Quality aspects Overview. QP declaration

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1 Quality aspects Overview QP declaration Standards for the quality part of the dossier with focus on: - Materials from animals, nosodes - Proof of microbiological quality, pesticides, heavy metals, organic farming - Stability testing QP declaration "The QP declaration template EMA/334808/ Guidance - QP responsibility - GMP compliance The signatory confirms that the manufacture of the active substance complies with GMP, that this is based on an audit and that the audit outcome confirms compliance with GMP. - Audit Ingrid Werner Expert Group Herbal Medicinal Products & Homeopathics Department Quality Assessment of Medicinal Products AGES-Gespräch Homeopathics: an Update Vienna, Active substance raw material o eg. Natrium chloratum D6: raw material = NaCl no GMP active substance = trituration D6 GMP Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbH 2 3 1

2 The quality part of the dossier S.1 General Information S.2 Manufacture Content has to follow - Annex I of Dir 2001/83/EC as amended - Note for Guidance of the HMPWG: Guidance on module 3 Nomenclature following Pharmacopoeia - + synonyms (old homeopathic names) S.2 Manufacture Manufacturer - All manufacturers! o Stock, dilution/trituration - Check application form Manufacturing process - Description, flow chart, sequential steps, times between steps, in-process controls - Homoeopathic manufacturing method from pharmacopoeia! no deviations (eg. different vehicle) - Check S.7 Stability o Storing of raw material/stock/dilution/final dilution?, duration?, immediate processing/testing before processing when? - Check batch analyses (date of testing)

3 S.2 Manufacture Ph Eur: Homoepathic prep. (1038) Guidance on module 3 Control of materials - Plant material: o similar to herbal medicinal products, exception: fresh plants testing of stock possible - Material from animals, nosodes o PhEur: Homoeopathic preparations (1038) o HMPWG: Guidance on module 3 of the homeopathic medicinal products dossier o HMPWG: Points to consider on the safety of homeopathic medicinal products of biological origin 7 For raw materials of zoological or human origin, adequate measures are taken to minimise the risk of agents of infection, including viruses (5.1.7), in the homoeopathic preparations. For this purpose, it is demonstrated that: - the method of production includes a step or steps that have been shown to remove or inactivate agents of infection; - where applicable, raw materials of zoological origin comply with the monograph Products with risk of transmitting agents of animal spongiform encephalopathies (1483); - where applicable, the animals and the tissues used to obtain the raw materials comply with the health requirements of the competent authorities for animals for human consumption; - for materials of human origin, the donor follows the recommendations applicable to human blood donors and to donated blood (see Human plasma for fractionation (0853)), unless otherwise justified and authorised. 8 Nomenclature of the raw materials For raw materials of biological origin, the scientific name (e.g., animal), -genus, species- tissue(s), fluid(s), parts of organ(s) or organ(s) used and other names should be provided. Description of the raw materials For raw materials of biological origin, information on the physical and/or anatomical and histological state (where applicable) should be provided. 9 3

4 Guidance on module 3 Supportive Data - Name and address of the supplier and supplier commitment and/or manufacturer and manufacturer's commitment, if different from the applicant - Data on the origin/source of the material - Synthetic or manufacturing route - Production: (for example) o For raw materials of biological (not botanical) origin o For raw materials of human origin Supportive data - production For raw materials of biological (not botanical) origin: o Age of the animal, culture history o Health status, method of breeding and feeding of animals, immunisation techniques (immune sera) with description of antigens, culture media (microbial strains) o Conditions of slaughter and dissection of animals, culture conditions o Size of organ, tissue, fluid pools o Method of acquisition, treatments, transport conditions and storage conditions of the organ or pool of organs or microbial cultures or immune sera o Provisions made for tracing the origin of the raw material(s) o Assessment of the risk of infectivity Supportive data - production For raw materials of human origin: - Origin of donation- clinical data - Identification of raw material biological fluid description, tissue description, cells nature, origin, name, reference, volume of sample, method of collection, transport, storage conditions pool - Assessment of the risk of infectivity

