The step-by-step regulatory requirements for a pharmaceutical company manufacturing Active Pharmaceutical Ingredients (APIs) in India that wants to sell its APIs in the US.
Key Regulatory Bodies:
- US
FDA (United States Food and Drug Administration):
The primary regulatory authority in the US for drugs and APIs.
- CDSCO
(Central Drugs Standard Control Organization):
The national regulatory authority for pharmaceuticals and medical devices
in India.
Assumptions:
- The
company is already a established API manufacturer in India.
- The
company aims to be the API supplier for a drug product manufacturer in the
US who will file an NDA (New Drug Application) or ANDA (Abbreviated New
Drug Application).
Steps:
1. Indian
API Manufacturer: The starting point, recognizing the company's origin.
2. Initial
Assessment & Planning:
o
Market Analysis: Evaluate the demand for
the specific API in the US.
o
Resource Allocation: Ensure sufficient
resources (personnel, finances, infrastructure) for compliance.
3. Understand
US FDA Regulatory Landscape: This is crucial for navigating the
requirements.
o
ICH Q7 GMP Guidelines for APIs: These are
the globally harmonized Good Manufacturing Practice guidelines specifically for
APIs, which the FDA has adopted.
o
21 CFR Part 210 & 211: While
primarily for finished pharmaceuticals, certain general GMP principles and
expectations apply to API manufacturing, especially regarding quality systems.
o
FDA Guidance for Industry: Drug Master Files:
This document provides detailed instructions on how to prepare and submit a
DMF.
o
FDA Guidance for Industry: Electronic Common
Technical Document (eCTD): This outlines the mandatory electronic format
for submissions to FDA.
4. Quality
System & Compliance:
o
Implement & Maintain cGMP (Current Good
Manufacturing Practices) per ICH Q7: This is foundational. The
manufacturing processes, controls, facilities, and personnel must adhere to
these standards.
o
Conduct Internal Audits & Address Gaps:
Regular self-inspections are vital to identify and correct non-compliance
before an FDA inspection.
o
Prepare for Potential FDA Inspections:
This involves maintaining thorough documentation, training personnel, and being
ready to host FDA investigators.
5. Documentation
Preparation:
o
Drug Master File (DMF) Preparation - Type II
for API: A DMF (specifically Type II for an API) contains confidential,
detailed information about the API's chemistry, manufacturing, and controls
(CMC). This allows the US drug product manufacturer (who will use your API) to
reference your confidential information in their application (NDA/ANDA) without
you having to disclose proprietary details to them.
§ Module
3: Quality: This is the core of the DMF for an API, including information
on the API's structure, properties, manufacturing process, impurities,
specifications, analytical methods, stability, and container closure system.
§ Module
2: Summaries: Includes the Quality Overall Summary, providing a high-level
overview of the quality information.
§ Administrative
Information: Details about the DMF holder, manufacturing sites, and contact
information.
§ Site
Master File (SMF): While not typically submitted as a standalone document
to the FDA for DMFs, the information usually contained within an SMF
(general site information, quality system, personnel, premises, equipment,
documentation, production, quality control) is essential and forms part of the
overall GMP documentation. It's often requested during inspections or can be
part of Module 3 of the DMF.
6. Electronic
Submission Readiness (eCTD):
o
Convert DMF to eCTD format: The FDA
requires electronic submissions in eCTD format for most applications, including
DMFs. This involves structuring the information according to the eCTD
specifications.
o
Utilize FDA Electronic Submissions Gateway
(ESG): This is the secure electronic platform for submitting regulatory
information to the FDA.
7. Registration
& Listing:
o
Establishment Registration (21 CFR Part 207):
Foreign drug manufacturers whose drugs are imported or offered for import into
the US must register their establishments with the FDA.
o
Drug Listing: APIs in commercial
distribution in the US must be listed with the FDA.
8. DMF
Submission to US FDA:
o
Submit Type II DMF via eCTD to FDA: The
prepared DMF in eCTD format is submitted to the FDA.
o
Obtain DMF Number from FDA: Upon receipt,
the FDA assigns a unique DMF number.
o
Communicate DMF Number to US Drug Product
Manufacturer: This number is critical for the US drug product manufacturer
to reference your API in their drug application.
9. US
Drug Product Manufacturer Files NDA/ANDA:
o
References Indian API Manufacturer's DMF:
The US drug product manufacturer submits their NDA or ANDA to the FDA,
explicitly referencing the Indian API manufacturer's DMF for the API's CMC
information.
10. FDA
Review Process:
o
FDA reviews the DMF: The FDA does not
"approve" a DMF in isolation. Instead, it reviews the technical
content of the DMF in support of the NDA or ANDA that references it.
o
Information Requests (IRs) or Complete
Response Letters (CRLs): The FDA may issue these if they have questions or require
further information regarding the DMF, or if there are deficiencies found in
the NDA/ANDA that relate to the API.
o
Pre-Approval Inspection (PAI) of API
manufacturing site in India: Before approving the drug product application,
the FDA will typically conduct a PAI at the Indian API manufacturing facility
to verify cGMP compliance and ensure the information in the DMF is accurate and
adhered to in practice.
11. Post-Approval
& Maintenance:
o
Ongoing cGMP Compliance: Continuous
adherence to cGMP is essential.
o
Regular Internal Audits: Continued
self-assessment.
o
Timely Reporting of Changes (Amendments to
DMF): Any significant changes to the API's manufacturing process,
specifications, or quality control must be submitted as amendments to the DMF
in a timely manner.
o
Annual Reports for DMF: While not an
"approval," DMFs require annual updates to confirm the information
remains current.
o
Responding to FDA Inquiries: Be prepared
to address any questions or concerns from the FDA.
o
Regular FDA Surveillance Inspections: Even
after initial approval, the FDA conducts periodic inspections to ensure ongoing
compliance.
o
Continual Improvement of Quality System:
Proactive measures to enhance quality and compliance.
12. API Sold
in US Market: The ultimate goal, achieved after successful navigation of
the regulatory pathway.