1.Approval of Manufacturers

Basic requirements

When setting up a new plant, adhering to the following basics will assist the approval process:

• It is more appropriate that an application for preliminary approval is submitted and get approval before starting construction of the facility. It would cost you more if changes are recommended to an existing building.
• When selecting a land for a pharmaceutical manufacturing plant, avoid dense residential areas. Setting up the plant in an industrial zone with pollution free surrounding is preferred.
• Constructing purposely assembled buildings is recommended. Avoid trying to convert already existing residential houses or buildings built for other purposes.
• Flow of material and flow of men within the premises need to be planned in a logical manner in order to avoid contamination, cross-contamination and mix-ups.
• Water supply of acceptable quality is essential. Water used for manufacturing processes, analytical work and cleaning of items that contact with the product need to be purified.
• Control of air supplied to production premises though Air Handling Units may be required, especially in medicine manufacturing.
• There should be sufficiently qualified and experienced staff to handle production and quality control aspects.
• There should be written Standard Operating Procedures (SOPs) for all the procedures;
• All activities taking place needed to be documented in a traceable manner.
• Quality control department should be independent from other department. There should be procedures to release each batch of starting material before production and to release each batch of finished product before marketing.

Tentative roadmap for the approval process

The approval of a new site is a step by step process and may include the following stages:

• Submission of an application for the preliminary approval of a local manufacturing site.
• Land inspection and approval for the proposed layout of the manufacturing plant.
• Initial building inspection, during or after completion of construction. Machinery equipment may or may not have been installed.
• Submission of the Site Master File along with the invitation for pre-approval GMP audit while trial batches/submission batches are being manufactured.
  • Machinery and equipment are installed and qualified
  • Validation Master Plan (VMP) in place. Water system (up to phase II) and environmental validation completed.
  • Cleaning, process validation, and stability study protocols are in place
  • Basic SOPs (QMS, cleaning, production and laboratory processes etc.) are in place.
  • Key staff has been recruited
  • Environmental certificate issued by the Central Environment Authority (or similar) has been obtained.
• Submission of application for manufacturing license for the premises along with relevant payment for the manufacturing license.
• Pre-approval audit while pilot/exhibit batches are being manufactured in relevant product lines.
  • The manufacturer can proceed to submit application for registration of individual products.
• Post approval GMP audit while commercial batches are being manufactured.
  • The manufacturer can apply for GMP certification.

The above is a tentative roadmap for a manufacturer of medicines and may vary for other product categories and there may also be follow up inspections if there were deficiencies observed during a particular inspection.

3).Approval of Foreign Manufacturing Facilities

The process applies for overseas manufacturers of medicines and medical devices who intended to get marketing authorization for their products in Sri Lanka. The procedure includes a desk review of essential documents including the site master file. A GMP inspection of the site may be necessary before approval of the site.

A foreign manufacturer who wants to register products in Sri Lanka needs to appoint a Sri Lankan business entity as its local authorized agent. The local agent will furnish an application for approval of an overseas manufacturer of medicines on behalf of its principle company, the foreign manufacturer. A separate application needs to be submitted to each manufacturing site from which the manufacturer plans to export products to Sri Lanka. A processing fee as per the fees regulations of NMRA will be charged for each application.

If the manufacturer fulfills all the requirements indicated in the application including documents submitted with the application, the next step would be to carry out a GMP inspection of the facility. The NMRA would exempt the onsite GMP inspection if the particular site had been inspected by a reference NRA or WHO, in terms of regulation 24 of the medicines regulations. After these procedures, an approved foreign manufacturer can submit application for marketing authorization of individual products through the local agent.

4).Site Master File(SMF)

A Site Master File is a set of documents required to be enclosed with applications for site approval which provides NMRA a description of the manufacturing site with regard to premises, personnel, processes, documentation, equipment  used in the manufacturing, processing, packaging, quality control , storage, distribution, complaint handling and recall of Medicines, Medical Devices, Borderline products and cosmetics.

