Our reference: FOI/12-332 Dear Ms Mallinson Thank you for your requests under the Freedom of Information Act 2000. Please find below responses to your questions. 1. Please e-mail copies of the minutes of any meetings of The British Pharmacopoeia Commission (BPC) and the Expert Advisory Groups (EAGs), Panels of Experts and Working Parties where Levothyroxine Formulated Products has been discussed and any reports, papers or internal correspondence relating to this matter. Response: Please find attached redacted copies of the relevant minutes and papers of the British Pharmacopoeia Commission (BPC) and Expert Advisory Group (EAG) Medicinal Chemicals 2 (MC2). Please note that some information in these documents is subject to exemptions and, as such, has been redacted in accordance with the following sections of the Act Section 22 (information intended for future publication) Section 38 (health and safety) Section 40 (personal information) Section 43 (commercial interests) The application of section 38 has been used because answers to FOIA requests are automatically in the public domain and release of this information without context could lead to a risk that some levothyroxine users may take inappropriate action with regard to their medication. We consider therefore that the public interest balance is in favour of withholding the information on this basis. We are unable to supply all internal correspondence because, in order to provide you with the information on the scale that you have requested would require extensive searches of multiple email accounts and folders. Section 12 of the Act makes provision for public authorities to refuse requests for information where the cost of dealing with them would exceed the appropriate limit, which for central government is set at 600. This represents the estimated cost of one person spending 24 working hours in determining whether the department holds the information, locating, retrieving and extracting the information. We estimate that it will take us in excess of 24 working hours to determine appropriate material and locate, retrieve and extract the information in reference to your request. Therefore, your request will not be processed further. You may wish to refine your request by narrowing its scope by being more specific about what information you particularly wish to obtain, including any dates or period of time relevant to the information required. Attachment: Annex 1 (minutes and papers of the BPC and EAG MC2) 2. Please provide a copy of the current (2012) British Pharmacopoeia monograph for Levothyroxine Tablets.
Response: Please find attached a copy of the current British Pharmacopoeia monograph for Levothyroxine Tablets. Attachment: Annex 2 (monograph) 3. Please provide copies of documentation with details of the revised dissolution test for Levothyroxine Tablets and the reasons why the current monograph should be revised. You state on your web site that 'Quality underpins both safety and efficacy and quality assurance is a continuous process' and that 'Pharmacopoeial standards are compliance requirements' which 'apply throughout the shelf-life of a product'. Response: I can confirm that the BPC holds the information you are seeking. Section 22 of the Freedom of Information Act exempts this information. This is because the information is intended for publication at a future date. At the present time, the draft Tablets monograph, which incorporates the inclusion of tests for Dissolution and Related substances, is still under consideration by Expert Advisory Group (EAG) Medicinal Chemicals 2 (MC2) and, as such, is exempt under Section 22 (information intended for future publication). In line with established BPC practice, once the EAG has agreed to the proposals they will be made public for consultation. The current monograph for Levothyroxine Tablets BP is being revised to introduce a dissolution test to implement a recommendation of the Commission on Human Medicines (CHM). This follows CHM s review of levothyroxine products on 09 March 2012. A discriminatory dissolution test will tighten the quality standard for levothyroxine tablets by specifying the amount of levothyroxine active substance that is released from the tablet over time (dissolution). The aim is to minimise the variability of a particular tablet product as well as variability between the different available products. CHM members advised that whilst it cannot conclusively be said dissolution is a measure of the availability of levothyroxine drug substance for absorption by the body (effectiveness) nevertheless it was considered a useful additional quality measure for standardising products. 4. Please provide documentary evidence of checks that have been made to ensure that suppliers have met the current published standards throughout the shelf life of Levothyroxine formulated products Response: We are unable to provide this information because the BP Commission does not hold the information requested. However, you may wish to note that the manufacture and control of medicines is governed by European and National legislation. Further guidance is available on the MHRA website (www.mhra.gov.uk)
