EMA´s Questions and Answers relating to Flexibility in Manufacturing Conditions

The European Medicines Agency (EMA) published Questions and Answers (Q&As) on "Improving the understanding of NORs, PARs, DSp and normal variability of process parameters" on July 13, 2017. The four-page document contains the following five Q&As:

• What is a Normal Operating Range (NOR) and how should NORs be presented in the marketing authorization dossier?

NOR (which is not an established ICH term) describes a region around the target operating conditions that contains common operational variability (variability that can’t always be controlled). NORs alone are not intended to introduce flexibility in the conditions for manufacturing but they can better quantify the actual uncontrollable operational variability of process parameters and therefore should be presented in marketing authorizations as what is practically achievable.

• What is a Proven Acceptable Range (PAR) and how should PARs be justified and presented in the marketing authorization dossier?

The PAR is defined as a "characterized range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria" (ICH Q8). PARs could be presented in the description of the manufacturing process of the drug substance (DS) and/or the drug product (DP) (in S.2.2 or P.3.3 of the Module 3, respectively) as ranges. Working within the approved PAR is not considered as a change. Changes to the target value within the registered PAR can be managed under the company’s Pharmaceutical Quality System (PQS) without regulatory action. Movement out of the PAR is considered to be a change and will require a post approval change process.

Where interaction effects between different parameters exist and the acceptable range for one process parameter depends on the setting of another parameter, the parameters should be included in a Design Space (see below).
Considerations for development (S.2.6/ P.2.3 of Module 3): Several PARs can be presented and investigated as part of the process understanding and development.

• What is a Design Space (DSp) and how should DSps be justified and presented in the marketing authorization dossier?

The DSp is defined by 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 approved DSp is not considered as a change. Movement out of the DSp is considered as a change and would normally require a regulatory post approval change process. The DSp is proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8).

A DSp can be restricted by ranges of process parameters only, input material attributes only, or a combination of process parameters and input material attributes. The justification of a DSp should be presented in the development of the manufacturing process of the DS and/or DP (S.2.6 or P.2.3 of Module 3, respectively). Regarding the required level of details the following should be considered:

• Does the DSp represent parameter ranges that are much wider than what would normally be accepted as NORs?
• Does any area of the DSp represent greater risk to quality than the rest of the DSp?
• To what extent do other elements of the control strategy contribute to ensuring output material quality? Examples include in-process controls,

PAT analytics and downstream processes and controls. If it is claimed that no interaction exists between (process) parameters, this should be adequately justified. Additionally, the development of the DSp should be based on risk management principles (ICH Q9).

• How to manage post-approval changes to approved DSps?

An Extension (i.e. introduction of new material attributes or process parameters, extension of the range of existing material attributes or critical process parameters) of a DSp should be submitted as a Type II variation (B.I.e.1 or B.II.g.1).

If the change has already been described in an approved post-approval change management protocol (PACMP), depending upon what was agreed, the change can either be submitted as a Type IAin or IB notification (B.I.e.5 or B.II.g.5). According to the variations classification guideline, changes foreseen in PACMP for a biological/immunological medicinal product are Type IB.

Restrictions to an approved DSp would typically only be necessary if part of the DSp was discovered to not produce satisfactory quality material. Substantial changes to a process that may have a significant impact on the quality, safety or efficacy of the product should be submitted as a Type II variation (B.I.a.2.b or B.II.b.3.b). Some changes to specifications or process parameters can be relevant to the DSp, even if the DSp does not specifically cover these parameters. These changes should be sought in accordance with the variations classification guideline, where, depending upon the nature of the changes and type of product, some will be possible as Type IA, whereas others will be possible as Type IB notifications. The variation categories related to changes to manufacturing sites apply regardless of DSp or not. "However, the continued relevance of any registered DSp should be considered whenever there is a manufacturing site change."

• What type of process flexibility can be acceptable in the marketing authorization dossier, regardless of any mentioning of NOR, PAR or DSp?

The EMA says, "the degree of process flexibility is dependent upon how the manufacturing process and its development is presented in the marketing authorization dossier. Irrespective of the development approach, the same requirements apply to the level of details in the manufacturing process description. Steps in the process should have the necessary details in terms of appropriate process parameters, along with their target values or ranges."

The establishment of a DSp is optional, but, "when a flexible manufacturing process is requested (i.e. ranges of process parameters that are wider than what would be accepted as a NOR; ranges of input material attributes that can affect the quality of the process output), then the process should be established within the framework of a DSp" (see also Q/A # 3). According to the EMA, "the process description is considered to be one element of the overall control strategy that is presented in an application". A one-sided parameter range (for example an upper range only) typically represents great flexibility and will have to be justified by scientific rationale.

Read more in EMA´s Questions and Answers document: "Improving the understanding of NORs, PARs, DSp and normal variability of process parameters" and in the "Guideline on Manufacture of the finished dosage form". Further information regarding these topics, also relating to analytical procedures, is expected with the release of the upcoming ICH Q12 Draft on "Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management".