Evaluation Guide For GMP Regulatory Compliance Programme

17 December 2012
EMA/INS/GMP/758453/2012
Compliance and Inspection
EVALUATION GUIDE FOR GMP REGULATORY

COMPLIANCE PROGRAMME
Audit Checklist
(Revision 2 including API and common with Canada and PIC/S)
7 Westferry Circus Canary Wharf London E14 4HB United Kingdom

Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8595
E-mail [email protected] Website www.ema.europa.eu
An agency of the European Union
European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
1 - Legislative and Regulatory Requirements and

Scope
Summary of the Audit Checklist

Sub-component
1A - Empowering legislation
1B - Conflict of interest
2 - Regulatory directives and policies
Importance
Critical
Very
important
Evaluation method
Documentation review
On-site evaluation at Inspectorate
2A - Procedures for designating inspectors
Very
important
2B - Enforcement Policies
Evaluated as part of sub-component

7B
2C - Code of conduct/ Code of ethics
Very
important
2D - Training certification policies/guidelines

4C
2E - Alert/crisis management
policies/procedures/guidelines

8A
2F - Organisational structure

11A
3A - Details/ scope of GMP
Critical
3B - Process validation

3A
4A - Staffing: Initial qualification
Very
important
4B - Number of inspectors
Very
important
4C - Training programme
Very
important
4D - QA mechanism to assure effectiveness of

training programme

4C
5A - Inspection strategy
Very
important
5B - Pre-inspection preparation
Very
important
Observed inspections
5C - Format and content of inspection reports
Very
important
5D - Inspection methodology
Evaluated as part of sub-components

5E
5E - SOP for conducting inspections
Critical
5F - Inspection procedures - Post-inspection

activities
Very
important
5G - Inspection procedures Storage of

inspection data
Important
6 - Inspection performance standard
6A - Performance standards
Very
important

11A
7 - Enforcement powers and procedures
7A - Provision for written notice of violations

7B
7B - Non-compliance management
Critical
7C - Appeal mechanism
Important
7D - Other measures
Evaluated as part of sub-components

7B
8A - Alert mechanisms
Critical
8B - Crisis management mechanisms

8A
8C - Alert performance standards
Important
9A - Access to laboratories
Critical
On-site evaluation at Laboratory
9B - SOPs for analytical support
Very
important
9C - Validation of analytical methods
Very
important
10A - Sampling and audit procedure
Very
important
3 - GMP Standards
4 - Inspection resources
5 - Inspection procedures
8 Alert and crisis systems
9 - Analytical capability
10 - Surveillance programme
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10B - Recall monitoring

7B
10C - Consumer complaint system
Critical
10D - Adverse reaction reporting system/

procedures
Not evaluated - not considered

within the scope of a GMP
regulatory compliance programme.
10E - Medicinal product defect reporting

system/ procedures

10C
Component
11 - Quality management system
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Sub-component
11A - Quality management system
Importance
Critical
Evaluation method
Glossary
Articles = Any item such as products (active pharmaceutical ingredient, finished medicinal products, investigational medicinal products, or any
intermediates), containers, packages, labels, documentation, etc.
Component/Sub-Component = Elements of a GMP regulatory compliance programme. For additional information on the level of importance and the
evaluation methods, refer to the table Summary of the Audit Checklist provided at the beginning of this document.
Dosage form = Pharmaceutical form
Equivalent = Not necessarily identical, but leading to the same result.
GMP regulatory compliance programme = Includes components such as the supporting infrastructure of legislative and regulatory requirements, GMP
standards, inspection/enforcement resources and procedures, performance standards, alert and crisis system, analytical capability, surveillance
programme and quality management systems.
Key performance indicators (KPI) = Performance indicators established for planning and reporting on the components/sub-components of a GMP
regulatory compliance programme.
Manufacture = Fabricate as defined in relevant GMP guidelines.
Medicinal products = Drug products
Official Medicines Control Laboratories (OMCL) = Laboratories used for the purpose of official testing.
Pharmacovigilance = Surveillance of adverse reactions reporting.
Product = Active pharmaceutical ingredient, finished medicinal product, investigational medicinal products, or any intermediate.
Product defect = Quality defect related to a product such as Out-of-Specifications (OOS), etc.
General Notes
The entire checklist must be used for the assessment/evaluation of GMP regulatory compliance programme as regards active pharmaceutical ingredients
and medicinal products.
This checklist is used as a high level document. It is meant to detail the WHAT and not the HOW. The HOW is expected to be covered in a lower
level document such as a guidance document or a procedure.
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Indicators
Indicator
Number
Method of Evaluation
DR: Documentation Review
OSEI: On-Site Evaluation at Inspectorate
OSEL: On-Site Evaluation at Laboratory
OI: Observed Inspection
DR
OSEI
Sub-component 1A Legislative and regulatory requirements and scope - Empowering legislation (Critical)
The legislation identifies key delegations/functions in the organisation/regulatory authority assigned
x
for overall responsibility of the GMP regulatory compliance programme.
x
x
The authority to designate inspectors is vested in legislation.
The identity of designated inspectors and scope of jurisdiction of legislation are available to
companies being inspected.
There is legal authority for an inspector to enter at any reasonable time in any place where active
pharmaceutical ingredients and medicinal products are manufactured, imported and exported.
There is legal authority for taking samples and submitting them to designated laboratories.
There is legal authority for obtaining evidence such as documents, photographs/videos of premises
and equipment.
There is legal authority to open and examine any article subjected to legislation.
There is the legal authority to seize or detain articles believed to be in violation.
The legislation allows entry to a private dwelling.
10
Legislation requires that the person who has the responsibility of the site where active pharmaceutical
x
x
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OSEL
OI
Indicators
Indicator
Number
DR
OSEI
ingredients and medicinal products are manufactured, imported and exported, to cooperate and not
obstruct an inspector.
11
Legislation requires a marketing authorisation holder and a manufacturer of medicinal product to