5. Please provide copies of the full specification for impurities that are acceptable for Levothyroxine formulated products Response: I can confirm that the BPC holds the information you are seeking. Section 22 of the Freedom of Information Act exempts this information. This is because the information is intended for publication at a future date. At the present time, the draft Tablets monograph is still under consideration by the EAG and, as such, is exempt under Section 22 (information intended for future publication). In line with established BPC practice, once the EAG has agreed to the proposals they will be made public for consultation. The Levothyroxine Oral Solution monograph, which includes a Related substances test, is currently under consultation and is freely available via the BPC website (http://www.pharmacopoeia.gov.uk/custom/new-monographs.php ). 6. Please provide a full and complete list of all the different products that constitute 'Levothyroxine formulated products' Response: We are unable to provide this information because the BP Commission does not hold the information requested. However for convenience, the MHRA Licensing Division has provided a list of authorised products, as at 12 September 2012, which is attached. Attachment: Annex 3 (list of authorised products as at 12 September 2012). 7. Please send me copy of the revised draft monograph for Levothyroxine Tablets. Response: I can confirm that the BPC holds the information you are seeking. Section 22 of the Freedom of Information Act exempts this information. This is because the information is intended for publication at a future date. At the present time, the draft Tablets monograph is still under consideration by Expert Advisory Group (EAG) Medicinal Chemicals 2 (MC2) and, as such, is exempt under Section 22 (information intended for future publication). In line with established BPC practice, once the EAG has agreed to the proposals they will be made public for consultation. The information supplied to you continues to be protected by copyright. You are free to use it for your own purposes, including for private study and non-commercial research, and for any other purpose authorised by an exception in current copyright law. Documents (except photographs) can be also used in the UK without requiring permission for the purposes of news reporting. Any other reuse, for example commercial publication, would require the permission of the copyright holder.
Most documents supplied will have been produced within government and will be Crown Copyright. For information about re-using Crown Copyright see the Office of Public Sector Information website at www.opsi.gov.uk. The copyright in some documents may rest with a third party. For information about obtaining permission from a third party see the Intellectual Property Office s website at www.ipo.gov.uk. For details on MHRA s copyright policy please visit: http://www.mhra.gov.uk/home/idcplg?idcservice=ss_get_page&nodeid=412 or e- mail the MHRA Information Services Central Enquiry Point If you are dissatisfied with the handling of your request, you have the right to ask for an internal review. Internal review requests should be submitted within two months of the date of receipt of the response to your original letter and should be addressed to the MHRA customer services team at: info@mhra.gsi.gov.uk. Please remember to quote the reference number above in any future communications. If you are not content with the outcome of the internal review, you have the right to apply directly to the Information Commissioner for a decision. The Information Commissioner can be contacted at: Information Commissioner s Office, Wycliffe House, Water Lane, Wilmslow, Cheshire, SK9 5AF Yours sincerely, British Pharmacopoeia Commission Secretariat 5Y 151 Buckingham Palace Road London SW1W 9SZ
Annex 1
Annex 2
