevant quality standards (ICH Q8 R2).

PAR allows for active adjustment of one parameter while keeping other parameters within their normal operating range/ target values for that parameter.PAR can be presented in range form in the production process description of active pharmaceutical ingredients and/ or formulations (corresponding to CTD module 3 S.2.2 or P.3.3 sections).

Individual parameters’ PAR is proposed by the applicant and accepted for regulatory assessment and approval.

Regardless of whether the process parameters are considered critical process parameters (ICH Q8 R2), sufficient scientific justification must be provided for PAR.

When there are interactions between different parameters, and the acceptable range of one process parameter depends on the setting of another parameter, such parameters should be included in the design space. An alternative is to define PAR for only one of the parameters in the process description, while other parameters are limited to target operating conditions or NOR range..

PAR can initially be established under conditions less than commercial production scale. If so, the applicant must ensure PAR is independent of production scale and applicable to different production sites in relevant cases. If necessary, verification of PAR at commercial scale can be included in the post-approval verification plan.

Operating within an approved PAR is not considered a change to the marketing authorization documents. Adjusting target values within the registered PAR range can be managed under the company’s drug quality system without initiating regulatory action. Therefore, there is no need to specifically indicate target set values in the registered PAR; however, if indicated, adjustments do not require a change application. Any unexpected results should be reported to the authorities immediately. Operations exceeding PAR range will be considered a change and require initiation of the regulatory approval change process.

Considerations during the development phase (module 3 S.2.6/ P.2.3 sections): As part of process understanding and development, multiple PARs can be proposed and studied.

3. What is the design space (DSp), and how should it be justified and presented in marketing authorization documents?

Answer: The design space is defined by input variables (such as material attributes) and process parameters in multidimensional combinations and interactions that have been demonstrated to ensure product quality. Operating within the approved design space is not considered a change, but exceeding the design space is considered a change, typically requiring initiation of the regulatory approval change process. The design space is proposed by the applicant and must be assessed and approved by the regulatory authority.(ICH Q8 R2).

The design space can involve individual independent process steps, and can also encompass parameters of multiple process steps. The design space can be supported by appropriate intermediate controls, or it may only require operation within the design space to ensure the quality of the output material. The boundaries of the design space can be defined solely by the range of process parameters, input material attributes or a combination of both.

Material attributes and process parameters that may affect quality but are not covered by the design space range must be controlled through their quality standards or target values/NOR . Critical processes must be included in the formal design space, even if they have been controlled. For process parameters that have been proven to be non-critical within their study range (i.e., non-critical process parameters), they can be defined outside the formalDSp through target values or range definitions.

Justification for the establishment ofDSp should be provided in the development of active pharmaceutical ingredients and/ or formulations, with the level of detail depending on the significance or impact of theDSp. The following aspects should be considered:

·DSp represents a parameter range that is much wider than what is typically accepted asNOR?

·Are certain areas of theDSp associated with higher quality risks than others?

·What is the contribution of other elements of the control strategy (such as intermediate controls, process analytical technology (PAT), and downstream process controls) to ensuring the quality of the output material?

It is essential to study theDSp parameter interactions among multiple variables. Especially when the acceptable range of one parameter in theDSp depends on other parameters, in-depth studies must be conducted, including considerations of scale factors. If it is claimed that there are no interactions between parameters, sufficient scientific evidence must be provided.

The development of the design space (DSp ) should be guided by its significance and, where appropriate, by risk management.

4. How to manage post-approval changes to an approved design space?

Answer: The extension of the design space (DSp ) should be submitted as Class II changes (B.I.e.1 orB.II.g.1). “Extension“ should be understood as:1) introducing new material attributes or process parameters,2) extending the range of existing material attributes or critical process parameters.

If the change has been predefined through an approved post-approval change management protocol (PACMP), it can be submitted as IA _in class or IB class notification (B.I.e.5 orB.II.g.5). According to the change classification guidelines, changes anticipated in thePACMP for biological/ immunological products are defaulted to IB class.

Typically, restrictions on the approved design space are only required when it is found that part of theDSp cannot produce satisfactory quality materials. Such production process changes should be submitted as Class II changes (B.I.a.2.b orB.II.b.3.b): that is, substantial changes to the process that may have a significant impact on product quality, safety, or efficacy.

Changes to input material attributes (quality standards) or process parameter settings/ ranges may be related toDSp, even ifDSp does not explicitly cover these parameters. For example,DSp establishment may be based on the condition that other non-critical process parameters (proven to be non-critical within the study range) must remain constant or operate within their range. Changes to such parameters must be submitted according to the change classification guidelines. Depending on the nature of the change and the product type, some changes may be submitted as IA class immediate notifications, while others must be handled as IB class notifications. However, in any case, the changed process must ensure that product quality, safety, and efficacy are equivalent to the original process and must not negatively impact the reproducibility of the process, while demonstrating that the criticality of the relevant parameters has not changed.

Regardless of whether it involves the design space, changes related to production site changes are subject to the same change classification. However, when a production site change occurs, the continued applicability of the registered design space must be reassessed.

It should be noted that this Q&A document is based on the current change classification system and follows the operational details outlined in the following regulations: the European Commission Regulation No. 1234/2008 (adopted on November 24, 2008) regarding the review of changes to marketing authorizations for human and veterinary medicinal products, including the procedural details specified in Chapters II, III, and IV; guidelines for classification standards, implementation conditions, and application document requirements for various types of changes.

5. In marketing authorization documents, what types of process flexibility are generally acceptable, regardless of whether NOR, PAR, or DSp are mentioned?

Answer: Process flexibility depends on how the production process and its development are presented in the marketing authorization application documents. Regardless of the development strategy used, the level of detail in the production process description must meet the same requirements.

Each step of the process should include necessary details, clearly listing appropriate process parameters and their target values or ranges. The establishment of the design space is optional. If scientifically justified, flexible production processes can be registered (i.e., parameter ranges), or fixed process parameters can be chosen. However, if a flexible production process (i.e., a range of process parameters wider than what is typically accepted asNOR, or a range of input material attributes that may affect process output quality) needs to be registered, it should be established based on the design space framework. Refer to Q&A#3, which states:DSp justification must correspond to the actual degree of flexibility it represents, the quality impact of the, and the risk level.

The process description is considered part of the overall control strategy in the application documents. Therefore, during the evaluation process, the necessary level of detail will be considered based on specific circumstances, for example, based on the applicability of any supportive process controls,PAT analysis, or downstream process and control. In general, unilateral parameter ranges (e.g., only upper limit ranges) represent significant flexibility and must be justified by scientific evidence.