report to the regulatory authority any serious adverse medicinal product reactions.
12
Legislation requires a marketing authorisation holder and a manufacturer of active pharmaceutical

ingredients or of medicinal product to document any product defect impacting its quality.
13
Legislation requires the marketing authorisation holder and the manufacturer to notify a competent
regulatory authority upon commencement of a recall of medicinal product and to submit pertinent
information.
All companies that manufacture, import, export medicinal products are required to hold a
manufacturing authorisation or be identified as holder of a manufacturing authorisation or as a
registered company for active pharmaceutical ingredients.
14
x
x
15
The holder of the manufacturing authorisation is required to notify the regulatory authority of
significant changes or of conditions, which may affect the quality, safety or efficacy of a medicinal
product.
16
Legislation requires that the manufacturing authorisation include: the address of each site, the
manufacturing activities, the category of medicinal products and the dosage form.
17
Legislation prohibits the sale and processing of active pharmaceutical ingredients and medicinal
products under unsanitary conditions or leading to adulteration.
18
GMPs are legal requirements.
19
The legislation specifies that a manufacturer and/or a person is liable for a defective medicinal
x
x
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OSEL
OI
Indicators
Indicator
Number
DR
OSEI
OSEL
product and provides for prosecution and/or penalties upon conviction

20
There is legislative authority to suspend, revoke or amend a manufacturing authorisation.
21
Active pharmaceutical ingredients and medicinal products intended for exportation only are covered
in the legislation as the products intended for the domestic market.
Sub-component 1B Legislative and regulatory requirements and scope - Conflict of interest (Very important)
22
A policy/guideline exists that details the situations regarded as conflict of interest.
23
Employees are required to declare their compliance with the conflict of interest policy.
x
x
Sub-component 2A Regulatory directives and policies - Procedures for designating inspectors (Very important)
24
A process for designation of inspectors exists.
Sub-component 2B Regulatory directives and policies - Enforcement Policies

Included under sub-component 7B. Enforcement powers and procedures - Non-compliance management.
25
Sub-component 2C Regulatory directives and policies - Code of conduct/ Code of ethics (Very important)
x
A policy/guideline exist that details situations regarded as Code Of Conduct/Code Of Ethics.
Sub-component 2D Regulatory directives and policies - Training certification policies/guidelines
Included under sub-component 4C. Inspection resources - Training programme.
Sub-component 2E Regulatory directives and policies - Alert/crisis management policies/procedures/guidelines
Included under sub-component 8A. Alert and crisis systems - Alert mechanisms.
Sub-component 2F Regulatory directives and policies - Organisational structure
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OI
Indicators
Indicator
Number
DR
OSEI
Included under sub-component 11A. Quality management system

Sub-component 3A GMP Standards - Details/ scope of GMP (Critical)
26
27
GMPs are covered within a regulatory framework.
The GMP regulatory framework covers all GMP requirements including but not limited to:
Quality management, premises, equipment, personnel, sanitation, raw material testing, manufacturing
control, quality control department, packaging material testing, finished product testing, records,
samples, stability and sterile products.
Sub-component 3B GMP Standards - Process validation

