Nepal Drug Product Registration

1.2.1.2 Repacking Industry for Manufacturing a few Conventional Externally used Products

• Initial Requirements
  • Obtain a valid recommendation letter as per Drug Registration Regulation (Same as 1.1).
  • Repacking involves dividing bulk products into small units, sealing, labelling, and packaging.
• Infrastructure Setup
  • Establish your own infrastructure as outlined in Section 1.2.1.
  • Ensure a sturdy structure (RCC or equivalent) for the premises/building with an approved layout design from the Department, detailing material and process flow.
• Qualified Supervision
  • Manufacturing activities should be overseen by a qualified and experienced individual with expertise in related work.
• Air Handling Units
  • Install adequate air handling units with at least 10-micron terminal filters to supply air to units designated for external repacking.
• Quality Control
  • Conduct in-house quality control activities. If not feasible, products can be tested by an authorized drug testing laboratory through a formal agreement (contract analysis) between the company and the laboratory.
• Application Submission
  • Apply in a prescribed format, providing details of the product, label, manufacturing license, and repacking procedures for prior approval.
  • Include information as per Schedule-3 & 4 (A) of the Drug Registration Regulation 2038 in a stepwise manner.

1.3 Manufacturing License Simplified Guide

Pre-requisites for Manufacturing License

• Compliance: Meet terms and conditions (Schedule-2).
• Industry Registration Certificate: Obtain industry registration.
• Site Visit (Optional): Visit the manufacturing site.
• Approved Layout: Get approval for the layout of the manufacturing section and plant.

Application and Issuance of Manufacturing License (Schedule-5)

• Application Submission
  • Submit the application in the prescribed form (Schedule-3) signed by an authorized person.
  • For brand name inclusion, provide the trademark registration certificate.
• Official Letter and Documentation
  • Include an official letter with F&D evidence and analytical testing capacity per pharmacopoeia regulations.
  • For dosage forms not in the pharmacopoeia, develop an in-house method validated by the company.
• Detailed Application Submission
  • Submit separate applications for different strengths, dosage forms, and pack sizes of the same entity.
  • Provide in-vitro/in-vivo drug release or BE study for specific cases.
• Bioavailability/Bioequivalence Requirements
  • Include tests based on therapeutic index, bioavailability, and kinetics.
  • For certain safer drugs, consider in-vitro dissolution tests with real-time stability data.
  • Compare profiles with the innovator/comparator brand.
• Brand Naming
  • Propose a brand name, ensuring it’s not like existing ones.
  • Declare non-usage/registration by other companies nationally and internationally.
• Manufacturing Process Format
  • Provide a tentative format of the manufacturing processes aligning with BMR requirements.
• Evidence of Capability
  • Submit additional evidence of physical and technical capability for new dosage forms.
• Laboratory Capability
  • Have a full-fledged testing lab; if not feasible, perform specific tests from an accredited lab.
• Application Review and License Issuance
  • Upon review, the department registers the drug and issues the manufacturing license (Schedule-5).
  • Submit the DDA inspection report.
• License Validity
• The license is valid for two years; if marketing authorization isn’t obtained within this period, it’s automatically cancelled.

1.4 Marketing Authorization Process Detailed

The marketing authorization process involves submitting a comprehensive dossier for commercial batch approval. The Drug Registration Regulation provides a structured guideline for applicants:

• Application Submission (Schedule- 4 A)
  • Submit an application using Schedule- 4 A of the Drug Registration Regulation.
• Stability Testing
  • Provide accelerated (0, 3, 6 months) and real-time stability test reports, following the Department’s stability test guideline (Zone IV(b)).
  • Expiry/shelf-life determination based on the stability test reports of three non-commercial batches.
  • Attach chromatograms of stability testing.
• Method of Analysis
  • Include a copy of the method of analysis for the product.
• National Medicines Laboratory (NML) Testing
  • Submit recent analytical test reports for the commercial batch from NML or a receipt of sample submission.
  • For products requiring longer testing, submit data from R&D or scale-up manufacturing documents.
  • Pilot batch size should be at least 1/8 of the commercial batch.
  • DDA will issue the marketing license based on submitted documents.
• Batch Manufacturing Records
  • Provide records of the commercial batch, detailing excipients, color, packaging, and their test reports.
• Product Specification
  • Submit product specifications with complete analytical test reports following pharmacopoeia monographs.
• License and Samples
  • Include a copy of the valid medicine manufacturing license (Schedule-5).
  • Submit product samples of the commercial batch (minimum quantities specified).
  • If the drug is extended/sustained/prolonged release, conduct invitro dissolution tests with a comparator brand.
• Research and Development Section
  • Every industry should establish its own Research and Development section.
• Package Inserts and Language Requirements
  • Submit package inserts for each medical product during marketing authorization.
  • Package inserts for Group “Ga” medicines should be in Nepali, while for other groups, it can be in Nepali, English, or both as needed.
• Bioavailability/Bioequivalence Study
  • Submit the BA/BE study report if applicable.

