Annex 1 - Word

Annex 2 - Changes in supplementary binder 6.8 to Ph. Eur. 6th. Ed Ed Ed

Annex 3 - drug quality

Annex 4 - Lists and standards

Annex 5 -Confirmations, symbols and definitions

Annex 6 - Love, announcements, etc.

Annex 7 - Important changes since last edition, DLS 2010.1

Annex 8 – Requirements and analytical specifications for analysis of Heparincalcium and sodium

Report on Danish Medicines Agency 20102

Pursuant to Section 52 of Act No 1180 of 12 December 2005 on medicinal products and § 19 of Act No 273 of 1 April 2006 on the requirements of quality and safety when dealing with human tissues and cells (the Danish Act) is established:

§ 1. This notice contains in the Annex 1 - 8 Danish Medicines Standards 2010.2

§ 2. The decision shall enter into force on 1 July 2010.

Substances. 2. Decision No 585 of 20 May 2010 on Danish Medicine Standards 2010.2 is repealed.

Annex 1 - Word

Annex 2 - Changes in supplementary binder 6.8 to Ph. Eur. 6th. Ed Ed Ed

New

Annex 3 - drug quality

Drug quality

Manufacture, control and storage of medicinal products must take place in accordance with the requirements set out in this chapter as well as the requirements that may be listed in the related pharmaceutical formula standards.

Manufacture of medicines - Raw goods

Manufacture of medicines – medicines

Non-sterile medicines

Non-sterile medicines must be manufactured under satisfactory hygienic conditions, and the incoming ingredients must be of satisfactory microbiological quality.

Drugs must adhere to the requirements of microbiel purity specified in Ph. Eur. 6th th Ed., 5.1.4 ‘Microbiological quality of non-sterile strain and dishonest for pharmaceutical use’. However, medicines for oral use must comply with the requirements of Ph.Eur. 6th th Ed. Suppl. 6.7, 5.1.8 “Microbiological quality of herbal products for oral use”

It is not permitted by the manufacturing of medicines to use medicinal products or substances of vegetable origin which have been treated with ethylene.

When it comes to a standard for a commodity in the European Farmakopé that national authorities may require a maximum permissible number of microorganisms or the absence of specific microorganisms, the requirements set out in the DLS standard for the commodity.

Sterile and aseptic prepared medicines

Sterile and aseptic prepared medicines must be manufactured and sterilized according to the ones in Ph. Eur. 6th th Ed., 5.1.1. “Methods of preparation of sterile products” stated guidelines. The validation process used biological indicators according to Ph. Eur. 6th th Ed., 5.1.2. “Biological indicators of sterilisation” can be recovered from the Statens Serum Institute, Artillerivej 5, 2300 Copenhagen S.

Parental medicines

Parental medicines must meet the requirements described in the section “Parenteral mediation” in Ph. Eur. 6th th Ed.

Endotoxin free and pyrogen free drugs

When it comes to the pharmaceutical form standard, the preparation must meet the sample of bacterial endotoxins or the sample of pyrogens, there must be used as far as possible raw materials that comply with a sample for endotoxins as described in “Bacterial endotoxins” Ph. Eur. 6th th Ed., 2.6.14. or the test for pyrogens described in “Pyrogens” Ph. Eur. 6th th Ed., 2.6.8. For a commodity, for which a standard in the European Farmakopé appears that national authorities may require “Bacterial endotoxins” Ph. 6.th th Ed., 2.6.14. or “Pyrogens” Ph. Eur. 6th th Ed., 2.6.8., is met, this sample constitutes part of it in DLS's registered standard, and the raw material must be branded accordingly.

Spongiforme encephalopaths from animals

A drug that partly consists of raw materials of animal origin, where there is the possibility for the transfer of spongiform encephalopathy (TSE) from animals must meet the quality requirements of the general section Ph. Eur. 6th th Ed., 5.2.8. “Minimising the risk of supplying animal spongiform encephalopathy via human and pharmaceutical products”, as well as the quality requirements of the general monography Products with risk of delivery agents of animal spongiform encephalopathies.

