Before starting the discussion about the deficiencies that we receive from the agencies…

Let me ask a question to all of the readers!

Have you received a CEP certificate without a single deficiency letter or request for additional information?


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The answer might be big “NO”.

So the today article mainly focuses on the top 10 deficiencies that we frequently receive from the regulatory authorities or agencies.

This article is in conjugation with PA/PH/CEP (16) 58 document, discussed to avoid the receipt of the deficiency letters. Because the management of CEP application policy allows only two deficiency letters to be issued to the manufacturing companies. If the dossier is still considered deficient the CEP application may be rejected.

So, by following the below checks, which are listed in the top 10 deficiencies in the CEP PA/PH/CEP (16) 58 document, while preparing the dossier may avoid the queries in the deficiency letter.  

Number 1: Genotoxic/ Mutagenic impurities

The CEP applications which are being filled by the manufacturing companies are lacking the discussion on Genotoxic and mutagenic impurities. Identifying the compounds that possess a structural alert and controlling the compounds below the TTC level could be the solution.

  1. Perform the genotoxic assessment of the Active pharmaceutical ingredient right from the Route of synthesis of the starting material.
  2. Calculate the TTC value and identify a suitable analytical method to show the absence or control measure in the final drug substance.


Number 2: Choose a suitable starting material

The 50% of the pharmaceutical companies receive this most common deficiency for choosing a suitable starting material for the API.

  1. The starting material should be choosed based on the ICH Q11 guideline.
  2. The starting material should not possess a complex structure and it should not have a major portion of the API.


Number 3:  Inadequate discussion of the manufacturing process.

The regulatory agencies look for the detailed information about the manufacturing process and the API manufacturers should completely provide the documents related to the manufacturing process.

  1. Recovery processes and Recovery solvents batch processing records are expected to be present in the section 3.2.S.2.2.
  2. Batch size mentioned in the section 3.2.S.2.2 should match with the Batch analysis section 3.2.S.4.4.


Number 4:  Carryover of starting material impurities to the final drug substances

Choosing the suitable starting material is a task, and setting a proper specification to the starting material is another task.

  1. Most of the starting materials may be isomers, so controlling the relative isomers in the starting material is one major check. In the current scenario, the regulatory agency asks the manufacturer to show the absence of isomers in the final drug substance.
  2. The specification of the starting material should have an identification test, limit for specified, unspecified and total impurities.


Number 5:  Improper Justification of the starting material specification

Even though the starting material specification is set with the limits with specified, unspecified and total impurities, without proper justification for set limits, the agency could not accept the specification and hence leads to the deficiency letter.

  1. The justification of the specification should include the evaluation of the risks and the ability of the subsequent steps to purge impurities.
  2. Technical write up for the process to purge the impurities should be included in the dossier.


Number 6:  Inadequate specifications for the solvents (recycled and recovered) used in the manufacturing process.

The usage of recovered solvents is not restricted in the manufacturing process but the specification should be set and testing should be performed to prove that the use of recovered solvents does not affect the quality of the drug substance.

  1. The set specification should include a purity test and the reasonable mass balance is expected to be in place.


Number 7:  Inadequate specifications for the reagents and elemental impurities

The manufacturing process may or may not use metals, but the manufacturing process including equipment, utilities should be screened for the presence of elemental impurities. The ICH Q3D guideline defines the elemental impurities and divided the elements into three classes namely 1, 2A, 2B and Class 3. The regulatory agencies expects a risk assessment summary for the 24 elements.

  1. Provide a risk assessment for all the 24 elements in the dossier section 3.2.S.3.2.
  2. Elements such as Boron, aluminium etc if used in the synthesis of the drug substance, a discussion about their absence in the final drug substances is expected.


Number 8:  Inadequate specifications for the isolated intermediates

It is presumed that the specification of the intermediates should be set in such a way that it captures all the related impurities in the intermediate specification.


Number 9:  Justification and carryover of isolated impurities

The impurities captured in the intermediate specification should have definite limit,  justification is supposed to the set limit and if any impurity limit in the intermediate is set more than 1.0%, then it absence in the final drug substance should be shown. The risks of having uncontrolled impurities in the final substance potentially above acceptable limits should be addressed

Number 10:  In adequate information about the starting materials.

The following information about the starting materials is necessary to be present in the dossier.

  1. Route of synthesis
  2. Address of the manufacturer
  3. Brief description with flow chart.

If more than one source of starting material is used in the process, batch equivalency report is to be provided in the dossier.

 Avoiding the above checks could bring us the quick approval.
























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