Changes from plenary report to adopted text

AddedAny other substances used for manufacturing or extracting the active substance(s) but from which this active substance is not directly derived, such as reagents, culture media, foetal calf serum, additives, and buffers involved in chromatography, etc. are known as raw materials.

Added3.2.1.2. M a n u f a c t u r i n g p r o c e s s o f t h e a c t i v e s u b s t a n c e ( s )

Addeda) The description of the active substance manufacturing process represents the applicant's commitment for the manufacture of the active substance. To adequately describe the manufacturing process and process controls, appropriate information as laid down in guidelines published by the Agency shall be provided.

Addedb) All materials needed in order to manufacture the active substance(s) shall be listed, identifying where each material is used in the process. Information on the quality and control of these materials shall be provided. Information demonstrating that materials meet standards appropriate for their intended use shall be provided.

AddedRaw materials shall be listed and their quality and controls shall also be documented.

AddedThe name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing shall be provided.

Addedc) For biological medicinal products, the following additional requirements shall apply.

AddedThe origin and history of starting materials shall be described and documented.

AddedRegarding the specific measures for the prevention of the Transmission of animal Spongiform Encephalopathies, the applicant must demonstrate that the active substance complies with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union.

AddedWhen cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used for the production and beyond.

AddedSeed materials, cell banks, pools of serum or plasma and other materials of biological origin and, whenever possible, the materials from which they are derived shall be tested for adventitious agents.

AddedIf the presence of potentially pathogenic adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures their elimination and/or inactivation, and this shall be validated.

AddedWhenever possible, vaccine production shall be based on a seed lot system and on established cell banks. For bacterial and viral vaccines, the characteristics of the infectious agent shall be demonstrated on the seed. In addition, for live vaccines, the stability of the attenuation characteristics shall be demonstrated on the seed; if this proof is not sufficient, the attenuation characteristics shall also be demonstrated at the production stage.

AddedFor medicinal products derived from human blood or plasma, the origin and the criteria and procedures for collection, transportation and storage of the starting material shall be described and documented in accordance with provisions laid down in Part III of this Annex.

AddedThe manufacturing facilities and equipment shall be described.

Addedd) Tests and acceptance criteria carried out at every critical step, information on the quality and control of intermediates and process validation and/or evaluation studies shall be provided as appropriate.

Addede) If the presence of potentially pathogenic adventitious agents is inevitable, the correspondent material shall be used only when further processing ensures their elimination and/or inactivation and this shall be validated in the section dealing with viral safety evaluation.

Addedf) A description and discussion of the significant changes made to the manufacturing process during development and/or manufacturing site of the active substance shall be provided.

Added3.2.1.3. C h a r a c t e r i s a t i o n o f t h e a c t i v e s u b s t a n c e ( s )

AddedData highlighting the structure and other characteristics of the active substance(s) shall be provided.

AddedConfirmation of the structure of the active substance(s) based on any physico-chemical and/or immuno-chemical and/or biological methods, as well as information on impurities shall be provided.

Added3.2.1.4. C o n t r o l o f a c t i v e s u b s t a n c e ( s )

AddedDetailed information on the specifications used for routine control of active substance(s), justification for the choice of these specifications, methods of analysis and their validation shall be provided.

AddedThe results of control carried out on individual batches manufactured during development shall be presented.

Added3.2.1.5. R e f e r e n c e s t a n d a r d s o r m a t e r i a l s

AddedReference preparations and standards shall be identified and described in detail. Where relevant, chemical and biological reference material of the European Pharmacopoeia shall be used.

Added3.2.1.6. C o n t a i n e r a n d c l o s u r e s y s t e m o f t h e a c t i v e s u b s t a n c e

AddedA description of the container and the closure system(s) and their specifications shall be provided.

