Technical articles

ICH Q12 application for the implementation of a change: example of a site transfer


The ICH Q12 guideline entitled « Technical and regulatory considerations for pharmaceutical product life cycle management” is a guideline intended to Marketing Authorisation Holder (MAH) for their post-approbation changes. These changes refer mainly to the quality part of the dossier (Module 3), linked to the Chemistry, Manufacturing and Controls (CMC). This guideline frames the relationship between the MAH and the Regulatory Agencies by bringing tools allowing for a better predictability of the change. ICH Q12 is also linked to the ICH Q8, Q9 and Q10 guidelines, dealing respectively with the pharmaceutical development and the application of Quality by Design (QbD), the quality risk management and the pharmaceutical quality system. The figure below summarizes the main solutions proposed by the ICH Q12 guideline: 

Regulatory categorization of the change Based on risk assessment, the categorization drives the type of communication expected between the MAH and the regulatory agencies 
The Established Conditions (ECs)  •       ECs are keys regarding the quality of the product
•       Any change on an EC must be communicated to the authorities according to the associated risk level 
•       ECs are legally binding 
Post-Approval Change Management Protocol (PACMP) •       The PACMP anticipates the change by sharing to the authorities the protocol of the expected change 
•       After a first approbation by the authorities, the industrial implements the change and submits the validation results to the authorities 
•       The second phase of approbation being faster, the PACMP allows therefore to be more predictive regarding the authorities’ position and finally, more efficient by optimizing the delays 
Product Life Cycle Management (PLCM) •       Main document that lists the different ECs and their regulatory categorization 
•       The document also describes how the product life cycle will be managed, notably about post-approbation commitments and PACMPs 
Pharmaceutical Quality System (PQS) and Change Management A PQS as described in ICH Q10 and compliant with the Good Manufacturing Practices (GMP) is necessary, particularly for manufacturing process changes
Relationship between the regulatory assessment and inspectionRegarding post-approbation changes, the ICH Q12 guideline highlights the complementary roles between the regulatory assessor and the GMP inspector
Structured approaches for frequent changes The guideline describes the strategy to be applied for frequent changes as well as the type of data that is expected 
Stability data supporting the changeImplementation of stability studies to assess the potential long-term impact of the changes 
  • Example of ICH Q12 application: the site transfer 

The site transfers represent for MAHs a major element in the drug product life cycle management, notably in the current reindustrialisation context. When a manufacturing process needs to be transferred, it is important for the MAH to demonstrate his product knowledge and the associated manufacturing process, as defined in ICH Q8:

1. Product definition 
Target Product Profile 
2. Identification of the Critical Quality Attributes (CQA)
List of CQAs (Critical Quality Attributes)
3. Identification of risk factors
List of Critical Material Attributes (CMA) and Critical Process Parameters (CPP)
4. Studies to mitigate the identified risks
Process robustness study or validation exercises 
5. Implementation of a Control Strategy (CS)
List of in-process controls (IPC), release tests and control of CMA/CPP

Once the product and process knowledge is demonstrated, several steps need to be followed to implement the change:

1. Definition of a multidisciplinary team  
Regulatory Affair, Quality Control, Validation, Industrial … 
2. Risk analysis   
Implementation of a risk analysis regarding the change between the site A and the site B 
3. Implementation of studies for the risk mitigation
Robustness study, filterability study, stability study, leachable study… 
4. Definition of the strategy for: validation, comparability, and stability studies 
•       The validation of the new process allows to demonstrate that the manufacturing process is under control 
•        The comparability exercises should demonstrate that the new process does not impact the product in terms of quality, safety and efficacy
•        The stability studies allow at last to assess the potential long-term impact of the change on the quality of the product 
5. Submission of the PACMP to the regulatory authorities
Description in the PACMP the whole strategy to manage the change: description of the change, risk analysis, strategy of validation, strategy of comparability, stability studies, complementary studies …
6. After approbation, execution of validation batches
•       Manufacturing of post-change batches at industrial scale in the same conditions than the future commercial lots 
•       Validation batches are potentially releasable   
7. Submission of results to the regulatory authorities
After data compilation, reporting to the agencies the results demonstrating that:
•       The new manufacturing process is under control in a validated state 
•       The product post-change attributes are comparable to those from the pre-change product 
•       The change does not impact the quality of the product after storage 
Update of the CTD sections impacted by the change (Module 3) 

The reporting of the results to the authorities could be done in the scope of a variation with a regulatory category (ex: variation type IB) that is less risky and more rapidly evaluable than a major variation (variation type II) that would be necessary without this two steps-strategy. This conducts to a faster and less risky review as the protocol will have already been approved previously. The MAH could thus accelerate for several months his regulatory pathway for the commercialization of his product.

Efor can support you in the implementation of your changes. Our experts can intervene at each step of your processes, in the regulatory or quality aspects, in compliance with the regulatory texts in force.

CMC section writing, project management, registration strategy, CMC statistics review, submission of variations, registration of pharmaceutical sites is a non-exhaustive list of activities managed by our operational consultants and Technical Direction.  

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