5).Guidance for Site master Files

• Links:   Site Master file of Medicines
• Site Master file of Medical Devices
• Site Master file of Borderline Products
• Site Master file of Cosmetics

References:

• WHO guideline for drafting a site master file, Annex 14, WHO TRS No. 961, 2011
• Explanatory notes for pharmaceutical manufacturers on the preparation of a site master file; PE 008 – 4, 1 January 2011, Pharmaceutical Inspection Co-operation Scheme (PIC/S)

6).Good Manufacturing Practices (GMP)

Good manufacturing practice (GMP) is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.

The National Medicines Regulatory Authority Act No. 5 of 2015 interprets GMP guidelines as ‘good manufacturing guidelines issued by the World Health Organization’. As such, the National Medicines Regulatory Authority (NMRA) adopts the WHO GMP guidelines along with its subsequent updates for the purpose of regulation of pharmaceutical manufacturers. The manufacturers are expected to adhere to the Good Manufacturing Practices throughout their activities.

Pharmaceutical manufacturers who intend to apply for marketing authorization in Sri Lanka may be subjected to one or several GMP inspections prior to their site approvals.

Useful guidelines published by WHO can be accessed through the following links:

https://www.who.int/teams/health-product-and-policy-standards/standards-and-specifications/norms-and-standards-for-pharmaceuticals/guidelines/production

WHO TRS 996 – Annex 3: WHO good manufacturing practices for biological products:

https://www.who.int/publications/m/item/trs996-annex3

7).GMP Audits

All pharmaceutical manufacturers are required to conform with the Guidelines on Good Manufacturing Practices of NMRA, which consists recommendations of the World Health Organization (WHO) relevant to GMP. NMRA conducts pre-approval and routine GMP audits on local manufacturers in order to assess them for conformance to GMP standards. Overseas manufacturers are inspected at the time of approval or if there are consistence and/or serious issues such as quality failure of products. Fees for both local and overseas GMP audits are charged as per the fees regulations of NMRA.

Pre–Audit

The composition of the GMP audit team will be notified to the company via email, after the relevant payment is made. The GMP audit team will request for an updated Site Master File for a pre-audit assessment of the site. The lead GMP auditor will discuss with the company for dates for the audit and will inform of the tentative audit agenda.

During Audit

On the first date of the audit, the GMP audit team will meet the key personnel of the manufacturer, introduce themselves, and give a brief description of the purpose of the visit and scope of activities. Then the manufacturer will be requested to present an update of the site and any recent significant changes, if any such as changes to key personnel, equipment and facilities etc.

The team will proceed with the audit of the plant and observations will be recorded. During the audit, the team will review previous non-conformities and corrective actions taken to rectify them. The manufacturer shall arrange a meeting room for the review of documents requested by the team.

After completion of the audit, a closing meeting will be held and the audit team will present a summary of observations. The audit ends after the closing meeting.

Post-Audit 

An inspection report along with a post-audit letter will be send to the manufacturer in which the non-conformities will be listed as critical, major, and other deficiencies. The manufacturer is expected to respond to the non –conformities observed with time frames required for correcting them. If necessary the audit team will make a follow up visit to audit the implementation of the corrective actions. 

If the audit team is satisfied with the corrective actions and time frames for rectification, the audit will be closed out. The due date for the next audit will be determined using a risk assessment system. In general, re-inspection of ‘high risk’ manufacturers (e.g. manufacturers of sterile products) will be more regular.

8).List of Approved Local Manufacturers

List of approved local manufacturers of medicine (table)

9).Guidelines

Guideline on Approval of an Overseas Manufacturing Plant of Medicines Rev. No;1

Guideline on Preparation of Site Master Files

Guideline for preparation and conduct of the GMP inspection

Guideline on Good Manufacturing Practices Rev. No.1

10).Application Forms

Application for preliminary approval of a new local manufacturing site 

Application for approval of an overseas manufacturer of medicines (Rev No_02)