30.04.2019 | LOGFILE Feature 16/2019

How to Manage ICH Q3D Risk Assessments with Change Control Management

How to Manage ICH Q3D Risk Assessments with Change Control Management

9 min. reading time | by Paulino Alonso

 

The ICH Q3D Guideline for Elemental Impurities came into effect on January 2018 for all the products for human use. To date, most of the companies have finished the implementation (maybe not at 100%, but ongoing) and now, the challenge is to keep the reports updated.

According to the ICH Q3D Guideline, the lifecycle management should follow the established rules for Quality Systems according to ICH Q10. It is crystal clear that “If changes to the drug product or components have the potential to change the elemental impurity content of the drug product, the risk assessment, including established controls for elemental impurities, should be re-evaluated”.

 

Taken from the ICH Q3D Guideline

The issue is then… how do I know if a change has the potential to change the elemental impurity content of the drug product?

In this post, we will try to help create a CHANGE CONTROL DECISION TREE through some examples ⇒ How to determine if a risk assessment of elemental impurities (ICH Q3D) requires to be updated:

The ICH Q3D risk assessments should consider all potential sources of contamination, and there are 5 sources of impurities that should have been considered in a risk assessment:

  • Manufacturing equipment and process;
  • water;
  • container closure system;
  • drug substance; and
  • excipients.

The fishbone diagram depicted in the ICH Q3D Guideline is useful for understanding the scope of the changes involved:

Taken from the ICH Q3D Guideline

As consequence, changes in all these sources should be considered in order to determine if a risk assessment report requires being re-evaluated. However, not all the changes have the potential to change the elemental impurity content in the drug product and therefore not all the changes would necessarily require a mandatory update… although you may voluntarily update the report if you want!

Let’s work now with examples (List of acronyms: CC = Change Control; EIs = Elemental Impurities; PW = Purified Water; CCS = Container Closure System):

  1. Changes in the manufacturing equipment and process
    1. Examples of CC that will require an update:
      • New equipment in the manufacturing site (when there was not identical equipment before). ⇒ Update all the risk assessment reports of the products that will be manufactured with this equipment
      • Change in the batch size (BS) or process that require the use of different equipment ⇒ Update the risk assessment report of the product with new BS/process.
    2. Examples of CC that will NOT require a mandatory update:
      • New equipment when there’s already an identical in place (new compressing machine identical to a previously assessed one, new stainless steel storage tank…).
      • Change in the batch size that does not require a different process or equipment (such as additional sub-batches or quantities).
      • Changes in process parameters (such as increased time in a fluid bed dryer, new mesh size for sieving…). In general, these changes should not modify the overall risk of inclusion of EIs... but there might be some special cases to consider (e.g. temperature from 25 ºC to 90 ºC).
    3. Changes in cleaning processes or detergents (not considered to be in contact with the product; cross contamination should be avoided by cleaning validation...)
  2. Changes in Water (and other utilities)
    1. Examples of CC that will require an update:
      • If the risk assessment of elemental impurities in PW determines a potential risk
      • Changes in the PW quality standard
    2. Examples of CC that will NOT require a mandatory update:
      • Changes in the PW plant and loop in which the water quality remains the same
      • Changes in the control strategy not related with conductivity or elemental impurities (such as TOC, microbial content…)
      • Changes in the control strategy related to the testing frequency, including conductivity measurements, when the risk assessment determines that there is no risk of inclusion of EIs
  3. Changes in the Container Closure System:
    1. Examples of CC that will require an update:
      • CC to include a new supplier of CCS of semi-solids and liquid dosage forms when the risk assessment report is based on the information provided by the previous supplier.
      • CC to change the composition (materials of construction) of the CCS
    2. Examples of CC that will NOT require a mandatory update:
      • CC to include a new supplier of CCS in solid dosage forms
      • CC to include a new supplier of CCS of semi-solids and liquid dosage forms when the risk assessment report is based on literature data and the risk has been assessed as sufficiently low.
  4. Changes in the Drug Substance:
    1. Examples of CC that will require an update:
      • CC to include a new API manufacturer
      • Changes in the manufacturing process of the API that updates the control strategy for elemental impurities (such as a new specification for Palladium because a Pd-catalysts will be used)
      • Changes in the content of elemental impurities (new information from supplier)
    2. Examples of CC that will NOT require a mandatory update:
      • CC to update the CEP version, in which there’s no modification of the statement of elemental impurities
      • CC to remove the ‘heavy metals test’ of the Article Master File.
  5. Changes in the Excipients:
    1. Examples of CC that will require an update:
      • Changes in the composition of the drug product
      • CC to include a new excipient manufacturer
      • Changes in the manufacturing process of the excipient that updates the control strategy for elemental impurities (e.g. new specification)
      • Changes in the content of elemental impurities (new information from supplier)
      • CC to remove from the Article Master File a specification for a certain element (such as Ni, As or Pb) that has been removed from an updated monograph in the Pharmacopoeia, when this specification was part of the control strategy for this element in the drug product.
    2. Examples of CC that will NOT require a mandatory update:
      • CC to update the Article Master File to update the testing of related impurities to new pharmacopeia requirements.
      • CC to include a new manufacturing site of an established supplier if the risk assessment (statement) provided has already considered the new site.
      • CC to remove from the Article Master File specifications of ‘heavy metals’ according to the updated Pharmacopoeia.
      • CC to remove from the Article Master File a specification for a certain element (such as Ni, As or Pb) that has been removed from an updated monograph in the Pharmacopoeia, when the risk assessment report is not including the specification as a control strategy.

In Azierta we have a team of experts in ICH Q3D and we can assist you in all the phases related to it: from the implementation (new reports) to the change management of existing reports.

 
 
Elemental impurities risk assessment according to ICH Q3D

Elemental impurities risk assessment according to ICH Q3D


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