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

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.

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

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

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 http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

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

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

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)

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

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

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

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

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) https://www.edqm.eu/en/ph-eur-9th-edition

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

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.

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).

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

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

Thank you for your attention!