Will The Updated CMC Guidelines Impact On Your Business?
Our overview will assist you in understanding the impact that the 2018 amendments will have on CMC guidelines. The updated CMC guidelines on the manufacture of the finished dosage form, CHMP/QWP/486/95, first issued in April 1996, were updated and the new version, EMA/CHMP/QWP/245074/2015, was made effective in February 2018.
CMC Guidelines Updated
The updated guideline is structured in the CTD format applied to Module 3 section 3.2.P.3 Manufacture.
The guideline was updated to provide clarification on the type and level of information that should be included in section 3.2.P.3 taking into consideration the ICH Q8 (R2) guidelines.
The description of the manufacturing process should;
- Include information on the critical steps
- Include information on the intermediates
- Demonstrate how pharmaceutical development, proposed control strategy and process validation are linked
- Consider the emergence of complex supply chains
- Consider issues with prolonged holding times
- Consider transportation conditions
The updated guideline applies to chemical and herbal medicinal products for human use. The general principles of the guideline apply to biological medicinal products, radiopharmaceuticals, and chemical investigational medicinal products. The updated guideline should be considered when submitting Manufacturing Authorisation applications and when submitting variations to the manufacturing processes of approved products.
Manufacturer(s) of Finished Dosage Form (3.2.P.3.1)
The information required on the manufacturers has been broadened to include contractors and sites where on-going stability is carried out if different from the named manufacturing sites.
Batch Formula (3.2.P.3.2)
The information required on the batch formula was broadened to include consideration for a range of batch sizes. The range should be stated and the batch formula for at least the largest and smallest batch sizes should be provided. A justification for the range of batch sizes with adequate information to demonstrate that the range does not adversely impact on the critical quality attributes (CQA) of the finished product in accordance with the guideline on process validation should be included.
The production batch size should be defined before any division into different presentations or packs. If the length of subsequent processes is considered critical, the worst-case scenario of the division should be indicated. A justification should be provided when combining sub-batches. Include information on the formula of each sub-batch and the number of sub-batches per intended batch size. It must be demonstrated that the final batch is homogeneous. If a batch is subdivided towards the end of a process due to equipment processing capabilities, this should be indicated. The number of sub-batches per intended batch size should be stated. In the case of continuous manufacturing, provide information on how a batch is defined be that in terms of a period of time or quantity of product.
Include a reference to the quality standards of all ingredients used. The removal of ingredients from the product during the production phase has been broadened from solvents to also include gases and granulation liquids.
Description of the Manufacturing Process and Process Control (3.2.P.3.3)
The updated guideline includes the use of proposed design spaces that must be adequately identified and described. The manufacturing process description must be adequately justified by data generated during the development process. When wide ranges or the use of only upper and lower limits are described for the manufacturing process, a thorough discussion and/or scientific rationale must be provided.
When the results of full-scale manufacturing process validation are not available at submission, the process parameter settings identified during the process development should be provided. Proposed changes to the process parameters on completion of the full-scale process validation should be applied for using the variation process. The process environmental conditions should be included for submission where relevant, e.g. low humidity requirements for effervescent tablets.
The duration time for critical steps should be provided along with hold times where relevant, e.g. sterile products. Identify the steps at which process controls, intermediate tests, and finished product controls are carried out. Every finished product manufacturing process should have a control strategy suitable for its intended use, i.e. the control strategies for real-time release testing, proposed design spaces, continuous manufacturing processes or standard manufacturing processes will be different.
The expectation is that the process description will be comprehensive. The process steps should be sequentially described. Include batch size(s), operating principles for each unit operation, the working capacity of equipment where relevant, the appropriate process parameter for each step along with their target values and ranges. The process parameters that are important for process consistency and critical process parameters must be included. Supportive information must be identified as such and it’s use justified. The updated guideline provides an example of the detail required in the manufacturing description.
Technical adaptions in the Manufacturing Process
Under particular circumstances, such as the availability of equipment within a manufacturing site or the availability of equipment at another site where more than one manufacturer is proposed, it may be necessary to have a technical adaption to the manufacturing process. If used, the adaptation must be adequately justified and evidence must be supplied to demonstrate that all proposed steps will consistently produce any intermediates and the finished product that will comply with the in-process controls and finished product specifications respectively. Irrespective of the process used, the finished product must comply with the same release and shelf-life specifications.
The proposed technical adaptations should be outlined in a flow chart. A comparison of the adaptations should be provided. Where different manufacturing sites are proposed, the information should be provided in the same M3 section, but, differentiated for each site. It is not acceptable to use an alternative manufacturing process which is based on a different operating principle.
Controls of Critical Steps and Intermediates (3.2.P.3.4)
List all critical steps and intermediates identified during the development process. In-process controls, applied methods, and acceptance criteria should be included. For complex control strategies, include frequency of in-process controls, state how to release testing and product release decisions are made, state how unexpected deviations from the manufacturing process would be detected and managed. Include monitoring of established acceptance criteria. Justify the identification of critical and non-critical steps.
Storage of Intermediate and Bulk Products
Intermediates are often stored and sometimes transported while awaiting further processing. When confirmatory tests on intermediates are required before further testing, details of these tests should be provided. Hold time validation on the intermediates is generally considered a GMP issue, however, for some products such as sterile and biologicals, it may be necessary to provide details of hold time validation studies, transportation studies, and the suitability studies for the intermediate container closure system. State if storage required before final packaging and provide details on the environmental conditions e.g. temperature and humidity. State the maximum hold time or the maximum batch manufacturing time from the start of product manufacture to completion of packaging into the final primary container for marketing. Generally, if storage is longer than 30 days for dosage forms and more than 24 hours for a sterile product, this should be stated.
Process Validation and/or Evaluation (3.2.P.3.5)
For information on process validation requirements, refer to the Guideline on process validation for finished products- information and data to be provided in regulatory submissions EMA/CHMP/CVMP/QWP/BWP/70278/2012 Rev. 1.
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