Document Type: Guidelines / Doc. Number / QMS/GDL/00
/ Title: GMP INSPECTION FOR FOREIGN PHARMACEUTICAL MANUFACTURING FACILITIES / Revision Number / 02
Revision Date: MARCH 2011
Effective Date March 2011
Review Due Date
March 2014
1.0 Objective
To ensure proper understanding of the National Drug Authority (NDA) Good Manufacturing Practice (GMP) inspection process by manufacturers and their representatives in order to assure smooth process flow and compliance to NDA regulations and guidelines.
2.0 Scope
This guideline applies to all foreign drug manufacturers (finished pharmaceutical formulations and active pharmaceutical ingredients) intending to supply products to the Ugandan market.
3.0 Policy
3.1 All pharmaceutical-manufacturing sites at which human and veterinary drug products (finished pharmaceutical products, biologicals, vaccines, herbal medicines) used in Uganda are manufactured (Storage of raw and packaging materials, dispensing, formulation, processing, packaging, quality control and release) shall be subject to current GMP inspection by National Drug Authority before the drugs are registered and assessment of conformity to the standards laid down by the Authority done at least once every three years.
3.2 NDA is mandated by the National Drug Policy and Authority Act Chapter 206 to control the quality of drugs, section 5(e) and to control the manufacture of drugs sold on the Ugandan market, section 38 and 39. The NDA current Good Manufacturing Practices (GMP) Guidelines shall be the basis against which National Drug Authority shall inspect foreign drug manufacturing sites for GMP compliance. The guidelines were developed with reference to the World Health Organization (WHO) and Pharmaceutical Inspection Cooperation/Scheme (PIC/S) guidelines on GMP.
3.3 The Drug Inspectorate Department of National Drug Authority shall coordinate current GMP inspection of all foreign drug manufacturing sites at which human and veterinary drug products used in Uganda are manufactured.
3.4 Each site of manufacture shall be inspected by at least two qualified cGMP inspectors for at least two days (depending on the number of production lines at each site) using the approved cGMP Inspection aide memoire.
3.5 The inspection shall be announced and based on all plant processes, systems and production lines except in special circumstances like investigations as deemed by the NDA.
4.0 Abbreviations
cGMP current Good Manufacturing Practice
GMP Good Manufacturing Practice
GPRC GMP Peer Review Committee
NDA National Drug Authority
PIC/S Pharmaceutical Inspection Cooperation Scheme
QC Quality Control
WHO World Health Organization
5.0 GMP Inspection process
5.1 Application for GMP Inspection
An application for a Manufacturer's GMP compliance assessment must be submitted in the prescribed form to:
The Executive Secretary/Registrar,
National Drug Authority
Plot 46-48 Lumumba Avenue,
P. Box 23096, Kampala Uganda.
The application form and the GMP guidelines may be obtained from the above address and also from the National Drug Authority website www.nda.or.ug. Before Inspection of the manufacturing facility, a GMP Inspection application form in the prescribed form together with the Site Master File and the prescribed fees must be submitted to NDA.
The Site Master File (SMF) contains a brief description of the manufacturing processes and systems employed by the company to attain compliance to GMP. It should not be more than 25 pages and may be submitted in electronic form. (See guidelines on developing a SMF online)
Inspection of a foreign drug manufacturing site may be initiated through any of the following ways:
a) Application for first time GMP inspection by the manufacturer or representative after submission of product dossiers to NDA.
b) Re – inspection of the site after the validity period of three years from the date of inspection.
c) Re-inspection of the site after failure to GMP compliance.
5.2 GMP Inspection fees
A GMP Inspection fee per facility shall be charged from the applicant to cover the cost of inspection and assessment. This fee shall be paid by the applicant to NDA before the site applied for is scheduled for inspection.
Cancellation of the inspection schedule by the applicant after confirmation of the schedule shall lead to forfeiture of the inspection fees subject to a valid reason e.g natural disasters.
