Inspections

1. Inspections Malaria product manufacturers Active Pharmaceutical Ingredients Finished Products

2. Policy and objectives Each manufacturer should be inspected by the organization to assess compliance with Good Manufacturing Practices. One of the objectives is to control and enforce the general standards of production for products that may be sourced as a result of the pre-qualification procedure.

3. Through sequential examination of production and control activities of the manufacturer of API or FP, the manufacturer of FP may be listed on the pre-qualification list as a manufacturer of pharmaceutical products for possible supply of products to organizations and agencies. • During inspections, the performance of the manufacturing of starting materials and finished products are verified. Compliance with WHO guidelines on Good Manufacturing Practice for pharmaceutical products is checked. ICH guideline on GMP for Active Starting Materials.

4. Type of inspections • A routine inspection is a full review of all aspects and components of GMP within a facility. A routine inspection is performed under the following circumstances: • When there is a new EOI from a manufacturer or a newly established manufacturer. • If there have been significant changes such as new products or new product lines, modification to manufacturing methods or processes, or changes in key personnel, premises, and or equipment. • If an inspection has not been carried out within the past 3–5 years.

5. A follow-up inspection is performed specifically to monitor the result of corrective actions of the manufacturer following a previous inspection. • Depending on the nature of the defects and the work required, the follow-up inspection could be carried out between 6 weeks and 6 months after the original inspection had taken place. • The inspection is limited to specific GMP requirements or specific dossier related issues that have not been found to be satisfactory during the routine inspection or that have been inadequately implemented or corrected by the manufacturer.

6. Organisation • An inspection can be performed over a period of a few days to several weeks. • The time taken will also depend on the size of the inspection team. One or more inspectors can perform the inspection as part of an inspection team. • Partners can be asked to participate like UNICEF, EDQM (Council of Europe). It allowes to reduce the number of inspections. • A specialist can be appointed to accompany the team during the inspection if necessary for particular dosage forms, chemistry or other aspect, e.g. the manufacture of biological, sterile products.

7. Site inspection • Opening meeting • Debriefing and closing meeting • During the inspection the activities, procedures and other documentation (e.g. records), premises, equipment in the area, personnel, materials used and validation in the relevant area will be observed and scrutinised. • The level of cleanliness, the storage of materials, components and products, as well as the space and movement of personnel and materials.

8. The actual existence, effectiveness, implementation and maintenance of procedures in each area will be examined and the relevant records will be check accordingly. • The conformity of the manufacturing and control process actually carried out and the process described in the submitted dossier may be verified as well as the information provided, (API manufacturer, contract manufacturing etc)

9. Inspection program Production • Receiving area • Cleaning and or de-dusting area • Quarantine area • Returned goods area • Rejected goods area • Released goods area • Sampling area • Starting materials, components, packaging materials and printed packaging materials

10. Weighing area • Manufacturing and in-process storage areas • Clean areas if relevant • In process quality control areas • Wash bay/area • Filling and packaging areas • Coding or overprinting Quality control • Retention samples • Chemistry • Instrumentation • Microbiology

11. Systems: • Water • Heating Ventilation and Air Conditioning (HVAC) • Steam • Gases (N2) • Compressed air

12. Documentation • Quality Management (including organizational chart, job descriptions) • Quality Manual • Validation Master Plan • SOPs such as complaints handling, recalls, self inspection, batch number allocation, annual product review, training, change control, deviation reporting, finished product release and others. • Specifications (e.g. starting materials, primary packaging components, printed packaging materials) • Batch Manufacturing Documents and records • Validation protocols and reports. • Training records

13. Deficiencies observed • Manufacturing site not meeting GMP • Poor design layout and construction. • Lack of validation (process utilities, equipment, clean rooms for aseptic production). • Hormones, antibiotics such as penicillin's in the same area. • Lack of raw data. • Cross contamination, contaminations. • Mix-ups.

14. Lack of quality control on starting materials and finished product. • Absence of consistent batch documentation. • Absence of suitable batch release. • Lack of personnel training in critical manufacturing areas. • No appropriate separation between different requirements and standards : local market/export.

15. What is expected • Manufacturing sites meeting basic GMP. • Upgrading of unsuitable facilities supported by a strong quality assurance system. • Strong quality assurance system supported by a consistent documentation. • Validation of manufacturing processes. • Qualification of all critical equipments. • Performance of studies to generate data for stability, bioequivalence.

16. Inspection report • The observations made during the inspection will be communicated, if necessary explained and discussed. • After the inspection, all the observations and recommendations made by the individual inspectors as part of the inspection team, are collated and written in a report signed by the inspectors and possible experts. • Any unsatisfactory findings will be listed and the irregularities and other observations will be outline. • Answers and corrective actions are expected.