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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on December 5, 2024

Lupin is recalling over 600,000 bottles of Ramipril capsules across different strengths (2.5 mg, 5 mg, and 10 mg) in the US. The recall was initiated following a notification from an API manufacturer that one of the key starting materials (KSMs) used in the production of the active pharmaceutical ingredient was sourced from an unapproved vendor, as per a California State Board of Pharmacy alert.

Ramipril is indicated for the treatment of hypertension to lower blood pressure. Initially approved by the USFDA in 1991, Ramipril capsules have several generics in US including from Aurobindo, Dr.Reddys, Cipla, Zydus, Teva.

Ramipril has several Active DMFs in US for the API. As per the latest quarterly updated list of USDMFs, there are 12 active USDMFs for Ramipril, including Lupin’s.

Active USDMFs for Ramipril (September 2024)

No.

DMF Number

DMF Holder

Status

1

15208

EUROAPI GERMANY GMBH

Available for Reference

2

16193

DR REDDYS LABORATORIES LTD

Available for Reference

3

16647

NEULAND LABORATORIES LTD

 

4

17033

CIPLA LTD

 

5

17570

APITORIA PHARMA PRIVATE LTD

 

6

18024

LUPIN LTD

 

7

18338

HETERO LABS LTD

 

8

19522

UNIMARK REMEDIES LTD

 

9

19714

AARTI PHARMALABS LTD

Available for Reference

10

20713

APOTEX PHARMACHEM INDIA PVT LTD

 

11

24650

ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD

 

12

37506

EUROAPI GERMANY GMBH

 

Ramipril is a dipeptide and the general route of synthesis for Ramipril involves coupling of serine derivative of phenyl butyric acid with an azabicyclo  octane-3-carboxyl acid benzylester intermediate. The manufacturing process for Ramipril involve several steps and could have more than one entity designated as key starting material. 

Key Starting Material & Changes in Key Starting Material

The key starting material(s) and their manufacturing process impact the quality of the drug substance, particularly in the formation, fate, and purge of impurities. The API DMF should define what are the API Key SMs and  Vendor details and the GMPs apply from the point of introduction of the KSM in the manufacturing process of API. According to FDA guideline (Postapproval Changes to Drug Substances), the API manufacturer is responsible for managing changes in starting materials, qualifying additional vendors, and updating the FDA and the drug product applicant (or ANDA holder) about changes. Specifications and analytical procedures must ensure the same degree of quality, regardless of the vendor, manufacturing process, or site and source.

The drug substance manufacturer / DMF holder must update the DMF for changes involving starting materials, along with the name and address of the vendor, in-house COA, and vendor COA. changes in the synthetic route of the starting material. However, no information needs to be submitted by the applicant (ANDA or NDA holder). The guidance does not specify the category of change notification required by the drug substance manufacturer or DMF holder (CBE-30, CBE-0, or annual report).

Several scenarios could lead to a manufacturer of a key starting material becoming unapproved, for example (but not limited to):

  • The API vendor introduces a new KSM vendor but has not yet notified the FDA or the applicant.
  • Significant changes in the manufacturing process of the KSM which could impact its quality and, in turn, the drug substance and product.
  • The API manufacturer did not perform a thorough risk assessment and impact evaluation of the change in the KSM or its source.
  • API starting material is re-designated in the DMF due to regulatory interventions, but changes are not updated in the vendor list and vendor qualification records.
  • A regulatory audit at the API site identifies lapses in the selection, qualification, and handling of changes to KSMs.
Key Learnings

The regulatory requirements for updating changes to KSMs are somewhat ambiguous, as the change notification category is not clearly specified and there is no specific requirement for the formulator (drug product applicant) to update the FDA. However, the applicant is directly impacted by any quality issues resulting from lapses in handling KSM changes. Therefore, drug product applicants should proactively track API KSM details and changes to prevent adverse impacts on drug product quality. Ways of doing this could include (but not limited to):

  • Strong contractual obligations with the API vendor through Supplier Quality Agreements, ensuring the API supplier updates the applicant on all changes, including KSMs and their sources. Although the API vendor may be confidentiality concerns, regulatory risks outweigh these concerns.
  • A system for annual “no change declarations” and change notifications by the API vendor to the applicant
  • On-site vendor audits, specifically checking for changes in KSM sources, impurity profiles of KSMs and the drug substance, and process changes in the KSM.
  • Define periodicity of the vendor audit prudently. The frequency of vendor audit should be linked to the maturity of the vendor’s quality management system and the vendor performance. Annual vendor audits should be considered where the vendor quality system maturity is not very high and risk of lapses is significant
Conclusion

The recall of Ramipril for unapproved API / KSM source by Lupin underscores the importance of proactive risk management, management of supply chain complexities, quality system governance of supply chain over the product lifecycle and an effective monitoring strategy for supply chain partners. Awareness of the API manufacturers process including key starting materials, quality systems and controls, and oversight over the API vendor is critical to ensure drug product quality and safety and avoid regulatory risks.

References:

  1. USFDA Enforcement Report – Lupin Recall of Ramipril (October 2024).
  2. USFDA Guidance: Postapproval Changes to Drug Substances
  3. A process for preparation of ramipril; WIPO PCT WO2009122433A2
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