The GMP inspection fees shall be determined as follows:
a) Physical GMP inspection per manufacturing site
Table 1:
Processes at the site / East Africa / the Rest of Africa / Outside Africa (Asia/Europe/America/Australia)1 / Site with all processes at one site for 5 product lines / US$3,000 / US$4,000 / US$6,000
2. / Any additional production line / $ 1000 per line
3 / For products moving through several sites, additional Sites in the same country as main site:
a) / Warehousing of raw materials up to finished bulk product / US $1,500 / US$2,000 / US$3,000
b) / Final packaging, quality control and final release / US$1,000 / US$1,500 / US$2,000
c) / Quality control and final release / US$500 / US$750 / US$1,000
b) GMP document evaluation (Desk Audits) shall be charged at $ 5000 per manufacturing site. NDA reserves the right to inspect the site anytime.
On special request and under exceptional circumstances, applicants with products that are manufactured at more than one site may be considered for a reduced fee as specified in the table 1 above for the extra site(s) if the extra site:
i. is located in the same country as the initial site and,
ii. does not fully manufacture any other product eligible for cGMP inspection that is or intended to be registered in Uganda,
Sites that manufacture orphan drugs (as defined by WHO) with no other registered source shall, on request and justification, either be inspected at a reduced fee and/or be evaluated using other methods like desk reviews or only assessment of GMP certificate issued by the local stringent regulatory authority.
Sites that manufacture vital drugs on the Essential Drug Lists of Uganda (EDLU/EVDLU) with no other or one registered source may, on written request and justification, be considered for inspection at a reduced fee and/or evaluation using other methods like desk reviews or only assessment of GMP certificate issued by the local stringent regulatory authority.
5.3 Scheduling for Inspections
Priority for GMP inspection shall be given to companies/sites based in countries with weak Drug Regulatory Agencies (DRAs) or DRAs of unknown strengths.
A company shall be placed on the schedule for inspection only after receipt of all the information specified in the “Application for GMP Inspection”, Site Master File and the appropriate fee.
Criteria for scheduling
The following criteria shall be used in making a schedule out of those due for GMP inspection:
a) Sites from which applications for registration (Dossiers) and inspection have been received.
b) Companies that were the first to submit a complete application for registration and inspection.
c) Sites whose inspection would be crucial in making an ongoing regulatory decision or meeting an emergency or a public health priority.
d) Other companies may be included on the schedule in order to make a particular inspection trip cost-effective and geographically logical because of their proximity.
Consideration shall be made to balance the activity of GMP inspection and other operations of NDA.
Each inspection trip shall cover at least four (4) manufacturing sites, unless expressly authorized by the Executive Secretary/Registrar NDA.
The NDA Inspectorate shall communicate the dates of inspection to the company and the Local Technical Representative. A response from the applicant regarding the suitability of the proposed dates shall be required within 10 working days. Where no response is received the department shall consider the dates as rejected by the manufacturer and will allow one more scheduling of the site before suspension of products from the national drug register (for renewing applicants)
5.4 Manufacturers profile
Manufacturers shall be profiled according to:
i) type of product manufactured or type of manufacture
ii) level of compliance after each audit
The manufacturers profile will be used to determine routine re-audit frequency
5.5 The Inspection
On the day of the site audit, the audit team will meet the manufacturer's representatives, introduce themselves, and give a brief description of the purpose of the visit and scope of activities. Then the manufacturer will be requested to give an update of the plant and any recent changes (e.g. changes to key personnel, major equipment and facilities, etc.), if any.
Following the update, there will be a review of the past non-conformities to GMP and the corrective actions taken to rectify them, and product recalls, if any. After this, the audit team will proceed with the audit of the plant, including the warehouse, production areas, filling and packaging areas, and the quality control (QC) laboratories. During the tour of the plant, observations will be made and recorded by the GMP auditors; this would include the recording of details of status labels for verification.