The applicant/the holder of a marketing authorisation must document that the drug is manufactured in accordance with the above requirements of the minimering of the risk of the transfer of spongiforme encephalopaths from animals via medicines. The documentation may be based on a “Certificate of Suitability” from EDQM.

Restsolvency in medicines

Medicines for human use must meet CPMP/ICH guideline Q3C “Impurities: Residenceual solvents” (CPMP/ICH/283/95), reproduced in Ph. Eur. 6th th Ed. 5.4. “Residual solvents”, regarding the content of residual sunns. For the identification of residues, the section “Identification and control of residual solvents” in Ph. Eur. 6th th Ed., 2.4.24. is used.

Pesticidester

When there is the possibility that a drug which is partly composed of raw materials of vegetable or animal origin may contain residues of pesticides or other combatants, the drug must meet in Ph. Eur. 6th th Ed. 2.8.13. “Pesticide dumps” specified quality requirements.

Control of medicines

Drugs must be checked according to applicable GMP rules, and adhere to the requirements listed below.

Medicine

The quantitative content of drug substances in a drug must at the time of manufacture usually deviate 5% from the declared.

On the basis of durability studies, a greater deviation, usually until 10% for the lower limit due to decomposition within the storage time could be approved.

Actual content

The average content of the drug in the consumer packaging must be sufficient for the clear content (number, mass or volume) to be taken during the use of usual technique.

Dosis and mass variations

The requirements of Ph. Eur. 2.9.40 “Uniformity of rake units” are mandatory for medicines applying for national marketing authorisation after 1 July 2005.

Drugs that have a current marketing authorisation issued before July 1, 2005 or which had applied for marketing authorisation before 1 July 2005 may continue to apply the requirements of mass and dose variation in Ph. Eur. 2.9.5 “Uniformity of mass of single-dose originate” and Ph. Eur. 2.9.6. “Uniformity of content of single-dose samurai”).

The requirements of Ph. Eur. 2.9.40 do not apply to herbal and traditional herbal products.

Quality requirements regarding dose variation in Ph. Eur. 6th th Ed., 2.9.6. “Uniformity of content of single dossiers” and in Ph. Eur. 2.9.40 “Uniformity of samurai units” does not apply to multivitamin and mineral preparations.

Oral drug forms in the multidose container must adhere to the sample in Ph. Eur. 2.9.27. “Uniformity of mass of contemplate from multidose containers”.

Microbiel purity

Drugs must adhere to the requirements of microbiel purity, which are stated in Ph. Eur. 6th th Ed., 5.1.4. “Microbiological quality of non-sterile strain and bias for pharmaceutical use”. However, medicines for oral use must comply with the requirements of Ph. Eur. 6th th Ed. Suppl. 6.7, 5.1.8 “Microbiological quality of herbal products for oral use”

Choice of analysis method

If using the samples must be selected between the analysis methods membrane filtration, plate count or serial dilution is selected one of the two first ones where the properties of the raw material allow. Serial dilution may only be used if the raw material/product has special properties that exclude the use of one of the two other methods.

Storage of medicines

Drugs must be kept in containers that protect the content from contamination. Storage containers may not affect the content in such a way that the drug does not continue to meet the specification. In addition, the pharmaceuticals must be kept in accordance with the terms of storage that appear in the specification and approved in connection with the registration.

Storage conditions

Storage conditions shall be set according to Guidelines on the declaration of storage arrangements for pharmaceutical products in the products specified in the products (CHMP/QWP/609/96/Rev 2. CVMP/422/99/Rev 3) and the applicable QRD-template.

For the marking and text of the product price for the drug, the following applies:

Other special storage conditions:

The above retention conditions may only be used if the application presented durability documentation shows that there are real problems with moisture or light sensitivity, and that these problems cannot be corrected using a more suitable packaging.

Storage conditions for sterile medicines after opening or reconstitution

Storage conditions are determined according to Guideline on Maximum Flood-life for sterile products for human use after first opening or denial refund (CHMP/QWP/159/96) or Guideline on Maximum Flood-life for sterile products after first opening or temporary recovery refund (CVMP/198/99).

