1. Good Practices (GMP, GLP, GCP), inspections including Pharmacopoeias
Product defects & recall
Parallel import
Jana Klimasová, PhD.
Department of pre-clinical and clinical assessment, Registration section, SIDC

2. Good manufacturing practice
that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use
Directive 2003/94/EC
Eudralex volume 4 – GMP guidelines
compliance with principles of GMP - mandatory within the EEA.

3. Directive 2003/94/EC
the manufacturer shall ensure that manufacturing operations are carried out in accordance with GMP and with the manufacturing authorisation
the importer shall ensure that the products have been manufactured in accordance with standards which are at least equivalent to the GMP standards
the manufacturer shall establish and implement an effective pharmaceutical quality assurance system
the manufacturer shall have a sufficient number of competent and appropriately qualified personnel at his disposal
premises and manufacturing equipment shall be located, designed, constructed, adapted and maintained to suit the intended operations

4. Directive 2003/94/EC
the manufacturer shall establish and maintain a documentation system (clear, free from error and kept up to date)
For medicinal products, any new manufacture or important modification of a manufacturing process of a medicinal product shall be validated
The manufacturer shall establish and maintain a quality control system placed under the authority of a person who has the requisite qualifications and is independent of production
The manufacturer shall inform the competent authority of any defect that could result in a recall or abnormal restriction on supply and, in so far as is possible, indicate the countries of destination
The manufacturer shall conduct repeated self-inspections

5. EudraLex - Volume 4 Good GMP Guidelines
Volume 4 of "The rules governing medicinal products in the European Union" contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use.
Introduction
Part I - Basic Requirements for Medicinal Products
Part II - Basic Requirements for Active Substances used as Starting Materials
Part III - GMP related documents
Annexes
Part I - Basic Requirements for Medicinal Products Pharmaceutical Quality System Personnel Premise and Equipment Documentation
Production
Quality control Contract Manufacture and Analysis Complaints and Product Recall Self Inspection

6. Annexes
1 Manufacture of Sterile Medicinal Products 2 Manufacture of Biological active substances and Medicinal Products for Human Use 3 Manufacture of Radiopharmaceuticals 4 Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products 5 Manufacture of Immunological Veterinary Medicinal Products 6 Manufacture of Medicinal Gases 7 Manufacture of Herbal Medicinal Products 8 Sampling of Starting and Packaging Materials 9 Manufacture of Liquids, Creams and Ointments 10 Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation 11 Computerised Systems (revision January 2011) 12 Use of Ionising Radiation in the Manufacture of Medicinal Products 13 Manufacture of Investigational Medicinal Products 14 Manufacture of Products derived from Human Blood or Human Plasma 15 Qualification and validation 16 Certification by a Qualified person and Batch Release 17 Parametric Release 19 Reference and Retention Samples

7. all manufacturers and importers of medicines located in the EEA must hold a manufacturing authorisation
supervised by medicines regulatory authorities in Member States - responsible for issuing authorisations for activities taking place in their territories
NCAs must perform inspections of manufacturing-authorisation holders to ensure that they are adhering to the principles and guidelines of GMP
products imported from countries outside the EU - NCAs is responsible for verifying that the manufacturer conforms to standards of GMP equivalent to those in force in the EU, unless the country has negotiated an appropriate agreement (mutual recognition agreement) with the EU establishing mutual recognition of GMP inspections

8. GMP certificate
certificate issued following a GMP inspection, by the competent authority responsible for carrying out the inspection, to confirm the GMP compliance status of the inspected site
site-specific, but can be restricted to particular activities depending on the scope of the inspection (e.g., manufacturing activities related to a specific product)
after every GMP inspection, and within 90 days of the inspection, a GMP certificate shall be issued to a manufacturer, if the outcome of the inspection shows that the manufacturer complies with GMP (Directives 2001/82/EC and 2001/83/EC)

9. http://eudragmdp. ema. europa. eu/inspections/gmpc/searchGMPCompliance

10. Inspections: Deficiencies: initial, repeated
product related, process related inspection and/or general GMP inspection
reason for the inspection - new marketing application, routine, investigation of product defect
Deficiencies:
Critical - A deficiency which has produced, or leads to a significant risk of producing either a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal.
Major
Others
Compilation of Community Procedures on Inspections and Exchange of Information