Upon completion of the site audit, the team will adjourn to the meeting room to review documentation such as batch records, analytical records, GMP training records, validation documents, records of self-inspection, product complaints, annual product review etc.
After the review of documentation, the lead auditor would request for some time to prepare the list of non-conformities observed, if any. Then a wrap-up meeting will be convened where, the audit team will present the findings to the manufacturer, including the handing over of the list of non-conformities to the manufacturer. The audit ends after the wrap-up or exit meeting. The Inspection agenda may be adjusted to suit the company set up or focus of inspection.
5.6 Criteria for approval
The most current version of the cGMP aide memoire and the NDA procedure for GMP inspection shall be used in conducting and preparing the report of the inspection
Observations shall be classified into critical, major or minor.
A critical non-conformity is one that can affect the quality and safety of the product, and may cause harm to the patients if administered. Such non-conformities would include mix-ups, mislabeling, and release of products where the potency is grossly above or below the labeled amounts. A critical non-conformity will lead to the manufacturer being given an "Unacceptable" GMP compliance rating.
A major non-conformity is one that may affect the quality and safety of the product, and includes unauthorized process changes, unvalidated manufacturing processes that have a major impact on product quality.
A minor non-conformity is one that is not likely to affect the quality and safety of the product. These include deficiencies arising out of lapses in discipline e.g. failure to review an SOP at the due date, using correction fluids to amend records, etc.
A site shall be considered compliant if it obtains:
No critical observation in the inspected areas including the production line and the quality systems following classification of all deficiencies as critical, major and minor (See “Guidelines for Risk Classification of cGMP Non-Compliances” for details).
Major and Minor deficiencies may be resolved through submission of written corrective action and follow up verification through subsequent inspection but Critical deficiencies and several major deficiencies can only be resolved through a physical re-inspection. The re-inspection shall be after submission of corrective action and an application together with payment of the inspection fee.
5.7 Risk based approach
NDA shall, through exchange of information and working experience over time, identify sites with consistent high profile of cGMP compliance and Drug Regulatory Agencies (DRAs)/Institutions with cGMP Inspection procedures and competencies that meet NDA guidelines for the purpose of establishing mutual recognition agreements (MRAs) or using their regulatory decisions. NDA shall thereafter either conduct joint inspections with, or recognize cGMP inspection reports from, such willing DRAs/Institutions.
Risk management principles shall be used in prioritizing sites for cGMP desk reviews. And this shall be based on various risk factors which include the strength of the DRA in the country of manufacture, type of dosage forms manufactured, results of the previous GMP audits, market complaints and products recalled since the last audit, if any.
Desk Reviews (Document assessment) may be used to assess the GMP status of sites from countries with stringent Drug Regulatory Agencies which may not be physically inspected either as a result of existing mutual recognition agreements, after the first mandatory GMP inspection or as a result of classification of the site located in exempted countries.
For the purposes of these guidelines the DRAs of the following countries shall be considered stringent:
PIC/S= Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme participating regulatory authorities (www.picscheme.org):
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Approved by / Page1 of 12
Title / Executive Secretary /Registrar
Signature & Date
National Drug Authority / Department
Document Type: Guidelines / Doc. Number / QMS/GDL/00
/ Title: GMP INSPECTION FOR FOREIGN PHARMACEUTICAL MANUFACTURING FACILITIES / Revision Number / 02
Revision Date: MARCH 2011
Effective Date March 2011
Review Due Date
March 2014
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1
Approved by / Page1 of 12
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Caution: Printed copy valid for only today: 03-Aug-2013
National Drug Authority / DepartmentDocument Type: Guidelines / Doc. Number / QMS/GDL/00
/ Title: GMP INSPECTION FOR FOREIGN PHARMACEUTICAL MANUFACTURING FACILITIES / Revision Number / 01
Revision Date: MARCH 2011
Effective Date
Review Due Date
ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use participating regulatory authorities (www.ich.org )