A review on USDMF on Indian Pharmaceutical Industries

The US FDA (Food and Drug Administration) audit process involves the following steps:

1. *Pre-Audit*: Notification of audit, review of company records, and preparation.

2. *Opening Meeting*: Introduction, audit purpose, scope, and procedures.

3. *Audit*: Review of documents, records, and processes; interviews with personnel.

4. *Inspection*: Observation of facilities, equipment, and operations.

5. *Sampling*: Collection of product samples for testing (if applicable).

6. *Closing Meeting*: Discussion of findings, observations, and recommendations.

7. *Audit Report*: Written report detailing findings, deviations, and corrective actions.

8. *Response*: Company response to audit report, addressing deviations and corrective actions.

9. *Follow-up*: FDA review of company responses and verification of corrective actions.

10. *Classification*: Audit classification (e.g., No Action Indicated, Voluntary Action Indicated, Official Action Indicated).

11. *Compliance*: Implementation of corrective actions and ongoing compliance.

Note: The FDA may also conduct follow-up audits to ensure compliance.

To file a US Drug Master File (USDMF) for an API from the manufacturing company, follow these steps:

1. _Determine the type of USDMF_: Type II for APIs, Type III for packaging materials, or Type IV for excipients.

2. _Prepare the USDMF_: Gather required documents, including:

- Company information

- API manufacturing process

- Quality control and assurance procedures

- Analytical methods

- Stability data

- Regulatory compliance information

3. _Format the USDMF_: Organize the document according to FDA guidelines (e.g., ICH Q7).

4. _Submit the USDMF_: Electronically submit the USDMF to the FDA's Office of Drug Master Files (ODMF) through the Electronic Submissions Gateway (ESG).

5. _Pay the fee_: Pay the required USDMF submission fee.

6. _Wait for acknowledgement_: Receive acknowledgement of USDMF receipt from the FDA.

7. _Wait for review_: The FDA reviews the USDMF (typically 30-60 days).

8. _Receive USDMF number_: If accepted, receive a USDMF number, which is used to reference the file in regulatory submissions.

Note: The FDA provides detailed guidance on USDMF preparation and submission in the "Guidance for Industry: Drug Master Files" document.

Please consult the FDA's website or contact the FDA directly for the most up-to-date information and guidance.

The various USDMF fees are as follows ¹ ²:

- *DMF fee*: This is a one-time fee incurred when a DMF is first referenced in a generic drug submission. The fee for FY 2025 is $95,084.

- *ANDA fee*: This fee is paid by the ANDA applicant and is used to fund the review process. The fee for FY 2025 is $321,920.

- *Program fee*: This is an annual fee paid by companies based on the number of approved ANDAs in their portfolio. The fee for FY 2025 ranges from $189,166 (small size) to $1,891,664 (large size).

- *Facility fee*: This fee is paid by facilities that manufacture APIs or finished dosage forms. The fee for FY 2025 ranges from $41,580 (domestic API) to $246,952 (foreign FDF).

Note that these fees are subject to change and may not reflect the current fees. It's always best to check with the FDA for the most up-to-date information.

The USFDA has recently made several observations in Indian pharmaceutical industries. Some of the observations include

- *Deficient records-keeping procedures*: Dr. Reddy’s Labs was cited for not maintaining a complete record of all data captured during testing.

- *Lack of employee training*: Dr. Reddy’s was also called out for a lack of employee training, with one employee in the quality unit being overdue on a required training for more than two years.

- *Unsanitary conditions*: Alkem Labs was cited for not maintaining areas of manufacturing, processing and packing in a good state of repair, including no hot water for production workers to wash their hands.

- *Broken equipment*: Alkem was also cited for failing to clean and sanitize equipment and utensils.

- *Poor recordkeeping*: Laurus Synthesis was cited for keeping incomplete records related to batch production and control.

- *Procedural observations*: Torrent Pharmaceuticals received five observations related to procedural issues, including failure to review batch discrepancies and not keeping equipment and tools clean enough.

- *Voluntary Action Indicated (VAI)*: Suven Pharmaceuticals received a VAI tag for its subsidiary’s Hyderabad manufacturing facility, indicating some objectionable conditions or practices but no formal administrative or regulatory actions.

- *Eight observations*: Natco Pharma received eight observations from the USFDA at the end of the inspection at the company's Pharma Division located in Kothur Hyderabad, India.