British Pharmacopoeia 2012 http://www.pharmacopoeia.co.uk/bp2012/ixbin/bp.cgi?a=print&id=5734&tab=search Page 1 of 2 19/09/2012 British Pharmacopoeia Volume III Formulated Preparations: Specific Monographs Levothyroxine Tablets General Notices NOTE: The name Thyroxine Tablets was formerly used in the United Kingdom. Action and use Thyroid hormone replacement. DEFINITION Levothyroxine Tablets contain Levothyroxine Sodium. The tablets comply with the requirements stated under Tablets and with the following requirements. Content of anhydrous levothyroxine sodium, C 15H 10I 4NNaO 4 90.0 to 105.0% of the stated amount. IDENTIFICATION A. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is the same as that of the peak in the chromatogram obtained with solution (2). B. To a quantity of the powdered tablets containing the equivalent of 0.5 mg of anhydrous levothyroxine sodium add a mixture of 3 ml of ethanol (50%) and 0.2 ml of hydrochloric acid, boil gently for 30 seconds, cool, filter, add 0.1 ml of a 10% w/v solution of sodium nitrite and boil; a yellow colour is produced. Cool and make alkaline with 5M ammonia; the solution becomes orange. Uniformity of content Comply with the requirements stated under Tablets using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. (1) Add sufficient 0.05M sodium hydroxide to one tablet to produce a solution containing the equivalent of about 6 µg per ml of anhydrous levothyroxine sodium, mix with the aid of ultrasound until the tablet is fully dispersed, cool and shake for 2 minutes. Add sufficient 0.05M sodium hydroxide to produce a solution containing the equivalent of 0.0004% w/v of anhydrous levothyroxine sodium, filter through glass microfibre filter paper (Whatman GF/C is suitable) and use the filtrate. (2) 0.0004% w/v of levothyroxine sodium EPCRS in 0.05M sodium hydroxide. CHROMATOGRAPHIC CONDITIONS (a) Use a stainless steel column (25 cm 4.6 mm) packed with nitrile silica gel for chromatography (5 µm) (Nucleosil 5 CN is suitable). (b) Use isocratic elution and the mobile phase described below. (c) Use a flow rate of 1 ml per minute. (d) Use an ambient column temperature. (e) Use a detection wavelength of 225 nm. (f) Inject 20 µl of each solution. MOBILE PHASE 5 volumes of orthophosphoric acid, 300 volumes of acetonitrile and 700 volumes of water. DETERMINATION OF CONTENT
British Pharmacopoeia 2012 http://www.pharmacopoeia.co.uk/bp2012/ixbin/bp.cgi?a=print&id=5734&tab=search Page 2 of 2 19/09/2012 Calculate the content of C 15H 10I 4NNaO 4 in each tablet using the declared content of C 15H 10I 4NNaO 4 in levothyroxine sodium EPCRS. ASSAY Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D. Prepare a mixture of equal volumes of methanol and 0.1M sodium hydroxide (solvent A). For tablets containing the equivalent of less than 50 µg of anhydrous levothyroxine sodium, use the following solutions. (1) Disperse with the aid of ultrasound for 10 minutes a quantity of the powdered tablets containing the equivalent of 50 µg of anhydrous levothyroxine sodium with 8 ml of solvent A. Shake for 2 minutes, cool, add sufficient solvent A to produce 10 ml, mix, filter through glass microfibre filter paper (Whatman GF/C is suitable) and use the filtrate. (2) 0.0005% w/v of levothyroxine sodium EPCRS in solvent A. (3) 0.0005% w/v of liothyronine sodium EPCRS and 0.0005% w/v of levothyroxine sodium EPCRS in solvent A. For tablets containing the equivalent of 50 µg of anhydrous levothyroxine sodium or more, use the following solutions. (1) Disperse with the aid of ultrasound for 10 minutes a quantity of the powdered tablets containing the equivalent of 0.1 mg of anhydrous levothyroxine sodium with 8 ml of solvent A. Shake for 2 minutes, cool, add sufficient solvent A to produce 10 ml, mix, filter through glass microfibre filter paper (Whatman GF/C is suitable) and use the filtrate. (2) 0.001% w/v of levothyroxine sodium EPCRS in solvent A. (3) 0.0005% w/v of liothyronine sodium EPCRS and 0.0005% w/v of levothyroxine sodium EPCRS in solvent A. CHROMATOGRAPHIC CONDITIONS The chromatographic conditions described under Uniformity of content may be used. SYSTEM SUITABILITY The assay is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the two principal peaks is at least 4.0. DETERMINATION OF CONTENT Calculate the content of C 15H 10I 4NNaO 4 in the tablets using the declared content of C 15H 10I 4NNaO 4 in levothyroxine sodium EPCRS. STORAGE Levothyroxine Tablets should be protected from light. LABELLING The quantity of active ingredient is stated in terms of the equivalent amount of anhydrous levothyroxine sodium. Crown Copyright 2011
Annex 3