For the marking and text of the product price for the drug, the following applies:

Storage time

The direction lines in the CHMP guideline “Start of the Rotary-life of the consecutive shape” (CPMP/QWP/072/96 and EMEA/CVMP/453/01) must be followed. The output date must be fixed from the release date of the batch. The release date may, under normal circumstances, not exceed 30 days from the date of manufacture. If the time between manufacturing and release exceeds 30 days, the manufacturing time must be used as the start of the storage time.

The above guideline does not apply biological, biotechnology and similar products.

Store a drug for a period of time as bulk goods (teamid), the batches used in the durability tests also have been stored as bulk goods for at least the corresponding holding time and then as finished.

The fixed storage time cannot be extended during cold storage of the drug.

The maximum storage time that can be approved is 5 years. This storage time includes any storage as bulk goods.

Instructions

For the specified types of medicines, the following instructions must be applied:

The design of the specified instructions can be changed when the meaning is not changed.

Other information that can be included in a instruction manual is, for example, ‘Munden is rinsed with water after each inhalation’, ‘Can discolor skin, hair and clothes’, ‘Can provide local irritation with transient, light the burning’, ‘Can cause the staining of urine/examination’, ‘Intens with at least 1⁄2 glass of water or other liquid’, ‘In meals in connection with/between’.

Quality of medicines

The drug produced at pharmacy or hospital pharmacy for the individual patient under the indication of declaration and without any other form of name declaration (see section 11, 1 of the law of medicines), is the magic-strelle medicines. They shall be manufactured, checked and stored in accordance with the applicable standards of the European Pharmacophé, Danish Medicines Standards and the Danish Medicines Agency’s Orders, however, with the adjustments shown in these Chapter adopted provisions on the quality of magistral medicinal products.

Pharmacies may not produce and negotiate magic-strelle medicines that can be replaced by medicines, for which marketing authorisation is issued (see section 13(2) of the Act on Drugstore).

If the Danish Medicines Agency for Safety reasons has refused to issue marketing authorisation or has the induction/suspended marketing authorisation to a drug, the pharmacies shall not produce and negotiate a magistral medicinal product with the same active ingredients (see section 13(3) of the pharmacy company).

The provisions of this chapter are used in the manufacture of pharmacies and hospital pharmacies of medicinal products together with pharmaceutical specialities, magistral medicinal products or medicines of special authorisation (see section 29(1) of the Act on Medicines) and the completion of pharmaceutical specialities, including, for example, solution or dispersion of dry substance preparations in suitable solvens and filling pharmaceutical specialities in a suitable packaging.

Manufacture of magic drugs

Magistrelle medicinal products must be manufactured under conditions and conditions that comply with the rules of the Danish Medicines Agency No 1242 of 12 December 2005 as referred to in Article 1101 of 12 November 2008 on the manufacture and import of medicines and intermediate products.

Raw goods

Raw materials for the manufacturing of magic drugs must be used in a purity and with technical characteristics suitable for the given purpose. It is the responsibility of the pharmacy or hospital pharmacy to ensure that the quality of the ingredients live up to the standard of the day. As a basis for the quality rating, the standard is used in the European Farmakopé or, if such is not found, a standard in another applicable pharmacopoeia (a national pharmacopoeia or the National Formulary) or in a former Danish or foreign pharmacopoeia. If there is no standard for the raw material, a quality rating must be made based on the principles of the applicable version of the European Farmakopé. The pharmacy or hospital pharmacy must in its own laboratory analyze the raw materials or have a contract with an analysis laboratory to conduct control of the raw materials to be used for the manufacturing of the magic-strelle drug. The scope of control must follow applicable GMP rules.

In the manufacture of a magic drug, it must also be taken into account the information available on the illicit, technical characteristics and guidelines of their heat treatment and other matters of their use which is relevant to the medicinal product concerned. There must also be taken into account the available information on the production of similar medicines.