Included under sub-component 3A GMP Standards - Details/ scope of GMP.
Sub-component 4A Inspection resources - Staffing: Initial qualification (Very important)
28
The minimum qualifications for GMP inspectors are defined
29
Duties of staff involved in the GMP regulatory compliance programme are defined.
30
Evidence exists that the GMP inspectors meet the minimum qualifications.
x
x
x
x
Sub-component 4B Inspection resources - Number of inspectors (Very important)

31
The number of inspectors dedicated to the GMP inspection programme is sufficient to meet the
prescribed inspection frequency/inspection programme.
Sub-component 4C Inspection resources - Training programme (Very important)

32
A training programme for inspectors is established and records are maintained.
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OSEL
OI
Indicators
Indicator
Number
33
A mechanism to evaluate the effectiveness of training exists.
DR
OSEI
OSEL
OI
Sub-component 4D Inspection resources - QA mechanism to assure effectiveness of training programme

Included under sub-component 4C Inspection resources - Training programme.
Sub-component 5A Inspection procedures - Inspection strategy (Very important)
34
Documents that describe the work expected, anticipated results and resources applied to fulfil the
functions of GMP inspections are available.
35
A scheduling system identifies companies due for inspections within a set time frame.
Sub-component 5B Inspection procedures - Pre-inspection preparation (Very important)

36
A procedure details the requirements for pre-inspection activities, and is followed.
37
The inspection plan is based on the companys GMP compliance history, critical activities and type(s)
of dosage forms or products manufactured.
x
x
x
x
Sub-component 5C Inspection procedures - Format and content of inspection reports (Very important)
38
A procedure for the format and content of inspection reports is available.
39
Observations are factual and are based on proper interpretation of applicable legislation.
40
Observations are classified/categorised according to risk.
41
Assessment of the companys overall compliance rating is in line with the inspection findings.
42
Inspection reports are completed in the required reporting format and timeframe.
Sub-component 5D Inspection procedures - Inspection methodology
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x
x
x
x
x
x
Indicators
Indicator
Number
DR
Included under sub-components 5E. Inspection procedures - SOP for conducting inspections
OSEI
OSEL
OI
Sub-component 5E Inspection procedures - SOP for conducting inspections (Critical)

43
A procedure details the requirements for conducting inspections and is followed.
44
Critical stages and parameters of manufacturing processes are assessed.
45
Qualification and validation are assessed.
46
The inspection plan is adjusted, where warranted, based on the findings of the inspection.
47
The depth of the inspection is in line with the inspection findings.
x
x
x
x
x
Sub-component 5F Inspection procedures - Post-inspection activities (Very important)

48
A procedure details the requirements for post-inspection activities, and is followed.
49
Inspection findings and conclusions are subject to an internal review.
x
x
x
x
Sub-component 5G Inspection procedures - Storage of inspection data (Important)

50
A policy/procedure is available for the storage of inspection data.
51
An inspection report database (or archive) is maintained in a secure and controlled manner.
Sub-component 6A Inspection performance standard - Performance standards (Very important)

Included under sub-component 11A Quality Management System - Quality management system
Sub-component 7A Enforcement powers and procedures - Provision for written notice of violations
Included under sub-component 7B Enforcement powers and procedures - Non-compliance management
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x
x
Indicators
Indicator
Number
DR
OSEI
Sub-component 7B Enforcement powers and procedures - Non-compliance management (Critical)
Recall procedures/mechanisms and records are available.
x
x
x
x
54
GMP certificates, manufacturing authorisation suspension/withdrawal procedures/mechanisms are

available and a list of suspended/withdrawn authorisations/GMP certificates is maintained.
55
Seizure procedures/mechanisms and records are available.
56
Prosecution procedures/mechanisms and records are available.
x
x
x
x
52
There is provision for written notice of violations to be sent to the company.
53
Sub-component 7C Enforcement powers and procedures - Appeal mechanism (Important)

57
Appeal procedures/mechanisms and records are available.
Sub-component 7D Enforcement powers and procedures - Other measures

Included under sub-components 7B Enforcement powers and procedures - Non-compliance management
Sub-component 8A Alert and crisis systems - Alert mechanisms (Critical)
58
Two-Way alert procedures/mechanisms and records are available.
Sub-component 8B Alert and crisis systems - Crisis management mechanisms