5 Points to consider on the safety Points to consider on the safety S.3 Characterisation 1. Introduction 2. Scope 3. Preparations involved in the manufacturing process 4. Biological starting material used for the production of homeopathic medicinal products 4.1 Sourcing of biological materials Animal origin Viral contamination Transmission of TSE Medicinal products Human origin Products derived from human, animal and microbial cell lines 5. Manufacturing process and safety of homeopathic medicinal products and of the first safe preparations 5.1. First safe preparations 5.2. Manufacturing of homeopathic medicinal products and of first safe preparations 5.3. Human origin 5.4. Transmission of TSE 5.5. Products derived from biotechnology 6. Risk assessment of homeopathic medicinal products from biological origin Impurities - Pesticides, heavy metals, aflatoxines organic farming testing for pesticides? soil analysis testing for heavy metals? skip testing, testing intervals should be discussed and justified - Microbiology o Microbiological quality of non-sterile pharmaceutical preparations and substances for pharmaceutical use o Microbiological quality of herbal medicinal products for oral use and extracts used in their preparation o Raw materials, stocks: resp o Dosage forms: cave: oral/oromucosal use, aqueous/non-aqueous

6 S.4 Control Specifications - Raw material, stock, final dilution Pharmacopoeia monograph: parameters, acceptance criteria Batch analyses - Data from recent batches (max. 5 years ago) incl. TLC images - 3 batches (if not otherwise justified) Justification of specification - Deviations from pharmacopoeia - In-house monograph S.6 Container Closure System Detailed description of container closure system for: - Raw material (if stored) - Stock - Intermediate dilution/trituration - Final dilution/trituration Suitability of container closure system for: - Storing - Shipping S.7 Stability Stock, final dilution - Manufacture of drug substance/drug product storage or immediate processing? - Data from stock transferable to dilutions - Data incl. TLC images Points to Consider on Stability Testing of Homeopathic Medicinal Products - About_HMA/Working_Groups/HMPWG/2009_07_Points_on_Stability_testing.pdf

7 P.1 Description & Composition P.2 Pharmaceutical development P.3 Manufacture Composition: - Check consistency with o SmPC section 2 o PIL section 6 o Application form Description of the finished product - Colour, odour, shape, Description of container closure system Additional information needed for special pharmaceutical forms - E.g. sterile products, eye drops, nasal preparations, gels etc. Justification for - Excipients - Preservatives - Test for efficacy of antimicrobial preservation Data on uniformity of dosage units delivered from multidose containers Batch formula Description of manufacturing process - Flow chart! Example: - Manufacturer 1: bulk product - Manufacturer 2: filling, batch release - Time between manufacture and filling - Container closure system for shipping

8 P.5 Control of the Drug Product P.7 Container Closure System P.8 Stability Specification - Appearance, physical parameters, - Microbiological quality: Pharm. Eur Batch analyses - Data from recent batches (max. 5 years ago) incl. TLC images - Description of batches o Date of manufacture, Batch size Example - Drug substance D1: o Applicant: dilution too high for TLC - Potency D4: if test for identity ( eg. TLC) is not possible include proof in dossier! 22 Detailed description, construction - Specification of all materials - Plastic materials: Conformity with EP - Regulation EU 10/2011: plastics intended to come in contact with food 23 Shelf life has to be based on data - in case of transfer from product with same specification the cited data have to be content of the dossier! - If no identification or assay of the active substance is possible due to the degree of dilution: o Stability data of the pharmaceutical form may be sufficient - Recent data incl. TLC images, description of packaging - Conclusion! Shelf life + storage conditions o Check consistency with application form, product information - Special precautions for storage o Labelling of storage conditions depend on test conditions o Cave! Need for temperature control for shipping of finished product 24 8

9 P.8 Stability Multidose containers: - Statement on the In-use stability obligatory! - Testdesign o Simulate use of product in practice Frequency of opening Duration of study - Result: o Define shelf-life after first opening Labelling of storage conditions after first opening according to test design o OR statement, why this is not necessary - Justification, if no tests are performed 25 Transferability of stability data Comparability of the homeopathic medicinal products may be expected if among others the following conditions apply: - same dosage form - same specifications - comparable composition in respect of other excipients - comparable * manufacturing procedure, comparable * vehicle and type of starting material (e.g. herbal) - same primary packaging material (complying with Ph. Eur.) - manufacture of the products of the same applicant under comparable * manufacturing conditions - - compliance with storage conditions and testing frequencies according to the Guideline on Stability Testing - - data from two pilot batches or two production batches from an appropriate number of reference products * has to be scientifically justified 26 9