Sources for information about raw materials and drug making are primarily the European Pharmacopoeia and the United States Pharmacopoeia/National Formulary; former official monographies and works as The Pharmaceutical Codex (The Pharmaceutical Press, London) and Martindale: The Extracopoeia (The Pharmaceutical Press, London) and The Pharmacopoeia ( Pharmaceutical Press, London). Also electronic media such as Micromedex may be a possible source of information.

In the use of the name of a pharmaceutical speciality, but in a deviating strength, the magic drug must be produced during the use of the same drug and the same relationship between the strength and the inbound amount of drug. To the extent that it is possible, the magic-strative drug is produced during the use of the same substances used in the pharmaceutical speciality.

A magic drug under the name of a drug described in an earlier existing monograph collection or in a foreign monograph collection, the magic-strative drug must be produced in accordance with the heading of that monograph collection.

A magic drug is made without the addition of preservatives, it must be seen from any provisions on the preservation of the medicinal product standard.

In the manufacture of magistral medicinal products, it should be widely used substances. Some magistrate medicinal products shall, as it is apparent in the case of drug-form standards later in this section, are mainly produced during the use of certain substances or intermediate products.

Magistrelle medicines that are prescribed as a solution in water, sprit or oil must be produced as solvents in either cleansed water, ethanol 96 % or peanut oil.

Between products

It is in the manufacture of magic drugs allowed to use intermediate products when the intended effect of the medicinal products is not affected. It must be handled in accordance with the relevant pharmaceutical standard and is called with the appropriate standard term.

Isotonic watery resolutions

Watery resolutions that have the same osmotic pressure as blood, toe and tissue fluids, are called iceoosmotic. A 0.9 % sodium chloride solution, a 1.6 % potassium nitrate solution, an 3.9 % sodium sulfate solution and a 2.3 % glycerol solution is ice creamemotic and has a freezing point immersion of 0.52 °C.

An ice creamotonic solution is isotope with blood, toe and tissue fluids, unless the dissolved substance molecules are able to pass over the current biological barrier.

Watery resolutions can usually be made isotope by adding sodium chloride in such a quantity that the freezing point of the solution is 0.52°C. For example, if sodium chloride causes precipitation, as isotoniising substance is used glycerol, potassium nitrate (especially eye drops and eye bathing water) or sodium sulfate. For magic eye drops and eye bathing water, it is usually not necessary to correct for the iodine change, which the conservative substance leads.

Calculation of the ice creamotising amount of substance can be done using the numbers in the table below. If the drug is not admitted to the table, the sodium chloride equivalent of the substance may be calculated as described in the following section. The calculated value must be tested experimentally by measuring the freezing point of the solution as described in “Osmolality”, Ph.Eur. 6th th Ed 2.2.35.

Isohydric watery medicinal products

Watery resolutions with a pH around 7.4 are called isohydrate, as the pH of blood, toe and tissue fluids is around 7.4. The pH of the blood is at the body temperature between 7.30 and 7.45 and maintained in this area using different cushion systems. Also the toe fluid holds a certain, weak cushion capacity, whereas the tissue fluids in most organs are without cushion capacity.

In the manufacture of magic-strelle medicines that are watery resolutions or dispersions intended to be brought in direct contact with blood, toe or tissue fluids, it should be endeavoured that the formulation is iohydrate and, in terms of the physiological conditions on the application site, without shock cushioning effect. The alternative adjustment of the pH of the formulation should therefore be performed using a solution of a strong acid or base, primarily salt acid or sodium hydroxide.

The existence of producing magistral medicinal products with deviating pH beror on a pharmaceutical assessment of the stability of the drug, the physiological conditions on the application site as well as the amount of medicinal products to be applicted. There are no general rules for the application of non-isohydrate resolutions and dispersions, but the following conditions can serve as a right cord.

Supplement for drug form standards

In the manufacture of magistral medicinal products, the rules set out in the accompanying medicinal products shall be supplemented or adapted in accordance with the following instructions and regulations.

Cream cream

In the manufacture of magic-strelle creams, solid substances that are not dissolved completely in the cream base immediately before the application is aimed at 125.