Included under sub-component 8A Alert and Crisis systems - Alert mechanisms
Sub-component 8C Alert and crisis systems - Alert performance standards (Important)
59
Performance standards for the transmission of two-way alert and management of crisis system are
established and are followed.
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OSEL
OI
Indicators
Indicator
Number
DR
61
Sub-component 9A Analytical capability - Access to laboratories (Critical)

The regulatory authority has access to laboratories capable of conducting necessary analyses for the
purpose of official testing.
Regulatory Authoritys or contract laboratories are qualified according to a recognised standard.
62
All reported products defects are documented and investigated.
60
OSEI
OSEL
x
x
x
x
Sub-component 9B Analytical capability - SOPs for analytical support (Very important)

63
Documents are available that detail the work expected, anticipated results and resources applied to
fulfil the functions of the laboratories.
64
Procedures covering all elements of laboratory operations are available and are followed.
Sub-component 9C Analytical capability - Validation of analytical methods (Very important)

65
The test method validation guideline is equivalent to the ICH standard and records are available.
Sub-component 10A Surveillance programme - Sampling and audit procedure (Very important)
66
The market surveillance programme for active pharmaceutical ingredients and medicinal products is
developed involving at least the inspection and laboratory departments using risk management
principles and covers dosage forms of different medicinal product types.
67
The market surveillance programme performance is reviewed annually and records of review are
available.
Sub-component 10B Surveillance programme - Recall monitoring

Included under sub-component 7B Enforcement powers and procedures - Non-compliance management
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OI
Indicators
Indicator
Number
DR
OSEI
OSEL
Sub-component 10C Surveillance programme - Consumer complaint system (Critical)

68
A consumer complaint system/procedure and records are available.
69
Issues of high risk are investigated immediately.
70
Compliance staff and or inspection staff can access complaint information.
71
All reported products defects are documented and investigated.
x
x
x
x
Sub-component 10D Surveillance programme - Adverse reaction reporting system/ procedures

Not evaluated - not considered within the scope of a GMP regulatory compliance programme.
Sub-component 10E Surveillance programme - Medicinal product defect reporting system/procedures
Included under sub-component 10C Surveillance programme - Consumer complaint system
Sub-component 11A Quality management system - Quality management system (Critical)
72
The quality management system is defined based on a recognised international standard.
73
The quality manual covers all elements of GMP regulatory compliance programme.
74
75
Key performance indicators (KPI) for the overall GMP regulatory compliance programme are
established and available.
The quality management system has been implemented and is followed.
76
A documentation control system is in place.
77
Quality audit plans and records are available.
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x
x
X
x
x
x
x
x
x
OI
Indicators
Indicator
Number
DR
78
Management reviews ensure the performance of the quality management system on an annual basis.
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OSEI
OSEL
OI
ANNEX EVALUATION GUIDE FOR GMP REGULATORY

COMPLIANCE PROGRAMME AUDIT CHECKLIST
IMPLEMENTATION OF EC LEGISLATION AND GUIDANCE RELATED TO GMP
HUMAN AND VETERINARY ALL RELEVANT ARTICLES TO BE CHECKED
EC requirement
Article
(Human)
Subject
Article
(Veterinary)
1. Directive 2001/83/EC, as amended by Directive 2004/27/EC Human Medicinal Products

2. Directive 2001/82/EC, as amended by Directive 2004/28/EC Veterinary Medicinal Products
40(1) (2)
40(3)
Authorisation for manufacture

Authorisation for import
44(1) (2)
44(3)
41
Requirements for applicant in order to obtain manufacturing authorisation
45
42
Granting of authorisation
46
43-45
46
Time limits for the handling of the application

Obligations of holder of manufacturing authorisation
47-49
50
(a) Services of the adequate staff

(b) Comply with national legislation of the Member State concerned
(c) Give prior notice of changes
(d) Allow inspections
(e) Enable qualified person to carry out its duties
(f) Comply with GMP rules
47
Implementation through Directive and Guidelines
51
Guidelines including annexes as published under EUDRALEX

Volume 4 - Medicinal Products for Human and Veterinary Use : Good
Manufacturing Practice
(http://pharmacos.eudra.org/F2/eudralex/vol-4/home.htm)
Principles of GMP for active substances used as starting materials
48
Requirement of qualified person
52
49
Conditions of qualification of qualified person and professional background
53
51
Responsibilities of qualified person
55
56
Enforcement of qualified persons obligations
56
53
Application to homeopathic medicinal products
57
111
Detailed Provisions for inspections at premises of manufacturers (please list in

detail each aspect of implementation of this article)
80
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EC requirement
Article
(Human)
113
114
Article
Subject
Article
(Veterinary)
MS to ensure that holder of a manufacturing authorisation furnishes proof of

the control tests to be carried out in compliance with marketing authorisation
(Administrative batch protocol review)
81
Official Control Batch Release Testing (May-Provision)
82
Subject
2. Directive 2003/94/EC (Human) and Directive 91/412/EEC (Veterinary) GMP