11. Good clinical practice (GCP)
an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects
compliance with GCP provides public assurance that the rights, safety and wellbeing of trial subjects are protected and that clinical-trial data are credible
Requirements for the conduct of clinical trials in the European Union:
the 'Clinical Trial Directive' (Directive 2001/20/EC)
the 'GCP Directive' (Directive 2005/28/EC)
Guideline for good clinical practice - ICH Harmonised Tripartite Guideline
EudraLex - Volume 10 Clinical trials guidelines

12. Good laboratory practice (GLP)
define a set of rules and criteria for a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, reported and archived.
Directive 2004/9/EC and 2004/10/EC

13. Pharmacopoeias in Europe – European Pharmacopoeia – Ph. Eur.
a single reference work for the quality control of medicines 
the official standards published within provide a legal and scientific basis for quality control during the development, production and marketing processes
contains the qualitative and quantitative composition and the tests to be carried out on medicines, on the raw materials used in production of medicines and on the intermediates of synthesis
all producers of medicines and/or substances for pharmaceutical use must therefore apply these quality standards in order to market their products in the signatory states
mandatory character of European Pharmacopoeia monographs when requesting marketing authorisation set in European Union Directives 2001/82/EC, 2001/83/EC, and 2003/63/EC
published by EDQM (European Directorate for the Quality of Medicines and Healthcare)

14. Product defects and recalls
In order to protect public health, it may become necessary to implement urgent measures such as the recall of one or more defective batch(es) of a medicinal product from the market
MAH - required to implement an effective procedure for the recall of defective products
required to notify the relevant NCA of any defect or abnormal restriction that could result in a recall
Batch recall
The action of withdrawing a batch from the distribution chain and users. A batch recall may be partial, in that the batch is only withdrawn from selected distributors or users.
Rapid Alert
An urgent notification from one competent authority to other authorities that a batch recall has been instituted in the country originating the rapid alert.
Level of recall
Class of recall
Compilation of Community Procedures on Inspections and Exchange of Information

15. Class I defects
potentially life threatening
rapid alert notification must be sent to all contacts of the rapid alert notification list irrespective of whether or not the batch was exported to that country
Wrong product (label and contents are different products)
Correct product but wrong strength, with serious medical consequences
Microbial contamination of sterile injectable or ophthalmic product
Chemical contamination with serious medical consequences
Mix-up of some products (rogues) with more than one container involved
Wrong active ingredient in a multi-component product, with serious medical consequences.

16. Class II defects
could cause illness or mistreatment, but are not Class I
rapid alert notification should be sent to all contacts of the rapid alert notification list as it might be difficult to know where a batch has been distributed
if the product distribution is known, the notification should be only sent to the contacts concerned
Mislabelling, e.g. wrong or missing text or figures
Missing or incorrect information (leaflets or inserts)
Microbial contamination of non-injectable, non-ophthalmic sterile product with medical consequences
Chemical/physical contamination (significant impurities, cross-contamination, particulates)
Mix up of products in containers (rogues)
Non-compliance with specification (e.g. assay, stability, fill/weight)
Insecure closure with serious medical consequences (e.g. cytotoxics, child- resistant containers, potent products).

17. Class III defects
may not pose a significant hazard to health, but withdrawal may be initiated for other reasons
not normally notified through the Rapid Alert System
Faulty packaging, e.g. wrong or missing batch number or expiry date
Faulty closure
Contamination, e.g. microbial spoilage, dirt or detritus, particulate matter

18. Parallel distribution and import
Centrally authorised medicinal products put on the market of one Member State can be marketed in any other Member State by a distributor, independently of the marketing-authorisation holder
Condition of parallel distribution checked by the European Medicines Agency 
Notification of parallel distribution to the EMA – mandatory
Parallel import
only nationally authorised products 
authorised by the national competent authority of the Member State of import based on the similarity to the product distributed in the Member State of destination by the marketing-authorisation holder

19. Thank you for your attention!