Magistrelle creams that must be preserved (emulsion creams containing more than 20% water) can be preserved with 0.1% parahydroxybenzoat in the form of methylparahydroxybenzoat or a mixture of methylparahydroxybenzoat and propylparahydroxybenzoat (8:2), possibly added in the form of a diluenedum on 10% in ethanol. 96%

Gel Gel Gel Gel

Magistrelle gels to be preserved can be preserved with 0.1% parahydroxybenzoat in the form of methylhydroxybenzoat or a mixture of methylparahydroxybenzoat and propylparahydroxybenzoat (8:2), possibly added in the form of a diluenedum on 10% in ethanol 96%.

Injection fluid

Magistrelle injections prescribed in single dose containers with a cleared volume of up to 20 ml must be added the following profit of injection, calculated according to the nominal volume:

Magistrelle injections to be preserved may be preserved with 1% benzyl alcohol, 0.5% phenol, 0.1% chlorcresol or 0.1% methylparahydroxybenzoat.

Kuta liquids

Magistrelle cumtane liquids that must be preserved (f. slim), can be preserved with 0.1% parahydroxybenzoat in the form of methylparahydroxybenzoat or a mixture of methylparahydroxybenzoat and propylparahydroxybenzoat (8:2), possibly added in the form of a diluenedum on 10% in ethanol 96%.

Nose drop

Magistrelle nose drops that must be preserved can be preserved with 0.01% benzalkonium chloride + 0.05% sodiumedetat.

Oral drops

Magistrelle drops that must be preserved may be preserved with 0.1% parahydroxybenzoat in the form of methylparahydroxybenzoat or a mixture of methylparahydroxybenzoat and propylparahydroxybenzoat (8:2), possibly added in the form of a diluenedum of 10% in ethanol 96%; or with 0.05% potassium absorbent.

Oral powder

In magic production of oral powder, if a commodity appears in qualities with different density, the quality that has the minimum density is selected.

Oral powder, single dose container

Magistrelle oral powders in an overdose containers must weigh at least 500 mg. Oral powders containing drug substances in less amounts are added to lactose or other indifferent aid, so that the mass of each powder is 500 mg.

In magic production of oral powders in an overdose container, if a commodity appears in qualities with different density, the quality that has the minimum density.

Oral liquids

Magistrelle oral liquids to be preserved may be preserved with 0.1% parahydroxybenzoat in the form of methylhydroxybenzoat or a mixture of methylparahydroxybenzoat and propylparahydroxybenzoat (8:2), possibly added in the form of a diluenedum on 10% in ethanol 96%; or 0,05% potassiumsorb.

Powder

In magic production of powder, if a commodity appears in qualities with different density, the quality that has the minimum density is selected.

Salve

In the manufacture of magistrate ointments, solid substances that are not dissolved completely in the ointment basis shall be immediately before the application is aimed at 125.

Magistrelle ointments to be preserved can be preserved with 0.1% parahydroxybenzoat in the form of methylhydroxybenzoat or a mixture of methylparahydroxybenzoat and propylparahydroxybenzoat (8:2), possibly added in the form of a diluenedum on 10% in ethanol 96%.

Suppositories

Magistrelle suppositories are produced when not otherwise prescribed, with hard fat as a base mass and preferably when casting.

Fixed substances that are insoluble in the base mass must immediately be aimed at 125.

For the manufacture of suppositories with a low content of drug (10 mg and below) it is allowed to use this in the form of a trituration with lactose.

Suppositories, made with a base mass on fat basis, must be kept cold

Tablets Tablet Tablets

In magic production of non-overned tablets, the specified system must be followed in the maximum possible extent.

The tablets must be made in circular form with flat surfaces and inclined edges and must be fitted with diameter 8‐13.5 mm with a divide. Tablets with diameter 6 mm must not be provided with parts nap. Prescribed tablets containing 50 mg of drug or less, provided with part care must be produced with diameter 8 mm (forth gross mass 180 mg).