1
Scope of application of GMP rules
Repeated inspections by MS
Comparable standards to Compilation of Community Procedures

(http://www.emea.eu.int/Inspections/GMPCompproc.html)
Quality Systems framework
Procedures related to Rapid Alerts
Procedures related to GMP Inspections
Forms used by Regulators (GMP inspection report format, manufacturers authorisation)
Procedures related to Centralised Procedures
Responsibility of manufacturer and importer

Compliance of medicinal products and investigational medicinal products manufacturing (in EC or
whether imported) with GMP
Obligations of the manufacturer:

Manufacturing operations in accordance with information in application
Adaptation to scientific and technical progress
Quality assurance system
Qualified personnel at the manufacturing site, job descriptions of qualified personnel, training
Hygiene programme
Premises and equipment
Documentation
Manufacturing procedures
Traceability of batches
Protection of data processing systems
10
Production
Pre-established procedures, resources
Validation
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11
Quality control
Quality control department
Quality control laboratories
Final control of finished products
12
Work contracted out

Written contract
Clearly defined responsibilities
No sub-contracting
Respect of GPM and allow inspections
13
Implementation of a system for recording and reviewing complaints

Implementation of a system for product recall
14
Article
Self inspection
Subject
3. Directive 2001/20/EC Good Clinical Practice

13 (1)
13 (2)
13 (3)
Article
Authorisation for total and partial manufacturing of investigational medicinal products

Qualified person for investigational medicinal products
GMP for manufacturing and testing of investigational medicinal products
Subject
4. Directive 2005/28/EC Good Clinical Practice

9
10
11-12
13
21
22
23
General conditions for a manufacturing and import authorisation

Applicants requirements to obtain an authorisation
Obligations of competent authority
Obligations of holder of an authorisation
Requirements related to inspectors
Teams of Inspectors
Inspection Procedures ( here: only in relation to GMP verification)
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Evaluation Guide For GMP Regulatory Compliance Programme

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What are the main requirements for manufacturing authorizations?

What are the main requirements for manufacturing authorizations?

What are the main obligations of the holder of a manufacturing authorization?

What are the main obligations of the holder of a manufacturing authorization?

17 December 2012

EVALUATION GUIDE FOR GMP REGULATORY

7 Westferry Circus Canary Wharf London E14 4HB United Kingdom

An agency of the European Union

1 - Legislative and Regulatory Requirements and

Summary of the Audit Checklist

2 - Regulatory directives and policies

2A - Procedures for designating inspectors

Evaluated as part of sub-component

2C - Code of conduct/ Code of ethics

2D - Training certification policies/guidelines

Evaluated as part of sub-component

Evaluated as part of sub-component

Evaluated as part of sub-component

3A - Details/ scope of GMP

Evaluated as part of sub-component

4A - Staffing: Initial qualification

4D - QA mechanism to assure effectiveness of

Evaluated as part of sub-component

5C - Format and content of inspection reports

Evaluated as part of sub-components

5E - SOP for conducting inspections

5F - Inspection procedures - Post-inspection

5G - Inspection procedures Storage of

6 - Inspection performance standard

Evaluated as part of sub-component

7 - Enforcement powers and procedures

7A - Provision for written notice of violations

Evaluated as part of sub-component

Evaluated as part of sub-components

8B - Crisis management mechanisms

Evaluated as part of sub-component

8C - Alert performance standards

9B - SOPs for analytical support

9C - Validation of analytical methods

10A - Sampling and audit procedure

8 Alert and crisis systems

JAP Audit Checklist

JAP Audit Checklist

10B - Recall monitoring

Evaluated as part of sub-component

10C - Consumer complaint system

10D - Adverse reaction reporting system/

Not evaluated - not considered

10E - Medicinal product defect reporting

Evaluated as part of sub-component

JAP Audit Checklist

JAP Audit Checklist

The authority to designate inspectors is vested in legislation.

There is the legal authority to seize or detain articles believed to be in violation.

The legislation allows entry to a private dwelling.

JAP Audit Checklist

Legislation requires a marketing authorisation holder and a manufacturer of medicinal product to

Legislation requires a marketing authorisation holder and a manufacturer of active pharmaceutical