1.5 Raw Material Import Recommendation Letter (Schedule-7)

Medicine manufacturing industries registered with the department must apply for and obtain an import recommendation letter for raw materials, including packaging materials. 

The required documents for obtaining this recommendation letter are outlined as follows:

• Application Submission (Schedule-6)
  • Submit an application as prescribed in the drug registration regulation using Schedule-6.
• Specification and Standards
  • Provide specifications and standards in Drug Master File (DMF) format.
  • If the product is non-pharmacopeial, submit in-house specifications in a format like the pharmacopeial format.
• Copy of Schedule-5
  • Include a copy of Schedule-5 in the application.
• Source Documentation
  • Furnish information about the source, including manufacturer/supplier details, certificate of origin, and release profile of modified raw materials.
  • For Vendor qualification, relevant details should be provided.
• R&D Special Import
  • If applying for R&D special import, submit a written application specifying the quantity required, source details (as in section 1.5.4), standards, proposed dosage under development, and material safety data for the material.
• Machinery/Equipment/Instruments Import
  • In case of recommending the importation of machines, equipment, or instruments, provide specifications, qualification details, source information, and cost.
  • Attach a proforma invoice.
• Packing Material Quantity and Specifications
  • Clearly state the required quantity and specifications of both primary and secondary packing materials.

1.6 Renewal of Licenses, Recommendation Letter, and Certificate

1.6.1 Raw Material (Schedule-7)

• Application for Renewal of Schedule-7
  • Submit a formal application requesting the renewal of Schedule-7.
• Original Recommendation Letter (Schedule-7)
  • Provide the original recommendation letter issued under Schedule-7.
• Consumption/Quantity and Projected Requirement (Annex E)
  • Include a document specifying the consumption/quantity of raw materials and the projected requirement (Annex E).
• Fee Payment
  • Pay the applicable fee after receiving approval for renewal.
• Real-Time Stability Data for API
  • If applicable, submit real-time stability data for Active Pharmaceutical Ingredients (API) either ongoing or finalized report.

1.6.2 Manufacturing License (Schedule-5)

• Application for Renewal of Schedule-5
  • Submit an application requesting the renewal of Schedule-5.
• Original Schedule-5
  • Provide the original Schedule-5 issued for manufacturing.
• Compliance Check with Terms and Conditions of Schedule-5
  • Ensure compliance with the terms and conditions specified in Schedule-5.
• Fee Payment
  • Pay the applicable fee after approval for the renewal.

1.6.3 Marketing Authorization (Schedule-4 B)

• Real-Time Stability Study Report:
  • Include a report on real-time stability studies with statistical analysis of shelf life/expiry date, following ICH guidelines or DDA guidelines.
• Commercial Product Sample:
  • Submit one unit of the market presentation as a commercial product sample.
• Original Schedule-4 (B):
  • Provide the original Schedule-4 (B) issued for marketing authorization.
• Latest Product Specification with Sample:
  • Include the latest product specification along with a product sample.
• Changes in Price or Latest MRP Approved from DDA:
  • Inform about any changes in pricing or provide the latest Maximum Retail Price (MRP) approved by DDA.
• Report of Deviation, Product Withdrawal, and Change Control:
  • Include a report detailing any deviation, product withdrawal, or change control made within the renewal period.
• Annual Product Review:
  • Provide an annual product review during the renewal of marketing authorization.
• Stability Chamber Data Logger:
  • Include data logger records for the stability chamber, along with an online computerized system printout paper, stress factors, and relevant documentation.
• Consumption Details for Quantification:
  • Declare the consumption in terms of quantity and price for quantification purposes (Annex-G).
• Declaration on ADR Reporting:
  • Provide a declaration on Adverse Drug Reaction (ADR) reporting for the product.

1.6.4 Export/Import recommendation letter (Schedule-7)

1.6.4.1 Application-Schedule-6

1.6.4.2 Schedule-5

1.6.4.3 Schedule-4 (B)

1.6.4.4 Certificate of pharmaceutical products (Annex F)

1.6.4.5 WHO-Good Manufacturing Practices certificate issued from the department

1.6.4.6 Site Master File along with copy of approved layout.

1.6.4.7 Quantity exported.

1.7 Variations (Schedule-5, 4-B, Schedule-7)

1.7.1 Application should be submitted to DDA for any variation in the certificates along with the justification for changes.

1.7.2 No changes will be made in the certificates without any valid scientific reason once it is issued.

1.8 Certificate of Pharmaceutical Products (CPP) Annex-F

An industry shall receive certificate of pharmaceutical products from the department if it wishes to export drug products into the international commerce. Following document should be submitted for issuing CPP from the department:

1.11.1 Current WHO-GMP certificates issued from the department

1.11.2 Process validation report of the concerned product(s)

1.11.3 Validated Method of analysis of the concerned product(s)

1.11.4 A copy of Drug marketing authorization certificate

1.11.5 Updated Site Master File (SMF) 1.11.6 Approved layout