In magic production of tablets, if a commodity appears in qualities with different density, the quality that has the greatest density is selected.

Drugs whose soluble in water is less than about 3 mg per ml must, unless the specified method A is used, meet the following sample of particle size:

The drug is distributed in a liquid with good dispersion properties in which the substance is not dissolved. By microscopic examination of suspension corresponding to 10 μg of the fixed stage must be no more than 20 particles, if the largest dimension exceeds 25 μm, and of which may exceed 50 μm, the maximum dimension of no particles must exceed 90 μm.

In the manufacture of tablets with a low content (5 mg and below) of drug substances, the mixture of drug substances and substances can be produced after one of the below specified methods, as method A should be used when the contents of drug is 1 mg and below.

Method Method Method Method A: The drug is dissolved in low heating, in a suitable volatile solution, after which the tablet making needed amount of lactose (which at least 60 % of the clogged gross mass) dehumidified with the solution, rinsed after 2 times, each time with approximately 10% of the amount used. The mixture is stirred to it is uniformly hydrated, and is added under stirring until it is dry. In the long term (sigt 180) the starch and any other substances and the mixture are aimed.

Method Method Method Method B: The medicinal product (sigt 125) is deducted with the necessary amount of lactose (sigt 125), and the mixture is aimed. The mixture and any other substances shall be aimed.

Vagitoris

Magistrelle vagitorier, produced by casting, is manufactured as indicated for suppositories.

Eye bathing water, eye drops and ear drops

Magistrelle eye bathing water, as well as watery eye drops and ear drops must be subject to a heat treatment at the highest temperature, the drug concerned must be exposed to; if the drug is produced ex tempore, it is rather permitted to use filtration through the germous filter, such as a membrane filter with pore width 0.22 μm.

Magistrelle eye bathing water and eye drops that must be preserved can be preserved with 0.5 % phenethanol or with 0.01 % benzal conium chloride + 0.05% sodium. Magistrelle ear drops to be preserved can be preserved with 0.5 % phenethanol.

Diluenda and solvents for the manufacture of eye bathing water, eye drops or ear drops that have been subject to a heat treatment in the storage containers must be kept for until 2 years if the containers are provided with close closing. When a container is breached, the content must not be kept 1 month; this limitation does not apply to diluenda of preservatives and medicinal products with adequate bacteriocid effect. In cold place, storage must only take place in unbreaked container with close closing.

Eyesalve

Magistrelle eye rests are produced when nothing else is prescribed, with the following eye rest:

Control of magistral medicines

General provisions

Pursuant to Section 27,(1) of the Danish Medicines Agency’s notice no. 1242 of 12 December 2005 in accordance with Regulation No 1101 of 12 November 2008 amending the Order on the manufacture and import of medicinal products and intermediate products, the manufacture of pellet medicinal products may be exempt from sampling, testing and storing the finished medicinal product in the cases where only one or a few packaging.

In addition to a quantitative provision as well as other relevant tests such as kim counting, decay time, etc., which at least be carried out in the following guidelines.

Storage of magistral medicines

Storage conditions

Storage in well-closed container must be made so that the content is protected from presumption, evaporation, evaporation or against the free approach of the humidity, oxygen and carbon dioxide m.v.

Storage in airtight sealed container must be made so that air exchange with the surroundings is excluded.

Storage of detergent must be made in well-closed container or cabinet, in which a suitable drying agent is placed.

Storage protected from the light must be done either on one of the light outreach place or in the container or packing of such material that the short wave, ultraviolet light is sufficiently absorbed to protect the content from breakdown or change caused by such a light, or in packing protected by an outer packaging which gives such protection.

Storage excluded from the light must be made in container or packing which is imprisonable for light.

Storage time

Magistrelle's storage time is determined on the basis of a durability documentation or a pharmaceutical professional assessment. The duration of the storage must be determined for 2 years, the assessment of durability for any intermediate products must be included. The Danish Medicines Agency may, on the basis of the results of the performance tests, allow for a longer retention time.

Annex 4 - Lists and standards

Raw goods