Added3.2.1.7. S t a b i l i t y o f t h e a c t i v e s u b s t a n c e (s)

Addeda) The type s of studies conducted, protocols used, and the results of the studies shall be summarised

Addedb) Detailed results of the stability studies, including information on the analytical procedures used to generate the data and validation of these procedures shall be presented in an appropriate format

Addedc) The post authorisation stability protocol and stability commitment shall be provided

Added3.2.2 Finished medicinal product

Added3.2.2.1 D e s c r i p t i o n a n d c o m p o s i t i o n o f t h e f i n i s h e d

Addedm e d i c i n a l p r o d u c t

AddedA description of the finished medicinal product and its composition shall be provided. The information shall include the description of the pharmaceutical form and composition with all the constituents of the finished medicinal product, their amount on a per-unit basis, the function of the constituents of:

Added— the active substance(s),

Added— the constituent(s) of the excipients, whatever their nature or the quantity used, including colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances, etc.,

Added— the constituents, intended to be ingested or otherwise administered to the patient, of the outer covering of the medicinal products (hard capsules, soft capsules, rectal capsules, coated tablets, films-coated tablets, etc.),

Added— these particulars shall be supplemented by any relevant data concerning the type of container and, where appropriate, its manner of closure, together with details of devices with which the medicinal product will be used or administered and which will be delivered with the medicinal product.

AddedThe ‘usual terminology’, to be used in describing the constituents of medicinal products, shall mean, notwithstanding the application of the other provisions in Article 8 (3) (c):

Added— in respect of substances which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States, the main title at the head of the monograph in question, with reference to the pharmacopoeia concerned,

Added— in respect of other substances, the international non-proprietary name (INN) recommended by the World Health Organisation, or, failing this, the exact scientific designation; substances not having an international non-proprietary name or an exact scientific designation shall be described by a statement of how and from what they were prepared, supplemented, where appropriate, by any other relevant details,

Added— in respect of colouring matter, designation by the ‘E’ code assigned to them in Council Directive 78/25/EEC of 12 December 1977 on the approximation of the rules of the Member States concerning the colouring matters authorised for use in medicinal products () and/or European Parliament and Council Directive 94/36/EC of 30 June 1994 on colours for use in foodstuffs ().

AddedIn order to give the ‘quantitative composition’ of the active substance(s) of the finished medicinal products, it is necessary, depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological activity, either per dosage-unit or per unit of mass or volume, of each active substance.

AddedActive substances present in the form of compounds or derivatives shall be designated quantitatively by their total mass, and if necessary or relevant, by the mass of active entity or entities of the molecule.

AddedFor medicinal products containing an active substance, which is the subject of an application for marketing authorisation in any Member State for the first time, the quantitative statement of an active substance, which is a salt or hydrate shall be systematically expressed in terms of the mass of the active entity or entities in the molecule. All subsequently authorised medicinal products in the Member States shall have their quantitative composition stated in the same way for the same active substance.

AddedUnits of biological activity shall be used for substances, which cannot be defined molecularly. Where an International Unit of biological activity has been defined by the World Health Organisation, this shall be used. Where no International Unit has been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the substances by using where applicable the European Pharmacopoeia Units.

Added3.2.2.2. P h a r m a c e u t i c a l d e v e l o p m e n t

AddedThis chapter shall be devoted to information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the intended use specified in the marketing authorisation application dossier.

AddedThe studies described in this chapter are distinct from routine control tests conducted according to specifications. Critical parameters of the formulation and process attributes that can influence batch reproducibility, medicinal product performance and medicinal product quality shall be identified and described. Additional supportive data, where appropriate, shall be referenced to the relevant chapters of Module 4 (Non Clinical Study Reports) and Module 5 (Clinical Study Reports) of the marketing authorisation application dossier.

Addeda) The compatibility of the active substance with excipients as well as key physicochemical characteristics of the active substance that can influence the performance of the finished product or the compatibility of different active substances with each other in the case of combination products, shall be documented.

Addedb) The choice of excipients, in particular relative to their respective functions and concentration shall be documented.

Addedc) A description of the development of the finished product shall be provided, taking into consideration the proposed route of administration and usage.

Addedd) Any overages in the formulation(s) shall be warranted.

Addede) As far as the physiochemical and biological properties are concerned, any parameter relevant to the performance of finished product shall be addressed and documented.

Addedf) The selection and optimisation of the manufacturing process as well as differences between the manufacturing process(es) used to produce pivotal clinical batches and the process used for manufacturing the proposed finished medicinal product shall be provided.

Addedg) The suitability of the container and closure system used for the storage, shipping and use of the finished product shall be documented. A possible interaction between medicinal product and container may need to be considered.

Addedh) The microbiological attributes of the dosage form in relation with non-sterile and sterile products shall be in accordance with and documented as prescribed in the European Pharmacopoeia.

Addedi) In order to provide appropriate and supportive information for the labelling the compatibility of the finished product with reconstitution diluent(s) or dosage devices shall be documented