S.L. 458.46 Art. 2Interpretation.

For the purposes of these regulations -

"active pharmaceutical ingredient" (API) means any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in the production of a medicinal product, becomes an active ingredient of the said product. These substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body;

"API manufacturer" means a person, group of persons or company involved in the manufacture of active pharmaceutical ingredients;

"certificate of a pharmaceutical product (CPP)" or "export certificate" means a certificate, complying with the format specified by World Health Organisation, providing details about a single named medicinal product, which may be licensed or unlicensed in Malta. It provides details about the product and its manufacture including, but not limited to, the marketing authorisation (MA) holder, where applicable, the active ingredients and excipients, the manufacturing and packaging sites and whether or not the product is placed on the market in Malta; "concerned Member State" means a Member State or States in which mutual recognition is sought in the mutual recognition and decentralised procedures; "decentralised procedure" means the decentralised procedure for human medicinal products provided for in Directive 2001/83/EC, as may be amended from time to time; "Directive 2001/83/EC" means Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, and its amendments as amended by Directive 2004/27/EC and Directive 2004/24/EC; "extension of a marketing authorisation" or "extension" means a variation which is listed in Annex I of Regulation 1234/2008/EC and fulfils the conditions laid down therein; "follow-up inspections" refers to inspections other than those referred to as major inspections; "GMP certificate" means a certificate issued by the Medicines Authority for the purpose of confirming to a manufacturer the overall conclusion of an inspection with respect to compliance with good manufacturing practice; "good clinical practice inspection" means an inspection performed to assess the standards for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials so as to provide assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are provided; "herbal medicinal product" means any medicinal product, exclusively containing as active ingredients one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations; "importer" means any person or group of persons or company involved in the importation of Medicinal products obtained from a source outside the European Union or the European Economic Area;

"importing activity" is the action by which medicinal products sourced from outside the European Union or the European Economic Area are obtained, stored and distributed; "major inspection" refers to inspections carried out for the first time in a particular area or site, or inspections to already existing sites that had major variations or alterations; "marketing authorisation transfer" is when a marketing authorisation is transferred from the existing marketing authorisation holder to another using a transfer procedure. A transfer may occur either during or after issue of a marketing authorisation and entails a change in legal entity; "mutual recognition procedure" means the mutual recognition procedure for human medicinal products provided for in Directive 2001/83/EC, as may be amended from time to time;

"partial manufacturing" has the same meaning as "assembly" in the Medicines Act;

"periodic safety update report" or "PSUR" refers to the periodical reports containing the records referred to in regulation 32 of the Pharmacovigilance Regulations; "pharmacovigilance inspection" means an inspection carried out to assess the pharmacovigilance programme of a market authorization holder during which the following are assessed:

(a) monitoring of adverse drug reactions endorsed by company for its licensed products;

(b) the assessment of risk and benefits of medicines used to determine what action should be taken to improve their safe use;

(c) supply of information to optimise safe and effective use of medicines;

(d) monitor impact of any action taken by the company; "post-authorisation safety study" or "PASS" means any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures; "reference Member State" means the Member State, which has produced the assessment report for a given medicinal product, which serves as the basis for the mutual recognition and decentralised procedures; "traditional herbal medicinal product" is a herbal medicinal substance that fulfils the conditions laid down in the Herbal Medicinal Products Regulations; "urgent safety restriction" means an interim change in the terms of the marketing authorisation due to new information having a bearing on the safe use of the medicinal product;

"variation relating to a pharmaceutical activity" means any change pertaining to the related activity that may or may not require an inspection. Variations not requiring an inspection are those changes in the administrative details appearing on the licence, such as changes in name of company or change in names of key personnel. Variations that require an inspection are changes that can have an effect on the quality system of the company and, or on the quality of the product directly or indirectly which hence requires an inspection, such as in a change in a particular stage of the manufacturing process or installation of new equipment; "variation to the terms of a marketing authorisation" means an amendment to the contents of the particulars and documents referred to in regulations 5 to 8 of the Medicines (Marketing

Authorisation) Regulations, as defined in Commission Regulation

(EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products, as may be amended from time to time, in the case of medicinal products for human use:

(1) "Minor variation of type IA" means a variation which has only a minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal product concerned;

(2) "Minor variation of type IB" means a variation which is neither a minor variation of type IA nor a major variation of type II nor an extension;

(3) "Major variation of type II" means a variation which is not an extension and which may have a significant impact on the quality, safety or efficacy of the medicinal product concerned. Major type II variations may be simple or complex;

(4) "Type II Complex variation" means a variation, when it falls within one or more of the following descriptions:

(a) the application relates to the results of clinical trials or other data (including pharmacological and toxicological tests as well as extensive evidence from post marketing experience or publications) that need to be newly assessed;

(b) the application is supported by substantial amounts of data, that have not previously been assessed;

(c) the application relates to changes in indications for use in a therapeutic area for which the product was not previously indicated for use;

(d) the application relates to changes in indications for use in respect of an organ, or any other part, of the human body for which the product was not previously indicated for use;

(e) the application is supported by data which comprises or includes the results of clinical trials or physico-chemical, microbiological or pharmacological and toxicological tests;

(f) the application relates to an increase in the maximum dose;

(g) the application relates to a new dosage regimen;

(h) the application relates to a change in the method of sale or supply of an active ingredient from prescription only to pharmacy sale;

(i) the application relates to a change in the conditions of prescribing;

(j) the application relates to the removal of a contra-indication;

(k) the application relates to an increased duration of treatment;

(l) the application relates to a change in the route of administration of the same dosage form;

(m) the application relates to a new route of synthesis that has not previously been assessed and a European Pharmacopoeia Certificate of Suitability is not available for the active ingredient;

(n) the application relates to a new method of sterilisation of the product;

(o) the application relates to a new container materials for a sterile product;

(p) the application relates to a new active ingredient manufacturer not previously approved to manufacture the active ingredient concerned and who does not hold a European Pharmacopoeia Certificate of Suitability for the substance concerned;

(q) the application relates to a major formulation change which affects more than one section in Module 3 of the dossier and, or requires a re-evaluation of the safety or efficacy of the product, such as -

(i) a change in more than one excipient, except for a change in a key excipient (such as a preservative, release-controlling excipient, or stabiliser);

(ii) when a change in the key excipient alone will be regarded as a major formulation change;

(iii) the inclusion for the first time of a novel excipient not used before in any product;

(iv) a change which requires an in-vivo bioavailability study to be carried out;

(v) a change which results in a change to the therapeutic characteristics of the product;

(r) the application relates to change in the method of manufacture of the active ingredient which introduces new impurities or changes the level of impurities and which requires further qualification in safety studies;

(s) the application relates to any change in the source materials, method of manufacture or analytical procedures for a product of biological or biotechnological origin which might significantly affect the quality of the product;

(t) the application relates to a change in the qualitative composition of the immediate packaging of a sterile product, where the container material has not been previously approved for such use;

(u) the application relates to the introduction of a novel method of analysis;

(v) the application relates to a new manufacturer or process for a flu vaccine;

(5) "Grouped variations" are variations that can be submitted in one application form; grouping must be in line with Annex III of Regulation 1234/2008 and official grouping guidelines; "wholesale dealer" means any person or group of persons or company involved in the wholesale dealing activity; "wholesale dealing activity" has the same meaning as "wholesale distribution" in the Medicines Act.