QbD: New EMA Guideline on Manufacture of the finished Dosage Form

The European Medicines Agency (EMA) published its new guideline on Manufacture of the finished dosage form on August 14, 2017. The guideline replaces the “Note for Guidance on Manufacture of the Finished Dosage Form” (dated April 1996) and will enter into effect on February 14, 2018.

The EMA says "the document provides clarification on the type and level of information that should be included in the common technical document module 3 of the marketing authorization application dossier with respect to the manufacturing process description. It also addresses aspects related to increased outsourcing and new manufacturing practices such as complex manufacturing chains or issues with prolonged holding times and transportation conditions". In addition, the content and QbD principles of the ICH Q8 guideline (pharmaceutical development) are also taken into account.

According to the EMA, the 15 pages of the guideline do not introduce new requirements on authorized medicinal products for human use. However, "after a marketing authorization (MA) has been approved, the authorization holder should, in respect of the methods of manufacture and control take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and controlled by means of generally accepted scientific methods".

The guideline contains a section "Definitions", defining Control Strategy (referring to ICH Q10), CPPs (Critical Process Parameter, referring to ICH Q8), CQAs (Critical Quality Attribute, referring to ICH Q8), Design Space (referring to ICH Q8), Hold Time (referring to Supplementary guidelines on GMP: General guidance on hold-time studies. In: Annex 4 (WHO Technical Report Series, No. 992)), RTRT (Real Time Release Testing, referring to ICH Q8), and a "References" section. Additionally, an Annex is included which shows an example of a manufacturing process description for a tablet (including granulation as process step) that aims at clarifying the regulatory expectations in terms of level of detail.

The following general aspects regarding the Description of Manufacturing Process and Process Controls are presented in the document:

• A narrative description of the full manufacturing process should be provided, accompanied by a flow chart describing each step of the process including in-process controls and showing at each stage where materials enter the process.
• If a design space is proposed, this should be clearly identified and described.
• The description of the manufacturing process should be adequately justified by development data, in particular as regards any process operating conditions or ranges. The description of a manufacturing process with wide ranges (wider than would normally be accepted as normal operating ranges) or described only by an upper or lower limit, generally requires a more thorough discussion and/or scientific rationale in the manufacturing process development section.
• Full scale manufacturing process validation is not requested at the time of application for certain types of products. If the result of such full scale study is not available at the time of submission, it is expected that process parameters' settings identified during manufacturing process development are laid down in the process description. In the event that any changes are required to the registered process parameters as a result of full scale process validation studies, these changes should be applied for via post approval variation, in accordance with the Variations Regulation.
• Where specifically relevant for the product, any required environmental conditions during manufacture should be stated e.g. low humidity for an effervescent tablet.
• Depending on the nature of the process and the product (e.g. sterile products), manufacturing durations of critical steps and hold times should be stated and justified.
• The steps at which process controls, intermediate tests or final product controls are conducted should be identified. Consideration should be given to what extent the assurance of quality of the finished product is founded on the manufacturing process itself. The significance of the process description and process controls as part of the overall control strategy should be outlined based on development studies and evaluated. Every finished product manufacturing process should have an associated control strategy suitable for its intended purpose. It is expected that different control strategies may be utilized in case real time release testing (RTRT) (see also EMA Guideline on RTRT, Draft Annex 17) is proposed, a design space is claimed, a continuous manufacture or a standard manufacture is performed.

The expected level of detail in the manufacturing process description is as follows:

• The process description is expected to be considered in relation to the control strategy and the manufacturing process should be described in relevant detail (since consistent quality of a product cannot be safeguarded by end product testing alone).
• The process description should be comprehensive, including process steps in a sequential manner with batch size(s), operating principle and equipment type(s) for each unit operation (mere reference to “suitable equipment” is not sufficient; conversely, details such as the serial number and model are not required).
• Equipment working capacity should be stated where appropriate. Steps in the process should have the necessary detail in terms of appropriate process parameters along with their target values or ranges (mere reference to “typical” set points is not acceptable). Where criticality is assigned to process parameters, the description of the process parameters should not only be restricted to CPPs, but also to those parameters important for manufacturing process consistency. Non-critical process parameters (also parameters for which the impact on quality attribute cannot be ruled out and which are considered to be important for the execution and/or the consistent performance of any particular process step, and consequently its output) should be described at an appropriate level of detail.
• Any information which is considered to be purely supportive should be justified and clearly identified.
• The same requirements apply to the level of detail in the manufacturing process description irrespective of the development approach, i.e. if the product has been developed by the minimal (traditional) or enhanced approach.
• In case of continuous manufacturing, the description of manufacturing process is expected to be provided in the same way.

Controls of Critical Steps and Intermediates:

• All critical steps and intermediates identified during the manufacture of the finished product should be listed in this section including any in-process controls, applied test methods and acceptance criteria.
• For complex control strategies (e.g. use of models for process control, continuous manufacturing) it should be clearly stated how release testing and product release decisions are made.
• Information of how unexpected deviations from the approved manufacturing process would be detected and managed should be provided to assure that the intended quality of the product is retained.
• The fact that a process parameter in a manufacturing step is controlled and verified to be within a range that does not affect a CQA does not make it non-critical by default. The justification for the identification of steps as critical or non-critical should be provided, including a link to experimental data in the pharmaceutical development section (e.g. risk assessment table), if applicable.

Storage of intermediate and bulk products:

• It should be stated whether storage is required before final packaging and if so, under what temperature, humidity or other environmental conditions. The level of information to be provided in the documentation is dependent on the nature of the bulk product.
• Where relevant, the maximum holding times of the bulk product or, alternatively, the maximum batch manufacturing time from start of product manufacture to completion of packaging into the final primary container for marketing should be stated, appropriately justified and supported by data.
• The reasons for any prolonged storage/processing times (e.g. more than 30 days for solid oral dosage forms and more than 24 hours for sterile products) should be stated and be consistent with GMP. Where relevant, stability data to support the holding time should be provided on at least two pilot scale batches.
• For transportation of bulk product (intermediate) between manufacturing sites guidance is given in GMP Annex 15 on how transport should be taken into consideration. The impact of short or longer excursions outside of the original storage conditions should be discussed and supported by accelerated or real time stability data.
• The suitability of the proposed bulk product (intermediate) container closure system for bulk storage (and transport if relevant) should be justified. The materials used for the bulk container closure system should be described along with the control specification for primary bulk packaging.

More information can be found in the EMA Guideline on manufacture of the finished dosage form and in EMA´s Questions and Answers document: "Improving the understanding of NORs, PARs, DSp and normal variability of process parameters".